A Multicenter, Open-label, Pilot Study of TAK-935 (OV935) in Patients With 15Q Duplication Syndrome or CDKL5 Deficiency Disorder (ARCADE Study)
Phase: PHASE2
Conditions: 15q Duplication Syndrome, CDKL5 Deficiency Disease
Sponsor: Takeda

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Title:  M U L TI C E N T E R, O P E N- L A B E L, PI L O T S T U D Y O F T A K- 9 3 5 ( O V 9 3 5) I N P A TI E N T S 
WI T H 1 5 Q D U P LI C A TI O N S Y N D R O M E O R C D K L 5 D E FI CI E N C Y DI S O R D E R ( A R C A D E 
S T U D Y)
N C T N u m ber: N C T 0 3 6 9 4 2 7 5
Pr ot oc ol A p pr o ve Date: 2 1 N o ve m ber 2 0 1 9
Certai n i nf or mati o n  w it hi n t his pr ot oc ol  has bee n  re dacte d (ie,  s pecific c o nte nt is mas ke d irre versi bl y fro m 
vie w wit h a blac k / bl ue bar) t o pr otect  eit her pers o nall y  i de ntifia ble i nf or mati o n ( P P D) or c o m pa n y 
c o nfi de ntial i nf or mati o n  ( C CI). 
T his ma y  i nclu de, b ut  is n ot li mited t o, re dacti o n of t he f oll o wi n g: 
Na me d pers o ns or or ga nizati o ns ass ociate d wit h t he st u d y.
Pr o prietar y i nf or mati o n, s uc h as scales or c o di n g s yste ms, w hic h are c o nsi dere d c o nfi de ntial  
i nf or mati o n u n der pri or a gree me nts wit h lice nse h ol der.
Ot her i nf or mati o n as nee de d t o pr otect c o nfi de ntialit y of Ta ke da or part ners, pers o nal  i nf or mati o n, or 
t o ot her wise pr otect t he i nte grit y of t he cli nical st u d y.

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 of 1 0 1
P R O T O C O L T A K -9 3 5 - 1 8-0 0 2 ( O V 9 3 5)
A M U L TI C E N T E R, O P E N -L A B E L, PI L O T S T U D Y O F T A K -9 3 5 ( O V 9 3 5) 
I N P A TI E N T S WI T H 1 5 Q D U P LI C A TI O N S Y N D R O M E O R C D K L 5 
D E FI CI E N C Y DI S O R D E R ( A R C A D E S T U D Y)
S p o ns or:
O vi d T hera pe ut ics I nc.
1 4 6 0 Br oa d wa y
Ne w Y or k, N Y 1 0 0 3 6
T el e p h o ne: + 1 ( 6 4 6) 6 6 1- 7 6 6 1
S p o ns or C o ntact:
Me dical M o nit or:
Date of A me n d me nt 2:
2 1 N o ve m ber 2 0 1 9
Date of A me n d me nt 1:
0 1 Fe br uar y 2 0 1 9
Date of Ori gi nal  Pr ot o c ol:
2 2 Ma y  2 0 1 8
P P 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

Pr ot o c ol T A K- 9 3 5- 1 8- 0 0 2 ( O V 9 3 5) A m e n d m e nt 2 
Date: 2 1 N o v e m b er 2 0 1 9 
S P O N S O R SI G N A T U R E P A G E 
O vi d T h er a p e uti cs I nc. 
P R O T O C O L TI T L E: A M U L TI C E N T E R, O P E N- L A B E L, PI L O T S T U D Y 
O F T A K- 9 3 5 ( O V 9 3 5) I N P A TI E N T S WI T H 1 5 Q D U P LI C A TI O N 
S Y N D R O M E O R C D K L 5 D E FI CI E N C Y DI S O R D E R ( A R C A D E S T U D Y) 
P R O T O C O L N U M B E R: T A K- 9 3 5- 1 8- 0 0 2 ( O V 9 3 5), A m e n d m e nt 2 
D at e 
P a g e 2 of 1 0 1 
P P 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 of 1 0 1
I N V E S TI G A T O R’ S A G R E E M E N T
I ha ve recei ve d a n d rea d t he I n vesti gat or’s Br oc h ure f or T A K-9 3 5. I ha ve rea d t he St u d y  
T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) pr ot oc ol ( A me n d me nt 2; 2 2 N o ve m ber 2 0 1 9) a n d a gree t o c o n d uct 
t he st u d y in acc or da nce wit h t his pr ot oc ol, all a p plica ble g o ver n me nt re g ulat i ons, t he pri nci ples 
of  t he I C H E 6 G ui deli nes f or G C P, a n d t he pri nci ples of t he W orl d Me dical Ass ociati o n 
Declarati o n of Helsi n ki. I als o a gree t o mai ntai n t he c o nfi de ntialit y of all i nf or mati o n recei ve d or 
de vel o pe d i n c o n nect i on wi t h t his pr ot oc ol.
Pri nte d Na me of I n vest i gat or
Si g nat ure of I n vesti gat or
Date
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 4 of 1 0 1
P R O T O C O L A M E N D M E N T 2 S U M M A R Y O F C H A N G E S
R ati o n ale f or A me n d me nt 2:
T his d oc u me nt descri bes t he c ha n ges t o Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) i m ple me nte d b y 
A me n d me nt N o. 2. T he pri mar y reas o n f or t his a me n d me nt is t o pr o vi de clarificat i on rel ate d t o 
t he sec o n dar y e n d p oi nts of Cli nical Gl obal I m pressi o n ( C GI) a n d Care gi ver Gl o bal I m pressi o n 
of  C ha n ge ( Care-GI -C ).
A d dit i onall y , t he a ge f or partici pat i on was i ncrease d t o 5 5 years beca use b ot h 1 5 Q d u plicat i on 
s y n dr ome ( D u p 1 5 q) a n d t he C D K L 5 deficie nc y dis or der ( C D D) occ ur i n c hil d h o o d a n d c o nti n ue 
i nto a d ul t ho o d; t h us, c urre nt cli nical sites ha ve i n dicate d p ote ntial ol der patie nts i n t heir cli nical 
practi c e for t his st u d y .
Ke y C h a n ges I m ple me nte d b y A me n d me nt 2:
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M o difie d i ncl usi o n /e xclusi o n crit eria t o i ncrease t he a ge f or partici pat i on i n t he trial 
t o 5 5 years ol d E x pa n d t he i ncl usi o n cri t eria t o all ow pati e nts wit h a dia g n osis of 
i nterst itial D u p 1 5 q.
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C orrect a n i na d verte nt err or i n t he wa y t he sec o n dar y e n d p oi nts C GI-S, C GI -C, a n d 
Care -GI -C were defi ne d, fr om “ perce nt c ha n ge” t o “c ha n ge”
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A d d t hat Jeju n ost o m y  t u be (J-t u be) ma y be c o nsi dere d base d o n a p pr o val fr o m 
Me dical M o nit or a n d
S p o ns or
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All o w a d h oc a nal ys es t hr o u g h o ut t he trial
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A d d a n a d dit i onal s u b gr o u p i n t he treat me nt res p o n der a nal ysis ( ≥7 5 % re d ucti o n i n 
m o t or seiz ure fre q ue nc y)
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Ma ke c orrecti o ns i n sc he d ule of assess me nt ta ble i ncl u di n g:
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Se parate o ut C GI -S fr o m C GI - C
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Re m o ve c ollect io n seiz ure diar y c hec ks o n Da y 8, Da y 2 2, Da y 5 7, Da y 1 1 3 
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Re vise d c o ntrace pti o n a n d pre g na nc y la n g ua ge
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Re m o ve d t he o pt i onal bl o o d sa m ple f or researc h a nal ysis
A d mi nistrati ve a n d m i n or gra m matical, e dit orial, a n d f or matti n g c ha n ges are i ncl u de d f or 
clarificatio n p ur p oses o nl y. A detaile d descri pt i on of a n d rati o nale f or c ha n ges i m ple me nte d b y 
A me n d me nt 2 are pr o vi de d i n  A p pe n di x 6 . 
C 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 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 5 of 1 0 1
1.
S Y N O P SI S
N a me of S p o ns or/ C o m p a n y:
O vi d T hera pe utics I nc.
N a me of St u d y dr u g:
T A K- 9 3 5
Title of St u d y: 
A m u ltice nter, o pe n-la bel, pil ot st u d y of T A K-9 3 5 ( O V 9 3 5) i n patie nts wit h 1 5 q d u plicati o n s y n dr o me or 
C D K L 5 deficie nc y dis or der ( A R C A D E S T U D Y)
St u d y N u m ber: T A K- 9 3 5- 1 8- 0 0 2 ( O V 9 3 5)
P h ase: 2
St u d y Desi g n: 
T his is a m ultice nter, o pe n -la bel, 2-c o h ort st u d y i n patie nts a ge d ≥2 a n d ≤5 5 years wit h 1 5 q d u plicati o n 
s y n dr o me ( D u p 1 5 q) or C D K L 5 deficie nc y dis or der ( C D D) de m o nstrati n g ≥3 m ot or seiz ures (i.e., dr o p seiz ures, 
t o nic-cl o nic, t o nic, bilateral cl o nic, at o nic, m y ocl o nic-at o nic, m y ocl o nic-t o nic-cl o nic, f ocal seiz ures wit h 
bilateral h y per ki netic m ot or feat ures . N ote - Is olate d m y ocl o nic seiz ures will n ot be part of t he m ot or seiz ure 
c o u nt) per m o nt h d uri n g t he 3 m o nt hs i m me diatel y pri or t o Scree ni n g ( base d o n t he I n vesti gat or’s assess me nt). 
A p pr o xi matel y 3 0 (t otal) patie nts wit h D u p 1 5 q or C D D (a p pr o xi matel y 1 5 patie nts i n eac h s y ndr o me) will be 
e nr olle d. 
St u d y Peri o ds:
T his st u d y c o nsists of 2 peri o ds:
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4 - t o 6-wee k Scree ni n g/ Baseli ne Peri o d
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2 0- wee k Treat me nt Peri o d
- 
8-wee k D ose O pti mizati o n Peri o d 
- 
1 2-wee k Mai nte na nce Peri o d
At t he Scree ni n g Visit ( Visit 1), i nf or me d c o nse nt a n d asse nt (if a p plica ble) will be o btai ne d fr o m t he patie nts 
a n d patie nts’ c ust o dial pare nt or g uar dia n. Patie nts will t he n u n der g o scree ni n g pr oce d ures t o assess st u d y 
eli gi bilit y i n acc or da nce wit h t he st u d y e ntr y criteria. At t his Scree ni n g visit a n d at s u bse q ue nt visits, patie nts 
a n d/ or patie nts’ care gi vers will be pr o vi de d wit h a seiz ure diar y a n d will be i nstr ucte d t o rec or d seiz ure data 
dail y , starti n g at Visit 1 ( Scree ni n g visit), a n d t o c o nti n ue t hr o u g h o ut t he st u d y. T he seiz ure diar y data will be 
c ol lecte d d uri n g t he pr os pecti ve Baseli ne Peri o d a n d will be use d as t he baseli ne seiz ure data f or e n d p oi nt 
a nal yses. 
At t he e n d of t he 4 -wee k Baseli ne Peri o d, patie nts will ret ur n t o t he cli nic ( Visit 2). Seiz ure diaries will be 
re vie we d b y t he Me dical M o nit or a n d if a patie nt does n ot meet t he eli gi bilit y criteria, i ncl u di n g mi ni m u m 
n u m ber of seiz ures re q uire d f or t he st u d y ( ≥3 m ot or seiz ures, e xcl u di n g m y ocl o nic seiz ures), t he patie nt will be 
disc o nti n ue d fr o m t he st u d y a n d c o nsi dere d a scree n fail ure. 
T h e patie nts w h o meet t he e ntr y criteria will be e nr olle d f or 2 0 wee ks ( 8 -wee k D ose O pti mizati o n Peri o d a n d 
1 2- wee k Mai nte na nce Peri o d) of o pe n -la bel treat me nt wit h T A K-9 3 5. After c o m pleti o n of t he treat me nt peri o d, 
t he patie nts will ha ve a ta per peri o d of ma xi mu m  1 4 da ys a n d a 2 -wee k F oll o w -u p Peri o d or will be e nr olle d t o 
a n o pe n-la bel e xte nsi o n st u d y. T he t otal st u d y d urati o n fr o m Scree ni n g t o t he last visit i n t his st u d y will be a 
ma xi m u m  of 3 0 wee ks.
D osi n g a n d Titrati o n Sc he d ule
T he t otal dail y d ose of T A K- 9 3 5 f or all patie nts is calc ulate d base d o n b o d y wei g ht at Visit 1 a n d will be gi ve n 
t wice a da y ( BI D) wit h or wit h o ut f o o d. Patie nts will recei ve t he i nitial d ose of st u d y dr u g, D ose 1, f or t he first 
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 6 of 1 0 1
7 da ys starti n g at Visit 2. T he st u d y dr u g d ose wil l be i ncrease d t o D ose 2 a n d D ose 3 at Da y 8 ( ± 2 da ys) a n d 
Da y 1 5 ( ± 2 da ys). T he ma xi m u m d ose f or a n y patie nt will be 6 0 0 m g/ da y ( 3 0 0 m g BI D). T he fi nal d ose le vel 
will be mai ntai ne d u ntil t he e n d of t he Mai nte na nce P e ri o d; h o we ver, t he d ose ma y be c ha n ge d d uri n g t he D ose 
O pti mizati o n Peri o d wit h a p pr o val fr o m t he Me dical M o nit or. Patie nts w h o ca n n ot t olerate D ose 1 will be 
wit h dra w n fr o m t he st u d y (a n d will c o m plete t he earl y ter mi nati o n a n d safet y f oll o w - u p visits).
D osi n g Sc he d ule b y Wei g ht:
Wei g ht ( k g)
D ose 1
D ose 2
D ose 3
( m g/ d a y)a
N o. T a blets/ 
Mi ni -t a blets
( m g/ d a y)a
N o. T a blets/ 
Mi ni -t a blets
( m g/ d a y)a
N o. T a blets/ 
Mi ni -t a blets
1 0- 1 4
8 0
0/ 4
1 6 0
0/ 8
2 2 0
0/ 1 1
1 5- 1 9
1 2 0
0/ 6
2 0 0
0/ 1 0
2 6 0
0/ 1 3
2 0- 2 4
1 2 0
0/ 6
2 4 0
0/ 1 2
3 2 0
0/ 1 6
2 5- 2 9
1 2 0
0/ 6
2 4 0
0/ 1 2
3 6 0
0/ 1 8
3 0- 3 4
1 6 0
0/ 8
2 8 0
0/ 1 4
4 0 0
0/ 2 0
3 5- 3 9
1 6 0
0/ 8
2 8 0
0/ 1 4
4 4 0
0/ 2 2
4 0- 4 4
1 6 0
0/ 8
3 2 0
0/ 1 6
4 8 0
0/ 2 4
4 5- 4 9
2 0 0
0/ 1 0
3 6 0
0/ 1 8
4 8 0
0/ 2 4
5 0- 5 4
2 0 0
0/ 1 0
3 6 0
0/ 1 8
5 2 0
0/ 2 6
5 5- 5 9
2 0 0
0/ 1 0
3 6 0
0/ 1 8
5 6 0
0/ 2 8
≥6 0
2 0 0
2/ 0
4 0 0
4/ 0
6 0 0
6/ 0
a T otal d ose a d mi nistere d t wice dail y.
T he st u d y will be gi n wit h a p hase d e nr oll me nt base d o n a ge a n d irres pecti ve of t he u n derl yi n g s y n dr o me: 
T w o patie nts a ge d ≥9 years will be e nr olle d f or assess me nt of safet y a n d p har mac o ki netics ( P K). T he 
i n de pe n de nt Data M o nit ori n g C o m mittee (i D M C) will re vie w safet y (a d verse e ve nts, cli nical la b orat or y tests) 
a n d a vaila ble P K data f or t hese 2 patie nts at t he e n d of i nitial u p -d osi n g or Da y 2 1 . T he i D M C ma y t he n 
r ec o m me n d treat me nt f or a d diti o nal patie nts a ge d ≥9 years a n d t he first 2 patie nts a ge d ≥2 t o < 9 years.  
Safet y a n d a vaila ble P K data f or t he first 2 patie nts a ge d ≥2 t o < 9 years will be re vie we d b y t he i D M C at t he 
e n d of i nitial u p- d osi n g or Da y 2 1 . T he i D M C ma y t he n rec o m me n d treat me nt f or a d diti o nal patie nts a ge d ≥2 t o 
< 9 years. Details will be o utli ne d i n t he i D M C c harter.
T he S p o ns or’s Me dical M o nit or a n d/ or P har mac o vi gila nce P h ysicia n will re vie w safet y data a n d a vaila ble P K 
of t h e first 2 patie nts a ge d ≥9 years a n d t he first 2 patie nts a ge d ≥2 t o < 9 years d uri n g eac h ste p of d ose 
es calati o n. 
F oll o wi n g c o m pleti o n of t he Mai nte na nce Peri o d, patie nts will ha ve t he o pti o n t o e nr oll i n a l o n g -t er m, o pe n-
la bel e xte nsi o n st u d y ( O L E) ( u nder a se parate pr ot oc ol [ St u d y T A K - 9 3 5- 1 8-0 0 1 ( O V 9 3 5)]) or t o e nter a ta per 
peri o d ( ma xi m u m 1 4 da ys). D uri n g t he ta per peri o d, t he T A K -9 3 5 d ose will be de -escalate d t o a l o wer d ose 
(ta per D ose 3 t o D ose 2, ta per D ose 2 t o D ose 1) e ver y 3 da ys or less fre q ue ntl y base d o n I n vesti gat or’s 
discreti o n u ntil t here is n o de -escalati o n a n d T A K-9 3 5 d ose is disc o nti n ue d. After ta peri n g, t he patie nts will 
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 7 of 1 0 1
c o m plete a Safet y F oll o w-u p visit a p pr o xi matel y 1 5 da ys after t he last d ose of T A K -9 3 5 a n d e xit t he st u d y.
P har mac o ki netic Assess me nts :
P har mac o ki netic assess me nt will start at Visit 2 ( Da y 1). All e nr olle d patie nts i n t he st u d y will recei ve t he first 
d ose of T A K -9 3 5 i n t he cli nic. Fi ve ( 5) P K bl o o d dra ws will occ ur at t hese f oll o wi n g ti me p oi nts o n t he first 
stu d y da y: pre- first d ose, 3 0 mi n utes ( ± 1 0 mi n utes), 1, 2, a n d 4 h o urs ( ± 1 0 mi n utes) p ost -first d ose. O n ot her 
st u d y visit da ys, t w o ( 2) P K bl o o d dra ws will be c ollecte d: o ne wit hi n 1 h o ur pri or t o t he m or ni n g d ose 
( pre-d ose) a n d t he ot her at 3 0 mi n utes ( ± 1 0 mi n utes) p ost -m or ni n g d ose.
C o nc o mita nt a n d Pr o hi bite d Me dicati o ns:
A dj u ncti ve a ntie pile ptic dr u g ( A E D) treat me nt, va gal ner ve sti m ulat or ( V N S) setti n gs, a n d ket o ge nic diet 
s h o ul d n ot be altere d d uri n g t he st u d y. C o nc urre nt treat me nt re gi me n data will be c ollecte d t hr o u g h o ut t he 
st u d y.
All me dicati o ns 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 her bal pre parati o ns 
i ncl u di n g ( me dical) marij ua na a n d ca n na bi di ol pr o d ucts will be d oc u me nte d t hr o u g h o ut t he st u d y. ( Me dical) 
Marij ua na
a n d ca n na bi di ol pr o d ucts s h o ul d n ot be altere d d uri n g t he st u d y. 
Us e of str o n g i n d ucers a n d i n hi bit ors of c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4 (e. g., prescri pti o n me dicati o ns, o ver -t he-
c o u nter me dicati o ns, dietar y s u p ple me nts, a n d certai n f o o ds s uc h as gra pefr uit/ gra pef r uit j uice) wit hi n 3 0 da ys 
bef or e e nr oll me nt t hr o u g h e n d of ta per is pr o hi bite d, e xce pt f or A E Ds t hat are str o n g i n d ucers or i n hi bit ors o nl y 
( e. g., car ba maze pi ne, p he n o bar bital, p he n yt oi n). Refer t o  A p pe n di x 4 for a list of pr o hi bite d C Y P 3 A 4 
i n d ucers.
Us e of pera m pa nel d uri n g t he st u d y is pr o hi bite d. 
Us e of tra diti o nal C hi nese me dici nes s h o ul d be a p pr o ve d b y t he Me dical M o nit or at scree ni n g.
Pr oce d ures:
Dail y seiz ure diaries (c ollecte d at eac h visit) will be use d t o deter mi ne t he m o nt hl y seiz ure fre q ue nc y f or t he 
e val uati o n of efficac y. 
Bl o o d sa m ples f or cli nical safet y la b orat or y tests i ncl u di n g he mat ol o g y a n d c he mistr y, will be c ollecte d at
Visit 1 ( Scree ni n g), Visit 2 ( Da y 1), Visit 3 ( Da y 1 5), Visit 4 ( Da y 3 6), Visit 5 ( Da y 8 5), a n d Visit 6 ( Da y 1 4 1), 
t he st u d y c o m pleti o n/e n d of st u d y visit. I n a d diti o n, uri nal ysis will be perf or me d at t he s pecifie d visits. Bl o o d 
sa mples t o assess A E D a n d plas m a 2 4 H C le vels will als o be c ollecte d.
Fi ve ( 5) P K bl o o d dra ws will occ ur at t he f oll o wi n g ti me p oi nts o n t he first st u d y da y: pre -first d ose, 3 0 mi n utes 
( ± 1 0 mi n utes), 1, 2, a n d 4 h o urs ( ± 1 0 mi n utes) p ost-first d ose. O n ot her st u d y visit da ys, 2 P K bl o o d dra ws 
will be c ollecte d; o ne wit hi n 1 h o ur pri or t o t he m or ni n g d ose ( pre -m or ni n g -d ose) a n d t he ot her at 3 0 mi n utes 
( ± 1 0 mi n utes) p ost-m or ni n g d ose.
T he t otal bl o o d v ol u me c ollecte d d uri n g t he st u d y will be a p pr o xi matel y 1 2 0 m L f or eac h patie nt. T he
ma xi m u m  bl o o d v ol u me c ollecte d d uri n g a 3 0-da y peri o d will be a p pr o xi matel y 4 0 m L a n d ma xi m u m bl o o d 
v ol u me c ollecte d d uri n g a si n gle visit will be a p pr o xi matel y 2 5 m L. T he t otal bl o o d v ol u me li mits are 
c o nsiste nt wit h p h ysi ol o gical mi ni mal ris k as s pecifi e d b y t he W H O g ui deli nes .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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 8 of 1 0 1
Pri m ar y O bjecti ve:

T o i n vesti gate t he effect of T A K -9 3 5 o n t he fre q ue nc y of m ot or seiz ures f or patie nts wit h D u p 1 5 q or 
C D D d uri n g t he Mai nte na nce Peri o d 
Sec o n d ar y O bjecti ves:

T o i n vesti gate t he effect of T A K -9 3 5 o n t he fre q ue nc y of m ot or seiz ures f or patie nts wit h D u p 1 5 q or 
C D D d uri n g t he Treat me nt Peri o d ( D ose O pti mizati o n a n d Mai nte na nce)

T o i n vesti gate t he pr o p orti o n of patie nts c o nsi dere d as treat me nt res p o n ders f or patie nt s wit h D u p 1 5 q or 
C D D t hr o u g h o ut t he Mai nte na nce Peri o d; treat me nt res p o n ders are defi ne d as t h ose wit h:
o
Re d ucti o n of 2 5 % or m ore i n m ot or seiz ures fr o m baseli ne
o
Re d ucti o n of 5 0 % or m ore i n m ot or seiz ures fr o m baseli ne
o
Re d ucti o n of 7 5 % or m ore i n m ot or seiz ures fr o m baseli ne 
o
Re d ucti o n of 1 0 0 % i n m ot or seiz ures fr o m baseli ne

T o i n vesti gate t he effect of T A K -9 3 5 o n t he fre q ue nc y of m ot or seiz ures lasti n g > 5 mi n utes f or 
patie nts wit h C D D t hr o u g h o ut t he Treat me nt Peri o d

T o i n vesti gate t he effect of T A K -9 3 5 o n t he perce nt/fre q ue nc y of seiz ure free da ys i n patie nts wit h 
D u p 1 5 q or C D D d uri n g t he Mai nte na nce Peri o d

T o assess t he Cli nical Gl o bal I m pressi o n of se verit y ( C GI- S-C) pr o vi de d ), as assesse d b y t he
I n vesti gat or

T o ass ess t he Cli nical Gl o bal I m pressi o n of c ha n ge ( C GI -C) pr o vi de d b y t he I n vesti gat or

T o assess t he Care gi ver Gl o bal I m pressi o n of C ha n ge ( Care GI -C) res p o nses of t he pare nt/fa mil y -
r ep orte d i m pressi o n of efficac y a n d t olera bilit y of st u d y dr u g

T o i n vesti gate t he relati o ns hi p bet wee n 2 4 H C le vel a n d m ot or seiz ure fre q ue nc y
E x pl or at or y O bjecti ves:
S afet y O bjecti ves:

T o e val uate safet y a n d t olera bilit y of T A K - 9 3 5

T o i n vesti gate t he effect of T A K -9 3 5 o n be ha vi or a n d a da pti ve f u ncti o n usi n g t he Vi nela n d A da pti ve 
Be ha vi or scales ( V A B S) a n d A b er ra nt Be ha vi or C hec klist C o m m u nit y q uesti o n naire ( A B C-C)

T o e val uate t he per ce nt of da ys free of a bse nce seiz ures , t o determi ne if t here is w orse ni n g of t his 
seiz ure t y pe d urin g treat me nt wit h T A K - 9 3 5
St u d y P o p ul ati o n: 
Patie nts a ge d ≥2 a n d ≤5 5 years wit h D u p 1 5 q or C D D
N u m ber of P atie nts: 
A p pr o xi matel y 3 0 male a n d fe male patie nts 
(a p pr o xi matel y 1 5 patie nts per s y n dr o me) will be 
e nr olle d
N u m ber of Sites: 
Esti mate d t otal: A p pr o xi matel y 1 0 sites
St u d y Dr u g:
Patie nts will be d ose d wit h T A K -9 3 5 (Ta ble 1)
R o ute of A d mi nistr ati o n: 
Oral or via gastr ost o m y t u be ( G -t u be)/p e rc uta ne o us 
C 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 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 9 of 1 0 1
e n d osc o pic gastr ost o m y ( P E G) t u be. Jej u n ost o m y 
t u be (J-t u be) ma y be c o nsi dere d f oll o wi n g a p pr o val 
b y t he S p o ns or a n d Me dical M o nit or
N ote - Patie nts e nr olle d i n cli nical sites i n C hi na are 
n ot t o recei ve st u d y dr u g via G -t u be/ P E G t u be/J-
t u be.
D u r ati o n of Tre at me nt: 
2 0 wee ks pl us a ma xi mu m t a p er peri o d of 1 4 da ys
Peri o d of E v al u ati o n: 
~ 3 0 wee ks (i ncl u des u p t o 4 - to 6 -wee k 
Scree ni n g/ Baseli ne peri o d, 2 0 -wee k Treat me nt 
Peri o d [ 8 -wee k D ose O pti mizati o n Peri o d, a n d 
1 2- wee k Mai nte na nce Peri o ds], 1 4- da y ta per, a n d 
2 -wee k safet y f oll o w - u p peri o d)
M ai n Criteri a f or I ncl usi o n: 
1.
T he patie nt has a d oc u me nte d dia g n osis of D u p 1 5 q or C D D s u p p orte d b y:

D u p 1 5 q , dia g n ose d p e r sta n dar d of care a n d c o nsiste nt wit h literat ure descri be d p he n ot y pe

C D D
-
A pat h o ge nic or li kel y pat h o ge nic varia nt i n C D K L 5
O R
-
A varia nt of u ncertai n si g nifica nce ( V U S) i n t he ki nase d o mai n of C D K L 5 t hat has 
bee n c o nfir me d t o be de n o v o. U nless b ot h pare nts ha ve bee n teste d a n d f o u n d t o n ot 
har b or t he V U S, a patie nt wit h a V U S ca n n ot be e nr olle d. Partici pa nts wit h a V U S 
f o u n d o utsi de of t he ki nase d o mai n will n ot be e nr olle d. 
-
A patie nt wit h m osaicis m f or a C D K L 5 varia nts is eli gi ble.
2.
T he patie nt or patie nt’s c ust o dial pare nt or g uar dia n are willi n g a n d a ble t o rea d, u n dersta n d, a n d si g n 
t he i nf or me d c o nse nt f or m a n d asse nt, if a p plica ble
3.
Male a n d fe male patie nts a ge d ≥2 a n d ≤5 5 years at t he ti me of i nf or me d c o nse nt 
4.
A hist or y of, o n a vera ge, ≥3 m ot or seiz ures (e xcl u di n g is olate d m y ocl o nic seiz ures) per m o nt h d uri n g 
t he 3 m o nt hs i m me diatel y pri or t o Scree ni n g base d o n t he I n vesti gator’s assess me nt, a n d t he patie nt has 
≥3 m ot or seiz ures (e xcl u di n g is olate d m y ocl o nic seiz ures) d uri n g t he 4 -wee k pr os pecti ve Baseli ne 
Peri o d
5.
Wei g ht of ≥1 0 k g at t he Scree ni n g visit ( Visit 1)
6.
C urre ntl y ta ki n g 1 t o 6 A E Ds at a sta ble d ose f or 4 wee ks pri or t o t he Scree ni n g visit ( Visit 1) ; 
be nz o diaze pi nes use d c hr o nicall y ( o n dail y fre q ue nc y) t o treat seiz ures are c o nsi dere d A E Ds. 
A ntie pile ptic dr u g treat me nt, ( me dical) marij ua na, ca n na bi di ol pr o d ucts, V N S setti n gs, a n d ket o ge nic 
diet s h o ul d n ot be altere d d u ri n g t he st u d y.
7.
T he use of ca n na bi di ol pr o d ucts m ust be sta ble f or 4 wee ks pri or t o scree ni n g
8.
If usi n g a V N S, m ust ha ve V N S place d at least 3 m o nt hs pri or t o t he Scree ni n g visit wit h sta ble setti n gs 
f or > 1 m o nt h; V N S para meters m ust re mai n c o nsta nt t hr o u g h o ut t he st u d y ( V N S will n ot be c o u nte d as 
a n A E D)
9.
If o n a ket o ge nic diet, m ust ha ve starte d t he ket o ge nic diet at least 3 m o nt hs pri or t o t he Scree ni n g visit 
( Visit 1), diet s h o ul d be sta ble f or 4 wee ks bef ore t he Scree ni n g visit ( Visit 1); a n d s h o ul d c o nti n ue 
t hr o u g h t he d urati o n of t he st u d y (ket o ge nic diet will n ot be c o u nte d as a n A E D)
1 0. Faile d t o bec o me a n d re mai n seiz ure -free wit h trials of at least 2 A E Ds
1 1. T he patie nt or patie nt’s le gal re prese ntati ve ( pare nts or le gal g uar dia n) is willi n g t o kee p t he A E D, 
( me dical) marij ua na, ca n na bi di ol pr o d ucts, V N S, a n d ket o ge nic diet re gi me n(s) sta ble t hr o u g h o ut 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 0 of 1 0 1
st u d y
1 2. T he patie nt is a ble t o carr y o ut all a p pr o priate assess me nts a n d ta ke st u d y dr u g i n t he o pi ni o n of t he 
I n vesti gat or a n d pare nt/care gi ver
1 3. Se x uall y acti ve fe male patie nts of c hil d beari n g p ote ntial ( defi ne d as first me narc he) m ust a gree t o use a 
hi g hl y effecti ve met h o d of c o ntrace pti o n d uri n g t he st u d y a n d f or 3 0 da ys after t he last d ose of st u d y 
dr u g . Se x uall y acti ve male patie nts ( p os t-p u bertal u nless per ma ne ntl y sterilize d b y bilateral 
orc hi dect o m y) m ust a gree t o use male c o ntrace pti o n (c o n d o m) d uri n g t he st u d y a n d f or a mi ni m u m of 
3 0 da ys f oll o wi n g t he last d ose of st u d y dr u g. Male patie nts m ust als o n ot d o nate s per m d uri n g t he 
Scree ni n g a n d Treat me nt Peri o ds a n d f or at least 3 0 da ys after t he last d ose of st u d y dr u g.
M ai n Criteri a f or E xcl usi o n: 
Patie nts will be e xcl u de d fr o m st u d y e nr oll me nt if t he y meet a n y of t he f oll o wi n g criteria:
1.
T he patie nt has bee n a d mitte d t o a me dical facilit y a n d i nt u bate d f or treat me nt of stat us e pile ptic us 2 or 
m or e ti mes i n t he 3 m o nt hs i m me diatel y pri or t o t he scree ni n g visit
2.
Patie nts wit h a hist or y of c o nfir me d cataract ( u ntreate d wit h s ur ger y)
3.
U nsta ble, cli nicall y si g nifica nt ne ur ol o gic ( ot her t h a n t he disease bei n g st u die d), ps yc hiatric, 
car di o vasc ular, o p ht hal m ol o gic, p ul m o nar y, he patic, re nal, meta b olic, gastr oi ntesti nal, ur ol o gic, 
i m m u n ol o gic, he mat o p oietic, or e n d ocri ne disease or ot her a b n or malit y, w hic h ma y i m pact t he a bilit y 
t o partici pate i n t he st u d y or t hat ma y p ote ntiall y c o nf o u n d t he st u d y res ults. It is t he res p o nsi bilit y of 
t he I n vesti gat or t o assess t he cli nical si g nifica nce; h o we ver, c o ns ultati o n wit h t he Me dical M o nit or ma y 
be warra nte d
4.
A n y hist or y of alc o h ol, o pi oi d, or ot her dr u g use dis or der, as per t he Dia g n ostic a n d Statistical Ma n ual 
of Me ntal Dis or ders, Fift h E diti o n ( D S M -V), wit hi n t he 2 years i m me diatel y pri or t o t he Scree ni n g 
Visit ( Visit 1)
5.
S uici de atte m pt wit hi n t he last year, at si g nifica nt ris k of s uici de (eit her i n t he o pi ni o n of t he 
I n vesti gat or or defi ne d as ‘ yes’ t o s uici dal i deati o n q uesti o n 4 or 5 o n t he C ol u m bia-S uici de Se verit y 
Rati n g Scale [ C -S S R S] at Scree ni n g), or a p peari n g s uici dal per I n vesti gat or j u d g me nt
6.
A b n or ma l a n d cli nicall y si g nifica nt electr ocar di ogra m ( E C G) a b n or malit y at Scree ni n g; Q T i nter val 
wit h Fri dericia’s c orrecti o n met h o d ( Q Tc F) > 4 5 0 ms ( males) or > 4 7 0 ms (fe males) or a b o ve u p per li mit 
of n or ma l f or a ge, c o nfir me d wit h o ne re peat testi n g, at t he Scree ni n g visit
7.
A b n or ma l cli nical la b orat or y test res ults at t he Scree ni n g visit t hat s u g gest a cli nicall y si g nifica nt 
u n derl yi n g disease t hat w o ul d c o m pr o mise t he well -bei n g of t he patie nt (if t he patie nt has 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] > 2. 5 × t he u p per li m it of n or mal 
[ U L N], t he Me dical M o nit or s h o ul d be c o ns ulte d) 
8.
C urre ntl y recei vi n g a st u d y dr u g or partici pate d i n a cli nical st u d y i n v ol vi n g a n ot her i n vesti gati o nal 
pr o d uct i n t he pre vi o us m o nt h ( or 5 half -li ves of t his i n vesti gati o nal pr o d uct, w hic he ver is l o n ger) 
9.
Recei ve d T A K -9 3 5 i n a pre vi o us cli nical st u d y or as a t hera pe utic a ge nt
1 0. I m me diate fa mil y me m bers, or i n a de pe n de nt relati o ns hi p wit h a st u d y site e m pl o yee w h o is i n v ol ve d 
i n t he c o n d uct of t his st u d y (e. g., c hil d, si bli n g)
1 1. 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 T A K -9 3 5 f or m ulati o n
1 2. C urre ntl y pre g na nt or breastfee di n g or is pla n ni n g t o bec o me pre g na nt wit hi n 3 0 da ys of t he last d ose of 
st u d y dr u g
E n d p oi nts:
Pri mar y Efficac y E n d p oi 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 1 of 1 0 1

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure fre q ue nc y per 2 8 da ys i n t he patie nts wit h C D D d uri n g 
t he Mai nte na nce Peri o d
O R

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure fre q ue nc y per 2 8 da ys i n t he patie nts wit h D u p 1 5 q
d uri n g t he Mai nte na nce Peri o d
Sec o n dar y Efficac y E n d p oi nts

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure fre q ue nc y per 2 8 da ys i n t he patie nts wit h C D D d uri n g 
t he Treat me nt Peri o d

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure fre q ue nc y per 2 8 da ys i n t he patie nts wit h D u p 1 5 q
d uri n g t he Tre at me nt Peri o d

Pr o p orti o n of patie nts c o nsi dere d treat me nt res p o n ders f or patie nts wit h C D D t hr o u g h o ut t he 
Mai nte na nce Peri o d; treat me nt res p o n ders are defi ne d as t h ose wit h: 
-
Re d ucti o n of 2 5 % or m ore i n me dia n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 5 0 % or m ore i n me dia n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 7 5 % or m ore i n me dia n m ot or seiz ures fr o m baseli ne 
-
Re d ucti o n of 1 0 0 % i n me dia n m ot or seiz ures fr o m baseli ne

Pr o p orti o n of patie nts c o nsi dere d treat me nt res p o n ders f or patie nts wi t h D u p 1 5 q t hr o u g h o ut t he 
Mai nte na nce Peri o d; treat me nt res p o n ders are defi ne d as t h ose wit h:
-
Re d ucti o n of 2 5 % or m ore i n me dia n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 5 0 % or m ore i n me dia n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 7 5 % or m ore i n me dia n m ot or seiz ures fr o m baseli ne 
-
Re d ucti o n of 1 0 0 % i n me dia n m ot or seiz ures fr o m baseli ne

Perce nt c ha n ge fr o m Baseli ne i n fre q ue nc y of m ot or seiz ures l o n ger t ha n 5 mi n utes i n patie nts wit h 
C D D

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure -free da ys fre q ue nc y i n patie nts wit h D u p 1 5 q or C D D
d uri n g t he Mai nte na nce Peri o d 

C ha n ge fr o m baseli ne i n C GI-S 

Assess me nt of rati n gs as assesse d b y t he cli nicia n usi n g t he C GI- C

Assess me nt of rati n gs as assesse d b y t he care gi ver usi n g t he Care GI -C 

T o c haracterize plas ma 2 4 H C le vels a n d c ha n ge i n m ot or seiz ure fre q ue nc y i n patie nts treate d wit h 
T A K- 9 3 5 as a n a dj u ncti ve t hera p y
E x pl orat or y Efficac y E n d p oi nts
Safet y E n d p oi nts

Perce nta ge of patie nts wit h at least 1 treat me nt -e mer ge nt a d verse e ve nt ( T E A E)

C ha n ge i n be ha vi oral a n d a da pti ve f u ncti o nal meas ures usi n g t he V A B S

C ha n ge i n be ha vi or meas ures usi n g t otal sc ores a n d s u bscale sc ores of A B C -C 

Perce nta ge of patie nts wit h at least 1 mar ke dl y a b n or mal val ue f or cli nical la b orat or y e val uati o ns, vital 
si g ns, b o d y wei g ht a n d hei g ht, a n d E C G para meters after T A K-9 3 5 treat me nt

C ha n ge fr o m Baseli ne i n cli nical la b orat or y e val uati o ns, vital si g ns, b o d y wei g ht, hei g ht, C- S S R S, a n d 
C 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 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 2 of 1 0 1
E C G para meter val ues after T A K -9 3 5 treat me nt

Perce nt of a bse nce seiz ure free da ys i n patie nts w h o re p ort a bse nce seiz ures d uri n g baseli ne .
S afet y:
A n i D M C will m o nit or t he patie nt safet y i n acc or da nce wit h t he i D M C c harter. 
T he st u d y will be gi n wit h a p hase d e nr oll me nt base d o n a ge a n d irres pecti ve of t he u n derl yi n g s y n dr o me:

T w o patie nts a ge d ≥9 years will be e nr olle d f or assess me nt of safet y a n d P K. T he i D M C will re vie w 
safet y (a d verse e ve nts, cli nical la b orat or y res ults) a n d a vaila ble P K data f or t hese 2 patie nts at t he e n d 
of i nitial u p -d osi n g or Da y 2 1 . T he i D M C ma y t he n rec o m me n d treat me nt f or a d diti o nal patie nts a ge d 
≥9 years a n d t he first 2 patie nts a ge d ≥2 t o < 9 years.

T he S p o ns or’s Me dical M o nit or a n d/ or P har mac o vi gila nce p h ysicia n will re vie w safet y data a n d 
a vaila ble P K of first 2 patie nts a ge d ≥9 years a n d first 2 p atie nts a ge d ≥2 t o < 9 years d uri n g eac h ste p of 
d ose escalati o n.
St atistic al C o nsi der ati o ns: 
All statistical a nal yses will be perf or me d usi n g S A S ® Versi o n 9. 4 or hi g her. All cli nical st u d y data will be 
prese nte d i n patie nt data listi n gs. Data s u m maries w ill be prese nte d f or all e n d p oi nts a n d will i ncl u de 
descri pti ve statistics ( n u m ber of patie nts [ n], mea n, sta n dar d de viati o n [ S D], first q uartile [ Q 1], me dia n, t hir d 
q uartile [ Q 3], mi ni m u m a n d ma xi m u m) f or c o nti n u o us varia bles, a n d fre q ue nc y a n d perce nta ge f or cate g orical 
a n d or di nal varia bles. If t here are missi n g val ues, t he n u m ber of missi n g will be prese nte d, b ut wit h o ut a 
perce nta ge.
F or all a nal yses, ‘ Baseli ne’ refers t o t he pr os pecti ve 4 -wee k Baseli ne Peri o d.
M o difie d I nte nt -t o-Tr e at ( mI T T) A nal ysis Set
All patie nts w h o ha ve recei ve d at least 1 d ose of st u d y dr u g a n d ha ve bee n assesse d f or efficac y (i.e., has at 
least o ne efficac y o utc o me meas ure) f or at least 1 da y i n t he Treat me nt Peri o d will be i ncl u de d i n t he m o difie d 
i nte nt-t o-treat ( mI T T) a nal ysis set. 
Efficac y A nal ysis P o p ulati o n
All mI T T s u bjects w h ose assess me nts are c o m plia nt wit h Pr ot oc ol A me n d me nt 2 will be i ncl u de d i n t he 
efficac y a nal ysis p o p ulati o n. Efficac y a nal yses f or pri mar y a n d sec o n dar y efficac y e n d p oi nts will be base d o n 
t he efficac y a nal ysis p o p ulati o n a n d t he mI T T set , a n d t h ose f or e x pl orat or y efficac y e n d p oi nts will be base d o n 
t he mI T T set.
Safet y A nal ysis Set
All patie nts w h o ta ke at least 1 d ose of st u d y me dicati o n will be i ncl u de d i n t he Safet y A nal ysis Set.
A nal ysis Gr o u ps
All a nal yses will be perf or me d o n 2 a nal ysis gr o u ps: t he D u p 1 5 q gr o u p a n d t he C D D gr o u p. 
Efficac y A nal yses
M ot or seiz ure ( wit h e xcl usi o n of is olate d m y ocl o nic seiz ures) fre q ue nc y per 2 8 da ys will be calc ulate d at eac h 
s pecifie d i nter val as [( n u m ber of seiz ures i n t hat i nter val) / ( da ys wit h n o missi n g seiz ure c o u nt i n t hat i nter val)] 
× 2 8. 
F or all patie nts, m ot or seiz ure fre q ue ncies per 2 8 da ys f or t he 4 -wee k pr os pecti ve Scree ni n g/ Baseli ne Peri o d, 
eac h 4-wee k i nter val i n t he Mai nte na nce Peri o d, t he Mai nte na nce Peri o d a n d t he 2 0 -wee k Treat me nt Peri o d will 
be calc ulate d. 
O bser ve d val ues, c ha n ge fr o m Baseli ne, a n d perce nt c ha n ge fr o m Baseli ne f or t he m ot or s eiz ur e fre q ue nc y ( per 
2 8 da ys) will be s u m marize d descri pti vel y b y a nal ysis gr o u p f or t he f oll o wi n g i nter vals: t he t hree 4 -wee k 
i nter vals i n t he Mai nte na nce peri o d, t he Mai nte na nce Peri o d a n d t he e ntire 2 0 wee ks of Treat me nt Peri o d. F 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 3 of 1 0 1
eac h a nal ysis gr o u p , t he medi a n of pri mar y e n d p oi nt will be prese nte d al o n g wit h its c orres p o n di n g 9 0 % 
c o nfi de nce i nter val. Hist o gra ms will be pr o d uce d f or t he pri mar y e n d p oi nt f or eac h a nal ysis gr o u p. T he a nal ysis 
will be re peate d f or all m ot or seiz ure t y pes.
T he ti me c o urse of seiz ure fre q ue ncies ( per 2 8 da ys) i n c o nsec uti ve 4 -wee k i nter vals i n t he Mai nte na nce Peri o d 
will be dis pla ye d i n a li ne gra p h b y a nal ysis gr o u p. 
T he pr o p orti o n of treat me nt res p o n ders base d o n ≥2 5 % w orse ni n g, < 2 5 % a n d > 1 % w orse ni n g, n o c ha n ge 
(W orse ni n g of 1 % t o Re d ucti o n of 1 %) , ≥2 5 % re d ucti o n, ≥5 0 % re d ucti o n, ≥7 5 % re d ucti o n, a n d 1 0 0 % 
re d ucti o n fr o m Baseli ne i n m ot or seiz ure fre q ue nc y d uri n g t he Mai nte na nce Peri o d will be s u m marize d at eac h 
4- wee k i nter val, t he 1 2 wee ks of mai nte na nce p er i o d, a n d t he e ntire 2 0 wee ks of t he Treat me nt Peri o d b y 
a nal ysis gr o u p.
O bser ve d val ues a n d c ha n ge fr o m Baseli ne i n Cli nical Gl o bal I m pressi o n of Se verit y ( C GI -S) will be a nal yze d 
descri pti vel y at eac h st u d y visit. R ati n gs of Cli nical Gl o bal I m pressi o n - C ha n ge ( C GI -C) a n d Care gi ver Gl o bal 
I mpressi o n of C ha n ge ( Care GI -C) res p o nses will be assesse d .  
T e c h ni q ues f or ha n dli n g missi n g i nf or mati o n wit h res pect t o re p orti n g of seiz ures i n t he treat me nt peri o d ( D ose 
O pti mizati o n a n d Mai nte na nce) will be s peci fie d i n detail i n t he statistical a nal ysis pla n ( S A P).
Safet y A nal yses
All safet y assess me nts will be s u m marize d usi n g descri pti ve statistics. All safet y a nal yses will be base d o n 
o bser ve d data o nl y, a n d n o missi n g val ues will be i m p ute d. Re p orte d A E ter ms will be c o de d usi n g t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) a n d s u m marize d b y preferre d ter m a n d s yste m or ga n class 
cate g ories. Seri o us a d verse e ve nts ( S A Es) a n d A Es lea di n g t o st u d y disc o nti n uati o n will als o be s u m marize d.
O bser ve d val u es a n d c ha n ge fr o m baseli ne i n la b orat or y para meters, vital si g ns, a n d E C G para meters will be 
s u m marize d b y st u d y visit. T he n u m ber a n d perce nta ge of patie nts w h o ha ve met p ote ntiall y cli nicall y 
si g nifica nt criteria at a n y p ost baseli ne visit will be s u m marize d f or la b orat or y, vital si g ns, a n d E C G para meters. 
T he n u m ber a n d perce nta ge of patie nts wit h s hifts i n la b orat or y will be s u m marize d. T he n u m ber a n d 
perce nta ge of patie nts wit h C -S S R S assess me nts of s uici dal i deati o n a n d be ha vi or will als o be s u m mariz e d.
Pri or a n d c o nc o mita nt me dicati o n use will be s u m marize d b y W orl d Healt h Or ga nizati o n A nat o mical 
T hera pe utic C he mical ( W H O -A T C) classificati o n s yste m. 
E x pl orat or y A nal yses
S a m ple Size J ustific ati o n:  
A f or mal sa m ple size calc ulati o n was n ot perf or me d f or t his st u d y. Gi ve n t he rare occ urre nce of t hese e pile ptic 
e nce p hal o pat h y s y n dr o mes a n d base d o n pri or cli nical de vel o p me nt pr o gra ms f or treat me nt of rare diseases, t he 
c urre nt sa m ple size is dee me d a p pr o priate t o e val uate t he efficac y a n d safet y of T A K -9 3 5 i n patie nts wit h 
D u p 1 5 q a n d C D D .
C 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 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 4 of 1 0 1
T A B L E O F C O N T E N T S
P R O T O C O L T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) ....................................................................................1
P R O T O C O L A M E N D M E N T 2 S U M M A R Y O F C H A N G E S ....................................................4
1.
S Y N O P SI S ...............................................................................................................5
T A B L E O F C O N T E N T S ..........................................................................................................1 4
2.
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S ...........................1 9
3.
I N T R O D U C TI O N..................................................................................................2 2
3. 1.
Bac k gr o u n d ............................................................................................................2 2
3. 2.
St u d y  Ratio nale ......................................................................................................2 2
3. 2. 1.
1 5 q D u plicat i on S y n dr o me ( D u p 1 5 q) .....................................................................2 2
3. 2. 2.
C D K L 5 Deficie nc y  Dis or der ( C D D).......................................................................2 3
4.
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S ...........................................................2 4
4. 1.
O bject i ves...............................................................................................................2 4
4. 1. 1.
Pri mar y O bject i ve...................................................................................................2 4
4. 1. 2.
Sec o n dar y  O bjecti ves .............................................................................................2 4
4. 1. 3.
E x pl or at or y  O bjecti ves ...........................................................................................2 4
4. 1. 4.
S af et y O bjecti ves ....................................................................................................2 5
4. 2.
E n d p oi nts ...............................................................................................................2 5
4. 2. 1.
Pri mar y Eff icac y E n d p oi nt......................................................................................2 5
4. 2. 2.
Sec o n dar y  Efficac y E n d p oi nts................................................................................2 5
4. 2. 3.
E x pl or at or y  Efficac y E n d p oi nts..............................................................................2 6
4. 2. 4.
S af et y E n d p o i nts.....................................................................................................2 6
5.
I N V E S TIG A TI O N A L P L A N .................................................................................2 7
5. 1.
S u m mar y  of St u d y Desi g n......................................................................................2 7
5. 1. 1.
E n d of St u d y  Defi niti on ..........................................................................................2 9
5. 1. 2.
St u d y  E xte nsi on ......................................................................................................2 9
5. 2.
S el ect i on a n d Ti mi n g o f D oses i n t he St u d y ............................................................2 9
5. 2. 1.
M o deli n g a n d Si m ulat i on of Cli nical Data ..............................................................2 9
6. 
S T U D Y P O P U L A TI O N .........................................................................................3 1
6. 1.
I ncl usi on Cri t eria ....................................................................................................3 1
6. 2.
E xcl usi o n Cri t eria ...................................................................................................3 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 5 of 1 0 1
6. 3.
Di sc o nti n uatio ns..................................................................................................... 3 4
6. 3. 1.
Di sc o nti n uatio n of  P atie nts .....................................................................................3 4
6. 3. 2.
Di sc o nti n uatio n of  St u d y Sites/ Site Ter mi nate d b y S p o ns or....................................3 6
6. 3. 3.
Di sc o nti n uatio n of  t he St u d y/ St u d y Ter mi nate d b y S p o ns or....................................3 6
7.
T R E A T M E N T ........................................................................................................3 7
7. 1.
Materi als a n d S u p plies ............................................................................................3 7
7. 1. 1.
St ora ge ...................................................................................................................3 7
7. 2.
Treat me nts A d mi nistere d ........................................................................................3 7
7. 2. 1.
D ose Ta peri n g ........................................................................................................3 9
7. 2. 2.
I n vestigat or Res p o nsi bilit ies f or Dr u g A d mi nistrati o n.............................................3 9
7. 3.
Met h o d of Assi g n me nt t o Treat me nt .......................................................................3 9
7. 4.
C o nti n ue d Access t o St u d y  Dr u g ............................................................................4 0
7. 5.
Bli n di n g ..................................................................................................................4 0
7. 6.
C o nc o mita nt Me d icatio ns a n d N o n -P har mac o l ogic T hera pies a n d 
Pr oce d ures ..............................................................................................................4 0
7. 7.
Treat me nt C o m plia nce ............................................................................................4 0
8.
S T U D Y A S S E S S M E N T S .......................................................................................4 1
8. 1.
St u d y  Pr oce d ures....................................................................................................4 1
8. 1. 1.
I nf or me d C o nse nt Pr oce d ure ...................................................................................4 1
8. 1. 1. 1.
St u d y  I nf or me d C o nse nt Pr oce d ure .........................................................................4 1
8. 1. 2.
D e m o gra p hics, Me di cal Hist or y, a n d Me dicati on Hi st or y Pr oce d ure.......................4 1
8. 1. 3.
P h ysical E xa mi nat i on Pr oce d ure .............................................................................4 1
8. 1. 4.
Ne ur ol o gi cal E xa mi nati on Pr oce d ure ......................................................................4 2
8. 1. 5.
Wei g ht a n d Hei g ht ..................................................................................................4 2
8. 1. 6.
Vi t al Sig ns Pr oce d ure .............................................................................................4 2
8. 1. 7.
S ei z ure Diar y Pr oce d ure.........................................................................................4 2
8. 1. 8.
D oc u m e nt atio n of  St u d y Dr u g ................................................................................4 3
8. 1. 9.
D oc u m e nt atio n of  C o nc omit a nt Me dic atio ns .......................................................... 4 3
8. 1. 1 0.
Pr oce d ures f or Cli nical La b orat or y  Sa m ples ...........................................................4 3
8. 1. 1 1.
C o ntrace pti o n a n d Pre g na nc y A v o i da nce Pr oce d ure ...............................................4 4
8. 1. 1 2.
E C G Pr oce d ure .......................................................................................................4 4
8. 1. 1 3.
Cli n ical Assess me nt of S uici dal I deati on a n d Be ha vi or ...........................................4 5
8. 1. 1 4.
Vi nela n d A da pt i ve Be ha vi or Scale..........................................................................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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 6 of 1 0 1
8. 1. 1 5.
A berra nt Be ha vi or C hec klist -C o m m u nit y ( A B C -C) ................................................4 5
8. 1. 1 6.
D oc u m e nt atio n of  C o nc urre nt Me dical C o n dit i ons .................................................4 6
8. 1. 1 7.
Care gi ver Gl o bal I m pressi o n of C ha n ge ( Care GI -C) ..............................................4 6
8. 1. 1 8.
Cli nical Gl o bal I m pressi o n o f Se verit y ( C GI-S) a n d Cli nical Gl o bal 
I mpressi o n – C ha n ge ( C GI - C) ...............................................................................4 6
8. 1. 1 9.
Se verit y Assess me nt i n C D K L 5 Deficie nc y Dis or der ..............................................4 7
8. 1. 2 0.
E xi t S ur ve y.............................................................................................................4 7
8. 1. 2 1.
P har mac o ki net ic Sa m ple C ollecti on a n d A nal ysis ...................................................4 7
8. 1. 2 1. 1.
C ollect i on of Plas ma Sa m ples f or T A K- 9 3 5 P K E val uat i on ....................................4 7
8. 1. 2 1. 2.
Bi oa nal y tic al Met h o ds f or T A K- 9 3 5.......................................................................4 7
8. 1. 2 1. 3.
P har mac o ki net ic Para meters...................................................................................4 8
8. 1. 2 2.
P har mac o d y na mic Sa m ple C o llecti on a n d A nal ysis ................................................4 8
8. 1. 2 2. 1.
C ollect i on of Plas ma Sa m ples f or P har mac o d y na mic E val uat i on ............................4 8
8. 1. 2 2. 2.
Bi oa nal y tic al Met h o ds f or 2 4 H C ............................................................................4 8
8. 1. 2 2. 3.
P har mac o d y na mic Para meters ................................................................................4 8
8. 1. 2 3.
D oc u m e nt atio n of  Scree n Fail ure............................................................................4 8
8. 1. 2 4.
D oc u m e nt atio n of  St u d y E ntra nce...........................................................................4 9
8. 2.
S a m ple C ollect i on a n d Test i n g ...............................................................................4 9
8. 3.
S af et y E val uat i ons ..................................................................................................4 9
8. 3. 1.
A d verse E ve nts .......................................................................................................4 9
8. 3. 1. 1.
Se verit y Assess me nt ...............................................................................................5 1
8. 3. 1. 2.
Ca usalit y Assess me nt .............................................................................................5 1
8. 3. 1. 3.
S eri o us A d verse E ve nts ..........................................................................................5 2
8. 3. 1. 4.
S us pecte d U ne x pecte d Seri o us A d verse React i ons ..................................................5 2
8. 3. 1. 5.
Re p orti n g A d verse E ve nts ......................................................................................5 3
8. 3. 1. 6.
S p o ns or Re p orti n g Re q uire me nts ............................................................................5 3
8. 3. 1. 7.
I n vesti gat or Re p orti n g Re q uire me nts......................................................................5 3
8. 3. 2. 
E x p os ure D uri n g Pre g na nc y a n d/ or Lactati o n .........................................................5 4
8. 3. 3.
S af et y M o ni t ori n g...................................................................................................5 4
8. 3. 3. 1.
Re p orti n g of A b n or mal Li ver F u ncti o n Tests ..........................................................5 4
8. 4.
A p pr o priate ness of Meas ure me nts ..........................................................................5 5
9.
D A T A Q U A LI T Y A S S U R A N C E ..........................................................................5 6
9. 1.
Data C ollect i on a n d St ora ge ....................................................................................5 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 s of U s e

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 7 of 1 0 1
1 0.
S T A TI S TI C A L M E T H O D S A N D P L A N N E D A N A L Y S E S ..................................5 8
1 0. 1.
Ge neral C o nsi derati o ns ...........................................................................................5 8
1 0. 2.
Deter mi nat i on of Sa m ple Size .................................................................................5 9
1 0. 3.
A nal ysis Sets ..........................................................................................................5 9
1 0. 3. 1.  
M o difi e d I nte nt -t o-Treat A nal ysis Set .....................................................................5 9
1 0. 3. 2.
Efficac y A nal ysis Set ..............................................................................................6 0
1 0. 3. 3.
S af et y A nal ysis Set ................................................................................................. 6 0
1 0. 3. 4 .
A nal ysis Gr o u ps .....................................................................................................6 0
1 0. 4.
D e m o gra p hics a n d Baseli ne C haracterist ics............................................................6 0
1 0. 5.
P ati e nt Dis p ositio n ..................................................................................................6 0
1 0. 6.
C o nc o mita nt Me dicati o ns a n d N o n -P har mac o l ogic T hera pies a n d 
Pr oce d ures ..............................................................................................................6 0
1 0. 7.
Treat me nt C o m plia nce ............................................................................................6 1
1 0. 8.
Efficac y A nal yses ...................................................................................................6 1
1 0. 8. 1.
Pri mar y Efficac y  A nal yses......................................................................................6 1
1 0. 8. 2.
Sec o n dar y  Efficac y A nal yses..................................................................................6 1
1 0. 8. 3.
E x pl or at or y  A nal ysis..............................................................................................6 2
1 0. 9.
S af et y A nal yses ......................................................................................................6 2
1 0. 9. 1.
P h ysical E xa mi nat i on, Vi t al Si g ns, a n d Ot her P h ysical Fi n di n gs.............................6 2
1 0. 9. 2.
Cli nical La b orat or y  Tests........................................................................................6 2
1 0. 9. 3.
A d verse E ve nts .......................................................................................................6 3
1 0. 1 0.
P har mac o ki net ic/ P har mac o d y na mic A nal yses ........................................................6 3
1 0. 1 1.
Ot her Statist ical Iss ues............................................................................................6 3
1 0. 1 1. 1.
Si g nifica nce Le vels ................................................................................................. 6 3
1 0. 1 1. 2.
Missi n g or I n vali d Data
..........................................................................................6 3
1 0. 1 2.
I nteri m A nal yses.....................................................................................................6 3
1 1.
I N F O R M E D C O N S E N T, E THI C A L R E VI E W, A N D R E G U L A T O R Y 
C O N SI D E R A TI O N S ..............................................................................................6 4
1 1. 1.
I nf or me d C o nse nt ...................................................................................................6 4
1 1. 2.
Data M o nit ori n g C o m mittee ...................................................................................6 4
1 1. 3.
Et hical Re vie w .......................................................................................................6 4
1 1. 4.
Re g ulat or y  C o nsi derati ons ......................................................................................6 5
1 1. 4. 1.
C o nfi de nt iality ........................................................................................................6 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 8 of 1 0 1
1 1. 4. 2.
I n vesti gat or I nf or mati on .........................................................................................6 5
1 1. 4. 3.
Pr ot oc ol  Sig nat ures ................................................................................................. 6 6
1 1. 4. 4.
Fi nal Re p ort Si g nat ure ............................................................................................6 6
1 1 . 5.
P u blicat i on P olic y ...................................................................................................6 6
1 2.
LI S T O F R E F E R E N C E S ........................................................................................6 7
A P P E N DI X 1.
S C H E D U L E O F A S S E S S M E N T S ................................................................. 6 9
A P P E N DI X 2.
S T U D Y T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5; A R C A D E S T U D Y): C LI NI C A L 
L A B O R A T O R Y T E S T S ........................................................................................7 3
A P P E N DI X 3.
S T U D Y T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5; A R C A D E S T U D Y): S A M P LI N G 
S U M M A R Y ...........................................................................................................7 4
A P P E N DI X 4.
S T R O N G C Y P 3 A 4 I N D U C E R S A N D I N HI BI T O R S ....................................7 5
A P P E N DI X 5.
O P TI O N A L C D K L 5 C LI NI C A L S E V E RI T Y A S S E S S M E N T 
( V E R SI O N 3. 5)1 7 ...................................................................................................7 6
A P P E N DI X 6.
O V E R VI E W O F M AJ O R C H A N G E S I M P L E M E N T E D B Y
A M E N D M E N T S ....................................................................................................8 9
LI S T O F T A B L E S
Ta ble 1:
D osi n g Sc he d ule b y  W eig ht ....................................................................................3 8
Ta ble 2:
Sc he d ule of Assess me nts ........................................................................................7 0
LI S T O F FI G U R E S
Fi g ure 1:
St u d y  Desi g n f or Cli nical Pr ot oc ol T A K- 9 3 5- 1 8-0 0 2 ( O V 9 3 5; A R C A D E 
St u d y ).....................................................................................................................2 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 1 9 of 1 0 1
2.
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S
Ter m
Defi niti o n
2 4 H C
2 4 S- h y dr o x y c h olester ol
A B C - C
A berra nt Be ha vi or C hec klist c o m m u nit y q uesti o n naire
A E
a d verse e ve nt
A E D
a ntie pile ptic dr u gs
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
A U C
area u n der t he 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 2 4,ss
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 at stea d y state
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
BI D
t wice dail y
Care GI - C
Care gi ver Gl o bal I m pressi o n of C ha n ge
C D D
C y cli n -De pe n de nt Ki nase -Li ke 5 Deficie nc y Dis or der
C D K L 5
C y cli n -De pe n de nt Ki nase -Li ke 5
C GI
Cli nical Gl o bal I m pressi o n
C GI - C
Cli nical Gl o bal I m pressi o n - C ha n ge
C GI - S
Cli nical Gl o bal I m pressi o n of Se verit y
C H 2 4 H
c h olester ol 2 4-h y dr o x y lase
CI
c o nfi de nce i nter val
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces
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 plas ma c o nce ntrati o n d uri n g a d osi n g i nter val, at stea d y state
C N S
ce ntral ner v o us s yste m
C- S S R S
C ol u m bia – S uici de Se verit y Rati n g Scale
C Y P
c yt oc hr o me P- 4 5 0
D E E
de vel o p me ntal a n d e pile ptic e nce p hal o pat h y
D S M - V
Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders – 5 t h e diti on
D u p 1 5 q
1 5 q D u plicati o n s y n dr o me
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
E D C
electr o nic data ca pt ure
E E G
electr oe nce p hal o gra 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 o t h e A p pli c a bl e T er m s of U s e

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 2 0 of 1 0 1
Ter m
Defi niti o n
E O
e nz yme occ u pa nc y
G A B A
γ-a mi n o b ut yric aci d
G C P
G o o d Cli nical Practice
G G T
γ-gl uta m yl tra nsferase
G- t u be 
g astr ost o m y t u be
h C G
h u ma n c h ori o nic g o na d otr o pi n
I A R
i nf usi o n-ass ociate d reacti o n
I B
I n vesti gat or Br oc h ure
I C F
inf or me d c o nse nt f or m
i D M C
i n de pe n de nt Data M o nit ori n g C o m mittee
I N R
int e r nati onal n o r malize d rati o
I R B/I E C
i nstit uti o nal re vie w b oar d/i n de pe n de nt et hics c o m mittee
I x R S/I W R S
I nteracti ve V oice/ We b Res p o nse S yste m
J-t u be
jej u n ost o m y t u be
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 T T
m o difie d i nte nt -t o-treat 
N M D A
N -met h y l- D-as partate
O L E
o pe n -la bel e xte nsi o n
O T C
o ver t he c o u nter
P D
p har mac o d y na mic(s)
P E G 
Perc uta ne o us e n d osc o pic gastr ost o m y
P E T
p ositr o n e missi o n t o m o gra p h y
P K
p har mac o ki netic(s)
P T
preferre d ter m
P W A C R
Pra der -Willi/ A n gel ma n critical re gi o n
Q 1
first q uartile
Q 3
t hir d q uartile
Q D
o nce dail y
Q Tc F
Q T i nter val wit h Fri dericia’s c orrecti o n met h o d
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S D
sta n dar d de viati o n
S O C
s yste m or ga n class
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 2 1 of 1 0 1
Ter m
Defi niti o n
S U S A R
sus pecte d u ne x pecte d seri o us a d verse reacti o n
T E A E
treat me nt-e mer ge nt a d verse e ve nt
tma x
ti me of first occ urre nce of Cma x
U L N
u p per li mit of n or mal
V A B S
Vi nela n d A da pti ve Be ha vi or scales
V N S
va gal ner ve sti m ulat or
V U S
varia nt of u ncertai n si g nifica nce
W H O -A T C
W orl d Healt h Or ga nizati o n A nat o mical T hera pe utic C he mical classificati o n s yste m
W H O -D D
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 2 2 of 1 0 1
3.
I N T R O D U C TI O N
3. 1.
B ac k gr o u n d
A d dit i onal i nf or mati o n a b o ut t he ris ks, k n o w n a n d e x pecte d be nefits, of T A K-9 3 5 m a y b e fo u n d 
i n t he c urre nt e diti on of t he I n vest i gat or’s Br oc h ure (I B). 
3. 2.
St u d y R ati o n ale
3. 2. 1.
1 5 q D u plic ati o n S y n dr o me ( D u p 1 5 q)
D u plicat i ons o f t he pr o xi mal ar m o f c hr o m o s o me 1 5 q 1 1. 2 -q 1 3. 1 res ult i n t he ge net ic c o n diti on 
D u p 1 5 q. M ul tiple ge nes i ncl u di n g U B E 3 A fr o m t his re gio n are i m plicate d i n t he pat h o ge nesis of 
a utis m s pectr u m dis or ders, e pile ps y, a n d sc hiz o p hre nia.3 I ncrease d d osa ge of t he U B E 3 A 
c o ntri b utes t o e pile p s y in D u p 1 5 q a n d it is t h o u g ht t o be t he u n derl yi n g ca use of t he a utist ic 
feat ures of t he s y n dr o me as well. W he n U B E 3 A is ele vate d i n glia, A T P α le vels are re d uce d, 
t hus i ncreasi n g t he c o nce ntrati o n of K + i n t he e xtracell ular s pace. Ele vate d e xtracell ular K + lea ds 
t o t he ne ur o nal d ysf u ncti o n via N M D A rece pt or acti vati on a n d has e mer ge d as a p ote ntial ca use 
C 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 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

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Pa ge 2 3 of 1 0 1
of  e pile ps y. T he most de vastati n g feat ure of D u p 1 5 q is diffic ult t o c o ntr ol seiz ures.4
A p pr o xi matel y  6 0 % of t he patie nts ha ve seiz ures a n d t he rate of seiz ures is hi g her i n pat ient s
wi t h idic 1 5 f or m . T he ot her most c o m m o n  seiz ure t ypes are i nfa nt ile s pas m a n d ge neralize d 
t o nic –clo nic seiz ures f oll o we d b y at o ni c, m yo cl o ni c, f o c al -o nset, a n d t o ni c seiz ures.5 P o orl y  
c o ntr olle d seiz ures se verel y i m pact t he q ualit y of  life of b ot h affecte d i n di vi d uals a n d t heir 
care gi vers. C urre nt treat me nt o pti o ns f or D u p 1 5 q -ass ociate d e pile ps y are ofte n i neffecti ve. 
G A B Aer gic pr o m oti n g a nt ie pile ptics are t ypicall y i neffect i ve w hile br oa d-s pectr u m a ntie pile ptic 
me dicat i ons s uc h as val pr o ic aci d a n d r ufi na mi de pr o vi de s ome relief.
3. 2. 2.
C D K L 5 Deficie nc y Dis or der ( C D D)
P ati e nts wit h c ycli n-de pe n de nt ki nase -li ke 5 ( C D K L 5) m utati o ns prese nt wit h earl y e pile ps y,
starti n g fr om 1 0 da y s t o 3 mo nt hs after birt h .6 I n partic ular, earl y dr u g- resista nt e pile ps y, us uall y 
starti n g i n t he first m o nt hs of life, te n ds to be t he m ost c o m m o n feat ure. Seiz ures are i n ge neral 
hi g hl y  p ol y mor p hic a n d ma n y  differe nt seiz ure t ypes ca n als o occ ur i n t he sa me pat ient , 
c ha n gi n g wit h ti me. C o m ple x partial seiz ures, i nfa nt ile s pas ms, m y ocl onic, ge neralize d 
t o nic- clo nic, a n d t o ni c s eiz ures ha ve all bee n re p orte d. Stere ot ypic ha n d m o ve me nts, se vere 
h y p ot o ni a, a n d i m paire d ps yc h o m o t or de vel o p me nt are us uall y ass ociate d wit h C D K L 5 
m utati o ns a n d c o m m o n t o t he ge neral cli nical ma nifestati o n of Referral t o Treat me nt patie nts. 
C D K L 5 pla ys a n i m p orta nt r ole i n c o ntr olli n g p osts y na ptic l ocalizati o n of t he Gl u N 2 B-S A P 1 0 2 
c o mple x i n t he hi p p oca m p us a n d t here b y re g ulates seiz ure s usce pt i bility, a n d t hat a berra nt 
N M D A rece pt or -me d iate d s y na ptic tra ns missi on u n derlies t he pat h ol o gical mec ha nis ms of t h e 
C D K L 5 l oss -of -f unct i on .7
 
. 
T he c urre nt st u d y  is desig ne d t o e x pl ore t he effects of T A K -9 3 5 o n seiz ure fre q ue nc y  usi n g a 
seiz ure diar y. A n a d ditio nal ai m  is t o c haracterize t he safety a n d t olera bilit y of mul tiple -d ose 
T A K -9 3 5 a d mi nistrati o n i n pat ient s wit h D u p 1 5 q or C D D . 
C 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 O n 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 CI

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
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Pa ge 2 4 of 1 0 1
4.
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
St u d y  o bject i ves a n d ass ociate d e n d p oi nts are prese nte d i n Secti o n 4. 1 a n d Secti o n 4. 2 , 
res pecti vel y; t he fre q ue nc y a n d ti mi n g of st u d y meas ure me nts is pr o vi de d i n t he Sc he d ule of 
Assess me nts (Ta ble 2 ). I nf or matio n re gar di n g sa m ple c ollect i on a n d safet y data c ollect i on are 
prese nte d i n Secti o n 8.
4. 1.
O bjecti ves
4. 1. 1.
Pri m ar y O bjecti ve
T he pri mar y  o bjecti ve of t his st u d y is:

T o i n vesti gate t he effect of T A K -9 3 5 o n t he fre q ue nc y of m ot or seiz ures f or patie nts 
wi t h D u p 1 5 q or C D D d uri n g t he Mai nte na nce Peri o d.
4. 1. 2. 
Sec o n d ar y O bjecti ves
T he sec o n dar y  o bjecti ves of t his st u d y are:

T o i n vesti gate t he effect of T A K - 9 3 5 o n t he fre q ue nc y of m ot or seiz ures f or patie nts 
wi t h D u p 1 5 q or C D D d uri n g t he Treat me nt Peri o d ( D ose O pti mizat i on a n d 
Mai nt e na nce) 

T o i n vesti gate t he pr o p orti o n of patie nts c o nsi dere d as treat me nt res p o n ders f or 
pati e nts wi t h D u p 1 5 q or C D D t hr o u g h o ut t he Mai nte na nce Peri o d; treat me nt 
res p o n ders are defi ne d as t h ose wit h:

Re d ucti o n o f 2 5 % or m ore i n m ot or seiz ures fr om basel i ne

Re d ucti o n o f 5 0 % or m ore i n m ot or seiz ures fr om baseli ne

Re d ucti o n o f 7 5 % or m ore i n m ot or seiz ures fr o m baseli ne

Re d ucti o n o f 1 0 0 % i n m ot or seiz ures fr o m baseli ne

T o i n vesti gate t he effect of T A K - 9 3 5 o n t he fre q ue nc y of m ot or seiz ures last i n g > 5 
mi n u tes f or patie nts wit h C D D t hr o u g h o ut t he Treat me nt Peri o d

T o i n vesti gate t he effect of T A K - 9 3 5 o n t he perce nt/fre q ue nc y o f seiz ure free da ys i n 
pati e nts wit h D u p 1 5 q or C D D d uri n g t he Mai nte na nce Peri o d

T o assess Cli nical Gl o bal I m pressi o n of  se verit y ( C GI- S) pr o vi de d b y t he I n vesti gat or

T o assess t he Cli nical Gl o bal I m pressi o n of  c ha n ge ( C GI- C) pr o vi de d b y t he 
I n vesti gat or

T o assess t he Care gi ver Gl o bal  I m pressio n  of C ha n ge ( Care GI-C)

T o i n vesti gate t he relati o ns hi p bet wee n 2 4 H C le vel a n d m ot or seiz ure fre q ue nc y
4. 1. 3. 
E x pl or at or y O bjecti ves
C 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 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

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4. 1. 4.
S afet y O bjecti ves
T he safet y o bj ect i ves of t his st u d y are:

T o e val uate safet y  a n d t olera bility of  T A K- 9 3 5 

T o i n vesti gate t he effect of T A K -9 3 5 o n be ha vi or a n d a da pt i ve f unct i on usi n g t he 
Vi nela n d A da pt i ve Be ha vi or scales ( V A B S) a n d A berra nt Be ha vi or C hec klist 
C o m m u nit y q uest i on naire ( A B C-C)

T o e val uate t he perce nt of da ys free of a bse nce seiz ures i n patie nts w h o re p ort 
a bse nce seiz ures at baseli ne, t o deter mi ne if t here is w orse ni n g of t his seiz ure ty pe 
d uri n g treat me nt wit h T A K - 9 3 5
4. 2.
E n d p oi nts
4. 2. 1.
Pri m ar y Effic ac y E n d p oi nt
T he pri mar y  efficac y e nd p oi nt i n t hi s st u d y is:

Perce nt c ha n ge fr o m Baseli ne i n me dia n m o t or seiz ure fre q ue nc y per 2 8 da ys i n t he 
pa tie nts wit h C D D d uri n g t he Mai nte na nce Peri o d 
O R

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure fre q ue nc y per 2 8 da y s i n t he patient s 
wi t h D u p 1 5 q d uri n g t he Mai nte na nce Peri o d 
4. 2. 2. 
Sec o n d ar y Effic ac y E n d p oi nts
T he sec o n dar y  efficac y e n d p oi nts i n t his st u d y are:

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure fre q ue nc y per 2 8 da y s i n t he patient s 
wi t h C D D d uri n g t he Treat me nt Peri o d

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure fre q ue nc y per 2 8 da y s i n t he patient s 
wi t h D u p 1 5 q d uri n g t he Treat m e nt Perio d

Pr o p orti o n of patie nts c o nsi dere d treat me nt res p o n ders f or patie nts wi t h C D D
t hr o u g h o ut t he Mai nte na nce Peri o d, treat me nt res p o n ders are defi ne d as t h ose wit h:

Re d ucti o n o f 2 5 % or m ore i n me d ia n m o t or seiz ures fr o m baseli ne

Re d ucti o n o f 5 0 % or m ore i n me d ia n m o t or seiz ures fr o m baseli ne

Re d ucti o n o f 7 5 % or m ore i n me d ia n m o t or seiz ures fr o m baseli ne

Re d ucti o n o f 1 0 0 % i n me dia n m o t or seiz ures fr om baseli ne

Pr o p orti o n of  patie nts c o nsidere d treat m e nt res p o n ders f or patie nts wi t h D u p 1 5 q
t hr o u g h o ut t he Mai nte na nce P eri o d, treat me nt res p o n ders defi ne d as t h ose wit h:
C 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 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

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
Re d ucti o n o f 2 5 % or m ore i n me d ia n m o t or seiz ures fr o m baseli ne

Re d ucti o n o f 5 0 % or m ore i n me d ia n m o t or seiz ures fr o m baseli ne

Re d ucti o n o f 7 5 % or m ore i n me d ia n m o t or seiz ures fr o m baseli ne

Re d ucti o n o f 1 0 0 % i n me dia n m o t or seiz ures fr om baseli ne

Perce nt c ha n ge fr o m Baseli ne i n fre q ue nc y o f m o t or seiz ures lo n ger t ha n 5 mi n utes i n 
pati e nts wit h C D D

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure -free da ys fre q ue nc y in pat ient s wit h 
D u p 1 5 q or C D D d uri n g t he Mai nte na nce Peri o d 

C ha n ge fr o m baseli ne i n C GI -S 

A ssessme nt of  rati n gs b y cli nicia n usi n g t he C GI - C

Assess me nt of rati n gs of care gi ver -pr o vi de d Care GI- C 

T o c haracterize plas ma 2 4 H C le vels a n d c ha n ge i n m ot or seiz ure fre q ue nc y i n 
pati e nts treate d wit h T A K -9 3 5 as a n a dj u nct i ve t hera p y
4. 2. 3.
E x pl or at or y Effic ac y E n d p oi nts
4. 2. 4.
S afet y E n d p oi nts
T he safet y e n d p o i nts i n t his st u d y are:

Perce nta ge of patie nts wit h at least 1 treat me nt -e mer ge nt a d verse e ve nt ( T E A E)

C ha n ge i n be ha vi oral a n d a da pt i ve f unct i onal meas ures usi n g t he V A B S

C ha n ge i n be ha vi or meas ures usi n g t otal sc ores a n d s u bscale sc ores of A B C -C 

Perce nta ge of patie nts wit h at least 1 mar ke dl y a b n or mal val ue f or cli nical la b orat or y  
e val uat i ons, vital si g ns, b o d y  w eig ht a n d hei g ht a n d el ectr ocar dio gr a m  ( E C G) 
para m eters after T A K-9 3 5 treat m e nt

C ha n ge fr o m Baseli ne i n cli nical la b orat or y  e val uatio ns, vital si g ns, b o d y  wei g ht, 
hei g ht, C o l um bia – S uici de Se veri t y Rati n g Scale ( C-S S R S), a n d E C G para meter 
val ues after T A K -9 3 5 treat m e nt

Perce nt of a bse nce seiz ure free da ys i n patient s w h o re p ort a bse nce seiz ures d uri n g 
baseli ne
C 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 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 2 7 of 1 0 1
5.
I N V E S TI G A TI O N A L P L A N
5. 1.
S u m m ar y of St u d y Desi g n
St u d y  T A K- 9 3 5- 1 8-0 0 2 ( O V 9 3 5; A R C A D E St u d y) is a m ult ice nter, o pe n-label, 2 -c o h ort st u d y 
i n patie nts (a ge d ≥2 a n d ≤5 5 years wit h D u p 1 5 q or C D D d e m o nstrati n g ≥3 m ot or seiz ures (i .e., 
dr o p sei z ures, t o nic-clo ni c, t o ni c, bilateral clo nic, at o ni c, m yo cl o nic -at o nic, m yo cl o nic -t o nic-
clo nic, f ocal  seiz ures wit h bilateral h y per ki netic m ot or feat ures. N ote - is olate d m yo cl o nic 
seiz ures are excl u de d) per m o nt h d uri n g t he 3 m o nt hs i m me diatel y pri or t o Scree ni n g ( base d o n 
t he I n vest i gat or’s assess me nt).
A p pr o xi matel y  3 0 t ot al p atie nts wit h D u p 1 5 q or C D D (a p pr o xi matel y 1 5 patie nts i n eac h 
s y n dr ome) will be e nr o lle d. T his st u d y  c o nsists of 2 mai n p eri o ds:

4- t o 6-wee k Scree ni n g/ Baseli ne Peri o d

2 0- wee k Treat me nt Peri o d

8- wee k D ose O pti mizat i on Peri o d

1 2- wee k Mai nte na nce Peri o d 
At  t he e n d of t he pr os pecti ve Scree ni n g/ Baseli ne Peri o d, patie nts will ret ur n t o t he cli nic ( Visit 2 
[ D a y 1]). Seiz ure diar ies will be re vie we d b y t he Me dical M o nit or a n d if a patie nt did n ot m e et 
t he eli gi bilit y crit eria, i ncl u di n g mi ni m u m n u m ber of seiz ures re q uire d f or t he st u d y  (≥3 m ot or 
seiz ures), t he patie nt will be disc o nt i n ue d fr om t he st u d y a n d c o nsi dere d a scree n fail ure. 
Fi g ure 1 ill ustrates t he st u d y desi g 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 2 8 of 1 0 1
Fi g ure 1 :
St u d y Desi g n f or Cli nic al Pr ot oc ol T A K - 9 3 5- 1 8- 0 0 2 ( O V 9 3 5; A R C A D E 
St u d y)
P ati e nts a n d/ or patie nts’ care gi vers will be pr o vi de d wit h a seiz ure diar y  a n d will be i nstr ucte d t o 
rec or d seiz ure data dail y st artin g at Visit 1 (scree ni n g visit) a n d t o c o nti n ue t hr o u g h o ut t he st u d y . 
T he seiz ure diar y data will b e c ollecte d d uri n g t he pr os pecti ve Baseli ne Peri o d a n d will be use d 
as t he baseli ne seiz ure data f or e n d p oi nt a nal yses. 
T he t otal dail y  d ose of T A K-9 3 5 is cal c ulate d base d o n b o d y wei g ht at Visit 1 a n d will be gi ve n 
t wice a da y ( BI D) orall y or via G-t u be/P E G t u be /J-t u be wit h or wi t ho ut f o o d ( p at ient s e nr olle d i n 
cli nical sites i n C hi na are n ot t o recei ve st u d y dr u g via G-t u be/ P E G t u be/J-t u be). Patie nts will 
recei ve t he i nitial d ose of st u d y dr u g, D ose 1, f or t he first 7 da ys starti n g at Visit 2 ( Da y 1). T he 
st u d y dr u g d ose will be i ncrease d t o D ose 2 a n d D ose 3 at Da y 8 ( ± 2 da ys) a n d Da y 1 5 ( ± 2 
da ys), res pecti vel y . T h e ma xi m u m d os e for a n y  p atie nt will be 6 0 0 mg/ da y  ( 3 0 0 mg BI D). T he 
d ose m a y be c ha n ge d d uri n g t he D ose O pti mizat i on Peri o d wi t h a p pr o val fro m  t he Me dical 
M o ni t or. T he fi nal d os e le v el will be mai ntai ne d u nt il t he e n d of t he Mai nte na nce Peri o d. 
P ati e nts w h o ca n n ot t olerate D ose 1 will be wit h dra w n fr o m t he st u d y  (a n d will c o mplete t he 
earl y ter mi nati on a n d safet y  fol l ow- u p visi ts). Refer t o Se ctio n 7. 2 f or a d ditio nal  inf or m at i on.
T he st u d y  will be gi n wit h a p hase d e nr oll me nt base d o n a ge:

T w o patie nts a ge d ≥9 y ears will be e nr olle d f or assess me nt of safet y a n d P K. T he 
i n de pe n de nt Data M o nit ori n g C om mittee (i D M C) will re vie w safet y (a d verse e ve nts 
a n d cli nical la b orat or y res ults) a n d a vaila ble P K data f or t hese 2 pati e nts at t he e n d of 
i nitial u p-d osi n g or Da y  2 1 
T A K -9 3 5 
D os e 1 *
D a y -4 2 t o - 1
D os e O pti miz ati o n P eri o d
( 8 w e e ks) 
D a y 1 - 7 
D a y 8 - 1 4 
D a y 1 5  - 5 6 
Scr e e ni n g/ B as eli n e P eri o d
( 4- t o 6-w e e k pr os p ecti v e)
M ai nt e n a nc e P eri o d
( 1 2 w e e ks) 
D a y 5 7 -1 4 1 
T A K -9 3 5
D os e 2 *
T A K -9 3 5
D os e 3 *
* I P gi v e n as 2 di vi d e d d os es BI D (r ef er t o T a bl e 1 f or w ei g ht -b as e d d osi n g)
* * P ati e nts w h o d o n ot e nt er t h e o p e n -l a b el e xt e nsi o n st u d y
Visit 1
Visit 2 ( D 1)
Visit 3 ( D 1 5)
Visit 4 ( D 3 6)
Visit 5 ( D 8 5)
Visit 6 ( D 1 4 1)
T a p er p eri o d f or p ati e nts 
n ot e nt eri n g OL E
Tr e at m e nt P eri o d
( 2 0 w e e ks) 
P h o n e C all 1
( D 8)
P h o n e C all 2
( D 2 2)
P h o n e C all 3
( D 5 7)
P h o n e C all 4
( D 1 1 3)
Visit 7 * * ( D 1 6 9)
E
D u p 1 5 q
( n = 1 5)
C D D
( n = 1 5)
E ntr y i nt o 
O p e n -L a b el 
E xt e nsi o n
( T A K-9 3 5 -1 8 -0 0 1)
S af et y 
F oll o w-u p * * 
D a y 1 4 1 t o 
1 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 2 9 of 1 0 1

T he i D M C ma y  t he n rec o m me n d treat me nt for a d dit i onal pat ient s a ge d ≥9 y ears a n d 
t he first 2 patie nts a ge d ≥2 t o < 9 y ears

S af et y a n d a vaila ble P K data f or t he first 2 patie nts a ge d ≥2 t o < 9 years will be 
re vie we d b y t he i D M C at t he e n d of i nitial u p-d osi n g or Da y  2 1

T he i D M C ma y  t h e n rec om me n d treat me nt f or a d dit i onal pat ient s a ge d ≥2 t o < 9 y ears

T he S p o ns or’s Me dical M o nit or a n d/ or P har mac o vi gila nce P h ysicia n will re vie w 
safety data a n d a vaila ble P K of t he first 2 patie nts a ge d ≥9 y ears a n d t he first 
2 pati e nts a ge d ≥2 t o < 9 years d u rin g eac h ste p of d ose escalat i on.
5. 1. 1.
E n d of St u d y Defi niti o n
T he e n d o f t he st u d y for a n i n di vi d ual pat ient  is defi ne d as t he last pr ot oc ol-s pecifie d c o ntact 
wi t h t hat patie nt. T he o verall e n d of t he st u d y is defi ne d as t he last pr ot oc ol-s pecifie d c o ntact 
wi t h t h e last patie nt o n g oi n g i n t he st u d y.
5. 1. 2.
St u d y E xte nsi o n
F o ll owi n g c o m plet i on of t he st u d y , p atie nts will ha ve t he o pti o n t o e nr oll i n a l o n g -t er m, 
o pe n -label e xte nsi o n ( O L E) st u d y  ( u n der a se parate pr ot oc ol [ T A K- 9 3 5- 1 8-0 0 1 ( O V 9 3 5)]) 
P ati e nts c urre ntl y partici pati n g i n t his trial ca n i m me diatel y r oll o ver t o t he o pe n -label e xte nsi o n 
as lo n g as t he y  meet t he crit eria s pecifie d i n t he O L E st u d y. 
5. 2.
Selecti o n a n d Ti mi n g of D oses i n t he St u d y
Precli nical data fr o m r o de nt e pile ps y  mo dels s u g g est p ote ntiall y efficacio us e x p os ures, a n d 
safety data fr o m n o ncli nical st u dies were use d t o deter mi ne e x p os ure -base d safet y mar gi ns. 
Cli nical safet y a n d t olera bilit y d at a fr o m si n gle- a n d m ult i ple-d ose P hase 1 st u dies i n a d ult 
healt h y v o l unt eers was use d t o perf or m P K, P D, a n d e nz y me occ u pa nc y ( E O) a nal yses with 
all o metric scali n g t o deter mi ne a n a p pr o priate d ose of T A K- 9 3 5 f or pe di atric pat ient s.
5. 2. 1.
M o deli n g a n d Si m ul ati o n of Cli nic al D at a
C 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 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 0 of 1 0 1
C CI
C
C
I
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 1 of 1 0 1
6.
S T U D Y P O P U L A TI O N
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y b e 
r e-scree ne d. Refer t o Secti o n 8. 1. 2 3 f or a d ditio nal  inf or m at i on o n rec or di n g scree n fail ures.
I n di vi d uals ma y be re-scree ne d f or u p t o 2 ti mes, after c o ns ultati o n wi t h t he Me dic al M o nit or. 
Pr os pecti ve a p pr o val o f pr ot oc ol  de viatio ns t o recr ui t me nt a n d e nr o ll me nt criteria, als o k n o w n as 
pr ot oc ol  wai vers or e xe m pti ons, are n ot per mitte d.
P ati e nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if t he y meet all t h e fol l owi n g cri t eria a n d 
n o ne of t he e xcl usi o n cri t eria.
6. 1.
I ncl usi o n Criteri a
P ati e nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if t he y meet all t h e fol l owi n g cri t eria:
1.
T he patie nt has a d oc u me nte d dia g n osis of D u p 1 5 q or C D D s u p p orte d b y:

D u p 1 5 q , dia g n ose d as per sta n dar d of care a n d c o nsiste nt wit h literat ure descri be d 
p he n ot y pe

C D D

A pat h o ge nic or li kel y pat h o ge nic varia nt i n C D K L 5
O R

A varia nt of u ncertai n si g nifica nce ( V U S) i n t he ki nase d o mai n of C D K L 5 t hat 
has bee n c o nfir me d t o be de n o v o. U nless b ot h pare nts ha ve bee n teste d a n d 
f ou n d t o n ot har b or t he V U S, a patie nt wit h a V U S ca n n ot be e nr olle d. 
P arti cip a nts wi t h a V U S f o u n d o utsi de of t he ki nase d o mai n will n ot be e nr olle d. 

A pat ient  wit h mosaicis m f or a C D K L 5 varia nts is eli gi ble.
2.
T he patie nt or patie nt’s c ust o dial pare nt or g uar dia n are willi n g a n d a ble t o rea d, 
u n dersta n d, a n d si g n t he i nf or me d c o nse nt f or m a n d asse nt, if a p plica ble
3.
Male a n d fe male patie nts a ge d ≥2 a n d ≤5 5 y ears at t he ti me of i nf or me d c o nse nt 
4.
A hist or y  of, o n a vera ge, ≥3 m ot or seiz ures (e xcl u di n g is olate d m yo cl o nic seiz ures) per 
m o nt h d uri n g t he 3 m o nt hs i m me diatel y pri or t o Scree ni n g base d o n t he I n vest i gat or’s 
assess me nt, a n d t he patie nt has ≥3 m ot or seiz ures (e xcl u di n g is o late d m yo cl o nic 
seiz ures) d uri n g t he 4-wee k pr os pecti ve Baseli ne Peri o d
5.
Wei g ht of ≥1 0 k g at t he Scree ni n g visit ( Visit 1)
6.
C urre nt l y ta ki n g 1 t o 6 A E Ds at a sta ble d ose f or 4 wee ks pri or t o t he Scree ni n g visit 
( Visit 1); be nz o diaze pi nes use d c hr o nicall y ( o n dail y fre q ue nc y) t o treat seiz ures are 
c o nsi dere d A E Ds . A ntie pile ptic dr u g treat me nt, ( me dical) marij ua na, ca n na bi di o l 
pr o d ucts , V N S setti n gs, a n d ket o ge nic diet s h o ul d n ot be altere d d uri n g t he st u d y.
7.
T he use of ca n na bi di o l pr o d ucts m ust be sta ble f or 4 wee ks pri or t o 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 2 of 1 0 1
8.
If usi n g a V N S, m ust ha ve V N S place d at l east 3 mo n t hs prior t o t he Scree ni n g visit 
( Visit 1) wit h sta ble setti n gs f or > 1 mo nt h; V N S para m eters must re m ai n c o nsta nt 
t hr o u g h o ut t he st u d y (V N S will n ot be c o u nte d as a n A E D)
9.
If o n a ket o ge nic diet, m ust ha ve starte d t he ket o ge nic diet at least 3 mo nt hs pri or t o t he 
Scree ni n g visit ( Visit 1), diet s h o ul d be sta ble f or 4 wee ks bef ore t he Scree ni n g visit 
( Visit 1); a n d s h o ul d c o nt i n ue t hr o u g h t he d urati o n of t he st u d y (ket o ge nic diet will n ot 
be c o u nte d as a n A E D)
1 0. Faile d t o bec o me a n d re ma i n seiz ure free with tri als of at least 2 A E Ds
1 1. T he patie nt or patie nt’s le gal re prese ntati ve ( pare nts or le gal g uar dia n) is willi n g t o kee p 
t he A E D, ( me dical) marij ua na a n d ca n na bi di o l pr o d ucts, V N S, a n d ket o ge nic diet 
re gi me n(s) sta ble t hr o u g h o ut t he stu d y
1 2. T he patie nt is a ble t o carr y  o ut all a p pr o priate assess me nts a n d ta ke st u d y dr u g i n t he 
o pi ni o n of t he I n vest i gat or a n d pare nt/care gi ver
1 3. 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 3 0 da ys 
aft er last d ose of st u d y dru g, fe male patie nts of c hil d beari n g p ote ntial * w h o are se x uall y 
acti ve wit h a n o nsterilize d male part ner * * m ust a gree t o use a hi g hl y effect i ve/effecti ve 
met h o d of c o ntrace pti o n (fr o m t he list bel o w). I n a d dit i on, t he y  must n ot t o d o nate o va 
d uri n g t hi s perio 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 are pri or t o first 
me narc he or 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 ≥1 year si nce la st re g ular 
me nses wit h a f o lliclesti m ulat i n g h or m o ne le vel > 4 0 I U/ L or ≥5 years si nce last 
re g ular me nses, c o nfir me d bef ore a n y st u d y dr u g is a d mi nistere d).
* * Sterilize d males s h o ul d be ≥1 -year p ost vasect o m y  a nd ha ve c o nfir me d t hat t he y  ha ve 
o btai ne d d oc u me nt atio n of  t he a bse nce of s per m i n t he ejac ulate.
A hi g hl y effect i ve 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 per y ear w he n use d c o nsiste nt l y a n d c orrectl y. I n t his st u d y, t he o nl y 
acce pta ble met h o ds of c o ntrace pti o n are as f o ll ows:
a.
C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wi t h in hi bit i on of o v ulati o n:

Or al

I ntra va gi nal

Tra ns der mal
b.
Pr o gest o ge n -o nl y  hor m o nal  c o ntrace ptio n ass oci ate d wit h in hi bit i on o f o v ul at i on:

Or al

I njectable

I mpla nta ble
c.
D o u bl e- barri er met h o ds (eac h ti me t he patie nt has i nterc o urse):
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 3 of 1 0 1

S p o n ge ( pl us s per mici dal crea m or jell y) P L U S male c o n d o m wi t h or wit ho ut 
s per mici dal crea m or jell y.

Ca p ( pl us s per mici dal crea m or jell y ) P L U S male c o n d o m wit h or wit ho ut 
s per mici dal crea m or jell y.

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 wit h or wit h o ut 
s per mici dal crea m or jell y.
d.
I ntra uteri ne de vice ( C o p per T P L U S c o n d o m)
e.
I ntra uteri ne h or m o ne-releasi n g s yste m
f.
Sterilizati o n:

Bilateral t u bal occl usi o n

V asect o mize d part ner ( pr o vi de d t hat t he part ner is t he s ole se x ual part ner of t he 
pati e nt a n d t he a bse nce of s per m i n t he ejac ulate has bee n c o nfir me d)
g.
Se x ual a bst i ne nce, if it is t he preferre d a n d us ual lifestyle of t he patie nt, will be 
c o nsi dere d a n acce p t a bl e met h o d of c o ntrace pti o n o n a case - b y-case basis u p o n pri or 
a p pr o val b y t he me dical m onit or. Pati e nts practici n g a bst i ne nce as a met h o d of 
c o ntrace pti o n m ust refrai n fr o m heter ose x ual i nterc o urse t hr o u g h o ut t he d urati o n of 
t he st u d y a n d for 3 0 da y s after last d ose of st u d y dr u g.
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 3 0 da ys 
aft er last d ose of st u d y dr u g, male patie nts ( p ost -p u bertal u nless per ma ne nt l y 
sterilize d * *) 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 a gree t o use barrier c o ntrace pti o n (e. g. , c o n d o m wit h or wit h o ut s per mici dal crea m 
or j ell y). I n a d ditio n, t he y  must n ot d o nate s per m d uri n g t his peri o d .
6. 2.
E xcl usi o n Criteri a
P ati e nts will be e xcl u de d fr o m st u d y e nr oll me nt if t he y meet a n y of t he f oll owi n g cri t eria:
1.
T he patie nt has bee n a d mitte d t o a me dical facilit y a n d i nt u bate d f or treat me nt of 
stat us e pile ptic us 2 or m ore ti mes i n t he 3 m o nt hs i m me diatel y pri or t o t he Scree ni n g 
visit
2.
P ati e nts wit h a hist or y of c o nfir me d cataract ( u ntreate d wit h s ur ger y)
3.
U nsta ble, cli nicall y  si g nifica nt ne ur olo gic ( ot her t ha n t he disease bei n g st u die d), 
ps yc hiatric, car di o vasc ular, o p ht hal m o l ogic, p ul m o nar y , he patic, re nal, meta b olic, 
gastr oi ntesti nal, ur ol o gic, i m m u n o l ogic, he mat o p oiet ic, or e n d ocri ne disease or ot her 
a b n or malit y, w hic h ma y i m pact t he a bilit y t o participate i n t he st u d y  or t hat ma y 
p ote nti all y c o nf o u n d t he st u d y res ults. It is t he res p o nsi bility of  t he I n vesti gat or t o 
assess t he cli nical si g nifica nce; h o we ver, c o ns ultati o n wi t h t he Me dical M o nit or ma y 
be warra nte d
4.
A n y hist or y  of alc o h o l, o pioi d, or ot her dr u g use dis or der, as per t he Dia g n ostic a n d 
Stati stical Ma n ual of Me ntal  Dis or ders, Fifth E di ti o n ( D S M-V), wit hi n t he 2 years 
i m me diatel y prior t o t he Scree ni n g Visit ( Visit 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 4 of 1 0 1
5.
S ui ci de atte mpt wi t hi n t he last year, at sig nifica nt ris k of s uici de (eit her i n t he o pi ni o n 
of  t he I n vesti gat or or defi ne d as ‘ yes’ t o s uici dal i deati o n q uesti on 4 or 5 o n t he 
C- S S R S at Scree ni n g) or a p peari n g s uici dal per I n vesti gat or j u d g me nt
6.
A b n or m al a n d cli nicall y si g nifica nt E C G a b n or malit y at Scree ni n g; Q T i nter val wit h 
Fr i dericia’s c orrectio n m et h o d ( Q Tc F) > 4 5 0 ms ( males) or > 4 7 0 ms (fe males) or 
a b o ve u p per li mit of n or mal f or a ge, c o nfir me d wit h o ne re peat testi n g, at t he 
Scree ni n g visit
7.
A b n or m al cli nical la b orat or y test res ults at t he Scree ni n g visit t hat s u g gest a cli nicall y 
sig nifica nt u n derl yi n g disease t hat w o ul d c o m pr o mise t he well -bei n g of t he patie nt (if 
t he patie nt has 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] > 2. 5 × t he u p per li mit of n or mal [ U L N] f or a ge, t he me dical m o nit or s h o ul d be 
c o ns ulte d) 
8.
C urre nt l y recei vi n g a st u d y dr u g or partici pate d i n a cli nical st u d y i n v ol vi n g a n ot her 
i n vesti gati onal pr o d uct i n t he pre vi o us m o nt h ( or 5 half -li ves of t his i n vestigat i onal 
pr o d uct, w hic he ver is l o n ger) 
9.
Recei ve d T A K - 9 3 5 i n a pre vi o us cli nical st u d y or as a t hera pe utic a ge nt
1 0. I m me diate fa mil y me m bers, or i n a de pe n de nt relati o ns hi p wit h a st u d y site e m pl oyee 
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., c hil d, si bli n g)
1 1. K n o w n h y perse nsit i vity t o a n y  c o mp o ne nt of t he T A K -9 3 5 f or m ulati o n
1 2. C urre nt l y pre g na nt or breastfee di n g or is pla n ni n g t o bec ome pre g na nt wit hi n 3 0 da ys 
of  t h e last d ose of st u d y dr u g
6. 3.
Disc o nti n u ati o ns
6. 3. 1.
Disc o nti n u ati o n of P atie nts
T he cri t eria for e n r oll me nt must be f o ll owe d e x plici tly.  If t he i n vesti gati ve site i de ntifies a 
pati e nt w h o did n ot m eet e nr oll me nt criteria a n d w h o was i na d verte ntl y e nr o lle d, t he S p o ns or 
m ust be n otifie d i m me diatel y. A disc ussi o n m ust occ ur bet wee n t he S p o ns or a n d t he I n ve sti gat or 
t o deter mi ne w het her t he patie nt ma y c o nti n ue i n t he st u d y, wit h or wit ho ut st u d y  dr u g. 
I na d verte ntl y e nr olle d patie nts ma y be mai ntai ne d i n t he st u d y a n d o n st u d y dr u g w he n t he 
S p o ns or a grees wit h t he I n vest i gat or t hat it is me dicall y a p pr o priate f or t hat patie nt. T he patie nt 
ma y n ot c o nti n ue i n t he st u d y  wit h or wit ho ut st u d y  dr u g if t he S p o ns or d oes n ot a gree wit h t he 
I n vesti gat or’s deter mi nati on it is me dicall y a p pr o priate f or t he patie nt t o c o nti n ue. T he 
I n vesti gat or m ust o btai n d oc u me nte d a p pr o val fr o m t he S p o ns or t o all o w t he i na d verte ntl y 
e nr o lle d patie nt t o c o nti n ue i n t he st u d y with or wit h o ut st u d y  dr u g.
I n a d diti on, pati e nts will be disc o nt i n ue d fr om t he st u d y dr u g (a n d/ or fr o m t he st u d y) i n t he 
f oll owi n g circ u msta nces:

Li ver F u nct i on Te st ( L F T) A b n or malities
St u d y  dr u g s h o uld be disc o nt i n ue d with a p pr o priate cli nical f o ll o w u p (i ncl 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 
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 5 of 1 0 1
n or m al/ baseli ne stat us, see Secti o n 8. 1. 1 0 ), if t he f oll o wi n g circ u msta nces occ ur at 
a n y ti me d uri n g st u d y dr u g treat me nt:

A L T or A S T > 8 × U L N f or a ge, or

A L T or A S T > 5 × U L N f or a ge a n d persists f or > 2 wee ks, or

A L T or A S T > 3 × U L N f or a ge i n c o nj u ncti o n wit h ele vate d t otal bilir u bi n 
> 2 × U L N or i nter nati o nal n or malize d rati o (I N R) > 1. 5, or

A L T or A S T > 3 × U L N f or a ge wit h a p peara nce of fat i g ue, na usea, v omit i n g, 
rig 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 %)

Q Tc F i nter val > 5 0 0 ms t hat is c o nfir me d wit h a re peat E C G 
St u d y  dr u g s h o uld be disc o nt i n ue d with a p pr o priate cli nical f o ll o w u p (i ncl u di n g 
re peat E C G)

Greater t ha n a 1 0 0 % i ncrease i n seiz ure fre q ue nc y fr o m t he 4-wee k pr os pecti ve 
Base li ne Peri o d a n d c o nsi dere d b y t he I n vesti gat or t o be cli nicall y si g nifica nt 
w orse ni n g of t he seiz ure fre q ue nc y 

N ot t olerat i n g D ose 1 (t he l o west d ose) f or t heir wei g ht cate g or y

E nr oll me nt i n a n y ot her cli nical st u d y  in v o l vi n g a st u d y dr u g or e nr oll me nt i n a n y 
ot her t y pe of me dical researc h j u d ge d n ot t o be scie nt ificall y or me dicall y c om pat i ble 
wi t h t his st u d y

I n vesti gat or Decisi on ( P h ysicia n Decisi o n)

T he I n vesti gat or deci des t hat t he patie nt s h o ul d be di sc o nti n ue d fr om t he st u d y

P ati e nt Decisio n  ( Wit hdra wal b y  P atie nt or Wit hdra wal  b y Pare nt/ G uar dia n)

T he pati e nt or t he patie nt’s le gal re prese ntati ve (i.e., pare nts or le gal g uar dia n) 
re q uests t o be wit h dra w n fr om t he st u d y

S p o ns or Decisi o n

T he S p o ns or or its desi g nee disc o nt i n ues t he st u d y or disc o nti n ues t he patie nt’s 
parti ci pat i on i n t he st u d y f or me dical, safety,  re g ulat or y, or ot her reas o ns 
c o nsiste nt wit h a p plica ble la ws, re g ulat i ons, a n d g o o d cli nical pract ice ( G C P)

T he S p o ns or or its desi g nee st o ps t he cli nical st u d y at a partic ular site

A d verse E ve nt  

If t he I n vesti gat or deci des t hat t he patie nt s h o ul d be wit h dra w n beca use of a n 
S A E or a cli nicall y  si g nifica nt la b orat or y val ue, t he st u d y dr u g is t o be 
di sc o nti n ue d a n d a p pr o priate meas ures are t o be ta ke n; t he S p o ns or or its desi g nee 
is t o be alerte d i m me diatel y (refer t o Secti o n 8. 3 )

De pressi o n a n d/ or S uici dal I deat i on
-
St u d y  staff trai ne d i n t he a d mi nistrati o n of t he C-S S R S will assess patie nt 
s uicidali t y usi n g t he C-S S R S, elicit i n g a ns wers fr o m t he patient  or t he patie 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 6 of 1 0 1
care gi ver; ult i matel y, t he deter mi nat i on of t he prese nce of s uici dal i deat i on or 
be ha vi or de pe n ds o n t he cli nical j u d g me nt of t he i n vesti gat or
P ati e nts w h o disc o nt i n ue t he stu d y dr u g a n d/ or st u d y earl y will ha ve earl y ter mi nat i on 
pr oce d ures perf or me d as s h o w n i n t he Sc he d ule of Assess me nts (Ta ble 2 ).
6. 3. 2.
Disc o nti n u ati o n of St u d y Sites/ Site Ter mi n ate d b y S p o ns or
St u d y  sit e p artici pat i on ma y be disc o nt i n ue d if t he S p o ns or or its desig nee , the I n vest i gat or, or 
t he i nstitut i on al  re vie w b oar d/i n de pe n de nt et hics c o m mittee (I R B/I E C) of t he st u d y sit e j u d ges it 
necessar y  f or me dical, safety,  r e g ulat or y, or ot her reas o ns c o nsiste nt wit h a p plica ble la ws, 
re g ulat i ons, a n d G C P.
6. 3. 3.
Disc o nti n u ati o n of t he St u d y/ St u d y Ter mi n ate d b y S p o ns or
T he st u d y  will b e disc o nti n ue d if t he S p o ns or or its desi g nee j u d ges it necessar y for m e dical, 
safety,  re g ulator y , or ot her reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulati ons, a n d G C P.
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 7 of 1 0 1
7.
T R E A T M E N T
7. 1.
M ateri als a n d S u p plies
T he S p o ns or will s u p pl y t he st u d y  sit es wit h T A K-9 3 5 2 0 -m g mi ni -ta blets a n d 1 0 0-m g ta blets. 
T A K -9 3 5 mi ni -ta blets/ta blets are ma n ufact ure d b y S PE R A P har ma I nc. ( Osa ka, Ja pa n) 
pre vi o usl y na me d as Ta ke da P har mace ut ical C o. Lt d. 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 inf or m at i on a n d ca uti o n state me nts.
Cli nical st u d y  materials will be la bele d acc or di n g t o t he c o u ntr y’s re g ulat or y  re q uire me nts.
7. 1. 1.
St or a ge
7. 2.
Tre at me nts A d mi nistere d
All patie nts will recei ve T A K -9 3 5 t wi ce a da y ( BI D) orall y or via gastr ost o m y t u be ( G-t u be)/ 
perc uta ne o us e n d osc o pic gastr ost o m y ( P E G) -t u be wit h or wit h o ut f o o d. Jeju n ost o m y t u be (J -
t u be) a d mi nistrati o n ma y be c o nsi dere d f o ll owi n g a p pr o val  b y t he Me dical M o nit or a n d S p o ns or.
P ati e nts e nr olle d i n cli nical sites i n C hi n a are n ot t o recei ve st u d y dr u g via G-t u be/ P E G t u be/J-
t u be.
F or pati e nts weig hi n g < 6 0 k g at Visit 1, t he t otal dail y  d ose of T A K-9 3 5 is calc ulate d base d o n 
b o d y  wei g ht at Visit 1 a n d will be gi ve n BI D (Fi g ur e 1 ; Ta ble 1 ) at Visit 2. T he selecte d d oses 
f or t he differe nt wei g ht gr o u ps are liste d i n Ta ble 1 . F or patie nts wei g hi n g ≥6 0 k g at Visit 1, 
d osi n g will be 2 0 0 m g/ da y ( 1 0 0 m g BI D) f o ll owe d b y  4 0 0 m g/ da y ( 2 0 0 m g BI D), t he n 
6 0 0 m g/ da y ( 3 0 0 m g B I D) (Fi g ure 1 ; Ta ble 1) . St u d y dr u g ca n be ta ke n wit h or wit h o ut f o o d.
P ati e nts weig hi n g < 6 0 k g will be dis pe nse d 2 0 m g mi ni -ta blets, a n d patie nts wei g hi n g ≥6 0 k g 
will be dis pe nse d 1 0 0 m g ta blets. If patie nts are u na ble t o s wall o w ta blets or mi ni -ta blets, t he 
f or mulat i on ca n be c ha n ge d. N o c ha n ge i n f or m ulati o ns will be ma de after Visit 4 ( Da y  3 6).
P ati e nts will recei ve t he i nitial d ose of st u d y dr u g, D ose 1, f or t he first 7 da ys starti n g at Visit 2 
( D a y 1). I n t he s u bse q ue nt p h o ne call a n d visit ( p h o ne call 1 [ Da y 8] a n d Visit 3 [ Da y 1 5]), t he 
st u d y dr u g d ose will be i ncrease d t o D ose 2 a n d D ose 3. Visit 3 [ Da y 8] will be a n o nsite visit 
o nl y  for t he first t w o pati e nts i n eac h a ge ra n ge (i.e. t he first t w o patie nts a ge d > 9 years a n d t he 
first t w o patie nts a ge d > 2 t o < 9 years). T he ma xi m u m d ose f or a n y pat ient  will be 6 0 0 m g/ da y 
( 3 0 0 m g BI D). Patie nts will be c o ntacte d b y  p h o ne wit hi n first 2 da ys f oll o wi n g escalati on t o t he 
ma xi m u m d ose t o assess safet y a n d t olera bilit y of t he st u d y  dr u g. After reac hi n g t he ma xi m u m 
d ose, a n a d dit i onal 6 wee ks will be all o we d t o a dj ust t he patie nt t o t he o pti mal d ose le vel, base d 
o n t he j u d g me nt of t he I n vest i gat or a n d wit h t he a p pr o val of t he Me dical M o nit or. T he fi nal d ose 
le vel will be mai ntai ne d u nt il t he e n d of t he Mai nte na nce Peri o d; h o we ver, t he d ose ma y be 
c ha n ge d d uri n g t he D ose O pti mizat i on Peri o d i n c o ns ul t atio n wi t h t he Me dic al M o nit or. F or 
C 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 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 8 of 1 0 1
e xa m ple, D ose 3 ma y be re d uce d t o D ose 2 a n d D ose 2 ma y be re d uce d t o D ose 1. If D ose 1 i s 
n ot t ol erate d, t he patie nt will be wit h dra w n fr o m t he st u d y. 
T he d ose ma y be i ncrease d per I n vest i gat or’s discreti o n wit h a p pr o val of t he Me dical M o nit or t o 
a ma xi m u m of D ose 3 ( ma xi m u m 6 0 0 m g/ da y). All d ose c ha n ges m ust be ma de d uri n g t he D ose 
O pti mizat i on Peri o d; d ose c ha n ges d uri n g t he Mai nte na nce Peri o d m ust be disc usse d a n d 
a p pr o ve d b y t he S p o ns or.
T a ble 1:
D osi n g Sc he d ule b y Wei g ht
Wei g ht ( k g)
D ose 1
D ose 2
D ose 3
( m g/ d a y)a
N o. T a blets/ 
Mi ni -t a blets
( m g/ d a y)a
N o. T a blets/ 
Mi ni -t a blets
( m g/ d a y)a
N o. T a blets/ 
Mi ni -t a blets
1 0 - 1 4
8 0
0/ 4
1 6 0
0/ 8
2 2 0
0/ 1 1
1 5 - 1 9
1 2 0
0/ 6
2 0 0
0/ 1 0
2 6 0
0/ 1 3
2 0 - 2 4
1 2 0
0/ 6
2 4 0
0/ 1 2
3 2 0
0/ 1 6
2 5 - 2 9
1 2 0
0/ 6
2 4 0
0/ 1 2
3 6 0
0/ 1 8
3 0 - 3 4
1 6 0
0/ 8
2 8 0
0/ 1 4
4 0 0
0/ 2 0
3 5 - 3 9
1 6 0
0/ 8
2 8 0
0/ 1 4
4 4 0
0/ 2 2
4 0 - 4 4
1 6 0
0/ 8
3 2 0
0/ 1 6
4 8 0
0/ 2 4
4 5 - 4 9
2 0 0
0/ 1 0
3 6 0
0/ 1 8
4 8 0
0/ 2 4
5 0 - 5 4
2 0 0
0/ 1 0
3 6 0
0/ 1 8
5 2 0
0/ 2 6
5 5 - 5 9
2 0 0
0/ 1 0
3 6 0
0/ 1 8
5 6 0
0/ 2 8
≥6 0
2 0 0
2/ 0
4 0 0
4/ 0
6 0 0
6/ 0
a T otal d ose a d mi nistere d t wice dail y.
T w o da ys after eac h d ose titrati o n or ta per, patie nts will be c o ntacte d b y  p h o ne t o mo ni t or st u d y 
dr u g c o m plia nce, c o nc o mita nt me dicat i on use, a n d T E A Es. A n y  c ha n ge i n d ose will be 
d oc u m e nte d i n t he patie nt’s cli nic c harts a n d seiz ure a n d d osi n g f or m. O n Da ys 2 2, 5 7, a n d 1 1 3, 
pati e nts will be c o ntacte d b y p h o ne t o mo ni t or c o m plia nce with st u d y  dr u g a n d seiz ure diar y a n d 
t o mo ni t or T E A Es. 
If a patie nt misses a d ose, t he misse d d ose s h o ul d be s ki p pe d, a n d t he patie nt s h o ul d c o nti n ue 
wi t h his/ her n or mal d osi ng sc he d ule. T he sc he d ule d d ose ca n be a d mi nistere d u p t o 4 h o urs after 
t he sc he d ule d t i me of d osi n g. If t he patie nt/care gi ver re me m bers after 4 h o urs of t he sc he d ule d 
ti me of d osi n g, t he d ose s h o ul d t he n be s ki p pe d a n d re p orte d as misse d i n t heir diar y a n d o n t he 
ne xt cli nic visit. S ki p pe d d oses s h o ul d be re p orte d as misse d d oses.
Ta blets/ mi ni -ta blets ma y be cr us he d a n d mi xe d well i n a p plesa uce or t hic k li q ui d pri or t o d osi n g. 
T he a m o u nt of  a p plesa uce or li q ui d nee de d is de pe n de nt u p o n t he n u m ber of ta blets / mi ni-ta blets 
t he patie nt is ta ki n g. O ne-half teas p o o n or 2. 5 m L of a p plesa uce or t hic k li q ui d is nee de d f or 
eac h ta blet/ mi ni-ta blets ta ke n.
F or pati e nts recei vi n g st u d y dr u g via G-t u be/ P E G t u be/J-t u be, st u d y dr u g will be cr us he d, 
s us pe n de d i n water, a n d the s us pe nsi o n will be a d mi nistere d via t he G -t u be/ P E G t u be/J-t u be
usi n g a s yri n ge. Ot her me dicat i ons or e nteral fee ds s h o ul d n ot be gi ve n c o nc urre nt l y with 
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 3 9 of 1 0 1
T A K -9 3 5. C o m plete i nstr ucti o ns will be pr o vi de d t o s u bjects/care gi vers i n a d oc u me nt pr o vi de d 
o utsi d e of t he pr ot oc ol.
7. 2. 1.
D ose T a peri n g 
F o ll owi n g c o m plet i on of t he st u d y , p atie nts will ha ve t he o pti o n t o e nr oll i n a l o n g -t er m, 
o pe n -label e xte nsi o n st u d y  ( u n der a se parate pr ot oc ol; see Sect i on 5. 1. 1 ) or t o e nter a ta per 
p eri o d ( m a xi m u m 1 4 da ys). D uri n g t he ta per peri o d, t he st u d y dr u g d ose will be de-escalate d t o a 
l ower d ose (ta per D ose 3 t o D ose 2, ta per D ose 2 t o D ose 1) e ver y  3 da ys or less fre q ue nt l y 
base d o n I n vest i gat or’s discreti o n u ntil t here is n o de-escalat i on a n d st u d y  dr u g d ose is 
di sc o nti n ue d. After ta peri n g, patie nts will c o m plete a safet y f oll ow- u p visit a p pr o xi matel y 
1 5 d a y s after t he last d ose of st u d y dr u g a n d e xit t he st u d y.
7. 2. 2.
I n vesti g at or Res p o nsi bilities f or Dr u g A d mi nistr ati o n
T he I n vesti gat or or his/ her desi g nee is res p o nsi ble f or t he f o ll owi n g:

E x plai ni n g t he c orrect use of t he i n vest i gati onal a ge nt(s) t o t he patie nt/site 
pers o n nel/le gal re prese ntati ve

Verif yi n g t hat i nstr ucti o ns are f o ll owe d pr o perl y

Mai ntai ni n g acc urate rec or ds of st u d y  dr u g dis pe nsi n g a n d acc o u nta bility

Ret ur ni n g or destr o yi n g all u n use d me dicat i on t o t he S p o ns or or its desi g nee at t he 
e n d of t he st u d y
N ote: I n s o me cases, sites ma y destr o y t h e material if, d uri n g t he I n vesti gat or site selecti on, t he 
e val uat or has verifie d a n d d oc u me nte d t hat t he site has a p pr o priate facilit ies a n d writte n 
pr oce d ures t o dis p ose cli nical st u d y  mat erials. 
P ati e nts a n d/ or t heir pare nt/c ust o dia n/le gal re prese ntati ve will be i nstr ucte d t o c o ntact t he 
I n vesti gat or as s o o n as p ossi ble if he or s he has a c o m plai nt or pr o ble m wit h t he st u d y dr u g s o 
t hat t he sit uati o n ca n be assesse d.
All cli nical trial material pr o vi de d t o t he I n vesti gat or will be st ore d i n a sec ure a n d l oc ke d place 
a n d all ocate d a n d dis pe nse d b y I nteracti ve V oice/ We b Res p o nse S yste m (I x R S/I W R S). Detaile d 
rec or ds of t he a m o u nts of t he st u d y dr u g recei ve d, dis pe nse d, a n d re mai ni n g at t he e n d of t he 
st u d y will be mai ntai ne d.
T A K -9 3 5 ta bl ets/ mi ni-ta blets s h o uld be a d mi nistere d at a p pr o xi m atel y t he sa me ti mes o n eac h 
d a y . T he act ual ti me of d ose a d mi nistrati o ns a n d all P K sa m ple c ollecti on will be rec or de d i n t he 
pati e nt’s s o urce d oc u me nts a n d i n t he electr o nic case re p ort f or m (e C R F). 
7. 3.
Met h o d of Assi g n me nt t o Tre at me nt
All s u bjects will recei ve t he sa me treat me nt t hr o u g h o ut t he st u d y. P atie nts w h o meet all criteria 
f or e nr oll me nt will be gi n treat me nt at Visit 2 ( Da y 1). Assi g n me nt t o treat me nt gr o u ps will be 
deter mi ne d b y t he seiz ure s y n dr o me: D u p 1 5 q or C D 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

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7. 4.
C o nti n ue d Access t o St u d y Dr u g
T A K -9 3 5 m a y b e ma de a vaila ble after c o ncl usi o n of t he st u d y t o patie nts w h o are still recei vi n g 
a n d be nefitti n g fr o m st u d y treat me nt i n a n O L E st u d y ( u n der a se parate pr ot oc ol; see 
Secti o n 5. 1. 1 ).
7. 5.
Bli n di n g
T his is a n o pe n -la bel st u d y.
7. 6.  
C o nc o mit a nt Me dic ati o ns a n d N o n -P h ar m ac ol o gic T her a pies a n d 
Pr oce d ures
A d j u ncti ve A E D treat me nt, V N S setti n gs, a n d ket o ge nic diet s h o ul d n ot be altere d d uri n g t he 
st u d y. C o nc urre nt treat me nt re gi me n data will be c ollecte d t hr o u g h o ut t he st u d y .
All me dicati o ns i ncl u di n g vita mi n s u p ple me nts, o ver- t he- c o u nter me d icati ons, a n d her bal 
pre parati o ns i ncl u di n g ( me dical) marij ua na a n d ca n na bi di o l pr o d ucts will  be c ollecte d 
t hr o u g h out t he st u d y. ( Me dical) Marij ua na a n d ca n na bi di o l pr o d ucts s h o ul d n ot be al tere d d uri n g 
t he st u d y. 
Use of pera m pa nel is pr o hi bite d d uri n g t he st u d y .
Use of tra dit i onal C hi nese me dici nes s h o ul d be a p pr o ve d b y  t he Me dical M o nit or at scree ni n g.
7. 7.
Tre at me nt C o m pli a nce
P ati e nt c o mplia nce wi t h st u d y me dicat i on will be assesse d at eac h visit. O n i n -cli nic d osi n g da ys, 
after a d mi nistratio n of  st u d y dr u g, a p pr o priate m o ut h a n d/ or ha n d c hec ks will be perf or me 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. If a site visit is n ot p ossi ble 
d uri n g t he m or ni n g h o urs, t he patie nt s h o ul d ta ke t heir m or ni n g d ose pri or t o atte n di n g t he visit 
d uri n g t he after n o o n h o urs. T he date a n d ti me of eac h d ose gi ve n i n t he cli nic 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. 
P ati e nts a n d/ or patie nts’ care gi vers will be re q uire d t o bri n g st u d y  dr u g b ottles/ u n use d st u d y 
dr u g a n d t he rec or di n gs i n t he d osi n g car d t o eac h dis pe nsi n g site visit. All pat ient s a n d/ or 
pati e nts’ care gi vers s h o ul d be re -i nstr ucte d a b o ut t he d osi n g re q uire me nts d uri n g st u d y c o ntacts. 
T he a ut h orize d st u d y  pers o n nel c o n d ucti n g t he re-e d ucati o n m ust d oc u me nt t he pr ocess i n t he 
pati e nt s o urce rec or ds.
P ati e nts w h o are si g nifica nt l y n o nc o m plia nt will  b e disc o nti n ue d fr om t he st u d y. A patient  will 
be c o nsi dere d si g nifica nt l y n o nc o m p lia nt if he or s he i nte nti o nall y misses m ore t ha n 2 0 % of 
st u d y me dicat i on d uri n g t he st u d y . Si milarl y, a patie nt will be c o nsi dere d si g nifica ntl y 
n o nc o m p lia nt if he or s he is j u d ge d b y t he I n vesti gat or t o ha ve i nte nt i onall y or re peate dl y  ta ke n 
m o re t ha n t he prescri be d a m o u nt of me dicati on.
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8.
S T U D Y A S S E S S M E N T S 
T he f o ll owi n g sect i ons descri be t he st u d y  pr oce d ures t o be perf or me d a n d data t o be c ollecte d. 
F or eac h pr oce d ure, patie nts are t o be assesse d b y t he sa me I n vest igat or or si te pers o n nel 
w he ne ver p ossi ble. St u d y  pr oce d ures a n d t heir ti mi n g (i ncl u di n g t olera nce li mits f or ti mi n g) are 
s u m marize d i n t he Sc he d ule of Assess me nts (A p pe n di x 1, Ta ble 2 ).
A p pe n di x 2 lists t he la b orat or y tests t hat will be perf or me d f or t his st u d y.
A p pe n di x 3 pr o vi des a s u m mar y  of t h e ma xi m u m nu m ber a n d v ol u me of i n vasi ve sa m ples, f or 
all sa m pli n g, d uri n g t he st u d y.
8. 1.
St u d y Pr oce d ures
8. 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 Sect i on 1 1. 1 .
8. 1. 1. 1.
St u d y I nf or me d C o nse nt Pr oce d ure
I nf or me d c o nse nt must be o btai ne d bef ore t he patie nt e nters i nt o t he st u d y , a n d bef ore a n y 
pr ot oc ol -di recte d pr oce d ures are perf or me d. 
T he i nf or me d c o nse nt f or m m ust be si g ne d b y t he patie nt’s le gall y a ut h orize d re prese ntati ve. A 
ver bal or writte n patie nt asse nt s h o ul d be o btai ne d fr o m t he patie nt, if a p plica ble, i n t he e ve nt t he 
pati e nt is n ot ca pa ble of pr o vi di n g a n i nf or me d c o nse nt. If t he patie nt is n ot ca pa ble of pr o vi di n g 
a n asse nt, t he reas o n s h o ul d be d oc u me nt e d b y t he I n vesti gat or.
A u ni q ue patie nt i de nt ificati on n u m ber ( patie nt n u m ber) will be assi g ne d t o eac h patie nt a n d will 
be use d t hr o u g h o ut t he st u d y .
8. 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 (as all o we d b y l ocal 
re g ulat i ons), ge n der, et h nicit y,  a n d race as descri be d b y t he patient /care gi ver. Hei g ht a n d wei g ht 
will be c o llecte d at Scree ni n g ( Visit 1).
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 patie nt has a n y si g nifica nt 
c o n ditio ns or di seases rele va nt t o t he disease u n der st u d y t hat res ol ve d at or bef ore si g ni n g of 
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.
Me dicat i on hist or y  inf or mat i on t o be o bt ai ne d i ncl u des a n y me dicat i on rel e va nt t o eli gi bilit y 
criteria a n d t he efficac y or safety e val uat i ons st o p pe d at or wit hi n 3 0 da ys bef ore si g ni n g of 
i nf or me d c o nse nt. A E D hist or y will be c ollecte d as part of t he me dicati on hist or y  inf or mat i on.
8. 1. 3.
P h ysic al E x a mi n ati o n Pr oce d ure
T he p h ysical e xa mi nat i on will  c o nsist of t he f oll o wi n g b o d y s yste ms: ( 1) hea d, ears, n ose, t hr oat; 
( 2) car dio vasc ular s yste m; ( 3) res pirat or y  s yste m; ( 4) gastr oi ntesti nal s yste m; ( 5) der mat ol o gic 
s yste m; ( 6) e xtre mities; ( 7) m u sc ulos keletal  s yste m; ( 8) l y m p h n o des; ( 9) ps yc hiatric stat us; 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

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( 1 0) ot her. All e xa mi nati ons are t o be perf or me d b y t he I n vest i gat or or a q ualifie d site staff 
me m ber. T he p h ysical e xa mi nat i on m ust be ca pt ure d i n t he s o urce d oc u me nt a n d e C R F.
8. 1. 4.
Ne ur ol o gi c al E x a mi n ati o n Pr oce d ure
A se parate ne ur o l ogical e xa mi nat i on will  be perf or me d a n d c ollecte d i n t he e C R F. T his will 
i ncl u de testi n g me ntal stat us, gait, cere bellar f u ncti o n, cra nial ner ves, m ot or f u ncti o n, a n d 
se nsati on.
8. 1. 5.
Wei g ht a n d Hei g ht
Wei g ht a n d hei g ht are t o be meas ure d w hile t he patie nt is weari n g i n d o or cl ot hi n g a n d wit h 
s h oes off. If u na ble t o o btai n hei g ht or wei g ht , data ma y be c ollecte d fr o m ot her s o urces 
(e. g., me d ical rec or ds or t he s u bject’s careta ker). T he I n vesti gat or m ust d oc u me nt i n t he s o urce 
d oc u m e nt t he reas o n f or n ot o btai ni n g hei g ht or wei g ht (e. g., t he s u bject is i n a w heelc hair).
8. 1. 6.
Vit al Si g ns Pr oce d u re
Vi t al si g ns t o be meas ure d are b o d y t e mperat ure, bl o o d press ure, heart rate ( beats per mi n ute), 
a n d res pirat or y rate.  
Vi t al si g ns s h o uld b e m eas ure d at t he sa me ti me o f da y acr oss visits, if p ossi ble. W he n vital 
sig 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 vital 
sig ns will be o btai ne d wit hi n 1 5 mi n utes bef ore or after t he sc he d ule d bl o o d dra w, if p ossi ble.
All vit al si g ns data c ollecte d at st u d y visits 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. 
8. 1. 7.
Seiz ure Di ar y Pr oce d ure
T he seiz ure diar y is a n o bser ver -re p orte d cli nical o utc o me assess me nt meas ure t hat ca pt ures t he 
t otal n u m ber a n d d urati o n of m ot or seiz ures (i.e., dr o p seiz ures, t o nic-clo nic, t o ni c, bilateral 
clo nic, at o ni c, m yo cl o ni c -at o nic, my o clo nic -t o nic- clo nic, f ocal  seiz ures wit h bilateral 
h y per ki net ic m o t or feat ures. N ote – e xcl u de - is olate d m y ocl onic seiz ures) b y t y pe, i n 
acc or da nce wit h t he ne w seiz ure classificat i on s yste m .9
P ati e nts a n d/ or patie nts’ care gi vers will be t he o bser vers a n d re p orters i n t he c urre nt st u d y . 
P ati e nts a n d/ or patie nts’ care gi vers ma y rec or d seiz ures t hr o u g h o ut t he da y b ut must e ns ure t hat 
t he dail y diar y assess me nt is c om p lete d eac h e ve ni n g, e ve n if n o seiz ures occ urre d.
At  t he Scree ni n g visit ( Visit 1) a n d at e ver y cli nic visit, t he patie nt a n d/ or patie nt’s care gi ver will 
be gi ve n a seiz ure diar y  a n d s pecific i nstr uctio ns t o e ns ure c o m plia nce wi t h t he seiz ure 
rec or di n g. T he seiz ure e ve nts will be rec or de d starti n g at t he Scree ni n g/ Baseli ne Peri o d u p u ntil 
t he F oll o w-u p Visi t a n d c ollecte d at eac h cli nic visit. Pri or t o t he first d ose at Da y 1 ( Visit 2), 
seiz ure diaries m ust be se nt t o t he Me dical M o nit ors f or re vie w a n d a p pr o val. At all ot her visits, 
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t he diar y ca n be re vie we d b y t he I n vesti gat or wit h t he patie nt a n d/ or patie nt’s care gi ver f or 
pr o per rec or di n g a n d acc o u nta bilit y.  
8. 1. 8.  
D oc u me nt ati o n of St u d y Dr u g
A Seiz ure diar y wit h d osi n g f or m will be pr o vi de d t o t he patie nt a n d/ or care gi ver at eac h cli nic visit 
t o rec or d A M a n d P M st u d y dr u g a d mi nistrati o n t hr o u g h o ut t he st u d y, i ncl u di n g c ha n ges i n d osi n g 
re gi me n ( de-escalati o n) t hat ma y occ ur bet wee n visits a n d d uri n g t he de -escalati o n peri o d of t he 
st u d y. T h ese will be rec or de d i nt o t he electr o nic case re p ort f or m (e C R F).
8. 1. 9.
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 dicat i on is a n y dr u g gi ve n i n a d diti on t o t he st u d y  dr u g. T hese ma y be 
prescri be d b y  a p h ysicia n or o btai ne d b y t he patient o ver t he c o u nter. C o nc o mita nt me dicat i on is 
n ot pr o vi de d b y  t he S p o ns or. At eac h st u d y visit, p atie nts a n d/ or care gi vers will be as ke d 
w het her patie nts ha ve ta ke n a n y me dicat i on ot her t ha n t he st u d y  dr u g ( 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 dicat i on i ncl u di n g vita mi n 
s u p ple me nts, o ver-t he-c o u nter me dicat i ons, a n d her bal pre parat i ons i ncl u di n g ( me dical) 
marij ua na m ust be rec or de d i n t he s o urce d oc u me nt a n d e C R F. D oc u me ntati o n will i ncl u de 
ge neric me dicat i on na me, d ose, u nit, f re q ue nc y, r o ute of a d mi nistratio n, start a n d e n d dates, a n d 
reas o n f or use.
A nt ie pile ptic dr u g treat me nt, ( me dical) marij ua na, ca n na bi di o l pr o d ucts, V N S setti n gs, a n d 
ket o ge nic diet s h o ul d n ot be altere d d uri n g t he st u d y .
8. 1. 1 0.
Pr oce d ures f or Cli nic al L a b or at or y S a m ples
Bl o o d a n d uri ne sa m ples are t o be c ollecte d at t he ti me p oi nts sti p ulate d i n t he Sc he d ule of 
Assess me nts (Ta ble 2 ). Sa mples 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. Details of t hese pr oce d ures a n d re q uire d safet y m o nit ori n g will be gi ve n i n t he 
la b orat or y ma n ual.
T he cli nical la b orat or y  tests t o be perf or me d are liste d i n A p pe n di x 2 .
F or a n i n di vi d ual pat ient , t he ma xi m u m v ol ume of bl o o d c ollecte d o ver t he c o urse of t he st u d y 
will be a p pr o xi matel y  1 1 8. 2 m L (A p pe n di x 3 ). 
Bl o o d v ol u me li mitat i ons will s o met i mes precl u de t he c ollecti on of all sa m ples i n a part ic ular 
st u d y visit. A p pe n di x 3 e n u merates t he pri orit ies f or bl o o d c ollecti on. 
I n ge neral, e xisti n g g ui deli nes f or bl o o d sa m ple v ol u me li mits (ma xi m u m of  1 2 0 m L f or eac h 
pati e nt wi t h ma xi m u m bl o o d v ol u me c o llecte d d uri n g a 3 0-d a y  p erio d of a p pr o xi matel y 4 0 m L
a n d ma xi m u m bl o o d v ol u me c o llecte d d uri n g a si n gle visit of a p pr o xi matel y 2 5 m L) are 
c o nsiste nt wit h t he li mite d e vi de nce a vaila ble o n “ mi ni mal ris k” t o c hil dre n. E xa m ples of 
g ui deli nes f or bl o o d dra w li mits i n pe diatrics ca n be f o u n d at: 
ht t p:// w w w. w h o.i nt/ b ulleti n/v o l umes/ 8 9/ 1/ B L T - 1 0- 0 8 0 0 1 0-ta ble-T 2. ht ml .
T he ce ntral la b orat or y  will perf or m la b orat or y tests f or he mat olo g y , ser u m c he mistr y, a n d 
uri nal ysis. T he res ults of cli nical 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. T he I n vesti 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 t he refere nce ra n ges f or t he la b orat or y  use d.
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If patient s e x perie nce A L T or A S T > 3 × U L N, f oll o w-u p la b orat or y tests (at a mi ni m u m, ser u m 
alkali ne p h os p hatase, A L T, A S T, t otal bilir u bi n , γ-gl uta m yl  tra nsferase [ G G T], a n d I N R) s h o ul d 
be perf or m e d prefera bl y wit hi n 4 8 t o 7 2 h o urs a n d n o later t ha n 5 days after t he a b n or malit y was 
n ote d. Pl ease refer t o Secti o n 6. 3. 1 f or disc o nti n uatio n cri t eria a n d Sect i on 8. 3. 3. 1 f or re p ortin g 
re q uire me nts relate d t o A L T or A S T > 3 × U L N i n c o nj u nct i on wi t h t ot al bilir u bi n > 2 × U L N.
If t he A L T or A S T 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 testi n g, cl ose 
m o nit ori n g, p ossi ble disc o nt i n uati on of st u d y  dr u g, a n d disc ussi o n of t he 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 b e rec or de d as a T E A E ( please refer 
t o Secti o n 8. 3. 3. 1 f or re p orti n g re q uire me nts).
If uri ne ca n n ot be c ollecte d d ue t o t he patie nt’s c o o perati o n or beca use t he patie nt is weari n g a 
di a per, t he reas o n s h o ul d be d oc u me nte d i n t he s o urce d oc u me nt a n d, f or fe male pat ient s, t he 
res ults of t he ser u m pre g na nc y test o btai ne d at Visit 1 must be c o nfir me d t o be ne gati ve b y t he 
I n vesti gat or pri or t o i nitiati on of treat me nt. 
8. 1. 1 1.
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
Pl ease refer t o Secti o n 6. 1 f or detaile d c o ntrace pti o n re q uire me nts.
P ati e nts will be pr o vide d wi t h inf or mati o n o n acce pta ble met h o ds of c o ntrace pti o n as part of t he 
pati e nt i nf or me d c o nse nt pr ocess a n d will be as ke d t o si gn 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 nts f or 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  a n d f or 3 0 da ys after t he last d ose of st u d y dr u g. T his ma y be 
sig ne d b y t he l e gall y a ut h oriz ed re prese ntati ve o f t he patient .
All se x uall y acti ve fe male patient s of c hil d beari n g p ote ntial m ust ha ve a ne gat i ve uri ne or ser u m 
h u ma n c h ori o nic g o na d otr o pi n ( h C G) pre g na nc y test at Scree ni n g ( Visit 1) bef ore recei vi n g a n y 
d ose of st u d y  dr u g. A d ditio nal  pre g na nc y tests ( uri ne o nl y ) m a y be perf or me d t hr o u g h o ut t he 
st u d y at t he I n vesti gat or’s discreti on. D uri n g t he st u d y , p atie nts will recei ve c o nti n ue d g ui da nce 
wi t h res pect t o t he a v oi da nce of pre g na nc y a nd o va or s per m d o nati o n as part of t he st u d y  
pr oce d ures. A n a d dit i onal ser u m hC G pre g na nc y test will be perf or me d at t he patie nt’s last cli nic 
visit.
Se x uall y  a cti v e male pat ient s ( p ost-p u bertal u nless per ma ne ntl y sterilize d b y bilateral 
orc hi dect o m y) m ust a gree t o use male c o ntrace pti o n (c o n d o m) d uri n g t h e st u d y a n d for 3 0 da y s 
f oll owi n g t he last d ose of st u d y  dr u g. Male patie nts must al s o n ot d o nate s per m d uri n g t he 
Scree ni n g a n d Treat me nt Peri o ds a n d f or 3 0 da y s after t he last d ose of st u d y dr u g. Fe males of 
c hil d beari n g p ote ntial w h o are part ners of male patie nts are als o a d vise d t o use a d dit i onal 
c o ntrace pti o n as s h o w n i n t he list c o ntai ni n g hi g hl y effecti ve/effecti ve c o ntrace pti o n i n
Secti o n 6. 1 .
8. 1. 1 2. 
E C G Pr oce d ure
A 1 2 -lea d E C G will be rec or de d at Scree ni n g ( Visit 1) a n d at 3 0 mi n utes ( ± 1 0 mi n utes) after t he 
m o r ni n g d ose at ot her visits. If t he patie nt ca n n ot t olerate bei n g s u pi ne, a sitti n g E C G ma y be 
o btai ne d. T he I n vesti gat or ( or a q ualifie d o bser ve r at t he st u d y site) will i nter pret t he E C G usi n g 
1 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 sig nifica nt, or 
a b n or mal a n d cli nicall y si g nifica nt. T he i nter pretati on of t he E C G will be rec or de d i n t he s o urce 
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

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Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 4 5 of 1 0 1
d oc u m e nts an d i n t he e C R F. T he ti me t hat t he E C G was perf or me d will be rec or de d. 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 pat ient ’s E C G trace: heart rate, 
res pirati on rate, P R i nter val, Q T i nter val, Q R S i nter val, a n d c orrecte d Q T i nter val. E C G t races 
rec or de d o n t her mal pa per will be p h ot oc o pie d t o a v oi d de gra dati o n of trace o ver ti me.
8. 1. 1 3.
Cli nic al Assess me nt of S uici d al I de ati o n a n d Be h a vi or
S ui ci dal id e ati o n a n d be ha vi or will  be assesse d i n pati e nts a ge d ≥6 y ears usi n g 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 dal i deati o n (e. g., patie nt e n d orses t h o u g hts a b o ut a 
wi s h t o be dea d or has ot her t h o u g hts of s uici de), i nte nsity of  ideat i on (fre q ue nc y), a n d s uici dal 
be ha vi or (act uall y, i nterr u pte d, or a b orte d atte m pts at s uici de) .1 0
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 -Vi sit C-S S R S.
St u d y  staff trai ne d i n t he a d mi nistratio n of  t he C-S S R S will assess patie nt s uici dalit y usi n g t he 
C- S S R S, elicit i n g a ns wers fr om t he patie nt or t he patie nt’s care gi ver. Ulti matel y, t he 
deter mi nat i on of t he prese nce of s uici dal i deati o n or be ha vi or de pe n ds o n t he cli nical j u d ge me nt
of  t he i n vesti gat or. 
If a patie nt e x hi bits si g ns of s uici dal i deati o n, t he patie nt ma y be disc o nt i n ue d as descri be d i n 
Secti o n 6. 3. 1 .
8. 1. 1 4.
Vi nel a n d A d a pti ve Be h a vi or Sc ale
T he V A B S, 3 r d E di tio n Pare nt Care gi ver F or m ( V A B S - 3 Pare nt Care gi ver F or m), is a pare nt-
re p ort q uesti o n naire of a da pti ve f unct i oni n g or h o w a n i n di vi d ual be h a ves i n t heir da y-t o-da y life 
at h o me a n d i n t he c o m m u nit y .1 2 It assesses a da pti ve f u ncti o ni n g acr oss 4 d o mai ns: be ha vi or, 
c o m m u nicat i on, dail y  li vi ng, s o ci alizat i on, a n d pr o ble m be ha vi or. T he i nter vie w ta kes a b o ut 
2 0 mi n utes t o c o m plete.
If t he patie nt is u na ble t o c o m pl y with t he V A B S f or e xa m ple d ue t o t he la n g ua ge barrier 
(e. g., u na vaila bilit y of  vali date d test i n patie nt’s la n g ua ge), t he I n vesti gat or ma y als o use cli nical 
j u d g me nt t o assess f or a da pti ve f u ncti on a n d be ha vi or.
8. 1. 1 5.
A berr a nt Be h a vi or C hec klist -C o m m u nit y ( A B C -C)
Be ha vi or will be assesse d b y  t he use of t he A B C-C q uesti o n naire, w hic h is a rati n g scale t hat 
meas ures t he se verit y of  a ra n ge of pr o bl e m be ha vi ors c o m mo nl y o bser ve d i n i n di vi d uals wit h 
i ntellect ual a n d de velo p m e nt al  disa bilities.1 1 It is c o m plete d b y t he care gi ver. It is a n e mpiricall y  
de vel o pe d scale desi g ne d t o meas ure ps yc hiatric s y m pt o ms a n d be ha vi oral dist ur ba nce e x hi bite d 
b y i n di vi d uals acr oss 5 d o mai ns with 5 8 i t e ms: irrita bilit y, a git atio n, a n d cr yi n g ( 1 5 ite ms); 
let har g y, s ocial wit hdra wal  ( 1 6 ite ms); stere ot yp y ( 7 i t ems); h y peract i vity/ n o nc o m p lia nce 
( 1 6 ite ms); a n d i na p pr o priate s peec h ( 4 ite ms).
If t he patie nt is u na ble t o c o m pl y with t he A B C -C d ue t o t he l a n g ua ge barrier 
(e. g., u na vaila bilit y of  vali date d test i n patie nt’s la n g ua ge) t he I n vesti gat or ma y als o use cli nical 
j u d g me nt t o assess f or be ha vi 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

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Date: 2 1 N o ve m ber 2 0 1 9
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8. 1. 1 6.
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 dit i ons are t h ose si g nifica nt o n g oi n g c o n dit i ons or di seases t hat are 
prese nt at si g ni n g of i nf or me d c o nse nt. T hese i ncl u de cli nicall y  si g nifica nt la b orat or y, E C G, or 
p h ysical e xa mi nat i on a b n or malit ies n ote d at Scree ni n g ( Visit 1), acc or di n g t he j u d g me nt of t he 
I n vesti gat or. T he c o n diti on (i .e., dia g n osis) s h o ul d be descri be d a n d rec or de d o n t he Me dical 
Hi st or y for m .
8. 1. 1 7.
C are gi ver Gl o b al I m pressi o n of C h a n ge ( C are GI -C) 
At  Visit 2 ( Da y 1; prior t o a d mi nistrati o n of t he first d ose of st u d y  dr u g), t he care gi ver will be 
as ke d t o write a brief descri pt i on of t he patie nt’s o verall c o n dit i on as a me m or y  ai d for t he 
Care GI -C at s u bse q ue nt visits.
T he Care GI -C c o mpri ses t he f ollo wi n g q uesti o n t o be rate d o n a 7 -p oi nt scale:
Si nce y o ur c hil d starte d treat m e nt, please assess t he stat us of yo ur c hil d’s o verall c o n dit i on 
( c o mpari n g t heir c o n dit i on n o w t o t heir c o n dit i on bef ore treat me nt) usi n g t he scale bel o w.

V er y  M uc h I m pr o ve d

M uc h I m pr o ve d

Sl i g htl y I m pr o ve d

N o C ha n ge

Sl i g htl y W orse

M uc h W orse

V er y  M uc h W orse
If t he mai n care gi ver is n ot a vaila ble at t he a p pr o priate visit t he n t his i nf or mati on ca n be 
ca pt ure d o ver t he tele p h o ne, i deall y o n t he da y of t he visit or ot her wise wit hi n 3 da ys.
8. 1. 1 8.
Cli nic al Gl o b al I m pressi o n of Se verit y ( C GI -S) a n d Cli nic al Gl o b al I m pressi o n –
C h a n ge ( C GI - C)
C GI -Se verit y ( C GI-S) is use d t o o b t ain a n assess me nt of s y m pt o ms se verit y.  T he C GI-C f oc uses 
o n cli nicia ns’ o bser vati o ns of c ha n ge i n t he pat ient ’s c o g niti ve, f u ncti onal, a n d be ha vi oral 
perf or m a nce si nce t he be gi n ni n g of t he st u d y. 
T he C GI -S is rate d o n a 7 -p oi nt scale, wit h t he se verit y of  ill ness scale usi n g a ra n ge of 
res p o nses fr om 1 ( n or m al) t hr o u g h t o 7 (a m o n gst t he m ost se verel y ill patient s). C GI-S sc ores 
ra n ge fr om 1 ( ver y  muc h i m pr o ve d) t hr o u g h t o 7 ( ver y  muc h w orse). 
F or t he C GI- C, treat me nt res p o nse rati n gs s h o ul d ta ke acc o u nt of b ot h t hera pe utic efficac y a n d 
treat me nt -relate d A Es a n d ra n ge fr om 0 ( mar ke d i m pr o ve me nt a n d n o s i de-effects) a n d 4 
( u nc ha n ge d or w orse a n d si de-effects o ut wei g h t he t hera pe utic effects). Eac h c o m p o ne nt of t he 
C GI is rate d se paratel y; t he i nstr u me nt d oes n ot yiel d a gl o bal sc ore. T he PI or desi g nee will 
c o mplete t he C GI -S a n d C GI -C at t he ti me p oi nts s pecifie d i n  Ta ble 2 ( A p pe n di x 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

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8. 1. 1 9.
Se verit y Assess me nt i n C D K L 5 Deficie nc y Dis or der
T he o pti o nal se verit y assess me nt will be c o n d ucte d i n o nl y t he C D D pat ient s a n d ca pt ures 
de grees of se verit y ass o ciat e d wit h mot or f u nct i on, c o g ni tio n, a n d visi o n a n d a ut o n o mic 
d y sf u ncti on. A c o p y  of t he q uestio n n ai re is pr o vide d i n A p pe n di x 5 . 
8. 1. 2 0.
E xit S ur ve y 
A n e xit s ur ve y will be c o n d ucte d at Visit 6 or at t he earl y ter mi nat i on visit wi t h Care GI-C, a n d it 
ta kes a p pr o xi matel y 2 mi n utes. T he s ur ve y ca pt ures wit h pare nt’s (a n d care gi vers’) e x perie nces 
wi t h T A K-9 3 5 i ncl u di n g i m pact of treat me nt wit h T A K -9 3 5 o n dail y life/f u nct i oni n g a n d o n 
m o st i mp orta nt b ot hers o m e s y m pt o ms. 
8. 1. 2 1.
P h ar m ac o ki ne tic S a m ple C ollecti o n a n d A n al ysis
8. 1. 2 1. 1.
C ollecti o n of Pl as m a S a m ples f or T A K -9 3 5 P K E v al u ati o n
8. 1. 2 1. 2.
Bi o a n al ytic al Met h o ds f or T A K -9 3 5
 
C CI
C 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 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 4 8 of 1 0 1
8. 1. 2 1. 3.
P h ar m ac o ki netic P ar a meters
8. 1. 2 2.
P h ar m ac o d y n a mic S a m ple C ollecti o n a n d A n al ysis
8. 1. 2 2. 1.
C ollecti o n of Pl as m a S a m ples f or P h ar m ac o d y n a mic E v al u ati o n
8. 1. 2 2. 2.
Bi o a n al ytic al Met h o ds f or 2 4 H C
8. 1. 2 2. 3.
P h ar m ac o d y n a mic P ar a meters 
T he P D para m eter of  c ha n ge fr o m Baseli ne i n plas ma 2 4 H C le vels will be s u m marize d. 
A d dit i onal P D para meters ma y  be calc ulate d a n d s u bjecte d t o a d dit i onal P K/ P D m o deli n g, as 
a p pr o priate.
8. 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 patient s wit h a si gne d i nf or me d c o nse nt. If t he patie nt is f o u n d 
t o be i neli gi ble f or t he st u d y at Visit 2 ( Da y 1), t he I x R S/I W R S s h o ul d be c o ntacte d as a 
n otificati o n o f scree n fail ure.
T he pri mar y  reas o n f or scree n fail ure is t o be rec or de d i n t he e C R F. 
C CI
C CI
C 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 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

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Date: 2 1 N o ve m ber 2 0 1 9
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P ati e nts ma y b e r e-scree ne d after a p pr o val of Me dical  M o nit or a n d S p o ns or.
P ati e nt n u m bers assi g ne d t o patie nts w h o fail scree ni n g s h o ul d n ot be re use d. If a patie nt fails 
scree ni n g, b ut is later s uccessf ull y rescree ne d, t he data f or t he patie nt will be e ntere d as if t hese 
were 2 se parate patie nts. T heref ore, t he data s h o ul d be e ntere d as f oll o ws:
1.
T he scree n fail ure data s h o ul d be e ntere d as a scree n fail ure pat ient
2.
Rescree ne d pat ient s s h o ul d be assi g ne d a ne w patie nt n u m ber a n d treate d as a sta n d-alo ne 
pati e nt
8. 1. 2 4.  
D oc u me nt ati o n of St u d y E ntr a nce
O nl y patie nts w h o meet all t he i ncl usi o n cri t eria a n d n o ne of t he e xcl usi o n criteria are eli gi ble f or 
e ntr y int o t he st u d y .
If t he patie nt is f o u n d t o be n ot eli gi ble, t he I n vesti 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.
8. 2.
S a m ple C ollecti o n a n d Testi n g 
A p pe n di x 1 lists t he sc he d ule f or sa m ple c ollecti ons i n t his st u d y .
A p pe n di x 2 lists t he la b orat or y tests t hat will be perf or me d f or t his st u d y. 
A p pe n di x 3 pr o vi des a s u m mar y  of t h e ma xi m u m nu m ber a n d v ol u me of i n vasi ve sa m ples, f or 
all sa m pli n g, d uri n g t he st u d y. 
8. 3.
S afet y E v al u ati o ns
I n vesti gat ors are res p o nsi ble f or m o nit ori n g t he safet y of patient s w h o ha ve e ntere d t his st u d y 
a n d f or alertin g t he S p o ns or or desi g nee t o a n y  e ve nt t hat see ms u n us ual, e ve n if t his e ve nt ma y 
be c o nsi dere d a n u na ntici pate d be nefit t o t he patie nt.
T he I n vesti gat or is res p o nsi ble f or t he a p pr o priate me dical care of pat ient s d uri n g t he st u d y.
T he I n vesti gat or re mai n s res p o nsi ble f or f oll o wi n g, t hr o u g h a n a p pr o priate healt h care o pti o n, 
A Es t hat are seri o us, c o nsi dere d relate d t o t he st u d y treat me nt or t he st u d y , or t hat ca use d t he 
pati e nt t o disc o nti n ue bef ore c o m plet i n g t he st u d y. T he patie nt s h o ul d be f oll owe d u nt il t he e ve nt 
is res ol ve d or e x plai ne d. Fre q ue nc y of f oll ow- u p e val uat i on is left t o t he discreti on of t he 
I n vesti gat or. 
8. 3. 1.
A d verse E ve nts
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce i n a pat ient  or cli nical st u d y patient  
a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal relat 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 or u ni nte n de d si g n (f or e xa m ple, a n 
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 
me di ci nal pr o d uct, w het her c o nsi dere d relate d t o t his me dici nal pr o d uct.
T he defi nit i on of a n A E als o c o vers me dicat i on err ors a n d uses o utsi de w hat is f oresee n i n t he 
pr ot oc ol  o nl y if a n A E res ults fr o m t he err or, i ncl u di n g i nte nti onal mis use, a b use, a n d o ver d ose 
of  t he pr o d uct. A d verse e ve nts (i ncl u di n g S A Es) ass ociate d wit h o ver d ose s h o ul d be re p orte 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

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acc or di n g t o t he pr oce d ure o utli ne d i n Sect i on  8 . 3. 1. 3. I n t he e ve nt of dr u g o ver d ose, t he patie nt 
s h o uld be treate d s y m pt o mat icall y.
Si t u atio ns w here a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or c o n ve nie nce 
a d missi o n t o a h os pital) a n d a ntici pate d da y -t o-da y fl uct uati o ns of pre -e xist i n g disease(s) or 
c o n ditio n(s) prese nt or detecte d at t he start of t he st u d y  t hat d o n ot w orse n are n ot A Es.·
Pr e pl a 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 A Es. H o we ver, if a pre pla n n e 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 xist i n g c o n diti on, t he w orse ni n g of t he c o n dit i on 
s h o uld be rec or de d as 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 uld be 
re p orte d as A Es.
Elect i 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 on 
s h o uld n ot be rec or de d as 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 plicat i ons res ult i n g fr om a n elect i ve s ur ger y s h o ul d be re p orte d as A Es. 
F or t he p ur p ose of t his st u d y , re p orti n g of seiz ures s h o ul d meet t he A E/ S A E re p orti n g 
re q uire me nts. As seiz ures are c o nsi dere d a baseli ne c o n diti on, seiz ures s h o ul d be re p orte d as a n 
A E/ S A E if: 1) t here is a clear i ncrease i n t he fre q ue nc y o f seiz ures c om pare d t o t he s u bject’s 
baseli ne, 2) t here is a n e mer ge nce of a ne w seiz ure t y pe, or 3) t he s u bject e x perie nces stat us 
e pile pt ic us, a n d a n y ot her ti me t he i n vesti gat or feels t he seiz ure s h o ul d be ca pt ure d as a n 
A E/ S A E, i n w hic h case t he I n vest i gat or s h o ul d d oc u m e nt his/ her reas o ni n g. All seiz ures will be 
ca pt ure d in t he seiz ure diar y  c ollecte d at t he site d uri n g t he st u d y a n d will be a nal yze d b y t he 
s p o ns or al o n g wit h t he re p orta ble S A Es i n e val uati n g ris k: be nefit. T he s p o ns or will re p ort t he 
S A E e ve nts of s eiz ure t hat meet t hese criteria i n a n a g gre gate d u n bli n de d re p ort at t he c o ncl usi o n 
of  t he st u d y.
T he S p o ns or has sta n dar ds f or re p orti n g A Es t hat are t o be f o ll owe d re gar dl ess of a p plica ble 
re g ulat or y r e q uire me nts t hat ma y b e less stri n ge nt. 
Lac k of dr u g effect is n ot a n A E i n cli nical st u dies, beca use t he p ur p ose of t he cli nical st u d y is t o 
esta blis h dr u g effect.
Cases of pre g na nc y t hat occ ur d uri n g mater nal or pater nal e x p os ures t o st u d y  dr u g are t o be 
re p orte d. Data o n fetal o utc o me a n d breast-fee di n g are c ollecte d f or re g ulat or y re p orti n g a n d 
dr u g safet y e val uat i on.
St u d y  site pers o n nel will rec or d t he occ urre nce a n d nat ure of eac h patie nt’s pre-e xist i n g 
c o n ditio ns, i ncl u di n g cli nicall y  sig nifica nt si g ns a n d s y m pt o m s of t he disease u n der treat me nt i n 
the st u d y.
After t he i nf or me d c o nse nt f or m (I C F) is si g ne d, site pers o n nel will rec or d a n y c ha n ge i n t he 
c o n ditio n(s) a n d t he occ urre nce a n d nat ure of a n y A Es. If a pat ient  e x perie nces a n A E after 
sig ni n g i nf or me d c o nse nt, b ut pri or t o recei vi n g st u d y  dr u g, t he e ve nt will be re p orte d, b ut will 
be i ncl u de d i n t he patie nt’s me dical hist or y u nless t he e ve nt is seri o us, or t he I n vesti gat or feels 
t he e ve nt ma y ha ve bee n ca use d b y a pr ot oc ol pr oce d ure.
I n a d diti on, all A Es occ urri n g after t he patie nt recei ves t he first d ose of st u d y dr u g must be 
re p orte d t o t he S p o ns or or its desi g nee via 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 5 1 of 1 0 1
8. 3. 1. 1.
Se verit y Assess me nt
I n vesti gat ors will be i nstr ucte d t o rate t he se verity of  A Es usi n g t he f oll owi n g cri teria:
Mil d
E ve nts re q uire mi ni mal or n o treat me nt a n d d o n ot i nt erfere wit h t he patie nt’s 
dail y  a cti vities
M o der ate
E ve nts res ult i n a l o w le vel o f i nc o n ve nie nce or c o ncer ns with t he t hera pe utic 
meas ures. M o derate e ve nts ma y ca use s o me i nterfere nce wit h f unct i oni n g
Se vere
E ve nts i nterr u pt a patie nt’s us ual dail y  activit y a n d ma y re q uire s yste mic dr u g 
t hera p y or ot her treat me nt. Se vere e ve nts are us uall y inca paci tati n g
C ha n ge i n se verit y of  a n A E s h o uld be d oc u m e nte d base d o n s pecific g ui deli nes i n t he e C R F 
C o m plet i on G ui deli nes.
Se verit y a n d serio us n ess m ust be differe ntiate d: se verit y descri bes t he i nte nsit y of  a n A E, w hile 
t he ter m serio us ness refers t o a n A E t hat has met t he criteria f or a n S A E.
8. 3. 1. 2.
C a us alit y Assess me nt
I n vesti gat ors will be i nstr ucte d t o re p ort t o t he S p o ns or or its desi g nee t heir assess me nt of the 
p ote nti al relate d ness of eac h A E t o pr ot oc ol pr oce d ure a n d/ or st u d y dr u g via t he C R F.
A n I n vest i gat or ca usality assess me nt must be pr o vi de d f or all A Es ( b ot h seri o us a n d n o n -
serio us). T hi s assess me nt m ust be rec or de d i n t he e C R F a n d a n y a d ditio nal f or m s as a p pr o priate.
Relati o ns hi p of A Es t o t he defi ne d st u d y  treat me nt ( T A K-9 3 5 [after t he start of T A K -9 3 5 o n 
D a y  1]), will be deter mi ne d b y t he I n vesti gat or acc or di n g t o t he f oll owi n g criteria. Please n ote 
t hat n ot all criteria m ust be prese nt t o be i n dicat i ve of a partic ular relati ons hi p.
N ot Rel ate d
E x p os ure t o t he defi ne d st u d y treat me nt di d n ot occ ur, or t he 
occ urre nce of t he A E is n ot reas o na bl y relate d i n ti me
U n li kel y Rel ate d
T he A E occ urre d i n a reas o na ble ti me after t he defi ne d st u d y 
treat me nt a n d is d o u btf ull y relate d t o t he i n vesti gati o nal 
a ge nt/ pr oce d ure
P ossi bl y Rel ate d
T he defi ne d st u d y treat me nt a n d t he A E were reas o na bl y relate d i n 
ti me, a n d t he A E c o ul d be e x plai ne d e q uall y well b y ca uses ot her 
t ha n e x p os ure t o t he defi ne d st u d y treat me nt
Rel ate d
T he defi ne d st u d y treat me nt a n d t he A E were reas o na bl y relate d i n 
ti me, a n d t he A E was m ore li kel y e x plai ne d b y e x p os ure t o t he 
defi ne d st u d y treat me nt t ha n b y ot her ca uses, or t he defi ne d st u d y 
treat me nt was t he m ost li kel y ca use of t he A E
If a patie nt’s d osa ge is re d uce d or treat me nt is disc o nti n ue d as a res ult of a n A E, st u d y  sit e 
pers o n nel m ust clearl y  re p ort t o t he S p o ns or or its desi g nee via C R F t he circ u msta nces a n d data 
lea di n g t o a n y s uc h d osa ge re d ucti o n or disc o nti n uati o n of treat me 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 5 2 of 1 0 1
8. 3. 1. 3.
Seri o us A d verse E ve nts
S eri o us a d verse e ve nt c ollect i on be gi ns after t he patie nt has si g ne d t he I C F. If a pat ient  
e x perie nces a n S A E after si g ni n g t he I C F, b ut pri or t o recei vi n g st u d y  dr u g, t he e ve nt will be 
re p orte d, b ut will be classifie d as a pre-treatme nt  S A E u nless t he I n vesti gat or feels t he e ve nt ma y 
ha ve bee n ca use d b y a pr oce d ure liste d i n t he pr ot oc ol.
Pl a n ne d s ur geries a n d/ or h os pitalizat i ons s h o ul d n ot be re p orte d as S A Es u nless t he u n derl yi n g 
me dical c o n dit i on has w orse ne d d uri n g t he c o urse of t he st u d y.
St u d y  site pers o n nel must al ert t he S p o ns or or its desi g nee of a n y S A E wit hi n 2 4 h o urs of 
I n vesti gat or a ware ness of t he e ve nt via a s p o ns or-a p pr o ve d met h o d. If alerts are iss ue d via 
t ele p h o ne, t he y are t o be i m me diatel y f oll ow e d wi t h official no tificati on o n st u d y -s pecific S A E 
f or ms. T his 2 4-h o ur n otificat i on re q uire me nt refers t o t he i nit ial S A E i nf or mati on a n d all 
f oll ow- u p S A E i nf or mat i on.
A n S A E is a n y  AE f r o m t his st u d y t hat res ults i n 1 or more of t he f o ll owi n g o utc o m es:

Res ults i n deat h 

Re q ui res or pr olo n gs h os pi talizati on

Is life t hreate ni n g (t hat is, i m me diate ris k of d yi n g)

Persi ste nt or sig nifica nt disa bilit y/ i nca pacity

C o n ge nital a n o ma l y or birt h defect

Ot her me dicall y i m p orta nt seri o us e ve nt
I mp orta nt m e dical e ve nts t hat ma y n ot res ult  i n deat h, be life-t hreate ni n g, or re q uire 
h os pi talizatio n ma y  be c o nsi dere d serio us w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y  
ma y je o par dize t he patie nt a n d ma y re q uire me dical or s ur gical i nter ve nt i on t o pre ve nt o ne of t he 
o utc o m es liste d i n t his defi niti on.
S eri o us a d verse e ve nts occ urri n g u p t o a n d i ncl u di n g t he patie nt’s last st u d y  visit will b e 
c ollecte d, re gar dless of t he I n vesti gat or’s o pi ni o n of ca usat i on.
If a n I n vesti gat or bec o mes a ware of S A Es occ urri n g t o a patie nt after t he patie nt’s partici pat i on 
i n t he st u d y has e n de d (i ncl u di n g a n y pr ot oc ol-r e q uire d p ost-treat me nt fol l ow- u p), t he 
I n vesti gat or s h o ul d re p ort t he S A Es t o t he s p o ns or, re gar dless of t he I n vesti gat or’s o pi ni on of 
ca usat i on.
8. 3. 1. 4.
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns
S us pecte d u ne x pecte d seri o us a d verse react i ons ( S U S A Rs) are seri o us e ve nts t hat are n ot liste d 
i n t he I B a n d t hat t he I n vesti gat or i de ntifies as relate d t o st u d y dr u g or pr oce d ure. U nite d States 
2 1 C F R 3 1 2. 3 2 a n d E ur o pea n U ni o n Cli nical Trial Directi ve 2 0 0 1/ 2 0/ E C a n d t he ass ociate d 
detaile d g ui da nce or nati o nal re g ulat or y  re q uire me nts i n partici pat i n g c o u ntries re q uire t he 
re p orti n g of S U S A Rs. T he S p o ns or has pr oce d ures t hat will be f oll ow e d f or t he rec or di n g a n d 
e x pe dite d re p orti n g of S U S A Rs t hat are c o nsiste nt wit h gl o bal re g ulat i ons a n d t he ass ociate d 
detaile d g ui da nce.
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 5 3 of 1 0 1
8. 3. 1. 5.
Re p orti n g A d verse E ve nts
All n o n- s erio us A Es m ust be rec or de d i n t he e C R F u p o n a ware ness. 
A n y A E t hat meets S A E criteria ( Secti o n 8. 3. 1. 3 ) m ust i m me diatel y (i. e., wit hi n 1 b usi ness da y) 
be se nt t o t he S p o ns or u p o n lear ni n g of a n y S A E t hat occ urs ( w het her or n ot attri b uta ble t o t he 
st u d y dr u g). It is t he I n vesti gat or’s res p o nsi bility t o e ns ure t hat S A E re p orti n g pr oce d ures are 
f oll owe d a p pr o pri atel y. All S A E re p orts a n d a n y re visi ons t o a n S A E m ust be se nt b y  
fa x n u m ber or e m ail. All s u p p orti n g s o urce i nf or mati o n c o ncer ni n g t he S A E (e. g., h os pital 
rec or ds) s h o ul d als o be pr o vi de d b y fa x or e mail.
C o u ntr y -s pecific F A X n u m bers will be pr o vi de d i n a se parate d oc u me nt.
E m ail:  
If t here is a q uesti o n c o ncer ni n g a n S A E, t he site nee ds g ui da nce re gar di n g t he re p orti n g of  a n 
S A E, t he site is ret ur ni n g a call fr o m t he S p o ns or’s safet y s pecialist, or t he site ur ge ntl y nee ds t o 
re p ort a n S A E or ma ke t he S p o ns or a ware of a n S A E, t he safety h otli ne s h o ul d be use d. C o u ntr y -
s pecific h otli ne n u m bers will be pr o vi de d i n a se parate d oc u me nt.
If a n S A E is re p orte d via t he h otli ne, t he site s h o ul d first s u b mit t he S A E pa per f or m a n d t he n 
e nter t he S A E i n t he e C R F. A n y AE t h at m eets S A E criteria (Secti o n 8. 3. 1. 3 ) must be e ntere d 
i nto t he el e ctr o nic data ca pt ure ( E D C) s yst e m i m m e diatel y (i.e., wit hi n 1 b usi ness da y) aft er sit e 
pers o n nel first lear n a b o ut t he e ve nt i n a d dit i on t o fa xi n g/e maili n g t he S A E Re p ort f or m. O nce 
t he q ualif yi n g S A E data are e ntere d i nt o E D C, O vi d will be n otifie d b y a n e mail alert, w hic h will 
c o ntai n hi g h-level safet y i nf or mati on. 
All S A Es m ust be re p orte d starti n g fr o m t he ti me t hat i nf or me d c o nse nt f or st u d y partici pat i on is 
pr o vi de d. If t he i n vesti gat or bec o mes a ware of a n S A E wit hi n 3 0 da ys after t he s u bject’s last 
d ose of st u d y  dr u g or wit hi n 3 0 da ys after t he last st u d y visit, t he S A E must be re p orte d. Seri o us 
A Es m ust be f o ll owe d u nt il t he e ve nt res ol ves, t he e ve nt or se q uelae sta bilize, or it is u nlikel y 
t hat a d ditio nal i nf or mat i on ca n be o btai ne d after de m o nstrati o n of d ue dili ge nce wit h f o ll ow- u p 
eff orts (i.e., t he s u bject or healt h care practiti o ner is u na ble t o pr o vi de a d diti onal i nf or mat i on, or 
t he s u bject is lost t o f oll o w -u p). Seri o us A Es t hat occ ur m ore t ha n 3 0 da y s after t he last d ose of 
st u d y dr u g d o n ot nee d t o be re p orte d u nless t he i n vesti gat or c o nsi ders t he m relate d t o st u d y 
dr u g.
8. 3. 1. 6.
S p o ns or Re p orti n g Re q uire me nts
T he S p o ns or or its le gal re prese ntati ve is res p o nsi ble f or n otif yi n g t he rele v a nt re g ulat or y 
a ut h orities of S A Es meet i n g t he re p orti n g criteria. T his pr ot oc ol will use A p pe n di x A of t he 
c urre nt I n vest i gat or’s Br oc h ure as t he Refere nce Safety D o c u m e nt. T he e x pecte d ness a n d 
re p orti n g criteria of a n S A E will be deter mi ne d b y t he S p o ns or fr o m t he Refere nce Safety 
I nf or mat i on.
8. 3. 1. 7.
I n vesti g at or Re p orti n g Re q uire me nts
T he I n vesti gat or m ust f ulfill all l ocal re g ulat or y  o bli gati ons re q uire d f or t he st u d y  I n vesti gat ors. 
It is t he PI’s res p o nsi bility t o n otif y t he I R B or I E C of all S A Es t hat occ ur at his or her site. 
I n vesti gat ors will als o be n otifie d of all S U S A R e ve nts t hat occ ur d uri n g t he cli nical st u d y. Eac h 
sit e is res p o nsi ble f or n otif yi n g its I R B/I E C of t hese a d dit i onal S A Es. 
P P 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 5 4 of 1 0 1
I n vesti gat ors will recei ve bli n de d i nf or mati on u nless u n bli n de d i nf or mati on is j u d ge d necessar y 
f or safety reas o ns.
8. 3. 2.
E x p os ure D uri n g Pre g n a nc y a n d/ or L act ati o n
T A K -9 3 5 s h o ul d n ot be a d mi nistere d t o pre g na nt a n d lactati n g fe males beca use t he p ote ntial f or 
a d verse reacti o ns t o T A K-9 3 5 i n pre g na nt fe males, fet uses, a n d n ur si n g i nfa nts is u n k n o w n.
If a n y patie nt 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 ors u p plie d dr u g s h o ul d be i m me diatel y disc o nti n ue d.
Pre g na nc y data will be c ollecte d d uri n g t his st u d y  for all  patient s. E x p os ure d uri n g pre g na nc y 
( als o referre d t o as e x p os ure i n-uter o) ca n be t he res ult of eit her mater nal e x p os ure or 
tra ns missi on of dr u g pr o d uct via se me n f o ll owi n g pater nal  e x p os ure.
F or all O vi d pr o d ucts, b ot h i n de vel o p me nt or p ost -a p pr o val, e x p os ure d uri n g pre g na nc y must be 
rec or de d a n d t he patie nt f oll owe d u nt il t he o utc o me of t he pre g na nc y is k n o w n (s p o nta ne o us 
miscarri a ge, electi ve ter mi nat i on, n or mal birt h, or c o n ge nital a b n or malit y), e ve n if t he patie nt 
di sc o nti n ues st u d y dr u g or disc o nti n ues fr om t he st u d y.
If a patie nt wi t hi n t his st u d y or a patie nt’s part ner bec o me s pre g na nt w hile treate d or e x p ose d t o 
st u d y dr u g, t he I n vesti gat or m ust s u b mit a pre g na nc y f or m t o t he S p o ns or via t he sa me met h o d 
as S A E re p ortin g. P har mac o vi gila nce will s u p pl y  t he I n vesti gat or wit h a c o p y of a “ Pre g na nc y 
Re p orti n g a n d O utc o me/ Breast Fee di n g” F or m. W he n t he o utc o me o f t he pre g na nc y be c o mes 
k n o w n, t he f or m s h o ul d be c o m p lete d a n d ret ur ne d t o O vi d or O vi d P har mac o vi gila nce dele gate
via t he sa me met h o ds as S A E re p orti n g. If a d dit i on al  fol l ow- u p is re q ui re d, t he i n vesti gat or will 
be re q ueste d t o pr o vi de t he i nf or mat i on.
E x p os ure of a n i nfa nt t o a S p o ns or pr o d uct d uri n g breast fee di n g m ust als o be re p orte d a n d a n y 
A Es e x perie nce d b y  t he i nfa nt must be re p orte d t o t he S p o ns or P har mac o vi gila n ce or desig nee 
via t he sa me met h o ds as S A E re p orti n g ( Secti o n  8. 3. 1. 5 ).
Pre g na nc y is n ot re gar de d as a n A E u nless t here is a s us pici o n t hat st u d y  dr u g ma y ha ve 
i nterfere d wit h t he effecti ve ness of a c o ntrace pti ve me dicati on. H o we ver, c o m plicat i ons of 
pre g na nc y a n d a b n or mal o utc o mes of pre g na nc y are A Es a n d ma y  me et crit eria for a n S A E 
(s uc h as ect o pic pre g na nc y, s p o nta ne o us a b orti o n, i ntra uteri ne fetal de mise, neo natal  deat h, or 
c o n ge nital a n o ma l y). Elect i ve a b orti o ns wit h o ut c o m plicati ons s h o ul d n ot be re p orte d as A Es .
8. 3. 3.
S afet y M o nit ori n g
T he S p o ns or’s Me dical M o nit or a n d/ or P har mac o vi gila nce p h ysicia n will m o nit or safet y data 
t hr o u g h o ut t he c o urse of t he st u d y.
8. 3. 3. 1.
Re p orti n g of A b n or m al Li ver F u ncti o n Tests
If a s u bject is n ote d t o ha ve A L T or A S T ele vate d > 3 × U L N o n 2 c o nsec uti ve occasi o ns, as 
s pecifie d i n S e cti o n 8. 1. 1 0 , t he a b n or mality s h o uld be rec or de d as a n A E.
If a s u bject is n ote d t o ha ve A L T or A S T > 3 × U L N a n d t otal bilir u bi n > 2 × U L N f or w hic h a n 
alter nati 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 Se ctio n 8. 3. 1. 5 . T he I n vesti gat or m ust c o ntact 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 
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 5 5 of 1 0 1
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 descri be d i n Sect i on 8. 1. 1 0 m ust als o be perf or me d.
8. 4.
A p pr o pri ate ness of Me as ure me nts
All efficac y a n d safet y assess me nts i ncl u de d i n t his st u d y are ge nerall y re gar de d as relia ble a n d 
acc urate wit h res pect t o t he efficac y a n d safet y assess me nts i n i n di vi d uals a n d p o p ul at i ons wit h 
D u p 1 5 q or C D 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 5 6 of 1 0 1
9.
D A T A Q U A LI T Y A S S U R A N C E
T o e ns ure acc urate, c o m plete, a n d relia ble data, t he S p o ns or or its re prese ntati ves will d o t he 
f oll owi n g:

Pr o vi de i nstr ucti o nal  mat erial t o t he st u d y sites, as a p pr o priate

S p o ns or start -u p trai ni n g t o i nstr uct t he I n vesti gat ors a n d st u d y c o or di nat ors. T his 
trai ni n g will gi ve i nstr ucti o n o n t he pr ot oc ol, t he c o m pleti on of t he e C R Fs, a n d st u d y  
pr oce d ures

Ma ke peri o dic visits t o t he st u d y  sit e

Be a vaila ble f or c o ns ultati o n a n d sta y  in c o ntact wit h t he st u d y site pers o n nel b y 
E mail, tele p h o ne, a n d/ or fa x

Re vie w a n d e val uate C R F data a n d use sta n dar d c o m p uter e dits t o detect err ors i n 
data c ollect i on

C o n d uct a q ualit y re vie w of t he data base
I n a d diti on, t he S p o ns or or its re prese ntati ves will peri o dicall y c hec k a sa m ple of t he patie nt data 
rec or de d a gai nst s o urce d oc u me nts at t he st u d y sit e. T he st u d y ma y be a u dite d b y t he S p o ns or or 
its re prese ntati ves, a n d/ or re g ulat or y a ge ncies at a n y time. I n vesti gat ors will be gi ve n n otice 
bef ore a n a u dit occ urs.
T o e ns ure t he safet y of  p artici pa nts i n t he st u d y, a n d t o e ns ure acc urate, c o m plete, a n d relia ble 
data, t he I n vest i gat or will kee p rec or ds of la b orat or y tests, cli nical n otes, a n d patie nt me dical 
rec or ds i n t he patie nt files as ori gi nal s o urce d oc u me nts f or t he st u d y. If re q ueste d, t he 
I n vesti gat or will pr o vi de t he s p o ns or, a p plica ble re g ulat or y a ge ncies, a n d a p plica ble I R Bs/I E Cs 
wi t h direct access t o origi nal  s o urce d oc u me nts.
9. 1.
D at a C ollecti o n a n d St or a ge
All cli nical ra w data will be rec or de d pr o m pt l y, acc uratel y, a n d le gi bl y, eit h er directl y i nt o t he 
data ca pt ure s y st e m as e-s o urce data, or i n deli bl y o n pa per (e. g., E C G rea di n gs). A detaile d list 
of  t h e t ype (el e ctr o nic or pa per) a n d l ocat i on f or all s o urce data will be i ncl u de d i n t he Trial 
Master File . W he n rec or de d electr o nicall y, case re p ort f or ms will be electr o nicall y ge nerate d. All 
ra w data will be preser ve d t o mai ntai n data i nte grit y. T he I n vesti gat or or desi g nee will ass u me 
t he res p o nsi bilit y of  e ns uri n g t he c o mplete ness, acc urac y , a n d ti meli ness of t he cli nical data.
T he E D C s yste m is f ull y vali date d a n d C o de of Fe deral Re g ulat i ons Ti tle 2 1 Part 1 1 c o mplia nt. 
T he E D C s yste m will mai ntai n a c o m p lete a u dit trail of all data c ha n ges. At eac h sc he d ule d 
m o nit ori n g visit, t he I n vesti gat or or desi g nee will c o o perate wit h t he S p o ns or’s re prese ntati ve(s) 
f or t he perio di c re vie w of st u d y d oc u me nts t o e ns ure t he acc urac y a n d c o mplete ness of t he data 
ca pt ure s yste m.
Electr o nic c o nsiste nc y c hec ks a n d ma n ual re vie w will be use d t o i de ntif y a n y err ors or 
i nc o nsiste ncies i n t he data. T his i nf or mati on will be pr o vi de d t o t he res pecti ve st u d y  sites b y 
mea ns of electr o nic or ma n ual q ueries.
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

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T he I n vesti gat or or desi g nee will pre pare a n d mai ntai n a de q uate a n d acc urate st u d y  d oc u me nts 
( me dical rec or ds, E C Gs, A E a n d c o nc o mita nt me dicat i on re p orti n g, ra w data c ollect i on f or ms) 
desi g ne d t o rec or d all o bser vati o ns a n d ot her perti ne nt data f or eac h patie nt recei vi n g st u d y  dr u g.
T he I n vesti gat or will all o w S p o ns or re prese ntati ves, c o ntract desi g nees, a ut h orize d re g ulat or y  
a ut h ori t y ins pect ors, a n d t he I R B/I E C t o ha ve direct access t o all d oc u me nts pertai ni n g t o 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

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1 0.
S T A TI S TI C A L M E T H O D S A N D P L A N N E D A N A L Y S E S
1 0. 1.
Ge ner al C o nsi der ati o ns
All st atistical a nal yses will be perf or me d usi n g S A S® Versi o n 9. 4 or hi g her. All cli nical st u d y  
data will be prese nte d i n patie nt data list i n gs. Data s u m maries will be prese nte d f or all e n d p oi nts 
a n d will i ncl u de descri pt i ve statistics ( n u m ber of patie nts [ n], mea n, sta n dar d de viati o n [ S D], 
first q uartile [ Q 1], me dia n, t hir d q uartile [ Q 3], mi ni m u m a n d ma xi m u m) for c o nti n u o us 
varia bles, a n d fre q ue nc y a n d perce nta ge f or cate g orical a n d or di nal varia bles. If t here are 
missi n g val ues, t he n u m ber of missi n g will be prese nte d, b ut wit h o ut a perce nta ge.
F or all a nal yses, ‘ Baseli ne’ refers t o t he pr os pecti ve 4 -wee k Baseli ne Peri o d.
Efficac y A nal yses
M ot or sei z ure fre q ue nc y per 2 8 da ys will be calc ulate d at eac h s pecifie d i nter val as:
F or all patie nts, m ot or seiz ure fre q ue ncies per 2 8 da ys f or t he 4 -wee k pr os pecti ve 
Scree ni n g/ Baseli ne Peri o d, eac h 4 -wee k i nt er val i n t he Mai nte na nce Peri o d, t he Mai nte na nce 
P eri o d a n d t he 2 0 -wee k Treat me nt Peri o d will be calc ulate d. T he perce nt c ha n ge fr o m Baseli ne 
t o t he Mai nte na nce Peri o d i n m ot or seiz ure fre q ue nc y per 2 8 d a y s is t he pri mar y efficac y 
e n d p o i nt. T he perce nt cha n ge fr o m Baseli ne t o t he Treat me nt Peri o d i n m ot or seiz ure fre q ue nc y 
per 2 8 da y s is t he sec o n dar y efficac y e n d p oi nt. 
O bser ve d val ues, c ha n ge fr o m Baseli ne, a n d perce nt c ha n ge fr o m Baseli ne f or t he m ot or seiz ure 
fre q ue nc y ( per 2 8 da ys) will be s u m marize d descri pti vel y  b y a nal ysis gr o u p f or t he f oll o wi n g 
i nter vals: t he t hree 4 -wee k i nter vals i n t he Mai nte na nce Peri o d, t he Mai nte na nce Peri o d, a n d t he 
e nt ire 2 0 wee ks of Treat me nt Peri o d. F or eac h a nal ysis gr o u p, t he mea n of pri mar y e n d p o i nt (t he 
perce nt c ha n g e f r o m Baseli ne t o t he Mai nte na nce Peri o d i n m ot or seiz ure fre q ue nc y per 2 8 da ys) 
will be prese nte d al o n g wit h its c orres p o n di n g 9 0 % c o nfi de nce i nter val ( CI). Hist o gra ms will be 
pr o d uce d f or t he pri mar y e n d p o i nt for eac h a nal ysis gr o u p. T he a nal ysis will be re peate d f or all 
m o t or seiz ure t ypes.
T he ti me c o urse of seiz ure fre q ue ncies ( per 2 8 da ys) i n c o nsec ut i ve 4-wee k i nter vals i n t he 
Mai nte na nce Peri o d will be dis pla ye d i n a li ne gra p h b y a nal ysis gr o u p. 
T he pr o p orti o n of  treat me nt res p o n ders base d o n  ≥2 5 % w orse ni n g, < 2 5 % a n d > 1 % w orse ni n g, 
n o c ha n ge (W o rse ni n g of 1 % t o Re d ucti o n of 1 %) , ≥2 5 % re d ucti o n, ≥5 0 % re d ucti o n, ≥7 5 % 
re d uctio n, a n d 1 0 0 % re d ucti o n f r o m Baseli ne i n m ot or seiz ure fre q ue nc y d uri n g t he Mai nte na nce 
P eri o d will  be s u m marize d at eac h 4 -we e k i nter val, t he Mai nte na nce peri o d, a n d t he e ntire 2 0 
wee ks of t he Treat me nt Peri o d b y  a nal ysis gr o u p.
O bser ve d val ues a n d c ha n ge fr o m Baseli ne i n C GI -S res p o nses of I n vesti gat or-re p orte d 
i m pressi o n of efficac y a n d t olera bilit y of  st u d y dr u g a n d i n Care GI-C res p o nses of pare nt/fa mil y 
re p orte d i m pressi o n of efficac y a n d t olera bilit y of  st u d y dr u g will be a nal yze d descript i vel y at 
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

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Pa ge 5 9 of 1 0 1
eac h st u d y visit. Rati n gs of C GI -C will be assesse d at Da y 3 6, Da y 8 5 a n d Da y 1 4 1. T he 
r elat i ons hi p bet wee n m ot or seiz ure fre q ue nc y a n d plas ma 2 4 H C will be e x pl ore d.
Tec h ni q ues f or ha n dli n g missi n g i nf or mat i on wi t h res pect t o re p orti n g of seiz ures i n t he 
treat me nt perio d ( D ose O pti mizat i on a n d Mai nte na nce) will be s pecifie d i n detail i n t he 
statistical a nal ysis pla n ( S A P).
S af et y A nal yses
All safety assess me nts will be s u m marize d usi n g descri pt i ve statistics. All safety a nal yses will be 
base d o n o bser ve d data o nl y, a n d n o missi n g val ues will be i m p ute d. Re p o rte d A E ter ms will be 
c o de d usi n g Me d D R A a n d s u m marize d b y preferre d ter m a n d s yste m or ga n class cate g ories. 
S eri o us A Es a n d A Es lea di n g t o st u d y  disc o nti n uati on will als o be s u m marize d.
O bser ve d val ues a n d c ha n ge fr o m baseli ne i n la b orat or y  para meters, vit al si g ns, a n d E C G 
para m eters will be s u m marize d b y st u d y visit. T he n u m ber a n d perce nta ge of patie nts w h o ha ve 
met p ote ntiall y cli nicall y  si g nifica nt crit eria at a n y p ost baseli ne visit will be s u m marize d f or 
la b orat or y, vital si g ns, a n d E C G para meters. T he n u m ber a n d perce nta ge of patie nts wit h s hift s 
i n la b orat or y will be s u m marize d. T he n u m ber a n d perce nta ge of patient s wit h C-S S R S 
assess me nts of s uici dal i deati o n a n d be ha vi or will als o be s u m marize d.
Pri or a n d c o nc o mita nt m e dicat i on use will be s u m mari ze d b y W H O -A T C classificat i on s yste m. 
E x pl or at or y  A nal yses
1 0. 2.
Deter mi n ati o n of S a m ple Size
A f or mal sa m ple size calc ulati on was n ot perf or me d f or t his st u d y. Gi ve n t he rare occ urre nce of 
t hese e pile pt ic e nce p hal o pat h y s y n dr ome s a n d base d o n pri or cli nical de vel o p me nt pr o gra ms f or 
treat me nt of rare diseases, t he c urre nt sa m ple size is dee me d a p pr o pri ate t o e val uate t he efficac y 
a n d safet y of  T A K-9 3 5i n patie nts wit h D u p 1 5 q or C D D .
1 0. 3.
A n al ysis Sets
1 0. 3. 1.
M o difie d I nte nt -t o-Tre at A n al ysis Set
All patie nts w h o ha ve recei ve d at least 1 d ose of st u d y  dr u g a n d ha ve bee n assesse d f or at least 
1 d a y  in t he Treat m e nt P erio d will be i ncl u de d i n t he m o difie d i nte nt- t o-treat ( mI T T) a nal ysis 
set. 
C 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 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

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1 0. 3. 2.
Effic ac y A n al ysis Set
All mI T T s u bjects w h ose assess me nts are c o m plia nt wit h Pr ot oc ol A me n d me nt 1 will be 
i ncl u de d i n t he efficac y a nal ysis p o p ulatio n. Efficac y  a nal yses f or pri mary a n d sec o n dar y 
efficac y e nd p oi nts will be base d o n t he efficac y  a nal ysis p o p ulat i on, a n d t h ose f or e x pl orat or y  
efficac y e nd p oi nts will be base d o n t he mI T T set. 
1 0. 3. 3.
S afet y A n al ysis Set
All patie nts w h o ta ke at least 1 d ose of st u d y  me dicatio n will be i ncl u de d i n t he Safety A nal ysis 
Set. Safet y a nal yses will be base d o n t he me dicati o n t hat was act uall y a d mi nistere d t o eac h 
patie nt.
1 0. 3. 4.
A n al ysis Gr o u ps
All a nal yses will be perf or me d b y 2 a nal ysis gr o u ps: t heD u p 1 5 q gr o u p a n d t he C D D gr o u p. 
1 0. 4.
De m o gr a p hics a n d B aseli ne C h ar acteristics
D e m o gra p hic c haracteri stics i ncl u de a ge, ge n der, race, et h nicity,  a n d st u d y ce nter. Baseli ne 
c haracterist ics i ncl u de baseli ne b o d y wei g ht a n d heig ht. S u m mar y  statistics b y tr e at me nt gr o u p 
a n d o verall will i ncl u de c o u nts a n d perce nta ges f or discrete varia bles, a n d mea ns, S D, Q 1, 
me dia ns, Q 3, mi ni m u m a n d ma xi m u m f or c o nti n u o us varia bles.
1 0. 5.
P atie nt Dis p ositi o n
All patie nts w h o disc o nt i n ue fr om t he st u d y will b e ide nt ifie d, a n d t he e xte nt of t heir 
parti ci pat i on i n t he st u d y will be re p orted. If k n o w n, a reas o n f or t heir disc o nt i n uati on will be 
gi ve n. Dis p osit i on data will be s u m marize d a n d pr o vi de d i n pat ient  listi n gs.
1 0. 6.
C o nc o mit a nt Me dic ati o ns a n d N o n -P h ar m ac ol o gic T her a pies a n d 
Pr oce d ures
C o nc o mita nt me dicat i ons will be c o de d usi n g t he W orl d Heal t h Or ga nizati on Dr u g Di ct i onar y  
(W H O -D D ). A b y-pat ient  listi n g of c o nc omit a nt me dicat i ons will i ncl u de all me dicat i ons ta ke n 
d uri n g t he st u d y  re gar dless of t he ti mi n g f or t he start of t he me dicat i on. All me dicati o ns starte d 
pri or t o t he a d mi nistrati o n o f t he st u d y dr u g will be i ncl u de d i n t he data b ut will be i de ntifie d as 
pri or i n t he list i n g. O nl y t he c o nc omit a nt me dicati o n use will be s u m marize d.
T he n u m ber a n d perce nta ge of patie nts w h o t o o k at least 1 d ose of st u d y  dr u g as well as t he 
n u m ber a n d perce nta ge of s u bjects w h o t o o k eac h t y pe of me dicat i on will be prese nte d f or eac h 
treat me nt gr o u p. Me dicat i ons will be liste d acc or di n g t o t heir W H O -D D A T C cl ass le vel 4 a n d 
preferre d dr u g na me wit hi n A T C class le vel 4 b y decreasi n g fre q ue nc y of i nci de nc e for all  acti ve 
treat me nt gr o u ps c o m bi ne 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

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1 0. 7.
Tre at me nt C o m pli a nce 
Treat me nt c o m plia nce will be s u m marize d b y treat me nt gr o u p o ver t he e ntire treat me nt peri o d. 
C o m plia nce rates d uri n g t he treat me nt peri o d will be deri ve d usi n g t he f o ll owi n g f or m ula:
E x pec te d n u m ber of ta blets/ mi ni-ta blets t o be ta ke n is base d o n t he date of first st u d y me dicat i on 
d ose a n d t he date of last st u d y me dicat i on d ose (i.e., [ date of last st u d y  me dicat i on d ose – date of 
first st u d y me dicat i on d ose] + 1). C o m plia nce rates will be pr ese nte d f or t he safet y a nal ysis set 
usi n g s u m mar y statist ics a n d perce nta ge f or t he fre q ue nc y distri b uti o ns ( 0 % t o < 2 0 %, 2 0 % t o 
4 0 %, 4 0 % t o < 6 0 %, 6 0 % t o < 8 0 %, 8 0 % t o < 1 0 0 %, 1 0 0 % t o ≤1 2 0 %) b y treat me nt gr o u p a n d 
o verall.
1 0. 8.
Effic ac y A n al yses
1 0. 8. 1.
Pri m ar y Effic ac y A n al yses
F or all patie nts t he f o ll owi n g will be calc ulate d: m ot or seiz ure fre q ue ncies per 2 8 da y s for t he 
4 -wee k pr os pecti ve Scree ni n g/ Baseli ne Peri o d a n d t he Mai nte na nce Peri o d. 
M ot or sei z ure fre q ue nc y per 2 8 da ys will be calc ulate d at eac h s pecifie d i nte r val as:
Perce nt c ha n ge fr o m Baseli ne t o t he m ot or seiz ure fre q ue nc y d uri n g t he Mai nte na nce Peri o d ( per 
2 8 d a y s) will be s u m marize d usi n g descri pti ve statistics.
1 0. 8. 2.
Sec o n d ar y Effic ac y A n al yses
Perce nt c ha n ge fr o m Baseli ne t o t he m ot or seiz ure fre q ue nc y d uri n g t he Treat me nt Peri o d will be 
s u m marize d f or eac h a nal ysis gr o u p.
T he pr o p orti o n of  treat me nt res p o n ders base d o n ≥2 5 % w orse ni n g, < 2 5 % a n d > 1 % w orse ni n g, 
n o c ha n ge (W o rse ni n g of 1 % t o Re d ucti o n of 1 %) , ≥2 5 % re d ucti o n, ≥5 0 % re d ucti o n, ≥7 5 % 
re d uctio n, a n d 1 0 0 % re d ucti o n fr o m Baseli ne i n m ot or seiz ure fre q ue nc y f or t he e ntire 2 0 -wee k 
Treat me nt Peri o d will  be s u m marize d.
T he c ha n ge i n C GI -S a n d C GI -C res p o nses of I n vesti gat or -re p orte d i m pressi on of efficac y a n d 
t olera bilit y of st u d y  dr u g a n d c ha n ge i n Care GI-C res p o nses o f pare nt/fa mil y re p orte d 
i m pressi o n of efficac y a n d t olera bilit y of  st u d y dr u g will be a nal yze d descri pti vel y.
T he rel at i ons hi p bet wee n m ot or seiz ure fre q ue nc y a n d plas ma 2 4 H C will be e x pl ore d.
Tec h ni q ues f or ha n dli n g missi n g i nf or mat i on wi t h res pect t o re p orti n g of seiz ures i n t he 
treat me nt perio d ( D ose O pti mizat i on a n d Mai nte na nce) will be s pecifie d i n detail i n t he S A P.
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

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1 0. 8. 3.
E x pl or at or y A n al ysis
1 0. 9.
S afet y A n al yses
All safety assess me nts will be s u m marize d usi n g descri pt i ve statistics. All safety a nal yses will be 
base d o n o bser ve d data o nl y, a n d n o missi n g val ues will be i m p ute d. Re p orte d A E ter ms will be 
c o de d usi n g Me d D R A a n d s u m marize d b y preferre d ter m a n d s yste m or ga n class cate g ories. 
S eri o us A Es a n d A Es lea di n g t o st u d y disc o nti n uati o n will als o be s u m marize d.
O bser ve d val ues a n d c ha n ge fr o m baseli ne i n la b orat or y  para meters, vit al si g ns, a n d E C G 
para m eters will be s u m marize d b y st u d y visit. T he n u m ber a n d perce nta ge of s u bjects w h o ha ve 
met p ote ntiall y cli nicall y  si g nifica nt criteria at a n y p ost baseli ne visit will be s u m marize d f or 
la b orat or y, vital si g ns, a n d E C G para meters. T he n u m ber a n d perce nta ge of s u bjects wit h s hifts 
i n la b orat or y will be s u m marize d. S u p p orti n g listi n gs will be pr o vi de d. T he n u m ber a n d 
perce nt a ge of s u bjects wit h C- S S R S assess me nts of s uici dal i deat i on a n d be ha vi or will als o be 
s u m marize d.
Pri or a n d c o nc o mita nt m e dicat i on use will be s u m marize d b y W H O -A T C classificat i on s yste m. 
List i n gs will be pr o vi de d f or all c o nc omit a nt me dicatio ns.
1 0. 9. 1.
P h ysic al E x a mi n ati o n, Vit al Si g ns, a n d Ot her P h ysic al Fi n di n gs
P h ysical e xa mi nat i ons ( ge neral a p peara nce; s ki n; hea d, ear, e y e, n ose, a n d t hr oat; nec k; l y m p h 
n o de; c hest; heart; a b d o mi nal; li m b; ce ntral ner v o us s yste m; a n d m usc ul o s keletal) at Baseli ne 
will be s u m m arize d. S hifts fr o m Baseli ne t o p ost-baseli ne st u d y  visits i n eac h b o d y s yste m/sit e 
will be s u m marize d b y  tr e at me nt gr o u p.
Vi t al si g ns (te mperat ure, heart rate, res pirat or y  rate, a n d s yst olic a n d diast olic bl o o d press ure), 
w ei g ht, a n d hei g ht will be s u m mar ize d descri pti vel y at Baseli ne a n d all p ost -baseli ne st u d y visit s 
b y treat me nt gr o u p. C ha n ge fr o m Baseli ne t o all p ost- baseli ne st u d y  visits als o will be 
s u m marize d descri pti vel y b y treat me nt gr o u p.
Data list i n gs will be pr o vi de d.
1 0. 9. 2.
Cli nic al L a b or at or y Tests
C ha n ges fr o m Baseli ne t o st u d y  ti me p oi nts i n cli nical c he mistr y, he mat olo g y , a n d uri nal ysis 
res ults will be s u m marize d descri pt i vel y. Eac h l a b orat or y para meter will be classifie d as l o w, 
n or m al, or hig h r el at i ve t o t he para meter’s refere nce ra n ge. La b orator y  a b n or malities f or eac h 
treat me nt will als o be s u m marize d wit h s hift ta bles. 
List i n gs of patient s wit h a b n or mal r es ults will be pr o vide d.
C CI
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Pa ge 6 3 of 1 0 1
1 0. 9. 3.
A d verse E ve nts
T he f o ll owi n g defi nit i ons will be use d f or A Es:

Treat me nt -e mer ge nt a d verse e ve nt ( T E A E): A n y A E t ha t starts or i ncreases i n 
se verity d uri n g or after t he first d ose of st u d y  dr u g

Treat me nt -e mer ge nt S A E: A T E A E t hat is seri o us
T he i nci de nce of T E A Es, disc o nt i n uati ons d ue t o T E A Es, dr u g -relate d, seri o us, a n d se vere 
T E A Es will be s u m marize d. All A Es will be c o de d usi n g Me d D R A a n d will be s u m marize d b y 
s yste m or ga n class ( S O C ) a n d pr ef erre d ter m (P T ) a n d treat me nt gr o u p. Detaile d listi n gs of A Es, 
S A Es, i nf usi on- ass o ciate d reacti o ns ( I A Rs), r elate d A Es, a n d disc o nt i n uati ons d ue t o A Es will 
be pr o vi de d.
1 0. 1 0.
P h ar m ac o ki netic/ P h ar m ac o d y n a mic A n al yses 
1 0. 1 1.
Ot her St atistic al Iss ues
1 0. 1 1. 1.
Si g nific a nce Le vels
A pri mar y  e nd p oi nt i s defi ne d a n d will be teste d at 0. 0 5 le vel of si g nifica nce.
 
1 0. 1 1. 2.  
Missi n g or I n v ali d D at a
Tec h ni q ues f or ha n dli n g missi n g i nf or mat i on wi t h res pect t o re p orti n g of seiz ures i n t he 
treat me nt perio d ( D ose O pti mizat i on a n d Mai nte na nce) will be s pecifie d i n detail i n t he S A P.
1 0. 1 2.
I nteri m A n al yses 
A d h oc a nal yses ca n be perf or me d base d o n t he discreti o n of t he S p o ns or f or pla n ni n g p ur p oses 
i n f urt her desi g ni n g of t he T A K-9 3 5 de vel o p me nt pr o gra m . Fi nal a nal yses will be perf or me d 
after t he last patie nt c o mpletes t he st u d y  a n d t he data base is l oc ke d. 
C CI
C 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 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

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Pa ge 6 4 of 1 0 1
1 1.
I N F O R M E D C O N S E N T, E THI C A L R E VI E W, A N D 
R E G U L A T O R Y C O N SI D E R A TI O N S
1 1. 1.
I nfor me d C o nse nt
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat t he patie nt u n dersta n ds t he p ote ntial ris ks a n d 
be nefits of part ici pati n g i n t he st u d y, i ncl u di n g a ns weri n g a n y q uesti o ns t he pati e nt ma y ha ve 
t hr o u g h o ut t he st u d y a n d s hari n g i n a ti mel y ma n ner a n y ne w i nf or mat i on t hat m a y b e r ele va nt t o 
t he patie nt’s willi n g ness t o c o nti n ue his or her partici pat i on i n t he st u d y.
T he I C F will be use d t o e x plai n t he p ote ntial ris ks a n d be nefits of  st u d y partici pat i on t o t he 
pati e nt i n si m ple ter ms bef ore t he patie nt is e ntere d i nt o t he st u d y, a n d t o d oc u me nt t hat t he 
pati e nt is sat isfie d wit h his or her u n dersta n di n g of t he ris ks a n d be nefits of partici pati n g i n t he 
st u d y a n d desires t o partici pate i n t he st u d y.
T he I n vesti gat or is res p o nsi ble f or e ns uri n g t hat i nf or me d c o nse nt is gi ve n b y eac h patie nt or 
le gal re prese ntati ve. T his i ncl u des o btai ni n g t he a p pr o priate si g nat ures a n d dates o n t he I C F pri or 
t o t he perf or ma nce of a n y pr ot oc ol pr oce d ures a n d pri or t o t he a d mi nistrati o n of st u d y dr u g.
A le gal re prese ntati ve m ust gi ve i nf or me d c o nse nt f or a c hil d t o partici pate i n t his st u d y. I n 
a d ditio n t o i nf or m e d c o nse nt gi ve n b y t he le gal re prese ntati ve, t he c hil d ma y  be re q uire d t o gi ve 
d oc u m e nte d asse nt, if ca pa ble.
1 1. 2.
D at a M o nit ori n g C o m mittee 
T he s pecific res p o nsi bilit ies of t he i D M C are descri be d i n t he i D M C C harter, w hic h is 
mai ntai ne d as a se parate d oc u me nt.
1 1. 3.
Et hic al Re vie w
T he S p o ns or or its re prese ntati ves m ust a p pr o ve all I C Fs bef ore t he y  are used at i n vesti gati ve 
sites(s). All I C Fs m ust be c o mplia nt wi t h t he I C H g uideli ne o n G C P. 
D oc u m e nt atio n of  I R B/I E C a p pr o val of t he pr ot oc ol a n d t he I C F must be pr o vi de d t o t he 
S p o ns or bef ore t he st u d y  ma y be gi n at t he i n vest i gati ve site(s). T he I R B/I E C(s) wi ll re vie w t he 
pr ot oc ol  as re q uire d.
T he st u d y  site’s I R B/I E C(s) s h o ul d als o be pr o vi de d wit h t he f oll o wi n g:

T he c urre nt I B a n d u p dates d uri n g t he st u d y

I C F

Rele va nt c urric ula vitae
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

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Pa ge 6 5 of 1 0 1
1 1. 4.
Re g ul at or y C o nsi der ati o ns
T his st u d y  will be c o n d ucte d i n acc or da nce with:

C o nse ns us et hics pri nci ples deri ve d fr o m i nter nat i o nal et hics g ui deli nes, i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizat i ons of Me dical 
S ci e nces ( CI O M S) I nter nati o nal Et hical G ui deli nes

T he I C H G C P G ui deli ne ( E 6)

A p plica ble l a ws a n d re g ulati o ns
T he I n vesti gat or or desi g nee will pr o m pt l y s u b mit t he pr ot oc ol t o a p plica ble I R B/I E C(s).
S o m e of t he o bli gati ons of t he s p o ns or ma y  be assi g ne d t o a T hir d -Part y  Or ga nizatio n.
A n i de ntificat i on c o de assi g ne d t o eac h patie nt will be use d i n lie u of t he patie nt’s na me t o 
pr otect t he patie nt’s i de ntit y w he n re p orti n g A Es a n d/ or ot her st u d y -r elate d data.
1 1. 4. 1.
C o nfi de nti alit y
T he S p o ns or affir ms t hat s u bject’s ri g hts t o pr otecti o n a gai nst i n vasi o n of pri vac y are i n 
c o mplia nce wi t h I C H a n d ot her lo c al  re g ulat i ons ( w hic he ver i s most stri n ge nt). I nf or m at i on 
a b o ut patie nts a n d t heir rec or ds will be ke pt c o nfi de nt ial b y t he S p o ns or a n d its re prese ntati ves. 
St u d y  r elate d rec or ds ide ntif yi n g patie nts will be ke pt c o nfi de nt ial a n d, t o t he e xte nt per mitte d b y 
a p plica ble la ws a n d/ or re g ulat i ons will n ot be ma de p u blicl y a vaila ble. 
All la b orat or y s peci me ns, e val uati on f or ms, re p orts, a n d ot her rec or ds will be i de nt ifie d i n a 
ma n ner desi g ne d t o mai ntai n s u bject c o nfi de nt iality.  All rec or ds will be ke pt i n a sec ure st ora ge 
area wit h li mite d access. Cli nical i nf or mati on will n ot be release d wit h o ut t he writte n per missi o n 
of  t he patie nt a n d/ or pati e nt ’s c ust o dial pare nt or g uar dia n, e xce pt as necessar y for m o ni t orin g 
a n d a u dit i n g b y t he s p o ns or, its desi g nee, F D A, Healt h A ut h orities, Et hics C om mittees, a n d/ or 
I R Bs.
T he i n vest i gat or a n d all e m pl oyees a n d c o w or kers i n v o l ve d wit h t his st u d y ma y n o t discl ose or 
use f or a n y  p ur p ose ot her t ha n perf or ma nce of t he st u d y a n y data, rec or d, or ot her u n p u blis he d, 
c o nfi de nt ial i nf or mati o n discl ose d t o t h ose i n di vi d uals f or t he p ur p ose of t he st u d y. Prior wri tte n 
a gree me nt fr o m t he s p o ns or or its desi g nee m ust be o btai ne d f or t he discl os ure of a n y sai d 
c o nfi de nt ial i nf or mati o n t o ot her parties.
If a n y of t he res ults of t he st u d y are p u blis he d, patie nt’s i de ntity will  re mai n c o nfi de ntial.
T he S p o ns or re q uires t he I n vest i gat or t o per mit s p o ns or re prese ntati ves an d, w he n necessar y , 
re prese ntati ves fr o m F D A a n d ot her re g ulat or y a ut h orities, mo ni t or, a u dit or, I R B t o ha ve access 
t o st u d y r elat e d me dical rec or ds i n acc or da nce wit h l ocal pri vac y la ws.
1 1. 4. 2.
I n vesti g at or I nf or m ati o n
P h ysicia ns wit h a s pecialt y i n ne ur o l og y  a nd/ or e pile ps y  dis or ders will p artici pate as 
I n vesti gat ors i n t his cli nical st u d y.
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Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 6 6 of 1 0 1
1 1. 4. 3.
Pr ot oc ol Si g n at ures
T he s p o ns or’s res p o nsi ble me dical o fficer will a p pr o ve t he pr ot oc ol, c o nfir mi n g t hat, t o t he best 
of  his or her k n o wle d ge, t he pr ot oc ol acc uratel y descri bes t he pla n ne d desi g n a n d c o n d uct of t he 
st u d y. 
After rea di n g t he pr ot oc ol, eac h pri nci pal I n vest i gat or will si g n t he pr ot oc ol si g nat ure pa ge a n d 
se n d a c o p y of t he si g ne d pa ge t o a S p o ns or re prese ntati ve.
1 1. 4. 4.
Fi n al Re p ort Si g n at ure
T he cli nical st u d y  re p ort c o or di nat i n g i n vesti gat or will si g n t he fi nal cli nical st u d y re p ort f or t his 
st u d y, i n dicati n g a gree me nt t hat, t o t he best of his or her k n o wle d ge, t he re p ort acc uratel y 
descri bes t he c o n d uct a n d res ults of t he st u d y . 
T he S p o ns or’s res p o nsi ble me dical off icer a n d statist icia n will  a p pr o ve t he fi nal cli nical st u d y 
re p ort f or t his st u d y, c o nfir mi n g t hat, t o t he best of his or her k n o wle d ge, t he re p ort acc uratel y 
descri bes t he c o n d uct a n d res ults of t he st u d y .
1 1. 5.
P u blic ati o n P olic y
T he f ull ter ms re gar di n g p u bli cat i on of t he res ults of t his st u d y  are o utli ne d i n t he Cli nical St u d y 
A gree me nt, State me nt of A gree me nt, or t he Master Cli nical St u d y  A gree me nt. P u blicati on is 
per mitte d o nl y after m ult i-ce nter res ults are a vaila ble a n d all discl o s ure re q uire me nts f or clinical 
st u d y re gistries ha ve bee n met. A n y data t o be s u b mitte d f or p u blicati on, i ncl u di n g a bstract 
s u b missi ons or prese ntati o ns, are re q uire d t o be s u b mitte d t o O vi d f or re vie w at least 3 0 da ys 
pri or t o s u b missi 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

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Pa ge 6 7 of 1 0 1
1 2.
LI S T O F R E F E R E N C E S
1.
H o wi e S. Blo o d sa m ple v o l umes i n c hil d healt h researc h: re vie w of safe li mit s. B ulleti n of 
t he W orl d Healt h Or ga nizat i on, 2 0 1 1; 8 9: 4 6 -5 3. D oi : 1 0. 2 4 7 1/ B L T. 1 0. 0 8 0 0 1 0. 
2.
P a ul  S M, D o hert y JJ, R o bic ha u d AJ, Belf ort G M, C h o w B Y, Ha m m o n d R S, et al. T he 
maj or brai n c h olester ol meta b o lite 2 4( S) -h y dr o x yc h o lester ol is a p ote nt all osteric m o d ulat or 
of  N-met h yl- D- as partate rece pt ors. J Ne ur osci 2 0 1 3; 3 3( 4 4): 1 7 2 9 0 - 3 0 0.
3.
Fi n uca ne B M, L us k L, Ar kil o D, et al. 1 5 q D u plicati o n S y n dr o me a n d Relate d Dis or ders. 
2 0 1 6 J u n 1 6. I n: A da m M P, Ar di n ger H H, Pa g o n R A, et al., e dit ors. Ge ne Re vie ws ® 
[I nter net]. Seattle ( W A): U ni versity of  Was hi n gt o n, Seattle; 1 9 9 3- 2 0 1 8.
4.
H o pe K A, Le D o u x M S, Reiter L T. Glial o vere x pressi o n of D u be 3a ca uses seiz ures a n d 
s y na ptic i m pair me nts i n Dr os o p hila c o nc o mit a nt wit h d o w n re g ulat i on of t he Na( +)/ K( +) 
p u m p A T P α. Ne ur o bi ol  Dis. 2 0 1 7 Dec; 1 0 8: 2 3 8- 2 4 8.
5.
C o na nt K D, Fi n uca ne B, Clear y  N, Marti n A, M uss C, Dela n y M, M ur p h y E K, Ra be O, 
L uc hsi n ger K, S pe nce SJ, Sc ha ne n C, De vi ns k y O, C o o k E H, La Salle J, Reiter L T, T hi bert 
R L. A s ur ve y  of seiz ures a n d c urre nt treat me nts i n 1 5 q d u plicati o n s y n dr o me. E pile psia. 
2 0 1 4 Mar; 5 5( 3): 3 9 6 -4 0 2. 
6.
Kilstr u p -Ni else n C, R usc o ni L, La M o nta nara P, Ciceri D, Ber g o A, Be d o g ni F, 
La n ds ber ger N. W hat we k n o w a n d w o ul d li ke t o k n o w a b o ut C D K L 5 a n d its i n v o l ve me nt 
i n e pile ptic e nce p hal o pat h y. Ne ural Plast. 2 0 1 2; 2 0 1 2: 7 2 8 2 6 7.
7.
O k u da K, K o ba yas hi S, F u ka ya M, Wata na be A, M ura ka mi T, Ha gi wara M, Sat o T, Ue n o 
H, O g o n u ki N, K o ma n o -I n o ue S, Ma na be H, Ya ma g uc hi M, O g ura A, Asa hara H, 
Sa ka ga mi H, Miz u g uc hi M, Ma na be T, Ta na ka T. C D K L 5 c o ntr ols p osts y na pt ic 
l ocalizat i on of Gl u N 2 B - c o ntai ni n g N M D A rece pt ors i n t he hi p p oca m p us a n d re g ulates 
seiz ure s usce pti bility.  Ne ur o biol  Dis. 2 0 1 7 Oct; 1 0 6: 1 5 8- 1 7 0.
8.
Wa g ner T, Tsai M, et al. Cli nical trial si m ulat i ons usi n g a p har mac o ki netic/e nz y me
occ u pa nc y/ p har mac o d y na mic m o del of T A K -9 3 5, a c h o lester ol 2 4 S-h y dr o x ylase i n hi bit or; 
p oster prese nte d at t he A merica n E pile ps y S ociet y 7 1 st A n n ual Meet i n g ( Was hi n gt o n, D. C. 
2 0 1 7).
9.
Fis her R S, Cr oss J H, Fre nc h J A, Hi g uras hi N, Hirsc h E, Ja nse n F E, et al. O p erati o nal 
classificat i on of seiz ure t y pes b y t he I nter nat i onal Lea g ue A gai nst E pile ps y : P ositio n Pa per 
of  t he I L A E C o m missi on f or Classificati on a n d Ter mi n o l og y . E pile psia 2 0 1 7.
1 0. 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 dit y a n d i nter nal c o nsiste nc y fi n di n gs 
fr om t hr e e 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 1. A ma n M G, Si n g h N N, Ste wart A W, Fiel d CJ. T he a berra nt be ha vi or c hec kl ist: a be ha vi or 
rati n g scale f or t he assess me nt of treat me nt effects. A m J Me nt Defic 1 9 8 5; 8 9( 5): 4 8 5-9 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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 6 8 of 1 0 1
1 2. de Bil dt A, Kraijer D, S y t e ma S, Mi n deraa R. T he Ps yc h o metric Pr o perties of t he Vi nela n d 
A da pt i ve Be ha vi or Scales i n C hil dre n a n d A d olesce nts wit h Me nt al Retar datio n. J A ut is m 
De v Dis or d. 2 0 0 5; 3 5( 1): 5 3 -6 2.
1 3. G u y  W. C GI Cli nical Gl obal I m pressi o n s. E C-D E U Assess me nt Ma n ual f or 
Ps y c h o p har ma c olo g y . 1 9 7 6; 7 6- 3 3 8.
1 4. Bretill o n L, L utj o ha n n D, Sta hle L, Wi d he T, Bi n dl L, E g gertse n G, et al. Pl as ma le vels o f 
2 4 S- h y d r o x yc h olest er ol reflect t he bala nce bet wee n cere bral pr o d ucti o n a n d he patic 
meta b o lis m a n d are i n versel y relate d t o b o d y s urface. J Lipi d Res 2 0 0 0; 4 1( 5): 8 4 0- 5.
1 5. Carta ge na C M, A h me d F, B ur ns M P, Paj o o hes h -Ga nji  A, Pa k D T, Fa de n AI, et al. C ortical 
i nj ur y inc reases c h olester ol 2 4 S h y dr o x ylase ( C y p 4 6) le vels i n t he rat brai n. J Ne ur otra u ma 
2 0 0 8; 2 5( 9): 1 0 8 7 -9 8.
1 6. Tia n G, K o n g Q, Lai L, Ra y -C ha u d h ur y  A, Li n C G. I ncrease d e x pressi on of c h o lester ol 
2 4 S- h y dr o x ylase res ults i n disr u pti o n o f glial gl uta mate tra ns p orter E A A T 2 ass ociat i on wi t h 
li pi d rafts: a p ote ntial r ole i n Alz hei mer ’s disease. J Ne ur oc he m 2 0 1 0; 1 1 3( 4): 9 7 8- 8 9.
1 7. D e m arest S, Be n ke T A. Se verit y Assess me nt i n C D K L 5 Deficie nc y Dis or der. I n press.
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

Pr ot oc ol T A K - 9 3 5- 1 8-0 0 2 ( O V 9 3 5) A me n d me nt 2
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A P P E N DI X 1. S C H E D U L E O F A S S E S S M E N T S
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A P P E N DI X 6. O V E R VI E W O F M A J O R C H A N G E S 
I M P L E M E N T E D B Y A M E N DM E N T S
A me n d me nt 1
1.
T he st u d y desi g n is re vise d
Descri pti o n of C h a n ge: T he st u d y d urati o n is e xte n de d fr o m 1 2 t o 2 0 wee ks ( 8 -wee k D ose O pti mizati o n peri o d a n d 
1 2- wee k Mai nte na nce Peri o d)
R ati o n ale f or C h a n ge:
 
 
Secti o ns I m p acte d:

S y n o psis

Secti o n 5. 1

Secti o n 7. 2

Fi g ure 1

A p pe n di x 1
2.
T he titr ati o n peri o d is n o w referre d t o as t he D ose O pti miz ati o n peri o d
Descri pti o n of C h a n ge: Descri pti o n of C h a n ge: Wit h t he c ha n ge is t he le n gt h of t he treat me nt peri o d, d ose 
o pti mizati o n better defi nes t his peri o d
R ati o n ale f or C h a n ge:
 
Secti o ns I m p acte d: 

S y n o psis

Secti o n 5. 1

Secti o n 7. 2

Secti o n 1 0. 1

Secti o n 1 0. 8. 2

Secti o n 1 0. 1 1. 2

A p pe n di x 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

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3.
T he pri m ar y a n d sec o n d ar y o bjecti ves are re vise d
Descri pti o n of C h a n ge:

T he pri mar y o bjecti ve is re v ise d t o c ha n ge t he assess me nt fr o m t he treat me nt peri o d t o t he mai nte na nce 
peri o d.

T he sec o n dar y o bjecti ve t o i n vesti gate t he effect of T A K -9 3 5 o n t he fre q ue nc y of m ot or seiz ures is 
c ha n ge d fr o m t he mai nte na nce peri o d t o t he treat me nt peri o d.

T he sec o n dar y o bjecti ves t o i n vesti gate t he fre q ue nc y of patie nts c o nsi dere d treat me nt res p o n ders are 
c ha n ge d fr o m t he treat me nt peri o d t o t he mai nte na nce peri o d. Treat me nt res p o n ders are defi ne d as t h ose 
wit h:
-
W orse ni n g of 2 5 % or m ore i n m ot or seiz ures fr o m baseli ne
-  
Wor se ni n g of 1 % t o 2 5 % i n m ot or seiz ures fr o m baseli ne
-
N o c ha n ge i n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 2 5 % or m ore i n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 5 0 % or m ore i n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 1 0 0 % i n m ot or seiz ures fro m baseli ne
R ati o n ale f or C h a n ge: T he c ha n ge is ma de t o a d dress t he fi n di n gs fr o m St u d y T A K - 9 3 5-2 0 0 1 a n d t o better 
u n dersta n d t he effect of t he dr u g o n d urati o n of seiz ures a n d o n d urati o n of seiz ure free d o m.
Secti o ns I m p acte d:

S y n o psis

Secti o n 4. 1. 1

Secti o n 4. 1. 2

Secti o n 4. 1. 3
4.
T w o sec o n d ar y o bjecti ves are a d de d
Descri pti o n of C h a n ge: 

T o i n vesti gate t he effect of T A K -9 3 5 o n t he d urati o n of m ot or seiz ures f or patie nts wit h C D K L 5 deficie nc y 
dis or der t hr o u g h o ut t he Treat me nt Peri o d

T o i n vesti gate t he effect of T A K -9 3 5 o n d urati o n of seiz ure free d o m i n patie nts wit h C D K L 5 deficie nc y 
dis or der i n patie nts wit h C D K L 5 deficie nc y dis or der d uri n g t he Mai nte na nce Peri o d.
R ati o n ale f or C h a n ge: T he o bjecti ves of t he st u d y ha ve bee n e x pa n de d t o u n dersta n d t he effect of t h e dr u g o n 
d urati o n of seiz ures a n d o n d urati o n of seiz ure free d o m
Secti o ns Affecte d:

S y n o psis

Secti o n 4. 1. 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

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5.
E x pl or at or y o bjecti ves are re vise d
6.
T he pri m ar y a n d sec o n d ar y e n d p oi nts are re vise d 
Descri pti o n of C h a n ge:

T he pri mar y efficac y e n d p oi nt is c ha n ge d fr o m d uri n g t he treat me nt peri o d t o d uri n g t he mai nte na nce 
peri o d. 

T he sec o n dar y efficac y e n d p oi nts f or p erce nt c ha n ge fr o m baseli ne i n m ot or seiz ure fre q ue nc y per 2 8 da y s 
are c ha n ge d fr o m d uri n g t he mai nte na nce peri o d t o d uri n g t he treat me nt peri o d. 

T he sec o n dar y e n d p oi nts f or pr o p orti o n of patie nts c o nsi dere d treat me nt res p o n ders are c ha n ge d fr o m 
d uri n g t h e treat me nt peri o d t o d uri n g t he mai nte na nce peri o d. treat me nt res p o n ders are defi ne d as t h ose 
wit h: 
-
W orse ni n g of
2 5 % or m o re i n m ot or seiz ures fr o m baseli ne
-
W orse ni n g of 1 % t o 2 5 % i n m ot or seiz ures fr o m baseli ne
-
N o c ha n ge i n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 2 5 % or m ore i n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 5 0 % or m ore i n m ot or seiz ures fr o m baseli ne
-
Re d ucti o n of 1 0 0 % i n m ot or seiz ures fro m baseli ne
R ati o n ale f or C h a n ge: T he preli mi nar y data fr o m t he T A K -9 3 5- 2 0 0 1 st u d y i n a d ult patie nts wit h e pile ptic 
e nce p hal o pat h y ma y i n dicate t hat f ull effects of T A K -9 3 5 are o bser ve d after 8 wee ks of treat me nt. Acc or di n gl y, 
si nce treat me nt d urati o n is e xte n de d t o 2 0 wee ks a n d t o o bser ve t he f ull effects, t he pri mar y a n d sec o n dar y e n d p oi nts 
are c ha n ge d.
Se cti o ns I m p acte d:

S y n o psis

Secti o n 4. 2. 1

Secti o n 4. 2. 2
C 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 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

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7.
Sec o n d ar y e n d p oi nts are a d de d

Descri pti o n of C h a n ge: T he f oll o wi n g e n d p oi nts are a d de d:

Perce nt c ha n ge fr o m Baseli ne i n fre q ue nc y of m ot or seiz ures l o n ger t ha n 5 mi n utes i n patie nts wit h 
C D K L 5 deficie nc y dis or der

Perce nt c ha n ge fr o m Baseli ne i n m ot or seiz ure -free da ys fre q ue nc y i n patie nts wit h 1 5 q d u plicati o n 
s yn dr o me d uri n g t he Mai nte na nce Peri o d 

T o c haracterize plas ma 2 4 H C le vels a n d c ha n ge i n m ot or seiz ure fre q ue nc y i n patie nts treate d wit h T A K -
9 3 5 as a n a dj u ncti ve t hera p y
R ati o n ale f or C h a n ge: T he sec o n dar y e n d p oi nts are a d de d t o a d dress t he sec o n dar y o bjecti ves.
Secti o ns Affecte d:

S y n o psis

Secti o n 4. 2. 2
8.
O ne e x pl or at or y o bjecti ve/e n d p oi nt is a d de d
Descri pti o n of C h a n ge: St u d y visits are c ha n ge d as f oll o ws:

St u d y visits at Da ys 8 a n d 5 7 are c ha n ge d t o p h o ne c o ntacts

St u d y visit at Da y 8 5 is c ha n ge d fr o m e n d of treat me nt visit t o a treat me nt peri o d visit

T he e n d of st u d y visit is c ha n ge d t o Da y 1 4 1

P h o ne c o ntacts are a d de d at Da ys 2 2 a n d 1 1 3

T he safet y f oll o w -u p visit is at Da y 1 6 9
R ati o n ale f or C h a n ge: Beca use t he d urati o n of treat me nt is c ha n ge d t o 2 0 wee ks, a d d iti o nal st u d y visits are 
i nc or p orate d.
Secti o ns I m p acte d:

A p pe n di x 1
C 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 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

Pa ge 9 3 of 1 0 1
1 0. Ti me p oi nts f or c ollecti o n of s a m ples f or p h ar m ac o ki netic a n al ysis are cl arifie d
Descri pti o n of C h a n ge: Fi ve ( 5) P K bl o o d dra ws will occ ur at t hese f oll o wi n g ti me p oi nts o n t he first st u d y da y : 3 0 
mi n utes ( ± 1 0 mi n utes), 1, 2, a n d 4 h o urs ( ± 1 0 mi n utes) p ost -first d ose. O n ot her st u d y visit da ys, t w o P K bl o o d 
dra ws will be c ollecte d; o ne wit hi n 1 h o ur pri or t o t he m or ni n g d ose ( pre -d ose) a n d t he ot her at 3 0 mi n utes ( ± 1 0 
mi n utes) p ost -m or ni n g d ose.
R ati o n ale f or C h a n ge: T hese ti me p oi nts will better c haracterize P K pr ofile of t he dr u g i n a pe diatric p o p ulati o n.
Secti o ns Affecte d:

S y n o psis

Secti o n 8. 1. 2 2. 1
1 1. T he a ge f or p artici p ati o n is i ncre ase d t o 3 5 ye ars
Descri pti o n of C h a n ge: T he u p per a ge li mit is c ha n ge d fr o m 1 7 years t o 3 5 years
R ati o n ale f or C h a n ge: B ot h d u p 1 5 Q s y n dr o me a n d t he C D K L 5 deficie nc y dis or der occ ur i n c hil d h o o d a n d 
c o nti n ue i nt o a d ult h o o d; t h us, c urre nt cli nical sites ha ve i n dicate d p ote ntial ol der patie nts i n t heir cli nical practice 
f or t his st u d y
Secti o ns I m p acte d:

S y n o psis

Secti o n 5. 1

Secti o n 6. 1
1 2. R o ute of a d mi nistr ati o n is e x p a n de d t o i ncl u de G -t u be/ P E G t u be/ J-t u be at all sites e xce pt t h ose i n C hi n a . 
Descri pti o n of C h a n ge: St u d y dr u g ma y be a d mi nistere d orall y or via G -t u be/ P E G t u be/J-t u be. J-t u be 
a d mi nistrati o n re q uires a p pr o val b y t he Me dical M o nit or a n d S p o ns or. Patie nts e nr olle d i n cli nical sites i n C hi na are 
n ot t o recei ve st u d y dr u g via G -t u be/ P E G t u be/J-t u be.
R ati o n a le f or C h a n ge: C ha n ge is necessar y t o acc o m m o date patie nts u na ble t o ta ke st u d y dr u g orall y.
Secti o ns I m p acte d:

S y n o psis

Secti o n 5. 1

Secti o n 7. 2
1 3. Per a m p a nel is a d de d as a pr o hi bite d me dic ati o n
Descri pti o n of C h a n ge: Pera m pa nel is a pr o hi bite d me dicati o n
R a ti o n ale f or C h a n ge:
 
Secti o ns I m p acte d:

S y n o psis

Secti o n 6. 1

Secti o n 7. 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 s of U s e

Pa ge 9 4 of 1 0 1
1 4. T he use of tr a diti o n al C hi nese me dici nes is cl arifie d
Descri pti o n of C h a n ge: T he use of tra diti o nal C hi nese me dici nes s h o ul d be a p pr o ve d b y t he Me dical M o nit or at 
scree ni n g.
R ati o n ale f or C h a n ge: T his clarificati o n is a d de d d ue t o i ncl usi o n of sites i n C hi na.
Secti o ns I m p acte d:

S y n o psis

Secti o n 7. 2

Secti o n 7. 6
1 5. I ncl usi o n criteri o n 1 is re vise d t o cl arif y t he defi niti o n of C D K L 5 deficie nc y dis or der
Descri pti o n of C h a n ge: C D K L 5 deficie nc y dis or der is defi ne d as: 

A pat h o ge nic or li kel y pat h o ge nic varia nt i n C D K L 5
O R
A varia nt of u ncertai n si g nifica nce ( V U S) i n t he ki nase d o mai n of C D K L 5 t hat has bee n c o nfir me d t o be de 
n o v o. U nless b ot h pare nts ha ve bee n teste d a n d f o u n d t o n ot har b or t he V U S, a patie nt wit h a V U S ca n n ot 
be e nr olle d. Partici pa nts wit h a V U S f o u n d o utsi de of t he ki nase d o mai n will n ot be e nr olle d. 
A patie nt wit h m osaicis m f or a C D K L 5 varia nts is eli gi ble.
R ati o n ale f or C h a n ge: T his clarificati o n is a d de d t o e ns ure c o nsiste nc y acr oss sites.
Secti o ns I m p acte d:

S y n o psis

Secti o n 6. 1
1 6. I ncl usi o n criteri a 6 a n d 7 are re vise d t o cl arif y t he c hr o nic use of be nz o di aze pi nes as a ntie pile ptic dr u gs 
a n d t o i ncl u de st a ble use of c a n n a bi di ol pr o d ucts
Descri pti o n of C h a n ge: C hr o nic use of be nz o diaze pi nes is defi ne d as dail y  fre q ue nc y t o treat seiz ures a n d t he use 
of ca n na bi di ol pr o d ucts m ust be sta ble f or 4 wee ks pri or t o scree ni n g.
R ati o n ale f or C h a n ge: 

Base d o n i n q uiries fr o m cli nical sites, f urt her clarificati o n was nee de d t o better defi ne t he “c hr o nic” use.

Wit h c urre nt use of le gal me dical marij ua na a n d t he a vaila bilit y of ca n na bi di ol pr o d ucts as A E Ds, t his 
i ncl usi o n was a d de d t o all o w eli gi ble patie nts usi n g t hese pr o d ucts t o e nr oll.
Secti o ns I m p acte d:

S y n o psis

Secti o n 6. 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

Pa ge 9 5 of 1 0 1
1 7. E xcl usi o n criteri o n 1 is re vise d re g ar di n g t he tre at me nt of st at us e pile ptic us
Descri pti o n of C h a n ge: T he c ha n ge re m o ve d t he a vera ge n u m ber of e pis o des t hat c o ul d be all o we d per wee k a n d 
t hat stat us e pile ptic us is defi ne d as a seiz ure or re peate d seiz ures t hat lasts 5 mi n utes or l o n ger a n d re q uire d resc ue 
t hera p y O R a seiz ure or re peate d seiz ures t hat lasts 1 5 mi n utes or l o n ger wit h o ut resc ue t hera p y. T he ne w e xcl usi o n 
re q uires t he patie nt has bee n a d mitte d t o a me dical facilit y f or treat me nt of stat us e pile ptic us 2 or m ore ti mes i n t he 3 
m o nt h s i m me diatel y pri or t o t he scree ni n g visit
R ati o n ale f or C h a n ge: Stat us e pile ptic us ca n be a l o n g seiz ure o ver 5 mi n utes a n d se veral patie nts, es peciall y wit h 
Dra vet s y n dr o me, ca n ha ve pr ol o n ge d seiz ures ( > 5 mi n utes) t hat are n ot se vere e n o u g h t o e xcl u de t he m fr o m t he 
st u d y. T heref ore, patie nts w h ose stat us e pile ptic us re q uire d h os pitalizati o n or i nt u bati o n will be e xcl u de d.
Secti o ns I m p acte d:

S y n o psis

Secti o n 6. 2
1 8. E xcl usi o n criteri o n 8 is delete d ( p ositi ve fi n di n gs i n t he scree ni n g C -S S R S assess me nt)
Descri pti o n of C h a n ge:
R ati o n ale f or C h a n ge: T his e xcl usi o n was c o nf usi n g si nce t here are a n u m ber of s y m pt o ms fr o m t he C -S S R S 
assess me nt t hat ma y n ot necessaril y dis q ualif y patie nts fr o m e nteri n g t he st u d y.
Secti o ns I m p acte d:

S y n o psis

Secti o n 6. 2
1 9. A n o pti o n al se verit y assess me nt f or C D K L 5 deficie nc y s y n dr o me is a d de d
Descri pti o n of C h a n ge: T he o pti o nal se verit y assess me nt is c o n d ucte d i n o nl y t he C D K L 5 deficie nt patie nts.
R ati o n ale f or C h a n ge: T his assess me nt will ca pt ure de grees of se verit y ass ociate d wit h m ot or f u ncti o n, c o g niti o n, 
a n d visi on a n d a ut o n o mic d ysf u ncti o n.
Secti o ns I m p acte d:

Secti o n 8. 1. 1 9
2 0. H a n dli n g of misse d d oses is cl arifie d
Descri pti o n of C h a n ge: If a patie nt misses a d ose, t he misse d d ose s h o ul d be s ki p pe d, a n d t he patie nt s h o ul d 
c o nti n ue wit h his/ her n or mal d osi n g sc he d ule. S ki p pe d d oses s h o ul d be re p orte d as misse d d oses.
R ati o n ale f or C h a n ge: Base d o n i n q uiries fr o m cli nical sites, clarificati o n  was re q uire d f or pr o per i nstr ucti o ns t o 
st u d y patie nts o n h o w t o ha n dle missi n g d oses.
Secti o ns I m p acte d:

Secti o n 7. 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

Pa ge 9 6 of 1 0 1
2 1. Re q uire me nt is a d de d t o disc o nti n ue a p atie nt if he/s he e x hi bits si g ns of s uici d al i de ati o n
Descri pti o n of C h a n ge: St u d y staff trai ne d i n t he a d mi nistrati o n of t he C -S S R S will assess patie nt s uici dalit y usi n g 
t he C-S S R S, eliciti n g a ns wers fr o m t he patie nt or t he patie nt’s care gi ver. Ulti matel y, t he deter mi nati o n of t he 
prese nce of s uici dal i deati o n or be ha vi or de pe n ds o n t he cli nical j u d g me nt of t he i n vesti gat or
R ati o n ale f or C h a n ge: T his c ha n ge pr o vi de d c o nsiste nc y bet wee n Secti o n 8. 1. 1 4 a n d Secti o n 6. 3. 1.
Secti o ns I m p acte d:

Secti o n 6. 3. 1

Secti o n 8. 1. 1 3
2 3. T w o a d diti o n al ti me p oi nts are a d de d f or c ollecti o n of pl as m a 2 4 H C 
Descri pti o n of C h a n ge: Da y  1 4 1 a n d F oll o w-u p visit ( Da y 1 6 9)
R ati o n ale f or C h a n ge: T hese ti me p oi nts are a d de d t o c orrelate 2 4 H C bl o o d le vel wit h c ha n ge i n seiz ure fre q ue nc y
Secti o ns I m p acte d:

A p pe n di x 1
2 4. A m o u nt of bl o o d s a m ples is c h a n ge d t o reflect a d diti o n al visits
Descri pti o n of C h a n ge: T he t otal ma xi m u m a m o u nt of bl o o d c ollecte d d uri n g t he st u d y per patie nt is 1 2 0. 2 m L.
R ati o n ale f or C h a n ge: I ncrease base d o n a d diti o nal st u d y visits
Secti o ns I m p acte d:

S y n o psis

Secti o n 8. 1. 1 0

A p pe n di x 3
C 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 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

Pa ge 9 7 of 1 0 1
2 5. C h a n ge i n d ose d uri n g t he st u d y is cl arifie d
Descri pti o n of C h a n ge: Patie nts will be c o ntacte d b y p h o ne wit hi n first t w o da ys f oll o wi n g e scalati o n t o t he 
ma xi m u m d ose t o assess safet y a n d t olera bilit y of t he st u d y dr u g. After reac hi n g t he ma xi m u m d ose, a n a d diti o nal 
6 wee ks will be all o we d t o a dj ust t he patie nt t o t he o pti mal d ose le vel, base d o n t he j u d g me nt of t he I n vesti gat or a n d 
wit h t h e a p pr o val of t he Me dical M o nit or. T he fi nal d ose le vel will be mai ntai ne d u ntil t he e n d of t he Mai nte na nce 
Peri o d; h o we ver, t he d ose ma y be c ha n ge d d uri n g t he D ose O pti mizati o n Peri o d i n c o ns ultati o n wit h t he me dical 
m o nit or.
R ati o n ale f or C h a n ge: T his c h a n ge will all o w fle xi bilit y t o ac hie ve o pti mal d ose d uri n g t he O pti mizati o n Peri o d.
Secti o ns I m p acte d:

S y n o psis 

Secti o n 7. 2
2 6. Wei g ht -b ase d d osi n g is u p d ate d t o reflect t he a d mi nistr ati o n of 1 0 0 m g t a blets
Descri pti o n of C h a n ge: T he n u m ber of ta blets b y wei g ht gr o u p is a d de d as t he ori gi nal ta ble o nl y s h o we d t he 
n u m ber of mi ni -ta blets.
R ati o n ale f or C h a n ge: T he st u d y is a me n de d t o i ncl u de a d ults
Secti o ns I m p acte d:

S y n o psis 

Secti o n 7. 2
2 7. Use of a n E E G c h arter is re m o ve d
Descri pti o n of C h a n ge: A detaile d descri pti o n of t he E E G para meters e val uate d, a n d eli gi bilit y criteria will be 
f urt her disc usse d i n wit h t he S p o ns or’s Me dical M o nit or.
R ati o n ale f or C h a n ge: T he S p o ns or me dical m o nit or will disc uss t he E E G para meters wit h t he cli nical sites, s o a 
c harter i s n o l o n ger re q uire d.
Secti o ns I m p acte d:

S y n o psis

Secti o n 8. 1. 2 1
2 8. A n a d diti o n al E C G assess me nt is a d de d
Descri pti o n of C h a n ge: A n  a d diti o nal assess me nt is i ncl u de d at Da y 1 5
R ati o n ale f or C h a n ge: Assess me nt a d de d d ue t o t he st u d y d urati o n e xte nsi o n
Secti o ns I m p acte d:
A p pe n di x 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

Pa ge 9 8 of 1 0 1
2 9. Cl arific ati o n is a d de d f or r olli n g o ver fr o m t he a ntece de nt tri al t o t he o pe n -l a bel e xte nsi o n
Descri pti o n of C h a n ge: T o clarif y t hat Patie nts c urre ntl y partici pati n g i n t his trial ca n i m me diatel y r oll o ver t o t he 
o pe n -la bel e xte nsi o n as l o n g as t he y meet t he criteria s pecifie d i n t he O L E st u d y.
R ati o n ale f or C h a n ge: T o a d d clarit y
Secti o ns I m p acte d:

Secti o n 5. 1. 2
3 0. O xc ar b aze pi ne is a d de d t o t he ass a y f or c o nc o mit a nt A E Ds
Descri pti o n of C h a n ge: O xc ar b aze pi ne is a d de d t o t he ass a y f or c o nc o mit a nt A E Ds
R ati o n ale f or C h a n ge: T his assa y was o mitte d i n t he pre vi o us versi o n of t he pr ot oc ol.
Secti o ns I m p acte d:

A p pe n di x 3
3 1. A n a n al ysis p o p ul ati o n ( Effic ac y A n al ysis P o p ul ati o n) is a d de d
Descri pti o n of C h a n ge: T he p o p ulati o n is defi ne d as All mI T T s u bjects w h ose assess me nts are c o m plia nt wit h 
Pr ot oc ol A me n d me nt 1 will be i ncl u de d i n t he efficac y a nal ysis p o p ulati o n. Efficac y a nal yses f or pri mar y a n d 
sec o n dar y efficac y e n d p oi nts will be base d o n t he efficac y a nal ysis p o p ulati on, a n d t h ose f or e x pl orat or y efficac y 
e n d p oi nts will be base d o n t he mI T T set.
R ati o n ale f or C h a n ge: O n l y a m o difie d I T T p o p ulati o n ha d i nitiall y bee n pr o p ose d.
Secti o ns I m p acte d:

S y n o psis

Secti o n 1 0. 1
3 2. St atistic al a n al yses are re vise d
Descr i pti o n of C h a n ge: Ti me p oi nts are c ha n ge d t o eit her mai nte na nce peri o d or treat me nt peri o d base d o n c ha n ges 
t o t he st u d y e n d p oi nts
R ati o n ale f or C h a n ge: A n al yses are re vise d t o reflect c ha n ges i n st u d y e n d p oi nts
Secti o ns I m p acte d:

S y n o psis

Secti o n 1 0. 8. 1

Secti o n 1 0. 8. 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

Pa ge 9 9 of 1 0 1
3 3. C o nfi de nti alit y of s u bject i nf or m ati o n is cl arifie d
Descri pti o n of C h a n ge: All la b orat or y s peci me ns, e val uati o n f or ms, re p orts, a n d ot her rec or ds will be i de ntifie d i n 
a ma n ner desi g ne d t o mai ntai n s u bject c o nfi de ntialit y. All rec or ds will be ke pt i n a sec ure st ora ge area wit h li mite d 
access. Cli nical i nf or mati o n will n ot be rel ease d wit h o ut t he writte n per missi o n of t he patie nt a n d/ or patie nt's 
c ust o dial pare nt or g uar dia n, e xce pt as necessar y f or m o nit ori n g a n d a u diti n g b y t he s p o ns or, its desi g nee, F D A, 
Healt h A ut h orities, Et hics C o m mittees, a n d/ or I R Bs.
T he i n vesti gat or a n d a ll e m pl o yees a n d c o w or kers i n v ol ve d wit h t his st u d y ma y n ot discl ose or use f or a n y p ur p ose 
ot her t ha n perf or ma nce of t he st u d y a n y data, rec or d, or ot her u n p u blis he d, c o nfi de ntial i nf or mati o n discl ose d t o 
t h ose i n di vi d uals f or t he p ur p ose of t he st u d y. Pri or writte n a gree me nt fr o m t he s p o ns or or its desi g nee m ust be 
o btai ne d f or t he discl os ure of a n y sai d c o nfi de ntial i nf or mati o n t o ot her parties.
R ati o n ale f or C h a n ge: T he clarificati o n is base d o n l ocal re g ulat or y a n d I R B re q uire me nts
Secti o ns I m p acte d:

S ecti o n 1 1. 4. 1
3 4. T he le n gt h of ti me s u bjects m ust a v oi d pre g n a nc y, d o n ati o n of o v a, a n d s per m d o n ati o n after t he l ast d ose 
of st u d y dr u g is cl arifie d a n d i nstr ucti o ns are i ncl u de d if uri ne c a n n ot be c ollecte d at Visit 2
Descri pti o n of C h a n ge: M o nt hs are c ha n ge d t o da ys a n d i nstr ucti o ns are pr o vi de d if uri ne ca n n ot be c ollecte d at 
Visit 2
R ati o n ale f or C h a n ge: T he ori gi nal te xt was n ot c o nsiste nt wit h ot her secti o ns of t he pr ot oc ol.
Secti o ns I m p acte d:

S y n o psis

Secti o n 6. 1

Secti o n 8. 1. 1 2
3 5. E n d of st u d y defi niti o n is a d de d
Descri pti o n of C h a n ge: T he e n d of st u d y is defi ne d f or a n i n di vi d ual patie nt is defi ne d as t he last pr ot oc ol -
s pecifie d c o ntact wit h t hat patie nt. T he o verall e n d of t he st u d y is defi ne d as t he last pr ot oc ol-s pecifie d c o ntact wit h 
t he last patie nt o n g oi n g i n t he st u d y.
R ati o n ale f or C h a n ge: T o clarif y t he e n d of st u d y f or a patie nt a n d t he e n d of t he o verall st u d y.
Secti o ns I m p acte d:

Secti o n 5. 1. 1
3 6. Descri pti o n of t he d osi n g c ar d is a d de d
Descri pti o n of C h a n ge: A d osi n g car d will be pr o vi d e d t o t he patie nt a n d/ or care gi ver at eac h cli nical visit t o 
rec or d act ual ti me of t he last 2 d ose a d mi nistrati o ns pri or t o P K sa m ple c ollecti o n a n d c ha n ge i n d osi n g re gi me n ( de-
escalati o n) t hat ma y occ ur bet wee n visits a n d d uri n g t he de -escalati o n peri o d of t he st u d y; t hese will be rec or de d i n 
t he patie nt’s s o urce d oc u me nts a n d tra nscri be d i nt o t he e C R F.
R ati o n ale f or C h a n ge: T o clarif y f or sites t he use of t he d osi n g car d.
Secti o ns I m p acte d:

Secti o n 8. 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

Pa ge 1 0 0 of 1 0 1
A me n d me nt 2
1.
T he a ge f or p artici p ati o n is i ncre ase d t o 5 5 ye ars
Descri pti o n of C h a n ge: T he u p per a ge li mit is c ha n ge d fr o m 3 5 years t o 5 5 years
R ati o n ale f or C h a n ge: B ot h D u p 1 5 q a n d t he C D D occ ur i n c hil d h o o d a n d c o nti n ue i nt o a d ult h o o d; t h us, c urre nt 
cli nical sites ha ve i n dicate d p ote ntial ol der patie nts i n t heir cli nical practice f or t his st u d y
Secti o ns I m p acte d:

S y n o psis

Secti o n 5. 1

Secti o n 6. 1
2.
I ncl usi o n Criteri a f or di a g n osis e x p a n de d
Descri pti o n of C h a n ge: Re m o ve d t he w or d ”is o dice ntric” a n d i ncl u de d pr o visi o n f or dia g n osis per sta n dar d of care 
a n d per literat ure descri be d p he n ot y pe
R ati o n ale f or C h a n ge: T o all o w patie nts wit h a dia g n osis of i nterstitial D u p 1 5 q.
Secti o ns I m p acte d:

S y n o psis

Secti o n 6. 1
3.
T he pri m ar y a n d sec o n d ar y e n d p oi nts are re vise d 
Descri pti o n of C h a n ge: Sec o n dar y e n d p oi nts C GI -S/ C ( n o me nclat ure) se parate d i nt o C GI -S a n d C GI -C a n d 
perce nt c ha n ge m o difie d t o c ha n ge. Perce nt c ha n ge als o m o difie d t o c ha n ge fr o m Care -GI -C. 
 
R ati o n ale f or C h a n ge: T o pr o vi de clarificati o n relate d t o t he a nal yses of t hese e n d p oi nts ( C GI). 
 
Secti o ns I m p acte d:

S y n o psis

List of A b bre viati o ns a n d Defi niti o ns of Ter ms

Secti o n 4. 1. 2

Secti o n 4. 2. 2

Secti o n 8. 1. 1 8

Secti o n 8. 1. 2 0

Secti o n 1 0. 1

Secti o n 1 0. 8. 2

A p pe n di x 1. Sc he d ule of Assess me nts
4.
A d diti o n of a d h oc a n al yses
Descri pti o n of C h a n ge: A d de d t he pr o visi o n t hat a d h oc a nal yses ma y be perf or me d at t he discreti o n of t he 
S p o ns or
R ati o n ale f or C h a n ge: T hese a nal yses ma y be necessar y f or pla n ni n g p ur p oses i n f urt her desi g ni n g of t he 
T A K -9 3 5 de vel o p me nt pr o gra m
Secti o n I m p acte d:

Secti o n 1 0. 1 2
C CI
C 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 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

Pa ge 1 0 1 of 1 0 1
5.
A d diti o n of J -t u be a n d descri pti o n
Descri pti o n of C h a n ge: Clarificati o n t hat Jej u n ost o m y t u be (J-t u be) ma y be c o nsi dere d f oll o wi n g a p pr o val b y t he 
S p o ns or a n d Me dical M o nit or . Patie nts e nr olle d i n cli nical sites i n C hi na are n ot t o recei ve st u d y dr u g via J -t u be.
R ati o n ale f or C h a n ge: Ma y  be necessar y t o acc o m m o date patie nts u na ble t o ta ke st u d y dr u g orall y.
Secti o ns I m p acte d:

S y n o psis

Secti o n 5. 1

Secti o n 7. 2
6.
C orrecti o ns m a de t o t he Sc he d ule of Assess me nts 
Descri pti o n of C h a n ge: Se parate d C GI -S fr o m C GI -C se parate d i nt o 2 r o ws a n d seiz ure diar y c ollecti o n re m o ve d 
fr o m P h o ne Visit da ys
R ati o n ale f or C h a n ge: Assess me nts se parate d f or clarit y a n d re m o val of diar y e ntries t o c orrect err or
Secti o ns I m p acte d:

A p pe n di x 1. Sc he d ule of Assess me nts
7.
Re vise d c o ntr ace pti o n l a n g u a ge
Descri pti o n of C h a n ge: C o ntrace pti o n a n d e x p os ure d uri n g pre g na nc y la n g ua ge u p date d t o c urre nt O vi d 
T hera pe utics sta n dar ds. I ncl u des c urre ntl y acce pt e d met h o ds.
R ati o n ale f or C h a n ge: T o ma ke c urre nt a n d c o nsiste nt wit h ot her st u dies s p o ns ore d b y O vi d T hera pe utics
Secti o ns I m p acte d:

Secti o n 6. 1 I ncl usi o n Criteria

Secti o n 8. 1. 1 1 C o n trace pti o n a n d Pre g na nc y A v oi da nce Pr oce d ures

Secti o n 8. 3. 2 E x p os ure D uri n g Pre g na nc y a n d/ or Lactati o n
8.
Re m o ve d o pti o n al bl o o d s a m ple f or rese arc h
Descri pti o n of C h a n ge: T he o pti o n al bl o o d s a m ple w as re m o ve d
R ati o n ale f or C h a n ge: t o mi ni mize t he c ollecti o n of bl o o d sa m ples a n d t here are n o c urre nt pla n ne d a nal yses f or 
t he sa m ple
Secti o ns I m p acte d:


A p pe n di x 3 Sa m pli n g S u m mar y
C 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 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