Clinical trial NCT03694275
Conditions: 15q Duplication Syndrome CDKL5 Deficiency Disease
Keywords: Drug Therapy 15q Duplication Syndrome (Dup15q) CDKL5 Deficiency Disorder (CDD) Brain Diseases Epilepsy Central Nervous System Diseases Autism Cholesterol 24S-hydroxylase inhibitor Anti-epilepsy drug Anticonvulsants
Sponsor: Takeda
Start date: 2018-09-10; Completion date: 2020-07-31
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate the effect of soticlestat on the frequency of motor seizures for participants with Dup15q or CDD during the Maintenance Period.

Detailed description:
The drug being tested in this study is called soticlestat. Soticlestat is being tested to treat people with Dup 15q or CDD. This study will assess the effects of TAK-935 on seizure frequency, safety.

The study will enroll approximately 30 participants. Participants will be enrolled into 2 groups based on their diagnosis as: Dup 15q or CDD.

All participants will be asked to take soticlestat tablets twice daily with or without food.

The study comprises of 2 periods: Screening/Baseline Period and Treatment Period (Dose Optimization and Maintenance). The overall time to participate in this study is approximately 30 weeks, including 4 to 6 weeks Screening/Baseline Period, 20 weeks Treatment Period, 2 weeks Taper, and 2 weeks safety follow up period. Participants completing this study will have an option to enroll in the open-label extension (OLE) study, under a separate protocol.

Arms: arm 1: Soticlestat tablets twice daily (BID) orally or via gastrostomy tube (G-tube)/ percutaneous endoscopic gastrostomy (PEG) tube, BID. Participants with Dup 15q weighing \<60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20. arm 2: Soticlestat tablets BID orally or via G-tube/ PEG tube, BID. Participants with CDD weighing \<60 kg at Baseline received total daily dose of study drug calculated based on body weight. Participants weighing ≥60 kg at Baseline, were administered with 200 mg/day followed by 400 mg/day, then 600 mg/day, up to Week 20.
Interventions: intervention 1: Soticlestat
Intervention descriptions: intervention 1: TAK-935 tablets

Protocol documents:
Prot_000.pdf: 
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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:

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.

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”

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:

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


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 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
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
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


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 5 of 1 0 1
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


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 6 of 1 0 1

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


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 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


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 6 of 1 0 1
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


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 7 of 1 0 1
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


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 9 of 1 0 1
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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Date: 2 1 N o ve m ber 2 0 1 9
Pa ge 5 0 of 1 0 1
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 
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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 .
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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.
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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 
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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
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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.
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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


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 2 of 1 0 1
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
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 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


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 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


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 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.
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 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


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 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
O vi d T hera pe utics I nc.
Date: 2 1 N o ve m ber 2 0 1 9
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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


Pa ge 9 0 of 1 0 1
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


Pa ge 9 1 of 1 0 1
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

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title:  MULTICENTER, OPEN-LABEL, PILOT STUDY OF TAK-935 (OV935) IN PATIENTS 
WITH 15Q DUPLICATION SYNDROME OR CDKL5 DEFICIENCY DISORDER (ARCADE 
STUDY)
NCT Number: NCT03694275
SAP Approve Date: 25June2020
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


OVID THERAPEUTICS INC.
STATISTICAL ANALYSIS PLAN
A MULTICENTER, OPEN-LABEL, PILOT STUDY OF TAK-935 (OV935) IN 
PATIENTS WITH 15Q DUPLICATION SYNDROME OR CDKL5 DEFICIENCY 
DISORDER (ARCADE STUDY)
TAK-935-18-002 (OV935)
Analysis Plan Version:
Date of Analysis Plan:
Final 2.0
25June2020
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


Ovid Therapeutics Inc.
TAK-935-18-002 (OV935)
Statistical Analysis Plan Final 2.0: 25Jun2020
Page 2 of 50
SIGNATURE PAGE
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
keda: For Non-Commerci l Use Only and Subject to the Applicable Term
cial Use Only and Subject to the Applicable T


Ovid Therapeutics Inc.
TAK-935-18-002 (OV935)
Statistical Analysis Plan Final 2.0: 25Jun2020
                  Page 3 of 50
Table of Contents
1
INTRODUCTION.............................................................................................10
2
STUDY SUMMARY ........................................................................................10
2.1
Study Objectives.........................................................................................10
2.2
Study Design..............................................................................................12
2.2.1
Number of Patients..............................................................................13
2.2.2
Enrollment Procedures ........................................................................13
2.2.3
Efficacy Assessments..........................................................................14
2.2.3.1
Seizure Diary ...............................................................................14
2.2.3.2
Caregiver Global Impression of Change (Care GI-C) ...................14
2.2.3.3
Clinical Global Impression of Severity/Change (CGI-S/C)...........14
2.2.3.4
Plasma 24HC Level......................................................................15
2.2.3.5
Pharmacokinetics of TAK-935 .....................................................15
2.2.3.6
Plasma Concentrations of AEDs...................................................15
2.2.4
Safety Assessments .............................................................................15
2.2.4.1
Adverse Events ............................................................................15
2.2.4.2
Serious Adverse Events................................................................16
2.2.4.3
Clinical Laboratory Evaluation.....................................................16
2.2.4.4
Vital Signs, Height, and Weight ...................................................16
2.2.4.5
Electrocardiogram (ECG).............................................................17
2.2.4.6
Physical Examination...................................................................17
2.2.4.7
Neurological Examination............................................................17
2.2.4.8
Clinical Assessment of Suicidal Ideation and Behavior ................17
2.2.4.9
Vineland Adaptive Behavior Scale ...............................................18
2.2.4.10
Aberrant Behavior Checklist-Community (ABC-C) .....................19
2.2.4.11
Absence Seizures .........................................................................19
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2.2.4.12
New seizure types ........................................................................20
2.2.5
Exit Survey .........................................................................................20
2.2.6
Other Assessments ..............................................................................20
3
STATISTICAL METHODS ..............................................................................25
3.1
General Methods ........................................................................................25
3.1.1
Computing Environment .....................................................................25
3.1.2
Presentation of Data Summaries..........................................................25
3.1.3
Reporting of Numerical Values ...........................................................25
3.1.4
Baseline Value and Change from Baseline ..........................................25
3.1.5
Study Day ...........................................................................................26
3.1.6
Handling of Missing/Incomplete Values..............................................26
3.1.7
Handling of Repeated Assessments .....................................................26
3.1.8
Handling of Missing/Incomplete Date/Time ........................................26
3.2
Analysis Sets..............................................................................................28
3.2.1
Modified Intent-to-Treat Analysis Set .................................................28
3.2.2
Safety Analysis Set..............................................................................28
3.3
Analysis Variables......................................................................................28
3.3.1
Primary Efficacy Endpoint ..................................................................28
3.3.2
Secondary Efficacy Endpoints.............................................................29
3.3.3
Exploratory Efficacy Endpoints...........................................................30
3.3.4
Safety Endpoints .................................................................................30
3.4
Patient Disposition and Evaluability ...........................................................30
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3.4.1
Patient Disposition ..............................................................................30
3.4.2
Protocol Deviations .............................................................................31
3.5
Demographics and Characteristics at Screening ..........................................31
3.5.1
Demographics and Characteristics at Screening...................................31
3.5.2
Medical History...................................................................................31
3.6
Prior and Concomitant Medications............................................................31
3.7
Treatment Compliance and Exposure..........................................................32
3.7.1
Compliance to Study Treatment ..........................................................32
3.7.2
Exposure to Study Treatment...............................................................33
3.8
Efficacy Analysis .......................................................................................33
3.8.1
Primary Efficacy Endpoint ..................................................................33
3.8.2
Secondary Efficacy Endpoints.............................................................34
3.8.2.1
All and Motor Seizure Frequency During the Treatment Period....34
3.8.2.2
Response to Treatment Based on Seizure Frequency ....................34
3.8.2.3
Duration of Motor Seizures ..........................................................35
3.8.2.4
All and Motor Seizure Freedom ...................................................35
3.8.2.5
CGI-S/C and Care GI-C ...............................................................35
3.8.2.6
Plasma 24HC Level......................................................................36
3.8.3
Exploratory Endpoints.........................................................................36
3.8.3.1
Plasma Concentration of TAK-935...............................................36
3.8.3.2
...........................................37
3.8.3.3
......................................................37
3.9
Safety Analysis...........................................................................................37
3.9.1
Adverse Events ...................................................................................37
CCI
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3.9.1.1
Summary of TEAEs .....................................................................38
3.9.1.2
Incidence of TEAEs .....................................................................38
3.9.1.3
Treatment-Related TEAEs ...........................................................38
3.9.1.4
TEAEs by Maximum Severity......................................................38
3.9.1.5
Severe TEAEs..............................................................................39
3.9.1.6
Severe Treatment-Related TEAEs................................................39
3.9.1.7
Serious TEAEs.............................................................................39
3.9.1.8
TEAEs Leading to Discontinuation from Study............................39
3.9.1.9
TEAEs of Special Interest ............................................................39
3.9.2
Clinical Laboratory Evaluation............................................................39
3.9.3
Vital Signs, Height, and Weight ..........................................................40
3.9.4
ECG....................................................................................................40
3.9.5
Physical Examination..........................................................................40
3.9.6
Neurological Examination...................................................................40
3.9.7
Clinical Assessment of Suicidal Ideation and Behavior .......................40
3.9.8
Vineland Adaptive Behavior Scale (VABS) ........................................41
3.9.9
Aberrant Behavior Checklist-Community............................................41
3.9.10 Absence Seizure-Free Days.................................................................41
3.9.11 New seizure types................................................................................41
3.9.12 Exit Survey .........................................................................................41
3.10 Other Analyses ...........................................................................................42
3.10.1 Severity Assessment for CDD .............................................................42
3.11 Modifications to the Statistical Section of the Protocol ...............................42
4
DATA HANDLING ..........................................................................................43
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4.1
Computation of Seizure Frequency.............................................................43
4.2
Seizure Frequency Intervals........................................................................43
4.3
Extended Treatment Period.........................................................................44
5
INDEX OF TABLES, LISTINGS, AND FIGURES...........................................46
6
INTERIM (AD HOC) ANALYSES...................................................................46
7
APPENDICES...................................................................................................46
Appendix 1: Classification of Seizure Types........................................................46
Appendix 2: Adverse Events of Special Interest...................................................47
Appendix 3: ABC-C Scoring ...............................................................................48
Appendix 4: Clinical Laboratory Tests.................................................................49
8
REFERENCES..................................................................................................50
List of Tables
Table 1.  Schedule of Assessments...........................................................................21
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LIST OF ABBREVIATIONS
Abbreviation
Full Term
ABC-C
Aberrant Behavior Checklist-Community
AE
adverse event
AED
antiepileptic drug
BID
twice a day
BLQ
below the limit of quantitation
BMI
body mass index
Care GI-C
Caregiver Global Impression of Change
CDD
CDKL5 deficiency disorder
CGI-C
Clinical Global Impression of Change
CGI-S
Clinical Global Impression of Severity
COVID-19
Coronavirus Disease 2019
CRF
case report form
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
Dup15q
15q duplication syndrome
ECG
electrocardiogram
EOT
end of treatment
ET
early termination
HLGT
high level group term
HLT
high level term
ICF
informed consent form
iDMC
independent Data Monitoring Committee
LLOQ
lower limit of quantitation
MedDRA
Medical Dictionary for Regulatory Activities
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mITT
modified intent-to-treat
OLE
open-label extension
PK
pharmacokinetics
PT
preferred term
Q1
1st quartile
Q3
3rd quartile
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
TEAE
treatment emergent adverse event
VABS
Vineland Adaptive Behavior Scales
WHO-DD
World Health Organization Drug Dictionary
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1
INTRODUCTION
TAK-935-18-002 (OV935) (ARCADE) is a multicenter, open-label, Phase 2 pilot 
study of TAK-935 (OV935) in patients aged ≥2 and ≤55 years with 15q duplication 
syndrome (Dup15q) or CDKL5 deficiency disorder (CDD) demonstrating ≥3 motor 
seizures excluding myoclonic seizures per month during the 3 months immediately 
prior to Screening.
The statistical analysis plan (SAP) contains a detailed description of the data 
presentations and statistical analyses that will be included in the clinical study report 
(CSR) for Protocol TAK-935-18-002. The statistical methods and analyses described 
here are based on those presented in the study protocol (Amendment 2 dated 
November 21, 2019). The two patients who completed the study under the original 
protocol (May 22, 2018) will be analyzed where the data allows. Special handling of 
the time intervals for efficacy analysis for these patients is described in Section 4.2.
An interim (ad hoc) analysis was performed in March 2020. The March 2020 analysis 
followed the Ad Hoc Analysis Plan Version 3.0.
This study is ongoing during the Coronavirus Disease 2019 (COVID-19) pandemic, 
and as a result, there are expected to be protocol deviations related to COVID-19, 
including virtual visits instead of clinic visits and use of local labs. Data will be
collected as closely as possible to the Schedule of Assessments (Table 1), and 
analysis will be performed using the observed data.
2
STUDY SUMMARY
2.1 Study Objectives
The primary objective of this open-label study is to investigate the effect of TAK-935 
on the frequency of motor seizures for patients with Dup15q or CDD during the 
Maintenance Period.
The secondary objectives are:

To investigate the effect of TAK-935 on the frequency of motor seizures for 
patients with Dup15q or CDD during the Treatment Period (Dose 
Optimization and Maintenance).

To investigate the proportion of patients considered as treatment responders
for patients with Dup15q or CDD throughout the Maintenance Period; 
treatment responders are defined as those with:
o
Reduction of 25% or more in motor seizures from baseline
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o
Reduction of 50% or more in motor seizures from baseline
o
Reduction of 75% or more in motor seizures from baseline
o
Reduction of 100% in motor seizures from baseline
!
To investigate the effect of TAK-935 on the frequency of motor seizures
lasting >5 minutes for patients with CDD throughout the Treatment Period
!
To investigate the effect of TAK-935 on the percent/frequency of motor 
seizure free days in patients with Dup15q or CDD during the Maintenance
Period
!
To assess Clinical Global Impression of Severity (CGI-S) provided by the 
Investigator
!
To assess the Clinical Global Impression of Change (CGI-C) provided by the 
Investigator
!
To assess the Caregiver Global Impression of Change (Care GI-C) responses 
of the parent/family-reported impression of efficacy and tolerability of study 
drug
!
To investigate the relationship between 24HC level and motor seizure 
frequency
The safety objectives are:
!
To evaluate safety and tolerability of TAK-935
!
To investigate the effect of TAK-935 on behavior and adaptive function using 
the Vineland Adaptive Behavior scales (VABS) and Aberrant Behavior 
Checklist Community questionnaire (ABC-C)
!
To evaluate the percent of days free of absence seizures in patients who report 
absence seizures at baseline, to determine if there is worsening of this seizure 
type during treatment with TAK-935
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2.2 Study Design
TAK-935-18-002 (OV935) is a multicenter, open-label, 2-cohort, Phase 2 study in 
patients aged ≥2 and ≤55 years with Dup15q or CDD demonstrating ≥3 motor 
seizures [i.e., hemiclonic, focal with motor signs, focal to bilateral tonic clonic 
convulsion, generalized tonic clonic convulsion, tonic, atonic, bilateral clonic, 
infantile spasms (if countable), epileptic spasms (if countable), convulsive status, 
cluster seizures with a code containing A, C, D, E, H, I, J, J, K, L, or N] per month 
during the 3 months immediately prior to Screening (based on the Investigator’s 
assessment). Myoclonic seizures are not part of the count of motor seizures.
The maximum study evaluation period is 30 weeks, comprised of the periods: 

4- to 6-week Screening/Baseline Period

20-week Treatment Period
o
8-week Dose Optimization Period
o
12-week Maintenance Period

For patients who do not enroll in the long-term, open-label extension (TAK-
935-18-001 ENDYMION OLE) study under a separate protocol:
o
2-week Taper Period
o
2-week Safety Follow-Up Period
At the end of the prospective Screening/Baseline Period, patients will return to the 
clinic (Visit 2 [Day 1]). Seizure diaries will be reviewed by the Medical Monitor and 
if a patient did not meet the eligibility criteria, including minimum number of seizures 
required for the study (≥3 motor seizures), the patient will be discontinued from the 
study and considered a screen failure.
The total daily dose of TAK-935 is calculated based on body weight at Visit 1 and 
will be given twice a day (BID) orally or via G-tube/PEG tube/J-tube with or without 
food (patients enrolled in clinical sites in China are not to receive study drug via G-
tube/PEG tube/J-tube). Patients will receive the initial dose of study drug, Dose 1, for 
the first 7 days starting at Visit 2 (Day 1). The study drug dose will be increased to 
Dose 2 and Dose 3 at Day 8 (± 2 days) and Day 15 (± 2 days), respectively. The 
maximum dose for any patient will be 600 mg/day (300 mg BID). The dose may be 
changed during the Dose Optimization Period with approval from the Medical 
Monitor. The final dose level will be maintained until the end of the Maintenance 
Period. Patients who cannot tolerate Dose 1 will be withdrawn from the study (and 
will complete the early termination [ET] and safety follow-up visits).
Following completion of the study, patients will have the option to enroll in a long-
term, OLE study (TAK-935-18-001 ENDYMION) or to enter a taper period 
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(maximum 14 days). During the taper period, the study drug dose will be de-escalated 
to a lower dose (taper Dose 3 to Dose 2, taper Dose 2 to Dose 1) every 3 days or less 
frequently based on Investigator’s discretion until there is no de-escalation and study 
drug dose is discontinued. After tapering, patients will complete a safety follow-up 
visit approximately 15 days after the last dose of study drug and exit the study.
The end of the study for an individual patient is defined as the last protocol-specified 
contact with that patient.
For the purpose of this SAP, ‘motor seizures’ refers to motor seizures excluding 
myoclonic seizures.
2.2.1 Number of Patients
Approximately 30 total male and female patients with Dup15q or CDD
(approximately 15 patients in each syndrome) will be enrolled.
2.2.2 Enrollment Procedures
All patients will receive TAK-935 throughout this open-label study. Assignment to 
analysis groups will be determined by the seizure syndrome: Dup15q or CDD. The 
study will begin with a phased enrollment based on age:

Two patients aged ≥9 years will be enrolled for assessment of safety and 
pharmacokinetics (PK). The independent Data Monitoring Committee 
(iDMC) will review safety (adverse events [AEs] and clinical laboratory 
results) and available PK data for these 2 patients at the end of initial up-
dosing or Day 21

The iDMC may then recommend treatment for additional patients aged ≥9 
years and the first 2 patients aged ≥2 to <9 years

Safety and available PK data for the first 2 patients aged ≥2 to <9 years will 
be reviewed by the iDMC at the end of initial up-dosing or Day 21

The iDMC may then recommend treatment for additional patients aged ≥2 to 
<9 years

The Sponsor’s Medical Monitor and/or Pharmacovigilance Physician will 
review safety data and available PK of the first 2 patients aged ≥9 years and 
the first 2 patients aged ≥2 to <9 years during each step of dose escalation.
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2.2.3 Efficacy Assessments
2.2.3.1
Seizure Diary
The seizure diary is an observer-reported clinical outcome assessment measure that 
captures the total number and duration of seizures by type. Seizure type will be 
recorded as one of: hemiclonic, focal without motor signs, focal with motor signs, 
focal to bilaterial tonic clonic convulsion, myoclonic, generalized tonic clonic 
convulsion, absence or atypical absence, tonic, atonic, bilaterial clonic, infantile 
spasms (if countable; in patients under 3 years of age), epileptic spasms (if countable; 
in patients 3 years of age and older), non-convulsive status (greater than 30 min),
convulsive status (greater than 30 min), or cluster seizures with a corresponding code. 
Myoclonic seizures are captured in the seizure diary although they are not part of the 
motor seizure count. Refer to Appendix 1 for the classification of seizure types.
Patients and/or patients’ caregivers may record seizures throughout the day but must 
ensure that the daily diary assessment is completed each evening, even if no seizures 
occurred. The seizure events will be recorded starting at the Screening/Baseline 
Period up until the Follow-up Visit and collected at each clinic visit: Day 1, Day 15, 
Day 36, Day 85, Day 141 End of Treatment (EOT)/ET, and Follow-up Day 169 (for 
patients under the original protocol: Day 1, Day 8, Day 15, Day 29, Day 57, Day 
85/ET, and Follow-up Day 86-Day 115).
2.2.3.2
Caregiver Global Impression of Change (Care GI-C)
The Care GI-C comprises a single question assessing the status of the patient’s 
overall condition compared to pre-treatment baseline rated on a 7-point scale (1=Very 
much improved to 7=Very much worse) that will be given at Day 36, Day 85, and 
Day 141 EOT/ET (for patients under the original protocol: Day 29, Day 57, and Day 
85/ET). If the main caregiver is not available at the appropriate visit then this 
information can be captured over the telephone, ideally on the day of the visit or 
otherwise within 3 days. At Visit 2 (Day 1; prior to administration of the first dose of 
study drug), the caregiver will be asked to write a brief description of the patient’s 
overall condition as a memory aid for the Care GI-C at subsequent visits. 
2.2.3.3
Clinical Global Impression of Severity/Change (CGI-S/C)
The CGI-S is a clinician-reported rating of illness severity. The Principal Investigator 
or designee will complete the CGI-S at Day 1, Day 36, Day 85, and Day 141 
EOT/ET (for patients under the original protocol: Day 29, Day 57, and Day 85/ET). 
Ratings are made on a 7-point scale from 1 (normal, not at all ill) through to 7 
(amongst the most extremely ill). A score of 0 may be recorded on the case report 
form (CRF), indicating “not assessed”; this score will be treated as missing for the 
calculation of descriptive statistics. 
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The CGI-C is a clinician-reported rated of change compared to the pre-treatment 
baseline.  The Prinicpal Investigator or designee will complete the CGI-C at Day 36, 
Day 85, and Day 141 EOT/ET (for patients under the original protocol: Day 29, Day 
57, and Day 85/ET). The rating considers both therapeutic efficacy and treatment-
related AEs.  The ratings range from 0 (marked improvement and no side-effects) 
through 4 (unchanged or worse and side-effects outweigh the therapeutic effect). 
Each component of the CGI is rated separately; the instrument does not yield a global 
score.
2.2.3.4
Plasma 24HC Level
A plasma sample to assess pharmacodynamics (concentration of plasma 24HC) will 
be collected pre-dose on Day 1, Day 15, Day 36, Day 85, Day 141 EOT/ET, and 
Follow-up Day 169 (for patients under the original protocol: Day 1, Day 29, and Day 
85/ET).
2.2.3.5
Pharmacokinetics of TAK-935
Five (5) PK blood draws will occur at the following time points on Day 1: within 1 
hour prior to first dose, 30 minutes (± 10 minutes), 1, 2, and 4 hours (± 10 minutes) 
post-first dose. On Day 15, Day 36, Day 85, and Day 141 EOT/ET, two PK blood 
draws will be collected; one within 1 hour prior to the morning dosing and the other 
at 30 minutes (± 10 minutes) post-morning dose. For patients under the original 
protocol, PK blood draws are at pre-dose and post-dose on Day 1; then additional PK 
samples at pre-dose and post-dose at Day 8 and Day 15, and a single PK draw at 
either pre-dose or post-dose at Day 29 and Day 85/ET.
2.2.3.6
Plasma Concentrations of AEDs
A plasma sample for AED analysis will be collected on Day 1, Day 36, Day 85, and 
Day 141 EOT/ET (for patients under the original protocol: Day 1, Day 29, and Day 
85/ET). The AEDs to be analyzed are listed in Appendix 4.
2.2.4 Safety Assessments
2.2.4.1
Adverse Events
After the informed consent form (ICF) is signed, site personnel will record any 
change in the condition(s) and the occurrence and nature of any AEs. If a patient 
experiences an AE after signing informed consent, but prior to receiving study drug, 
the event will be reported, but will be included in the patient’s medical history unless 
the event is serious, or the Investigator feels the event may have been caused by a 
protocol procedure. All AEs occurring after the patient receives the first dose of study 
drug must be reported to the Sponsor or its designee via the CRF. Serious adverse 
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events (SAEs) must be reported as such, starting from the time that informed consent 
for study participation is provided.
Investigators will rate the severity of AEs (mild, moderate, or severe) using the 
criteria in Protocol Section 8.3.1.1 and will report the potential relatedness of each 
AE to protocol procedure and/or study drug using the criteria in Protocol Section 
8.3.1.2.
For the purpose of this study, reporting of seizures should meet the AE/SAE reporting 
requirements. As seizures are a baseline condition among subjects in the study, 
seizures should be reported as an AE/SAE if: 1) there is a clear increase in the 
frequency of seizures compared to the patient’s baseline, 2) there is an emergence of
a new seizure type, or 3) the patient experiences status epilepticus, and any other time 
the investigator feels the seizure should be captured as an AE/SAE, in which case the 
Investigator should document his/her reasoning. All seizures will be captured in the 
seizure diary collected at the site during the study and will be analyzed by the 
Sponsor along with the reportable SAEs in the risk-benefit evaluation.
2.2.4.2
Serious Adverse Events
Serious adverse event collection begins after the patient has signed the ICF. If a 
patient experiences an SAE after signing the ICF, but prior to receiving study drug, 
the event will be reported, but will be classified as a pre-treatment SAE unless the 
Investigator feels the event may have been caused by a procedure listed in the 
protocol.
2.2.4.3
Clinical Laboratory Evaluation
The central laboratory will perform laboratory tests for hematology, serum chemistry, 
and urinalysis. Local laboratory tests may be performed as needed. Samples are to be 
collected at Screening, Day 1, Day 15, Day 36, Day 85, and Day 141 EOT/ET (for 
patients under the original protocol: Screening, Day 1, Day 29, Day 85/ET). The 
clinical laboratory tests to be performed are listed in Appendix 4.
2.2.4.4
Vital Signs, Height, and Weight
Vital signs should be measured at the same time of day across visits, if possible. Vital 
signs to be measured are oral body temperature, blood pressure (sitting, standing, and 
supine), heart rate [beats per minute] (sitting, standing, and supine), and respiratory 
rate. Height and weight will also be measured. Measurements will be taken at 
Screening, Day 1, Day 15, Day 36, Day 85, Day 141 EOT/ET, and Follow-up Day 
169 (only vitals at Day 169). For patients under the original protocol, measurements 
were taken at Screening, Day 1, Day 8 (height and weight only), Day 15, Day 29, 
Day 57, and Day 85/ET. Weight at screening is used to determine the dosing 
schedule.
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2.2.4.5
Electrocardiogram (ECG)
A 12-lead ECG will be recorded at Screening and at 30 minutes (± 10 minutes) after 
the morning dose at Day 1, Day 15, Day 36, Day 85, and Day 141 EOT/ET (for 
patients under the original protocol: Screening, Day 1, Day 29, and Day 85/ET). If the 
patient cannot tolerate being supine, a sitting ECG may be obtained. The Investigator 
(or a qualified observer at the study site) will interpret the ECG using one of the 
following categories: within normal limits, abnormal but not clinically significant, or 
abnormal and clinically significant. The following parameters will be recorded on the 
CRF from the patient’s ECG trace: heart rate, RR interval, PR interval, QT interval, 
QRS interval, and corrected QT interval.
2.2.4.6
Physical Examination
The physical examination will be performed at Screening, Day 1, Day 15, Day 36, 
Day 85, Day 141 EOT/ET, and Follow-up Day 169 (for patients under the original 
protocol: Screening, Day 1, Day 15, Day 29, Day 57, and Day 85/ET), and will assess
the following body systems: head, eyes, ears, nose, throat; cardiovascular; respiratory; 
gastrointestinal; dermatologic; extremities; musculoskeletal; lymph nodes; psychiatric 
status; and additional results for other systems may be specified. At Day 15, the 
physical examination can be limited to general appearance; head, ears, nose, and 
throat; cardiovascular; respiratory; and abdominal.
2.2.4.7
Neurological Examination
A separate neurological examination will be performed at Screening, Day 1, Day 15, 
Day 36, Day 85, Day 141 EOT/ET, and Follow-up Day 169 (for patients under the 
original protocol: Screening, Day 1, Day 15, Day 29, Day 57, and Day 85/ET) and 
collected in the CRF. This will include testing mental status, gait, cerebellar function, 
cranial nerves, motor function, reflex, and sensation.
 
2.2.4.8
Clinical Assessment of Suicidal Ideation and Behavior
Suicidal ideation and behavior will be assessed in children aged ≥6 years using the 
Columbia-Suicide Severity Rating Scale (C-SSRS) at Screening, Day 1, Day 85, Day 
141 EOT/ET, and Follow-up Day 169 (for patients under the original protocol: 
Screening, Day 1, Day 29, and Day 85/ET). The C-SSRS is a 3-part scale that 
measures suicidal ideation, intensity of ideation, and suicidal behavior.
Two versions of the C-SSRS will be used in this study, the Screening/Baseline C-
SSRS Lifetime and the Since-Last-Visit C-SSRS. The investigator will use clinical 
judgment to determine presence of suicidal ideation or behavior.
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2.2.4.9
Vineland Adaptive Behavior Scale
The Vineland Adaptive Behavior Scale, 3rd Edition, Comprehensive Parent 
Caregiver Form (VABS-3 Parent Caregiver Form), is a caregiver-report questionnaire 
that assesses adaptive functioning across the following 4 domains and 11 subdomains.
The following domain and subdomain scores will be provided by Pearson’s Qglobal
and will be used for analysis. They are consistent with VABS-3 Parent Caregiver 
form manual pages 25-26.
The Motor domain data was collected prior to the current protocol amendment and 
will be presented in the listing.
Domain 
Subdomains 
Communication 
Receptive
Expressive 
Written 
Daily Living Skills
Personal 
Domestic 
Community 
Socialization 
Interpersonal Relationships 
Play and Leisure 
Coping Skills
Maladaptive Behaviors 
Internalizing 
Externalizing 
Each item is scored from 0 to 2. If a caregiver estimates a response, the item score is 
reported as a 97, 98, or 99 on the CRF to indicate that they are estimates, but for the 
calculation of domain and subdomain totals, 97 is mapped to 2, 98 is mapped to 1 and 
99 is mapped to 0. 
For the Communication, Daily Living, and Socialization and Maladaptive behavior
domains, each domain yields a normative-based standard score. Each subdomain 
within these three domains yields a v-scale score, age equivalent score, and total raw 
score. For the Problem Behavior domain, the Internalizing (Section A) and 
Externalizing (Section B) subdomains yield a v-scale score and total raw score. All 
raw score calculations respect the basal and ceiling rules of the scale. Scoring will be 
completed using the publisher’s scoring software program, Pearson’s Qglobal.
The VABS-3 will be administered at Screening and Day 141 EOT/ET (Day 85/ET for 
patients who completed the study under the original protocol).
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2.2.4.10 Aberrant Behavior Checklist-Community (ABC-C)
The ABC-C measures psychiatric symptoms and behavioral disturbance exhibited by 
individuals across 5 subscales with 58 items: irritability, agitation, and crying 
(Irritability subscale: 15 items); lethargy, social withdrawal (Lethargy/Social 
Withdrawal subscale: 16 items); stereotypy (Stereotypic Behavior subscale: 7 items); 
hyperactivity/noncompliance (Hyperactivity subscale: 16 items); and inappropriate 
speech (Inappropriate Speech subscale: 4 items). Each item is rated on a scale of 0 to 
3 (“not at all a problem” to “the problem is severe in degree”).
The total score is calculated by summing the scores on all 58 items. Each subscale 
score is calculated by summing the items below:
The scale includes the following 5 subscales with the sub scores derivation:
Subscales
Sum of Questions*
Irritability
2, 4, 8, 10, 14, 19, 25, 29, 34, 36, 41, 47, 50, 52, 
57
Lethargy/Social Withdrawal
3, 5, 12, 16, 20, 23, 26, 30, 32, 37, 40, 42, 43, 53, 
55, 58
Stereotypic Behavior
6, 11, 17, 27, 35, 45, 49
Hyperactivity
1, 7, 13, 15, 18, 21, 24, 28, 31, 38, 39, 44, 48, 51, 
54, 56
Inappropriate speech
9, 22, 33, 46
*For missing data, the following upper limits will apply (number of missing items tolerated for each 
subscale before discarding the data for that subscale): (I) Irritability (15-item scale): 3 items; (II) 
Lethargy/Social Withdrawal (16-item scale): 3 items; (III) Stereotypic Behavior (7-item scale)” 2 
items; (IV) Hyperactivity/Noncompliance (16-item scale): 3 items; (V) Inappropriate Speech (4-item 
scale): 1 item. If more items than the stated upper limit have been left blank, the subscale will not be 
computed. If the subscale has the required minimum number of items, the subscale scores will be 
prorated as follows: (a) Take the total number of items on the subscale and divide this by the number 
of completed items. This will result in a number larger than 1.00. (b) Multiply that number by the total 
score for that subscale. (c) This becomes the new total score for this subscale for the given subject.
The ABC-C questionnaire is completed by the caregiver at Screening and at Day 141 
EOT/ET (Day 85/ET for patients who completed the study under the original 
protocol).
2.2.4.11 Absence Seizures 
Patients and/or patients’ caregivers will also observe and report absence seizures 
using the seizure daily diary (seizure type “absence or atypical absence”).
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2.2.4.12 New seizure types
New seizure types are defined as any seizure type that was not listed at screening or 
during baseline period but were observed and reported during treatment period. The 
number of patients with at least 1 new seizure type will be listed.
2.2.5
2.2.6 Other Assessments
Demographics, medical history, and medication history will be collected at 
Screening. Ongoing comorbidities are considered concurrent medical conditions and 
will also be documented. Additionally, an optional severity assessment may be 
conducted in only the CDD patients at Screening and at the end of treatment to 
capture degrees of severity associated with motor function, cognition, and vision and 
autonomic dysfunction.
A serum/urine pregnancy test will be given at Screening, Day 1, and Day 141 
EOT/ET (Screening, Day 1, and Day 85/ET for patients under the original protocol). 
Concomitant medications (including AEDs) will be reported on an ongoing basis.
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Table 1. Schedule of Assessments
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3
STATISTICAL METHODS
3.1 General Methods
3.1.1 Computing Environment
All statistical analyses will be performed using SASVersion 9.4 or higher for 
Windows.
3.1.2 Presentation of Data Summaries
Unless otherwise specified, tables will be presented by analysis group (Dup15q or 
CDD) within analysis set. An “All Patients” column will be included as appropriate.
All clinical study data will be presented in patient data listings.
3.1.3 Reporting of Numerical Values
Descriptive statistics (number of patients [n], mean, standard deviation [SD], first 
quartile [Q1], median, third quartile [Q3], minimum, and maximum) will be 
calculated by analysis group for all continuous variables. Confidence intervals will be 
provided where appropriate.
Frequencies and percentages will be presented by analysis group for categorical and 
ordinal variables. If there are missing values, the number of missing will be 
presented, but without a percentage.
Means, quartiles, and confidence intervals will be reported to one decimal place more 
than the data reported on the CRF or by the laboratory/vendor. Standard deviations 
will be reported to two decimal places more than the data reported. Minimum and 
maximum will be reported to the same number of decimal places displayed on the 
CRF or by the laboratory/vendor. 
3.1.4 Baseline Value and Change from Baseline
For seizure endpoints (frequency and duration) based on the seizure diary, baseline 
values will be calculated over the 4 to 6 week Screening/Baseline Period prior to first 
dose (starting at date of initial screening visit). The period from the initial screening visit 
until the day prior to the first dose will be considered baseline even in the case of an 
extended screening period. For measures taken at a single time point, the baseline 
value will be defined as the most recent non-missing value obtained immediately 
prior to administration of first dose. Change from baseline will be calculated by 
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subtracting the baseline value from the post-dose assessment for each patient (i.e., 
post-dose – baseline).
3.1.5 Study Day
Study day will be defined in relation to date of the first dose of study treatment. For pre-
dose records, study day will be calculated as (date of record – date of first dose). For 
records on or after the first dose of study treatment, study day will be calculated as (date 
of record – date of first dose + 1).
3.1.6 Handling of Missing/Incomplete Values
To the extent possible, attempts will be made to minimize the amount of missing data 
through measures planned in the study conduct. . Missing data will be kept as 
missing, no imputation will be done for missing data.  All analyses will be conducted
using observed values.
3.1.7 Handling of Repeated Assessments
If multiple results are available for a post-dose assessment at the same scheduled time 
point, then the earliest result recorded for that time point will be used in all 
descriptive summaries. All results will be displayed in patient data listings.
3.1.8 Handling of Missing/Incomplete Date/Time
Adverse Events
All analyses of AEs will be based on the principle of treatment emergence. An AE is 
considered to be treatment emergent if it has a start date/time or increases in severity
on or after the date/time of first dose of study treatment; if the AE is missing a start 
time, it is considered to be treatment emergent if it has a start date on or after the date 
of first dose of study treatment. Furthermore, for the presentation of AE incidences, 
non-serious treatment emergent adverse events (TEAEs) starting on or before 7 days 
after the last dose date or last visit date and SAEs starting on or before 30 days after 
the last dose date or last visit date will be included. If an AE start date is incomplete 
or missing, imputation and the AE end date will be used to determine treatment 
emergence and occurrence within the 7- or 30-day window. First, partial AE start/end
dates will be imputed as follows:

Missing end day: Impute as the last day of the month.

Missing end day and month: Impute as Dec 31.

Missing start day: If the partial date contains the same month and year as the 
treatment start date, impute as the treatment start date; otherwise, impute as 
the first day of the month.
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
Missing start day and month: If the partial date contains the same year as the 
treatment start date, impute as the treatment start date; otherwise, impute as 
January 1.
After the imputation of partial dates, use the following criteria:

First, for treatment emergence:
o
If the start date is on or after the date of first dose, then the AE is 
considered treatment emergent. 
o
If the start date is before the date of first dose, then the AE is not
considered treatment emergent unless it worsens.
o
If the start date is missing and the end date is on or after the date of 
first dose or the AE is ongoing, then the AE is considered treatment 
emergent. 
o
If the start date is missing and the end date is before the date of first 
dose, then the AE is not considered treatment emergent. 
o
If both the start and end dates are missing, then the AE is considered 
treatment emergent.

If treatment emergent, for occurrence within the 15-day or 30-day window:
o
The start date can be used to determine whether the AE is within the 
15-day (for non-serious AEs) or 30-day (for SAEs) window.
o
If the start date is completely missing, the non-serious AE will be 
considered within the 15-day window, or for an SAE, it will be 
considered within the 30-day window.
Prior and Concomitant Medications
A concomitant medication is any drug taken on or after the first dose of study drug. A 
prior medication is any drug started before the first dose of study drug. Medications 
that are ongoing on the date of the first administration of study drug will be 
considered both prior and concomitant. For the purpose of computation, a medication 
or procedure is considered to be concomitant if it has an end date/time on or after the 
first dose or if it is indicated as ongoing on the CRF. Similarly, a medication is 
considered to be prior if it has either a start date/time or end date/time before the first 
dose. If time is not available, then only date will be used (e.g. end date on or after the 
date of first dose). In order to determine concomitance, partial end dates will be 
imputed as follows:

Missing end day: Impute as the last day of the month.

Missing end day and month: Impute as Dec 31.
After the imputation of partial dates, the following criteria will be used:
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
If the end date is on or after the first dose, the medication will be considered 
concomitant.

If the end date is prior to the first dose, the medication will not be considered 
concomitant.

If the end date is missing, then the medication will be considered concomitant.
In order to determine whether a medication is prior, partial start dates will be imputed 
as follows:

Missing start day: Impute as the first day of the month.

Missing start day and month: Impute as Jan 1.
After the imputation of partial dates, the following criteria will be used:

If the start date or end date is before the first dose, the medication will be 
considered prior.

If the start date is on or after the first dose, the medication will not be 
considered prior.

If the start date is missing, then the medication will be considered prior.
3.2 Analysis Sets
3.2.1 Modified Intent-to-Treat Analysis Set
The Modified Intent-to-Treat (mITT) Analysis Set will include all patients who have 
received at least 1 dose of study drug and have been assessed for at least 1 day in the 
Treatment Period. All efficacy analyses will be based on the mITT Analysis Set.
3.2.2 Safety Analysis Set
The Safety Analysis Set will include all patients who have received at least 1 dose of 
study drug. Safety analyses will be based on the Safety Analysis Set.
3.3 Analysis Variables
3.3.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the percent change from baseline in motor seizure 
frequency per 28 days during the Maintenance Period.
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3.3.2 Secondary Efficacy Endpoints
The secondary efficacy endpoints in this study are:

Percent change from Baseline in motor seizure frequency per 28 days at each 
4-week interval within the Treatment Period, and over the entire 20-week 
Treatment Period

Percent change from Baseline in all seizure frequency per 28 days at each 4-
week interval within the Treatment Period, the 12-week Maintenance Period, 
and over the entire 20-week Treatment Period

Percent change from Baseline in frequency of each seizure type per 28 days at 
each 4-week interval within the Treatment Period, the 12-week Maintenance 
Period, and over the entire 20-week Treatment Period

Proportion of patients considered treatment responders at each 4-week interval
within the Treatment Period, the 12-week Maintenance Period, and over the 
entire 20-week Treatment Period, where treatment responders are defined as 
those with:
o
Reduction of 25% or more in motor seizures from baseline
o
Reduction of 50% or more in motor seizures from baseline
o
Reduction of 75% or more in motor seizures from baseline
o
Reduction of 100% in motor seizures from baseline

Proportion of motor seizures longer than 5 minutes during Baseline period, at 
each 4-week interval within the Treatment Period, the 12-week Maintenance 
Period, and over the entire 20-week Treatment Period

Proportion of motor seizure-free days during Baseline period, at each 4-week 
interval within the Treatment Period, the 12-week Maintenance Period, and 
over the entire 20-week Treatment Period

Proportion of all seizure-free days during Baseline period, at each 4-week 
interval within the Treatment Period, the 12-week Maintenance Period, and 
over the entire 20-week Treatment Period

Change from baseline in CGI-S responses 

Ratings by clinician using the CGI-C

Ratings of caregiver-provided Care GI-C

To characterize plasma 24HC levels and change in motor seizure frequency in 
patients treated with TAK-935 as an adjunctive therapy
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3.3.3 Exploratory Efficacy Endpoints
3.3.4 Safety Endpoints
The safety endpoints in this study are:
!
Percentage of patients with at least 1 treatment emergent adverse event
!
Change in behavioral and adaptive functional measures using the VABS
!
Change in behavior measures using total scores and subscale scores of ABC-C 
!
Percentage of patients with at least 1 markedly abnormal value for clinical 
laboratory evaluations, vital signs, body weight and height, and ECG 
parameters after TAK-935 treatment
!
Change from Baseline in clinical laboratory evaluations, vital signs, body 
weight, height, C-SSRS, and ECG parameter values after TAK-935 treatment
!
Percent of absence seizure free days in patients who report absence seizures
during baseline
!
Number of patients with new seizure types during the treatment period
3.4 Patient Disposition and Evaluability
3.4.1 Patient Disposition
Patient disposition will be presented by analysis group and overall for all enrolled 
patients. The number of patients screened, failed screening, and eligible will be 
presented. The number and percentage of patients in each analysis set (mITT and 
Safety Analysis Sets), completing and not completing the study, as well as reasons for 
patient discontinuations will be summarized.
Disposition data (extent of study participation) and inclusion/exclusion criteria not 
met will be provided in patient listings.
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A separate patient listing of disposition data will be provided for patients affected by 
COVID 19.
3.4.2 Protocol Deviations
All protocol deviations will be shown in a patient listing, with a flag for whether the 
deviation was related to COVID-19.
3.5 Demographics and Characteristics at Screening
3.5.1 Demographics and Characteristics at Screening
Patient demographics and characteristics at screening will be summarized by analysis 
group and overall for all analysis sets. If any of the analysis sets are equivalent to 
each other, the demographics summary will only be presented for one of the 
equivalent sets. Descriptive statistics will be provided for age (as reported on the 
CRF), height at screening, weight at screening, and body mass index (BMI) at 
screening. Frequencies and percentages will be tabulated for sex, race, and ethnicity.
Demographic information and characteristics at screening will be listed by patient.
3.5.2 Medical History
Medical history will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA) at the time of the data cut and presented by analysis 
group and overall for the Safety and mITT Analysis Sets, summarized by MedDRA 
system organ class (SOC) and preferred term (PT).
All medical history and concurrent medical conditions will be listed by patient.
3.6 Prior and Concomitant Medications
A concomitant medication is any drug taken after the first dose of study drug. 
Medications that are ongoing on the date of the first administration of study drug will 
be considered both prior and concomitant. Rules for determining whether medications 
with missing or incomplete dates/times are concomitant and/or prior are provided in 
Section 3.1.8.
Prior and concomitant medication use will be coded using the latest version of the 
World Health Organization Drug Dictionary (WHO-DD) at the time of the data cut. 
All concomitant medications will be summarized by Anatomic Therapeutic Class 
(ATC) Level 2, ATC Level 4 and Preferred Term (PT). Prior and concomitant AEDs 
will be summarized by PT and presented by analysis group and overall in the Safety 
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and mITT Analysis Sets. Medications will be sorted by decreasing frequency of 
incidence for both analysis groups combined. 
All prior and concomitant medications will be presented in a listing, with AEDs and
prior medications flagged. A separate listing of AEDs started during the Treatment 
Period [i.e. after the first dose of study drug, but before the tapering period (for any 
patients who do not roll over to the OLE)] will be presented.
3.7 Treatment Compliance and Exposure
3.7.1 Compliance to Study Treatment
Treatment compliance will be summarized by analysis group over the entire 
Treatment Period. Compliance rates during the Treatment Period will be derived 
using the following formula:
100 × (Total number of tablets/mini-tablets dispensed - Total number of tablets/mini-tablets returned)
(Expected number of tablets/mini-tablets)
Total dose administered will primarily be based on the drug accountability (Total 
dose dispensed – total dose returned).  If the “bottle returned” information on the drug 
accountability eCRF page is missing, the dose administered will be based on the 
dosing eCRF page for that period. All non-missing doses are considered full dose for 
calculating the “dose administered”.   Expected numbers of tablets/mini-tablets is 
based on the date of first study medication dose, date of last study medication dose, 
and date and amount of each study drug titration approved by the Investigator. 
According to Protocol Table 1, a patient will take either only mini-tablets (20 mg) or 
only regular tablets (100 mg) throughout the study. This calculation assumes that all 
study drug not returned was taken by the patient.
Patient dosing is based on Protocol Table 1, but the daily dose may be adjusted per 
Investigator’s discretion with approval of the Medical Monitor during the Dose 
Optimization Period; dose changes during the Maintenance Period must be discussed 
and approved by the Sponsor. Each time a new dose level (mg) and corresponding 
date of dose change is recorded, this will be considered the patient’s planned daily 
dose until the date of the next reported dose change or end of treatment.
Compliance rates will be presented for the Safety and mITT Analysis Sets using 
summary statistics and percentage for the frequency distributions (0% to <20%, 20% 
to <40%, 40% to <60%, 60% to <80%, 80% to <100%, 100% to ≤120%) by analysis 
group and overall. Compliance >120% is not expected, but if it occurs, the category 
“>120%” will be included in the summary.
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3.7.2 Exposure to Study Treatment
Treatment duration (weeks on treatment) will be described for the Safety and mITT 
Analysis Sets using summary statistics and frequency distributions (0 to <8 weeks, 8 
to <12 weeks, 12 to <20 weeks, ≥20 weeks) by analysis group and overall. Treatment 
duration in weeks will be calculated as follows: [(Last dose date – First dose date + 
1)/7].
Study drug dosing, exposure and compliance, and accountability will be listed by 
patient.
3.8 Efficacy Analysis
Unless otherwise specified, all efficacy analyses will be based on the mITT Analysis
Set and will be presented by analysis group and overall.  
3.8.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the percent change from baseline in motor seizure 
frequency per 28 days during the 12-week Maintenance Period, calculated according 
to Section 4.1. The start and end of the 12-week Maintenance Period are defined in 
Section 4.2.
The motor seizure types include hemiclonic, focal with motor signs, focal to bilateral 
tonic clonic convulsion, generalized tonic clonic convulsion, tonic, atonic, bilateral 
clonic, infantile spasms (if countable), epileptic spasms (if countable), convulsive 
status (greater than 30 min), and cluster seizures with a code containing A, C, D, E, 
H, I, J, J, K, L, or N.
Observed values, change from baseline, and percent change from baseline for motor 
seizure frequency per 28 days will be summarized separately for the patients with 
CDD and for the patients with Dup15q in the mITT Analysis Set. The mean of the 
change from baseline and of percent change from baseline will be presented along 
with its corresponding 90% confidence interval, separately for each analysis group 
and overall. Seizure frequency for each patient will be calculated using all available 
observed data within the 12-week Maintenance Period.
Histograms will be produced for the primary endpoint for each analysis group and 
will be repeated for all motor seizure types.
Compliance for seizure diary assessments will be summarized overall by subject 
group (<=80%, >80% to <100% and 100%) for the Treatment Period.
This primary analysis for the primary endpoint will be repeated for the all patients 
who completed the study.
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3.8.2 Secondary Efficacy Endpoints
Unless otherwise specified, all secondary efficacy analyses will be based on the mITT 
Analysis Set and will be presented by analysis group and overall.
3.8.2.1
All and Motor Seizure Frequency During the Treatment Period
The observed values, change from baseline, and percent change from baseline for all 
and motor seizure frequency per 28 days will be summarized for each 4-week interval 
within the Treatment Period, the 12-week Maintenance Period, and over the entire 20-
week Treatment Period. The start and end of each interval are defined in Section 4.2, 
and seizure frequency is calculated according to Section 4.1.
The time course of the mean ± SD of seizure frequency at baseline and over each 4-
week interval in the Treatment Period will be displayed in a line graph by analysis 
group. This will be repeated for percent change from baseline in motor seizure 
frequency.
A line plot will be presented for each patient showing the patient’s motor seizure 
frequency and all seizure frequency (two lines per patient) at baseline and over each 
4-week interval in the Treatment Period.
 
This figure will be repeated to show the 
percent change from baseline in motor seizure frequency and all seizure frequency for 
each patient over each 4-week interval in the Treatment Period.
The observed values, change from baseline, and percent change from baseline for 
frequency of each type of seizure per 28 days at each 4-week interval within the 
Treatment Period, the 12-week Maintenance Period, and over the entire 20-week 
Treatment Period.
Motor seizure frequencies will be listed by patient for each of the nine intervals. This 
will be repeated for each seizure type. Additionally, all seizure diary data will be 
listed.
3.8.2.2
Response to Treatment Based on Seizure Frequency
Response to treatment will be summarized by the number and percentage of patients 
with ≥25% reduction, ≥50% reduction, ≥75% reduction, and 100% reduction from 
baseline in motor seizure frequency at each 4-week interval within the Treatment 
Period, the 12-week Maintenance Period, and over the entire 20-week Treatment 
Period. For exploratory purposes, this tabulation will be repeated for the categories in 
percent seizure reductions: </=0, >0 to <25, >/=25 to <50, >/=50 to <75, >/=75 to 
100.
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3.8.2.3
Duration of Motor Seizures
A summary of motor seizures longer than 5 minutes will be presented, calculated 
according to the formula in Section 4.1. The proportion of patient with motor seizures 
longer than 5 minutes during the Baseline period, at each 4-week interval within the 
12-week Maintenance Period, and the 20-week Treatment Period will be presented as 
defined in Section 4.2.
The frequency of motor seizures longer than 5 minutes will be included in the seizure 
frequency listing described in Section 3.8.2.1.
3.8.2.4
All and Motor Seizure Freedom
The number of motor seizure-free days during the 20-week Treatment Period will be 
summarized only for patients who have completed the study. The proportion of motor 
seizure-free days during Baseline period, at each 4-week interval within the 12-week 
Maintenance Period, and over the entire 20-week Treatment Period will also be 
summarized for these patients and is calculated for each patient as:
Number of days with 0 motor seizures during the Treatment Period
Number of days patient was in the Treatment Period (observed)
A separate summary will be presented for only patients who have completed the 
study and will include the number and percentage of these patients who were motor 
seizure-free during the Baseline period, at each 4-week interval within the 12-week 
Maintenance Period, and over the entire 20-week Treatment Period.
Additionally, each patient’s longest motor seizure-free duration will be calculated as 
the longest number of consecutive days that the patient had a motor seizure count of 0 
recorded in the seizure diary during the 12-week Maintenance Period and over the 20-
week Treatment Period using observed data. These patient-specific longest motor 
seizure-free durations will be listed, along with the number and proportion of motor 
seizure-free days for each patient during the 12-week Maintenance Period and over 
the 20-week Treatment Period, whether each patient was motor seizure-free over the 
last 28 days of the Treatment Period, and the number of days each patient was in the 
Treatment Period.
All seizure-free days will be analyzed similarly to motor seizure-free days.
3.8.2.5
CGI-S/C and Care GI-C
For CGI-S assessments, the observed values and change from baseline in CGI-S score 
will be summarized with descriptive statistics by visit.
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Additionally, the number of subjects and percentage of each category in CGI-S will 
be summarized by visit.  A shift in CGI-S categories will also be summarized from 
Baseline to the end of Maintenance Period.
For CGI-C, and Care GI-C, the number of subjects and percentage for each category 
in the readings will be listed by visit during the Maintenance Period.  A shift from 
baseline in the category of the ratings will be summarized at the end of Maintenance 
Period.  The proportion of subjects who achieved positive improvement will be 
summarized by visit.
CGI-S, CGI-C and Care GI-C Scores will be listed by subject.
3.8.2.6
Plasma 24HC Level
Observed and change from baseline in plasma 24HC levels will be summarized by 
visit by subject group.  BLQ values will be treated as missing for the calculation of 
summary statistics. The level of plasma 24HC at each visit will be listed by patient.  
BLQ will be listed as not detectable. 
Additionally, the relationship between motor seizure frequency and the level of 
plasma 24HC will be explored. The motor seizure frequency line plots for each 
patient, described in Section 3.8.2.1, will be annotated with the 24HC levels. A 
corresponding listing will present the 24HC levels side-by-side with the observed and 
change from baseline in motor seizure frequencies at each 4-week interval in the 20-
week Treatment Period. The 24HC collection visits will be paired with the 4-week 
seizure frequency intervals as follows:
24HC Collection Visit
Seizure Frequency Interval
Baseline
Baseline Period
Day 15
Day 1 – Day 28
Day 29/Day 36
Day 29 – Day 56
-
Day 57 – Day 84
Day 85
Day 85 – Day 112
Day 141 EOT/ET
Day 113 – Day 141
3.8.3 Exploratory Endpoints
3.8.3.1
Plasma Concentration of TAK-935
The plasma concentration of TAK-935 will be summarized descriptively by visit and 
planned time point. A line plot of the mean ± SD of the TAK-935 plasma 
concentration will be displayed by planned time point and analysis group. 
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Additionally, spaghetti plots of TAK-935 plasma concentration over time will be 
shown separately for each analysis group. For both plots, all time points will be 
shown on one plot, with wider spacing along the x-axis between days. For the 
calculation of descriptive statistics for tables and figures, BLQ concentration values 
will be set to undetectable.
Plasma concentrations at each planned time point will also be listed by patient.  For 
BLQ concentrations, the undetectable values will also be listed.
3.9 Safety Analysis
All safety assessments will be based on the Safety Analysis Set and presented by 
analysis group and overall, unless otherwise indicated.
3.9.1 Adverse Events
All AEs will be coded using the latest version of MedDRA at the time of the data cut
and will be classified by MedDRA SOC, high level group term (HLGT), high level 
term (HLT), and PT.
Analyses of AEs will be based on the principle of treatment emergence. A TEAE is 
any AE that starts or increases in severity during or after the first dose of study drug.
For presentations of AE incidences, non-serious TEAEs starting on or before 15 days 
after the last dose date or last visit date and SAEs starting on or before 30 days after 
the last dose date or last visit date will be included, unless otherwise specified below. 
Refer to Section 3.1.8 for the handling of incomplete or missing date/time in 
determining treatment emergence and occurrence within the 15- or 30-day window. 
The SOCs, HLGTs, and HLTs will be sorted alphabetically, and within SOC, HLGT, 
or HLT, the PT will be presented by decreasing total frequency in all patients and 
then alphabetically. If a patient has more than one occurrence of the same PT, then 
the PT will be counted only once for that patient. Similarly, if a patient has more than 
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one PT within the same SOC, HLGT, or HLT, the patient will be counted only once 
in that SOC, HLGT, or HLT.
All serious and non-serious AEs will be presented in a data listing, with flags for 
treatment emergence and occurrence after the 15- or 30-day window.
3.9.1.1
Summary of TEAEs
The numbers and percentages of patients who experienced any TEAE, treatment-
related TEAE, severe TEAE, severe treatment-related TEAE, serious TEAE, TEAE 
leading to permanent withdrawal of study drug, and TEAE leading to discontinuation 
from study will be presented. Treatment-related TEAEs will be defined as events with 
a study drug causality of “Possibly Related” or “Related”.
3.9.1.2
Incidence of TEAEs
The number and percentage of patients who experienced any TEAE as well as the 
number and percentage of patients who experienced any TEAE within each specific 
SOC and PT will be presented. Three similar summary tables will also be presented: 
(1) TEAEs by PT; (2) TEAEs by SOC, HGLT and PT; (3) TEAEs by SOC, HLT and 
PT. The SOC/PT and PT summaries will be presented once where occurrence within 
the 15- or 30-day window is required for a TEAE to be included, and again where 
occurrence within the 15- or 30- day window is not required. The last two summaries 
that use HGLT and HLT will be presented once, with TEAEs required to be within 
the 15- or 30- day window in order to be included.
3.9.1.3
Treatment-Related TEAEs
TEAEs with a study drug causality of “Possibly Related” or “Related” occurring 
within the 15- or 30-day window will be classified as treatment-related and presented 
by SOC and PT. TEAEs with missing relationship will be classified as treatment-
related in the summarization.
All treatment-related TEAEs will be listed by patient.
3.9.1.4
TEAEs by Maximum Severity
The incidence of TEAEs occurring within the 15- or 30-day window will be 
presented by maximum severity for each SOC and PT. If a patient experiences more 
than one occurrence of the same PT, the patient will be counted only once under the 
maximum severity at which it was experienced. Missing severity will remain 
classified as missing, and will be considered to be the maximum severity only if the 
patient never had the same TEAE with a non-missing severity; if missing severity is 
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considered to be the maximum, the TEAE will be counted in only the “Total” column 
of the table.
3.9.1.5
Severe TEAEs
The incidence of TEAEs classified as severe occurring within the 15- or 30-day 
window will be presented by SOC and PT.
3.9.1.6
Severe Treatment-Related TEAEs
The incidence of severe treatment-related TEAEs occurring within the 15- or 30-day 
window will be presented by SOC and PT.
3.9.1.7
Serious TEAEs
The incidence of SAEs starting on or before 30 days after the last dose date or last 
visit date will be summarized by SOC and PT. All SAEs will be listed by patient.
3.9.1.8
TEAEs Leading to Discontinuation from Study
The incidence of TEAEs leading to discontinuation from study will be summarized 
by SOC and PT. TEAEs leading to discontinuation from study will be listed by 
patient.
3.9.1.9
TEAEs of Special Interest
3.9.2 Clinical Laboratory Evaluation
A list of hematology, coagulation, chemistry, and urinalysis parameters collected 
during the study is provided in Appendix 4.
Observed values and change from baseline to each visit for continuous chemistry, 
hematology, coagulation, and urinalysis results will be summarized descriptively. For 
each continuous laboratory parameter, results will be categorized as low, normal, or 
high based on the laboratory normal ranges. Frequencies and percentages will be 
presented for the shifts from baseline to each post-baseline visit (i.e., low to normal, 
low to high, high to low, etc.) for each parameter.
All laboratory results will be listed by patient, with out of normal range values 
flagged. A separate listing of abnormal results will be provided, as well as a listing of 
serum and urine pregnancy test results.
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3.9.3 Vital Signs, Height, and Weight
Observed values and change from baseline in oral body temperature, heart rate
(sitting, standing, and supine), respiratory rate, systolic and diastolic blood pressure
(sitting, standing, and supine), height, and weight will be summarized descriptively 
by visit.
All vital sign measurements, height, and weight, will be listed by patient.
3.9.4 ECG
Observed values and change from baseline in heart rate, RR interval, PR interval, QT 
interval, QRS interval, and corrected QT interval will be summarized by study visit.
All ECG results will be listed by patient, with a flag for clinical significance.
3.9.5 Physical Examination
For each body system (head, eyes, ears, nose, throat; cardiovascular; respiratory; 
gastrointestinal; dermatologic; extremities; musculoskeletal; lymph nodes; psychiatric 
status), shifts from baseline to final visit (no change, normal to abnormal, or abnormal 
to normal) will be presented.
All physical examination results will be listed by patient.
3.9.6 Neurological Examination
For each component of the neurological examination (mental status, gait, cerebellar 
function, cranial nerves, motor function, reflex, and sensation), shifts from baseline to 
final visit (no change, normal to abnormal, or abnormal to normal) will be presented.
 
3.9.7 Clinical Assessment of Suicidal Ideation and Behavior
A patient will be considered to have suicidal ideation if the response to either C-SSRS 
Suicidal Ideation question 1 or 2 (Wish to be Dead, Non-Specific Active Suicidal 
Thoughts) is “Yes”.  A patient will be considered to have suicidal behavior if the 
response to any of the six C-SSRS Suicidal Behavior questions (Actual Attempt, 
Interrupted Attempt, Aborted Attempt, Preparatory Acts or Behavior, Suicidal 
Behavior, Completed Suicide) is “Yes”.
The number and percentage of patients aged ≥6 years considered to have suicidal 
ideation, and the number and percentage of patients considered to have suicidal 
behavior based on the C-SSRS will be summarized by visit. The results of all C-
SSRS assessments will be listed by patient.
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3.9.8 Vineland Adaptive Behavior Scale (VABS)
VABS raw domain scores for behavior, communication, daily living, socialization, 
and problem behavior will be reported along with the relevant raw subdomain scores. 
Observed and change from baseline in the VABS raw domain and subdomain scores 
will be summarized descriptively. All VABS results will be listed by patient.
3.9.9 Aberrant Behavior Checklist-Community
ABC-C total score and subscale scores will be calculated according to Appendix 3. 
Observed and change from baseline in the ABC-C total score and subscale scores will 
be summarized descriptively. All ABC-C questionnaire results will be listed by 
patient.
3.9.10 Absence Seizure-Free Days
The percentage of absence seizure-free days will be calculated over the 4 to 6 week 
prospective Screening/Baseline Period, during the 12-week Maintenance Period, and 
during the 20-week Treatment Period. Observed values and change from baseline will 
be summarized for patients who reported absence seizures at baseline using 
descriptive statistics.
The percentage of absence seizure-free days at each specified interval will be 
calculated as:
Number of days with 0 absence seizures during the Treatment Period
Number of days patient was in the Treatment Period (observed)
The percentage of absence seizure-free days at baseline, during the 12-week 
Maintenance Period, and during the 20-week Treatment Period will be listed by 
patient.
3.9.11 New seizure types
For each subject, any new seizure type is defined as a seizure type that was not listed 
at screening or during baseline period but was observed and reported during treatment 
period.   Subjects with at least one new seizure will be summarized by seizure type 
and overall.  All subjects with at least 1 new seizure type will be listed.
3.9.12 Exit Survey
The frequency and percentage for each response option (“Most Improved”, “Much 
Improved”, “Slightly Improved”, “No Change”, “Slightly Worsened”, “Much 
Worsened”, “Most Worsened”) will be summarized for each of the six exit survey 
questions. All exit survey results will be listed by patient.
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3.10 Other Analyses
3.10.1 Severity Assessment for CDD
The results of the optional severity assessment for CDD will be listed by patient.
3.11Modifications to the Statistical Section of the Protocol
All efficacy analyses will be based on the Modified Intent-to-Treat Analysis Set, in 
order to include the two patients who completed the study under the original protocol, 
dated May 22, 2018. The Efficacy Analysis Set was originally defined in Protocol 
Amendment 1 to be used for primary and secondary efficacy analyses. The following
endpoints were updated or added to the SAP in comparison to Protocol Amendment 
2:
!
Additional secondary endpoints
o
Percent change from Baseline in all seizure frequency per 28 days at 
each 4-week interval with the Treatment Period, the 12-week 
Maintenance Period and over the entire 20-week Treatment Period
o
Percent change from Baseline in the frequency of each seizure type per 
28 days at each 4-week interval within the Treatment Period, the 12-
week Maintenance Period, and over the entire 20-week Treatment 
Period
o
Proportion of all seizure-free days during Baseline Period, at each 4-
week interval within the 12-week Maintenance Period, and over the 
entire 20-week Treatment Period.
!
Updated secondary efficacy endpoint
Original
Percent change from Baseline in motor seizure-free days frequency in patients 
with Dup15q or CDD during Maintenance Period
Update
Proportion of motor seizure-free days during the baseline period, at each 4-week 
interval within the 12-week Maintenance Period, and over the entire 20-week 
Treatment Period
!
Additional exploratory efficacy endpoint
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4
DATA HANDLING
4.1 Computation of Seizure Frequency
Seizure frequency per 28 days may be calculated over nine different intervals: the 4 to 
6 week prospective Screening/Baseline Period, each of the two 4-week intervals in 
the 8-week Dose Optimization period, each of the three 4-week intervals in the 12-
week Maintenance Period, the 8-week Dose Optimization Period, the 12-week 
Maintenance Period, and the entire 20-week Treatment Period. The start and end of 
each interval are defined by study day and/or visit date according to Section 4.2. 
Only days with no missing seizure count will be included in the calculation of seizure 
frequency. Seizure frequency per 28 days will be calculated at each specified interval 
as:
(number of seizures in that interval)
(days with no missing seizure count in that interval) × 28
4.2 Seizure Frequency Intervals
Seizure frequency may be calculated over the following intervals, defined by
visit/phone call date and/or study day:
Interval Name
First Day in Interval
Last Day in Interval
Study Periods
Baseline
date of initial Screening 
visit
study day -1
20-week Treatment 
Period
date of first dose 
(study day 1)
Day 141 EOT/ET visit date
[Patients under original 
protocol: Day 85/ET (+/- 7 
days)] 
8-week Dose 
Optimization Period
date of first dose 
(study day 1)
date of Day 57 phone call – 1 
day (+/- 7 days)
[For patients under original 
protocol, Day 57 is a clinic 
visit. For patients who 
discontinue from the study 
prior to Day 57, use date of 
study discontinuation.]
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Interval Name
First Day in Interval
Last Day in Interval
12-week 
Maintenance Period
date of Day 57 phone call 
[For patients under 
original protocol, this is 
an in-person visit]
Day 141 EOT/ET visit date
(+/- 7 days)[Patients under 
original protocol: Day 85/ET]
4-Week Intervals
Day 1 – Day 28
date of first dose 
(study day 1)
study day 28 (+/- 2 days)
Day 29 – Day 56
study day 29
date of Day 57 phone call – 1 
day(+/- 7 days)
[For patients under original 
protocol, Day 57 is a clinic
visit. For patients who 
discontinue from the study 
prior to Day 57, use date of 
study discontinuation.]
Day 57 – Day 84
date of Day 57 phone call
[For patients under 
original protocol, Day 57 
is a clinic visit.]
study day 84 (+/- 7days)
*Day 85 – Day 112
study day 85
study day 112 (+/- 7 days)
*Day 113 – Day 141
study day 113
Day 141 EOT/ET visit date(
+/- 7 days)
*The two patients who completed the study under the original protocol do not have 
sufficient data to calculate seizure frequency for these intervals.
4.3 CCI
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ng 
 
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5
INDEX OF TABLES, LISTINGS, AND FIGURES
The table of contents of the tables, listings and figures can be separate documents.
6
INTERIM (AD HOC) ANALYSES
An interim (ad hoc) analysis was performed in March 2020. The March 2020 analysis 
followed the Ad Hoc Analysis Plan Version 3.0.   The purpose of this analysis was 
exploratory and not for decisions on study conduct.
7
APPENDICES
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CCI
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8
REFERENCES
Berglund, P. & Heeringa, S. (2014). Multiple Imputation of Missing Data Using
SAS®. SAS Press.
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