Clinical trial NCT02926898
Conditions: Dravet Syndrome
Keywords: Seizure Tonic clonic Epilepsy Myoclonic Encephalopathy
Sponsor: Zogenix International Limited, Inc., a subsidiary of Zogenix, Inc.
Start date: 2017-01-27; Completion date: 2018-06-05
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to evaluate the safety, tolerability, and efficacy of ZX008 (fenfluramine hydrochloride) when added to adjunctive antiepileptic stiripentol treatment in children and young adults with Dravet syndrome.

Detailed description:
This is a multicenter, 2-cohort trial to first assess the pharmacokinetic and safety profile of a single dose of ZX008 (fenfluramine hydrochloride) oral solution when added to a standard Dravet syndrome treatment regimen containing valproate (VPA) and clobazam (CLB), with or without stiripentol (STP) (Cohort 1), followed by a randomized, double-blind, placebo-controlled parallel group evaluation of the efficacy, safety, and tolerability of ZX008 as adjunctive therapy for seizures in children and young adults with Dravet syndrome (Cohort 2).

Arms: arm 1: ZX008 0.5 mg/kg/day (maximum 20 mg/day) dose supplied as an oral solution administered twice a day (BID) in equally divided doses with food. arm 2: Matching placebo administered twice a day (BID) in equally divided doses with food.
Interventions: intervention 1: ZX008 (Fenfluramine Hydrochloride) intervention 2: Matching Placebo
Intervention descriptions: intervention 1: ZX008 0.5 mg/kg/day (maximum 20 mg/day). ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and provided in concentrations of 2.5 mg/mL.

\*Note: The 0.5 mg/kg/day dose of ZX008 fenfluramine hydrochloride in this study is equivalent to 0.4 mg/kg/day (maximum 17 mg/day) dose of fenfluramine base. intervention 2: Matching Placebo

Protocol documents:
Prot_000.pdf: 
T his  pr ot o c ol i n cl u d es i nf or m ati o n  a n d  d at a t h at  c o nt ai n tr a d e s e cr ets  a n d  pri vil e g e d  or  c o nfi d e nti al i nf or m ati o n,  w hi c h is t h e  pr o p ert y  of t h e s p o ns or. 
T his i nf or m ati o n  m ust  n ot  b e  m a d e  p u bli c  wit h o ut  writt e n  p er missi o n fr o m t h e s p o ns or.  T h es e r estri cti o n s  o n  dis cl os ur e  will  a p pl y  e q u all y t o  all f ut ur e 
i nf or m ati o n s u p pli e d t o  y o u.  T his  m at eri al  m a y  b e  dis cl os e d t o  a n d  us e d  b y  y o ur p ers o n n el  a n d  ass o ci at es  as  m a y  b e  n e c ess ar y t o  c o n d u ct t h e  cli ni c al 
st u d y. 
C o nfi d e nti al  
 
C li ni c al  St u d y P r ot o c ol  
 
St u d y  Titl e:  
 
A  M ulti c e nt er,  2 -C o h ort  Tri al t o  First  Ass ess  t h e  P h ar m a c o ki n eti c  a n d 
S af et y  Pr ofil e  of  a  Si n gl e  D os e  of  Z X 0 0 8 ( F e nfl ur a mi n e  H y dr o c hl ori d e) 
Or al  S ol uti o n  W h e n  A d d e d t o  St a n d ar d  of  C ar e  ( C o h ort  1),  F oll o w e d  b y  a 
R a n d o mi z e d,  D o u bl e -bli n d,  Pl a c e b o -c o ntr oll e d  P ar all el  Gr o u p  E v al u at i o n 
of  t h e  Effi c a c y,  S af et y,  a n d  T ol er a bilit y of  Z X 0 0 8  as  A dj u n cti v e 
A nti e pil e pti c  T h er a p y  t o  Stiri p e nt ol  Tr e at m e nt i n  C hil dr e n  a n d  Y o u n g 
A d ults  wit h  Dr a v et  S y n dr o m e  ( C o h ort  2)  
St u d y  N u m b e r:   
Z X 0 0 8 -1 5 0 4  
St u d y  P r o d u ct:   
F e nfl ur a mi n e  H y dr o c hl ori d e  O r al S ol uti o n;  Z X 0 0 8  
I N D  N u m b e r:   
1 2 5 7 9 7  
E u d r a C T  N u m b e r:   
2 0 1 6 -0 0 0 4 7 4 -3 8  
S p o ns o r:  
Z o g e ni x I nt er n ati o n al  Li mit e d   
A  w h oll y  o w n e d  s u bsi di ar y  of  Z o g e ni x, I n c.  
Si e n a  C o urt,  Br o a d w a y  
M ai d e n h e a d,  S L 6  1 NJ,  U K  
S p o ns o r's  M e di c al 
R e p r es e nt ati v e  
Ar u n  Mistr y , M B C h B  M R C P  ( U K) 
M e di c al  Dir e ct or  
 
D at e  ( v e rsi o n) of 
St u d y  P r ot o c ol:  
 
2  F e br u ar y  2 0 1 8 ( Pr ot o c ol  A m e n d m e nt  3. 3 [ U S A/ C N])  
2 1  J u n e  2 0 1 7 ( Pr ot o c ol  A m e n d m e nt  2. 3 . 8 [U S A/ C N ]) 
2 7  M ar c h  2 0 1 7 ( Pr ot o c ol  A m e n d m e nt  2. 3 . 1. 1 [ U S A/ C N])a 
2 0  F e br u ar y  2 0 1 7  (Pr ot o c ol  A m e n d m e nt  2. 3. 1 [ U S A/ C N]) a 
2 9  D e c e m b er  2 0 1 6 ( Pr ot o c ol  A m e n d m e nt  2. 3 [ U S/ U K/ C N ]) 
3 0  S e pt e m b er  2 0 1 6 ( Pr ot o c ol  A m e n d m e nt  1 .1 ,  V ersi on  3 . 0) 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2  of  1 9 4   
 
2 5  M a y  2 0 1 6 ( A m e n d m e nt  1,  V ersi o n  2. 0)  
0 8  F e br u ar y  2 0 1 6 ( V ersi o n  1. 0)  
a A m e n d m e nts  2. 3 . 1 a n d  2. 3. 1. 1  w er e  i nt er n al a m e n d m e nts  at t h e  S p o ns or  a n d  n ot 
r el e as e d t o t h e I n v e sti g ati v e  Sit es 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  3  of  1 9 4   
 
LI S T  O F  P E R S O N N E L  A N D  O R G A NI Z A TI O N S  R E S P O N SI B L E  F O R 
C O N D U C T  O F  S T U D Y  
A list  of  p ers o n n el  a n d  or g a ni z ati o ns r es p o nsi bl e f or t h e  c o n d u ct  of t h e st u d y  will  b e s u p pli e d t o 
st u d y sit es  as  p art  of t h e I n v esti g at or  St u d y  Fil e.  T his list  will  b e  u p d at e d  b y t h e  S p o ns or  or t h e 
S p o ns or 's  a g e nt  a n d  pr o vi d e d t o st u d y sit es  as  n e e d e d. 
 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4  of  1 9 4   
 
T A B L E  O F  C O N T E N T S  
LI S T  O F  T A B L E S  ................................................................................................. 1 2  
LI S T  O F  FI G U R E S  ............................................................................................... 1 4  
SI G N A T U R E  O F  S P O N S O R  ............................................................................... 1 5  
SI G N A T U R E  O F  C O O R DI N A TI N G I N V E S TI G A T O R  ................................. 1 5  
SI G N A T U R E( S)  O F  P RI N CI P A L I N V E S TI G A T O R( S ) .................................. 1 7  
LI S T  O F  A B B R E VI A TI O N S  ............................................................................... 1 8  
S T U D Y  S Y N O P SI S  ............................................................................................... 2 1  
1.  
I N T R O D U C TI O N ............................................................................ 3 8  
1. 1  
B A C K G R O U N D I N F O R M A TI O N  O N I N DI C A TI O N  S T U DI E D  ............... 3 8  
1. 1. 1  
E xisti n g  T r e at m e nt f o r  D r a v et  S y n d r o m e  ........................................................ 3 8  
1. 1. 2  
Ot h e r  A nti e pil e pti c  M e di c ati o ns  ....................................................................... 3 9  
1. 2  
B A C K G R O U N D I N F O R M A TI O N  O N  S T U D Y  P R O D U C T  ........................ 4 0  
1. 3  
P R E C LI NI C A L  D A T A  ...................................................................................... 4 0  
1. 4  
B A C K G R O U N D I N F O R M A TI O N  O N  R E F E R E N C E  P R O D U C T  ............. 4 1  
1. 5  
R A TI O N A L E  F O R  C U R R E N T  S T U D Y .......................................................... 4 1  
1. 6  
RI S K -B E N E FI T  A S S E S S M E N T  ...................................................................... 4 2  
2.  
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  .................................. 4 5  
2. 1  
P RI M A R Y  E F FI C A C Y  O B J E C TI V E  ............................................................. 4 5  
2. 2  
K E Y  S E C O N D A R Y  E F FI C A C Y  O B J E C TI V E S ............................................ 4 5  
2. 3  
A D DI TI O N A L  S E C O N D A R Y  E F FI C A C Y  O B J E C TI V E S  .......................... 4 5  
2. 4  
E X P L O R A T O R Y  O B J E C TI V E  ....................................................................... 4 6  
2. 5  
S T U D Y  E N D P OI N T S  ......................................................................................... 4 7  
2. 5. 1  
Effi c a c y  E n d p oi nts ( C o h o rt  2  o nl y)  ................................................................... 4 7  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5  of  1 9 4   
 
2. 5. 2  
S af et y  E n d p oi nts  ................................................................................................. 4 7  
2. 5. 3  
P h a r m a c o ki n eti c  E n d p oi nts  ............................................................................... 4 8  
2. 5. 4  
E x pl o r at o r y  E n d p oi nts  ....................................................................................... 4 8  
3.  
I N V E S TI G A TI O N A L  P L A N  .......................................................... 4 9  
3. 1  
O V E R A L L  S T U D Y  D E SI G N  A N D  P L A N  ...................................................... 4 9  
3. 2  
N U M B E R  O F  S U B J E C T S  ................................................................................. 5 1  
3. 3  
S T U D Y  D U R A TI O N  .......................................................................................... 5 1  
3. 4  
N U M B E R  O F  S T U D Y  C E N T E R S  .................................................................... 5 2  
3. 5  
R A TI O N A L E  F O R  S T U D Y  D E SI G N  A N D  C H OI C E  O F  
T R E A T M E N T  ..................................................................................................... 5 2  
3. 6  
P R E M A T U R E  T E R MI N A TI O N  O F  S T U D Y  ................................................. 5 6  
3. 7  
S T U D Y  M O NI T O RI N G  P R O C E D U R E S  ........................................................ 5 7  
3. 7. 1  
I n d e p e n d e nt  D at a  a n d  S af et y  M o nit o ri n g  C o m mitt e e  .................................... 5 7  
3. 7. 2  
I nt e r n ati o n al  P e di at ri c  C a r di a c  A d vis o r y  B o a r d (I P C A B)  ............................ 5 7  
4.  
S E L E C TI O N  O F  S T U D Y  P O P U L A TI O N  .................................... 5 8  
4. 1  
I N C L U SI O N  C RI T E RI A  ................................................................................... 5 8  
4. 2  
E X C L U SI O N  C RI T E RI A  .................................................................................. 6 0  
4. 3  
R A N D O MI Z A TI O N I N C L U S I O N  C RI T E RI A –  C O H O R T  2  ..................... 6 1  
4. 4  
S U B J E C T S  O F  R E P R O D U C TI V E  P O T E N TI A L  .......................................... 6 1  
4. 4. 1  
S p e r m  a n d  E g g  D o n ati o n  ................................................................................... 6 2  
4. 4. 2  
P r e g n a n c y  ............................................................................................................ 6 2  
4. 5  
R E M O V A L  O F  S U B J E C T S  F R O M  T H E R A P Y  O R  A S S E S S M E N T  .......... 6 3  
4. 6  
T E R MI N A TI O N  O F  T H E  C LI NI C A L  S T U D Y  ............................................. 6 5  
4. 7  
R E P L A C E M E N T  O F  S U B J E C T S  .................................................................... 6 6  
4. 8  
E LI GI BI LI T Y  F O R  E X T E N SI O N  T RI A L  ..................................................... 6 6  
5.  
I N V E S TI G A TI O N A L  M E DI CI N A L  P R O D U C T 
I N F O R M A TI O N ............................................................................... 6 6  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6  of  1 9 4   
 
5. 1  
I D E N TI T Y  O F I N V E S TI GA TI O N A L  M E DI CI N A L  P R O D U C T  ............... 6 7  
5. 1. 1  
P a c k a gi n g  a n d  L a b eli n g  ..................................................................................... 6 7  
5. 2  
D E S C RI P TI O N  O F  R E F E R E N C E  T R E A T M E N T,  C O M P A R A T O R, 
A N D/ O R  P L A C E B O  .......................................................................................... 6 8  
5. 2. 1  
P a c k a gi n g  a n d  L a b eli n g  ..................................................................................... 6 8  
5. 3  
S HI P M E N T  A N D  S T O R A G E  ........................................................................... 6 8  
5. 4  
I M P  A C C O U N T A BI LI T Y  ................................................................................. 6 8  
5. 5  
T R E A T M E N T  A D MI NI S T R A TI O N  ............................................................... 6 9  
5. 5. 1  
C o h o rt  1:   R a n d o mi z ati o n  .................................................................................. 6 9  
5. 5. 2  
C o h o rt  2:   R a n d o mi z ati o n  .................................................................................. 6 9  
5. 5. 3  
C o h o rt  2:   Tit r ati o n  P e ri o d  ................................................................................ 7 0  
5. 5. 4  
C o h o rt  2:   M ai nt e n a n c e  P e ri o d  ......................................................................... 7 1  
5. 5. 5  
C o h o rt  2:   T a p e r  P e ri o d  ..................................................................................... 7 1  
5. 5. 6  
C o h o rt  1:   T r a nsiti o n  P e ri o d  .............................................................................. 7 1  
5. 5. 7  
C o h o rt  2:   T r a nsiti o n  P e ri o d  .............................................................................. 7 2  
5. 6  
B LI N DI N G ( C O H O R T  2)  .................................................................................. 7 2  
5. 7  
P RI O R  A N D  C O N C O MI T A N T  M E DI C A TI O N S .......................................... 7 3  
5. 7. 1  
V a g al  N e r v e  Sti m ul ati o n  .................................................................................... 7 3  
5. 7. 2  
K et o g e ni c  Di et  ..................................................................................................... 7 4  
5. 7. 3  
R e s c u e  M e di c ati o n f o r  S ei z u r es  ......................................................................... 7 4  
5. 7. 4  
P r o hi bit e d  C o n c o mit a nt  m e di c ati o ns  a n d  F o o d ............................................... 7 4  
5. 8  
T R E A T M E N T  C O M P LI A N C E  ........................................................................ 7 5  
6.  
V I SI T  S C H E D U L E .......................................................................... 7 6  
6. 1  
C O H O R T  1:   S T U D Y  P R O C E D U R E S  ............................................................ 7 7  
6. 1. 1  
S c r e e ni n g ( U p t o  1 4  d a ys  p ri o r t o  d osi n g)  ........................................................ 7 7  
6. 1. 2  
S T U D Y  D A Y  -1  ................................................................................................... 7 8  
6. 1. 3  
S T U D Y  D A Y  1  .................................................................................................... 7 9  
6. 1. 4  
S T U D Y  D A Y  2  .................................................................................................... 7 9  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7  of  1 9 4   
 
6. 1. 5  
S T U D Y  D A Y  1 5  .................................................................................................. 7 9  
6. 1. 6  
T r a n siti o n  P e ri o d  ................................................................................................ 8 0  
6. 1. 6. 1  
P h o n e  Visits  6,  8,  1 0,  1 2,  1 4,  a n d  1 6 ( St u d y  D a ys  2 9,  5 7,  8 5,  1 1 3,  1 4 1,  a n d 
1 6 9)  ....................................................................................................................... 8 0  
6. 1. 6. 2  
Cli ni c  Visits  7,  9,  1 1,  1 3,  a n d  1 5 ( St u d y  D a ys  4 3,  7 1,  9 9,  1 2 7,  a n d  1 5 5)  .......... 8 1  
6. 1. 6. 3  
Cli ni c  Visit  1 7 ( D a y  1 8 3):   E n d  of  St u d y/ E a rl y  T e r mi n ati o n  .......................... 8 2  
6. 2  
C O H O R T  2:   S T U D Y  P R O C E D U R E S  ............................................................ 8 3  
6. 2. 1  
B A S E LI N E  P E RI O D ( S T U D Y  D A Y  -4 2  T O  S T U D Y  D A Y  -1)  ..................... 8 3  
6. 2. 2  
S C R E E NI N G,  C LI NI C  VI SI T  1 ( S T U D Y  D A Y  -4 2  A N D  S T U D Y  D A Y  -
4 1)  ......................................................................................................................... 8 4  
6. 2. 3  
P H O N E  VI SI T  2 ( S T U D Y  D A Y  -2 1)  ................................................................ 8 5  
6. 2. 4  
C LI NI C  VI SI T  3 ( S T U D Y  D A Y  -1):  R A N D O MI Z A TI O N  ............................ 8 6  
6. 2. 5  
TI T R A TI O N  A N D  M AI N T E N A N C E  P E RI O D S  ........................................... 8 7  
6. 2. 5. 1  
Tit r ati o n  P e ri o d:  D a y  1  ...................................................................................... 8 7  
6. 2. 5. 2  
P h o n e  o r  Cli ni c  Visit  4 ( Tit r ati o n  P e ri o d:  D a y  8)  ............................................ 8 7  
6. 2. 5. 3  
Cli ni c  Visit  5 ( Tit r ati o n  P e ri o d:  D a y  1 5) ........................................................... 8 7  
6. 2. 5. 4  
Cli ni c  Visit  6 ( M ai nt e n a n c e  P e ri o d:  D a y  2 2)  .................................................... 8 8  
6. 2. 5. 5  
P h o n e  Visit  7 ( M ai nt e n a n c e  P e ri o d:  D a y  3 6)  ................................................... 8 9  
6. 2. 5. 6  
Cli ni c  Visit  8 ( M ai nt e n a n c e  P e ri o d:  D a y  5 0)  .................................................... 8 9  
6. 2. 5. 7  
P h o n e  Visit  9 ( M ai nt e n a n c e  P e ri o d:  D a y  6 4)  ................................................... 9 0  
6. 2. 5. 8  
Cli ni c  Visit  1 0 ( M ai nt e n a n c e  P e ri o d  D a y:  7 8)  .................................................. 9 0  
6. 2. 5. 9  
P h o n e  Visit  1 1 ( M ai nt e n a n c e  P e ri o d:  D a y  9 2)  ................................................. 9 1  
6. 2. 5. 1 0  
Cli ni c  Visit  1 2 ( E n d  of  St u d y/ E a rl y  T e r mi n ati o n:  D a y  1 0 6)  ........................... 9 1  
6. 2. 5. 1 1  
F oll o w -u p  Visit ( Cli ni c  Visit  1 3;  D a y  1 2 0)  ........................................................ 9 3  
6. 2. 6  
C A R DI A C  F O L L O W -U P  VI SI T ( C O H O R T  1:  C LI NI C  VI SI T S  1 8, 
1 9/ C O H O R T  2:  C L I NI C  VI SI T  1 4;  3 -6  M O N T H S  A F T E R  L A S T  D O S E 
O F  S T U D Y  M E DI C A T I O N)  ............................................................................. 9 4  
6. 3  
E S TI M A T E D  B L O O D  V O L U M E  C O L L E C TI O N  ........................................ 9 5  
7.  
E F FI C A C Y,  S A F E T Y,  A N D  P H A R M A C O KI N E TI C 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8  of  1 9 4   
 
A S S E S S M E N T S  ................................................................................ 9 7  
7. 1  
E F FI C A C Y  A S S E S S M E N T S :  C O H O R T  2 ..................................................... 9 7  
7. 1. 1  
S ei z u r e  Ass ess m e nts  ............................................................................................ 9 7  
7. 1. 2  
Cli ni c al  Gl o b al I m p r essi o n  - I m p r o v e m e nt ( E x pl o r at o r y  E n d p oi nt)  ............ 9 8  
7. 1. 3  
Sl e e p  Q u alit y  a n d  M e alti m e  B e h a vi o r  Q u esti o ns ( E x pl o r at o r y  E n d p oi nt)  ... 9 9  
7. 1. 4  
K a r oli ns k a  Sl e e pi n ess  S c al e ( E x pl o r at o r y  E n d p oi nt)  ...................................... 9 9  
7. 1. 5  
Q u alit y  of  Lif e i n  C hil d h o o d  E pil e ps y  S c al e ................................................... 1 0 0  
7. 1. 6  
P e ds Q L  S c al e  ..................................................................................................... 1 0 0  
7. 1. 7  
P a r e nt/ C a r e gi v e r  Q u alit y  of  Lif e  ..................................................................... 1 0 0  
7. 1. 8  
H e alt h c a r e  Utili z ati o n  Q u esti o ns ( E x pl o r at o r y  E n d p oi nt)  ........................... 1 0 1  
7. 1. 9  
D r a v et  S y n d r o m e  O ut c o m e  M e as u r es ( E x pl o r at o r y  E n d p oi nt)  ................... 1 0 1  
7. 2  
S A F E T Y  A S S E S S M E N T S  ............................................................................... 1 0 2  
7. 2. 1  
D e m o g r a p hi cs,  M e di c al/ N e u r ol o gi c al/ E pil e ps y  Hist o r y,  a n d  P r e -St u d y 
M e di c ati o n  ......................................................................................................... 1 0 2  
7. 2. 2  
P h ysi c al  E x a mi n ati o ns  ...................................................................................... 1 0 2  
7. 2. 3  
N e u r ol o gi c al  E x a mi n ati o ns  .............................................................................. 1 0 2  
7. 2. 4  
Vit al  Si g ns  .......................................................................................................... 1 0 2  
7. 2. 5  
L a b o r at o r y  M e as u r e m e nts  ............................................................................... 1 0 3  
7. 2. 6  
Pl as m a  S a m pl e f o r  C o n c o mit a nt  A nti e pil e pti c  D r u g(s)  ................................ 1 0 4  
7. 3  
A D V E R S E  E V E N T S  ........................................................................................ 1 0 4  
7. 3. 1  
El e ct r o c a r di o g r a ms ........................................................................................... 1 0 4  
7. 3. 2  
D o p pl e r  E c h o c a r di o g r a p h y  .............................................................................. 1 0 5  
7. 3. 3  
T a n n e r  St a gi n g  .................................................................................................. 1 0 5  
7. 3. 4  
C ol u m bi a -S ui ci d e  S e v e rit y  R ati n g  S c al e  ........................................................ 1 0 5  
7. 3. 5  
B e h a vi o r  R ati n g I n v e nt o r y  of  E x e c uti v e  F u n cti o n ( B RI E F)  ........................ 1 0 5  
7. 4  
P H A R M A C O KI N E TI C  A S S E S S M E N T S ...................................................... 1 0 6  
7. 5  
A P P R O P RI A T E N E S S  O F  M E A S U R E M E N T S  ............................................ 1 0 6  
8.  
A D V E R S E  E V E N T S  ...................................................................... 1 0 7  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9  of  1 9 4   
 
8. 1  
D E FI NI TI O N S  .................................................................................................. 1 0 7  
8. 1. 1  
A d v e rs e  E v e nts  .................................................................................................. 1 0 7  
8. 1. 2  
S e ri o us  A d v e rs e  E v e nts  .................................................................................... 1 0 8  
8. 1. 3  
A d v e rs e  E v e nts  of  S p e ci al I nt e r est  .................................................................. 1 0 9  
8. 1. 4  
A d v e rs e  E v e nts  R e q ui ri n g  H os pit ali z ati o n  ..................................................... 1 1 0  
8. 2  
S E V E RI T Y  O F  A D V E R S E  E V E N T S  ............................................................ 1 1 0  
8. 3  
C A U S A LI T Y  O F  A D V E R S E  E V E N T S  ......................................................... 1 1 1  
8. 4  
O B S E R V A TI O N  P E RI O D  F O R  A D V E R S E  E V E N T  R E P O R TI N G  ......... 1 1 2  
8. 5  
A D V E R S E  E V E N T  R E P O R T I N G ................................................................. 1 1 2  
8. 5. 1  
A d v e rs e  E v e nts  .................................................................................................. 1 1 2  
8. 6  
S E RI O U S  A D V E R S E  E V E N T S  R E P O R TI N G  ............................................. 1 1 2  
8. 6. 1  
R e q ui r e m e nts f o r I m m e di at e  R e p o rti n g  of  S e ri o us  A d v e rs e  E v e nts  ........... 1 1 3  
8. 7  
R E P O R TI N G  O F  S E RI O U S  A D V E R S E  E V E N T S  B Y 
I N V E S TI G A T O R  T O I E C/ I R B ...................................................................... 1 1 4  
8. 8  
R E P O R TI N G  O F  E V E N T S  O T H E R  T H A N  S E RI O U S  A D V E R S E 
E V E N T S  B Y I N V E S TI G A T O R  T O  S P O N S O R  ........................................... 1 1 4  
8. 9  
F O L L O W -U P  O F  A D V E R S E  E V E N T S  ........................................................ 1 1 4  
8. 9. 1  
F oll o w -u p  of  E c h o c a r di o g r a m  Fi n di n gs  ......................................................... 1 1 5  
8. 1 0  
P R E G N A N C Y  ................................................................................................... 1 1 7  
9.  
D A T A  H A N D LI N G  P R O C E D U R E S  ........................................... 1 1 8  
9. 1  
R E C O R DI N G  O F  D A T A  ................................................................................. 1 1 8  
9. 2  
D A T A  Q U A LI T Y  A S S U R A N C E  .................................................................... 1 1 8  
9. 3  
R E C O R D  R E T E N TI O N  .................................................................................. 1 1 9  
1 0.  
S T A TI S TI C S  ................................................................................... 1 1 9  
1 0. 1  
D E T E R MI N A TI O N  O F  S A M P L E  SI Z E  ....................................................... 1 1 9  
1 0. 2  
A N A L Y SI S  P O P U L A TI O N S  ( C O H O R T  2) .................................................. 1 2 0  
1 0. 2. 1  
S af et y ( S A F)  P o p ul ati o n  ................................................................................... 1 2 0  
1 0. 2. 2  
M o difi e d I nt e nt -t o-T r e at ( mI T T)  P o p ul ati o n  ................................................ 1 2 0  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0  of  1 9 4   
 
1 0. 2. 3  
P e r  P r ot o c ol ( P P)  P o p ul ati o n  ........................................................................... 1 2 0  
1 0. 3  
T R E A T M E N T  G R O U P S  ................................................................................. 1 2 0  
1 0. 4  
T R E A T M E N T  P E RI O D S  ................................................................................ 1 2 1  
1 0. 4 . 1 
C o h o rt  1  T r e at m e nt  P e ri o ds  ............................................................................ 1 2 1  
1 0. 4. 2  
C o h o rt  2  T r e at m e nt  P e ri o ds  ............................................................................ 1 2 1  
1 0. 5  
S T A TI S TI C A L  A N A L Y S E S  A N D  M E T H O D S  ............................................ 1 2 2  
1 0. 5. 1  
Effi c a c y  A n al ys es  .............................................................................................. 1 2 2  
1 0. 5. 2  
S af et y  A n al ys es  .................................................................................................. 1 2 3  
1 0. 5. 3  
P h a r m a c o ki n eti c  A n al ys es  ............................................................................... 1 2 4  
1 0. 5. 4  
A n al ysis  of  E x pl o r at o r y  E n d p oi nts  ................................................................. 1 2 5  
1 0. 6  
A N A L Y S E S  P R O VI D E D  T O  A N I N D E P E N D E N T  D A T A  A N D 
S A F E T Y  M O NI T O RI N G  C O M MI T T E E  ..................................................... 1 2 5  
1 1.  
E T HI C A L  &  R E G U L A T O R Y  C O N SI D E R A TI O N S  ................ 1 2 5  
1 1. 1  
E T HI C A L  C O N SI D E R A TI O N S  ..................................................................... 1 2 5  
1 1. 2  
I N F O R M E D  C O N S E N T  .................................................................................. 1 2 6  
1 1. 3  
R E G U L A T O R Y  C O N S I D E R A TI O N S  A N D I N D E P E N D E N T  E T HI C S 
C O M MI T T E E/I N S TI T U TI O N A L  R E VI E W  B O A R D  ................................ 1 2 7  
1 1. 4  
P R O T O C O L  C O M P LI A N C E  ......................................................................... 1 2 8  
1 2.  
A D MI NI S T R A TI V E  A S P E C T S  ................................................... 1 2 9  
1 2. 1  
C LI NI C A L  T RI A L  A G R E E M E N T  ................................................................ 1 2 9  
1 2. 2  
FI N A N CI A L  DI S C L O S U R E  B Y I N V E S TI G A T O R  .................................... 1 2 9  
1 2. 3  
C LI NI C A L  S T U D Y  R E GI S T R A TI O N  A N D  R E S U L T S  DI S C L O S U R E  .. 1 2 9  
1 2. 4  
S T U D Y  FI L E S  A N D  M A T E RI A L S ................................................................ 1 3 0  
1 2. 5  
I NI TI A TI O N  O F  T H E  S T U D Y  ....................................................................... 1 3 0  
1 2. 6  
S U B J E C T  R EI M B U R S E M E N T  ..................................................................... 1 3 0  
1 2. 7  
LI A BI LI T Y  A N D I N S U R A N C E  ..................................................................... 1 3 0  
1 2. 8  
S U B J E C T I D E N TI FI C A TI O N  A N D  C O N FI D E N TI A LI T Y  ...................... 1 3 1  
1 2. 9  
M O NI T O RI N G  O F  T H E  S T U D Y  .................................................................. 1 3 1  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1  of  1 9 4   
 
1 2. 1 0  
P R O T O C O L  A M E N D M E N T S  ....................................................................... 1 3 3  
1 2. 1 1  
A U DI T S  A N D I N S P E C TI O N S  ........................................................................ 1 3 3  
1 2. 1 2  
C LI NI C A L  S T U D Y  R E P O R T  ........................................................................ 1 3 3  
1 2. 1 3  
U S E  O F  D A T A  A N D  P U B L I C A TI O N S ......................................................... 1 3 4  
1 3.  
R E F E R E N C E  LI S T  ........................................................................ 1 3 5  
1 4.  
A P P E N DI C E S  ................................................................................. 1 3 7  
A P P E N DI X  1  –  LI S T  O F  P R O HI BI T E D  C O N C O MI T A N T 
M E DI C A TI O N S  A N D  F O O D S  ..................................................... 1 3 8  
A P P E N DI X  2  –  C O L U M BI A  –  S UI CI D E  S E V E R T Y  R A TI N G  S C A L E  ..... 1 4 0  
A P P E N DI X  3  –  B E H A VI O R  R A TI N G I N V E N T O R Y  O F  E X E C U TI V E 
F U N C TI O N  ..................................................................................... 1 4 6  
A P P E N DI X  4  –  Q U A LI T Y  O F  LI F E I N  C HI L D H O O D  E PI L E P S Y 
S C A L E  ............................................................................................. 1 5 6  
A P P E N DI X  5  –  T A N N E R  S T A GI N G  ............................................................... 1 6 9  
A P P E N DI X  6  –  P E D S Q L  .................................................................................... 1 7 1  
A P P E N DI X  7  –  E Q -5 D -5 L  Q U E S TI O N N AI R E  ............................................... 1 8 2  
A P P E N DI X  8  –  K A R O LI N S K A  S L E E PI N E S S  S C A L E  ................................. 1 8 4  
A P P E N DI X  9  –  M A XI M U M  A L L O W A B L E  B L O O D  D R A W  V O L U M E S  1 8 5  
A P P E N DI X  1 0  –  S U M M A R Y  O F  P R O T O C O L  A M E N D M E N T  2. 3. 8 3. 3  ... 1 8 6  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2  of  1 9 4   
 
 LI S T  O F  T A B L E S  
T A B L E  1.  
S C H E D U L E  O F  A S S E S S M E N T S  .............................................................................. 3 2  
T A B L E  2.  
C O H O R T  2:  S C H E D U L E  O F  A S S E S S M E N T S  ........................................................ 3 5  
T A B L E  3.  
C O H O R T  1  D O SI N G  R E GI M E N S ............................................................................. 5 0  
T A B L E  4.  
I N V E S TI G A TI O N A L  M E DICI N A L  P R O D U C T  –  Z X 0 0 8  ....................................... 6 6  
T A B L E  5.  
TI T R A TI O N  A L G O RI T H M  ....................................................................................... 7 0  
T A B L E  6.  
T A P E R  A L G O RI T H M  ................................................................................................ 7 1  
T A B L E  7.  
T R A N SI TI O N  A L G O RI T H M ..................................................................................... 7 2  
T A B L E  8.  
C O H O R T  1:  TI M E  WI N D O W S  F O R  A S S E S S M E N T S  D U RI N G  T H E 
T R A N SI TI O N  P E RI O D  ............................................................................................................... 7 6  
T A B L E  9.  
C O H O R T  2:  TI M E  WI N D O W S  F O R  A S S E S S M E N T S  ............................................ 7 7  
T A B L E  1 0.  
S C H E D U L E  O F  P O S T -T R E A T M E N T  C A R DI A C  F O L L O W -U P  ........................... 9 4  
T A B L E  1 1.  
E S TI M A T E D  B L O O D  V O L U M E  C O L L E C TI O N  F O R  C O H O R T  1  ....................... 9 5  
T A B L E  1 2.  
E S TI M A T E D  B L O O D  V O L U M E  C O L L E C TI O N  F O R  C O H O R T  2  ....................... 9 6  
T A B L E  1 3:  
P RI O RI TI E S  F O R  B L O O D  S A M P L E  C O L L E C TI O N S  ........................................... 9 7  
T A B L E  1 4.  
A D V E R S E  E V E N T S  O F  S P E CI A L I N T E R E S T ...................................................... 1 1 0  
T A B L E  1 5.  
S E V E RI T Y  D E FI NI TI O N  O F  A D V E R S E  E V E N T S  ............................................... 1 1 1  
T A B L E  1 6.  
C LI NI C A L  M E A S U R E S  E N A C T E D  U P O N I N C R E A SI N G  S E V E RI T Y  O F  E C H O 
FI N DI N G S  ................................................................................................................................. 1 1 6  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3  of  1 9 4   
 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4  of  1 9 4  
LI S T  O F  FI G U R E S  
FI G U R E  1 A:  F E N F L U R A M I N E  0. 8  M G/ K G/ D A Y,  MA XI M U M  3 0  M G/ D A Y,  N O  S T P  O R 
C L B;  A N D  FI G U R E  1 B:  F E N F L U R A MI N E  0. 5  M G/ K G/ D A Y,  M A XI M U M  2 0 
M G/ D A Y,  S T P  1 0 0 0  M G/ D A Y,  C L B  1 0  M G/ D A Y  ......................................................... 5 5  
 
 






Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7  of  1 9 4  
SI G N A T U R E( S)  O F  P RI N CI P A L I N V E S TI G A T O R ( S) 
St u d y  N u m b e r:   Z X 0 0 8 -1 5 0 4  
St u d y  Titl e:   
A  M ulti c e nt er,  2 -C o h ort  Tri al t o  First  Ass ess t h e  P h ar m a c o ki n eti c  a n d  S af et y 
Pr ofil e  of  a  Si n gl e  D os e  of  Z X 0 0 8 ( F e nfl ur a mi n e  H y dr o c hl ori d e)  Or al 
S ol uti o n  W h e n  A d d e d t o  St a n d ar d  of  C ar e ( C o h ort  1),  F oll o w e d  b y  a  
R a n d o mi z e d,  D o u bl e -bli n d,  Pl a c e b o -c o ntr oll e d  P ar all el  Gr o u p  E v al u ati o n  of 
t h e  Effi c a c y,  S af et y,  a n d  T ol er a bilit y of  Z X 0 0 8  as  A dj u n cti v e  A nti e pil e pti c  
T h er a p y  t o  Stiri p e nt ol  Tr e at m e nt i n  C hil dr e n  a n d  Y o u n g  A d ults  wit h  Dr a v et 
S y n dr o m e  ( C o h ort  2) 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
I  h a v e r e a d t his st u d y  pr ot o c ol, i n cl u di n g all  a p p e n di c es . B y si g ni n g t his  st u d y pr ot o c ol, I  a gr e e 
t o  c o n d u ct t h e  cli ni c al st u d y, f oll o wi n g  a p pr o v al  b y  a n In d e p e n d e nt  E t hi cs C o m mitt e e  
(I E C)/Instit uti o n al  R e vi e w  B o ar d  (I R B), i n  a c c or d a n c e  wit h t h e st u d y pr ot o c ol,  t h e c urr e nt 
I nt er n ati o n al  C o nf er e n c e  o n  H ar m o ni z ati o n (I C H)  G ui d eli n e f or G o o d  Cli ni c al  Pr a cti c e ( G C P ), 
a n d  a p pli c a bl e r e g ul at or y r e q uir e m e nts. I  will  e ns ur e t h at  all  p ers o n n el i n v ol v e d i n t h e st u d y 
u n d er  m y  dir e cti o n  will  b e  i nf or m e d  a b o ut t h e  c o nt e nts  of t his st u d y pr ot o c ol  a n d  will r e c ei v e 
all  n e c ess ar y i nstr u cti o ns f or  p erf or mi n g t h e st u d y  a c c or di n g t o t h e  st u d y  pr ot o c ol. 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
N a m e  a n d  affili ati o n t o  b e  fill e d  o ut  b y t h e i n v esti g at or 
 
 
P ri n ci p al  I n v esti g at o r   
N a m e  a n d  affili ati o n:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 ( Si g n at ur e)  
( D at e [D a y/ M o nt h/ Y e ar ])  
 
 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8  of  1 9 4  
LI S T  O F  A B B R E VI A TI O N S  
A B B R E V A TI O N   
D E FI NI TI O N  
A E  
a d v ers e  e v e nt  
A E D  
a nti e pil e pti c  dr u g  
A E SI  
a d v ers e  e v e nt  of  sp e ci al  int er est  
A L T  
al a ni n e  a mi n otr a nsf er as e  
A N C O V A  
a n al ysis  of  c o v ari a n c e  
A S T  
as p art at e  a mi n otr a nsf er as e  
A U C  
ar e a  u n d er t h e  c o n c e ntr ati o n -ti m e  c ur v e 
A U C 0 -t 
ar e a  u n d er t h e  c o n c e ntr ati o n -ti m e  c ur v e fr o m ti m e  z er o t o ti m e =t 
BI D  
bis i n  di e; t w o ti m es  p er  d a y  
B MI  
b o d y  m ass  in d e x  
B M S  
Bi o M e di c al  S yst e ms, I n c.  
B RI E F  
B e h a vi or  R ati n g I n v e nt or y f or  E x e c uti v e  F u n cti o n  
B RI E F -P  
B e h a vi or  R ati n g I n v e nt or y f or  E x e c uti v e  F u n cti o n,  Pr es c h o ol  V ersi o n  
C -S S R S  
C ol u m bi a -S ui ci d e  S e v erit y  R ati n g  S c al e  
C B D  
c a n n a bi di ol  
C F R  
C o d e  of  F e d er al  R e g ul ati o ns  
C GI -I 
Cli ni c al  Gl o b al I m pr essi o n  - I m pr o v e m e nt 
C L B  
cl o b a z a m  
C R U  
Cli ni c al  R es e ar c h  U nit  
C T  
c o m p ut e d t o m o gr a p h y  
C Y P  
c yt o c hr o m e  P 4 5 0  
E C G  
e l e ctr o c ar di o gr a m 
E C H O  
e c h o c ar di o gr a m  
e C R F  
el e ctr o ni c  C as e  R e p ort  F or m  
E D C  
el e ctr o ni c  d at a  c a pt ur e  
E O S  
e n d  of st u d y  
E P A R  
E ur o p e a n  P u bli c  Ass ess m e nt  R e p ort  
E Q -5 D -5 L  
st a n d ar di z e d m e as ur e  of  h e alt h st at us  
E T  
e arl y  ter mi n ati o n  
F D A  
F o o d  a n d  Dr u g  A d mi nistr ati o n  
F S H  
folli cl e  sti m ul ati n g h or m o n e  
G C P  
G o o d  Cli ni c al  Pr a cti c e  
G G T  
g a m m a -gl ut a m yl tr a nsf er as e  or  g a m m a -gl ut a m yl tr a ns p e pti d as e  
G H  
g r o wt h h or m o n e  
G M P  
G o o d  M a n uf a ct uri n g  Pr a cti c es  
G P  
g e n er al  pr a ctiti o n er  
H R Q O L  
h e alt h -r el at e d  q u alit y of  lif e 
I C F 
I nf or m e d  C o ns e nt  F or m 
I C H 
I nt er n ati o n al C o nf er e n c e  o n  H ar m o ni z ati o n  
I D S M C 
I n d e p e n d e nt  D at a  a n d  S af et y  M o nit ori n g  C o m mitt e e 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 9  of  1 9 4  
A B B R E V A TI O N   
D E FI NI TI O N  
I E C 
I n d e p e n d e nt  Et hi cs  C o m mitt e e 
I G F-1  
ins uli n -li k e g r o wt h fa ct or -1  
I M P 
in v esti g ati o n al  m e di ci n al  p r o d u ct 
I P C A B 
I nt er n ati o n al  P e di atri c  C ar di ol o g y  A d vis or y  B o ar d 
I Q R 
i nt er  q u artil e r a n g e 
I R B 
I nstit uti o n al  R e vi e w  B o ar d 
I U 
int er n ati o n al  u nit  
I V R 
I nt er a cti v e  V oi c e  R a n d o mi z ati o n 
I W R 
I nt er a cti v e  W e b  R es p o ns e ( S yst e m) 
K D  
k et o g e ni c  di et  
k g  
k il o gr a m 
L H  
lut ei ni zi n g  h or m o n e  
L L N  
l o w er li mit  of  n or m al 
M C S F  
m e a n  c o n v ulsi v e  sei z ur e  fr e q u e n c y 
M e d D R A  
M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es  
m g  
m illi gr a m 
m g/ k g/ d a y  
milli gr a m  p er  kil o gr a m  p er  d a y  
mI T T  
m o difi e d I nt e nt -t o-Tr e at  
m L  
m illilit er 
N -C L B  
n -d es m et h yl cl o b a z a m  
M RI  
m a g n eti c r es o n a n c e i m a gi n g  
P B P K  
P h ysi ol o gi c all y -b as e d  p h ar m a c o ki n eti cs  
P e ds Q L  
P e di atri c  Q u alit y  of  Lif e I n v e nt or y  
P B P K  
p h ysi ol o gi c all y -b as e d  p h ar m a c o ki n eti cs  
P K  
p h ar m a c o ki n eti cs  
P P  
p er  p r ot o c ol 
Q o L  
q u alit y  of  lif e 
Q O L C E  
Q u alit y  of  Lif e i n  C hil d h o o d  E pil e ps y  
Q T c F  
c orr e ct e d  Q T  i nt er v al  usi n g  Fr e d eri ci a  m et h o d 
S A E  
seri o us  a d v ers e  e v e nt  
S A F  
s af et y  p o p ul ati o n 
S A P  
st atisti c al a n al ysis  pl a n  
S D  
st a n d ar d d e vi ati o n  
S E   
st at us e pil e pti c us  
S M EI  
se v er e  m y o cl o ni c  e pil e ps y  o f inf a n c y  
S T P  
stiri p e nt ol 
S U D E P  
su d d e n  u n e x p e ct e d  d e at h  i n e pil e ps y  
T  +  M  
Titr ati o n  pl us  M ai nt e n a n c e  P eri o ds  
T H C  
t etr a h y dr o c a n n a bi n ol 
T S H  
th yr oi d  sti m ul ati n g h or m o n e  
U L N  
u p p er  li mit of  n or m al  
U S A  
U nit e d  St at es  of  A m eri c a  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 0  of  1 9 4  
A B B R E V A TI O N   
D E FI NI TI O N  
V N S  
v a g al  n er v e  sti m ul at or/sti m ul ati o n 
V P A  
v al pr o at e ; s o di u m  v al pr o at e;  v al pr oi c  a ci d 
Z X 0 0 8  
fe nfl ur a mi n e  h y dr o c hl ori d e  o r al sol uti o n  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 1  of  1 9 4  
S T U D Y  S Y N O P SI S  
St u d y  Titl e:   A  M ulti c e nt er,  2 -C o h ort  Tri al t o  First  Ass ess t h e  P h ar m a c o ki n eti c  a n d  S af et y  Pr ofil e  of 
a  Si n gl e  D os e  of  Z X 0 0 8 ( F e nfl ur a mi n e  H y dr o c hl ori d e)  Or al  S ol uti o n  W h e n  A d d e d t o  St a n d ar d  of 
C ar e ( C o h ort  1),  F oll o w e d  b y  a  R a n d o mi z e d,  D o u bl e -bli n d,  Pl a c e b o -c o ntr oll e d  P ar all el  Gr o u p 
E v al u ati o n  of t h e  Effi c a c y,  S af et y,  a n d  T ol er a bilit y  of  Z X 0 0 8  as  A dj u n cti v e  A nti e pil e pti c  T h er a p y t o 
Stiri p e nt ol  Tr e at m e nt i n  C hil dr e n  a n d  Y o u n g  A d ults  wit h  Dr a v e t  S y n dr o m e ( C o h ort  2) 
St u d y  N u m b e r:  Z X 0 0 8 -1 5 0 4  
St u d y  P r o d u ct:  F e nfl ur a mi n e  H y dr o c hl ori d e  Or al  S ol uti o n,  Z X 0 0 8  
T y p e  of  St u d y:  
Effi c a c y, s af et y,  a n d  p h ar m a c o ki n eti cs st u d y  
I n di c ati o n  St u di e d:  
A dj u n cti v e t h er a p y i n  Dr a v et s y n dr o m e  
P h as e  of  D e v el o p m e nt:  P h as e III   
C o u nt r i es: C a n a d a,  Fr a n c e,  G er m a n y,  th e 
N et h erl a n ds ,  U nit e d  Ki n g d o m, U nit e d  St at es , 
S p ai n  
S p o ns o r:  Z o g e ni x I nt er n ati o n al  Li mit e d   
C o o r di n ati n g I n v esti g at o r:    
Ri m a  N a b b o ut ,  M D 
 
S er vi c e  d e  N e ur o m èt a b olis m e  
 
C H U  P aris  - H ȏ pit al  N e c k er -E nf a nts  M al a d es  
 
1 4 9  R u e  d e  S è vr es  
 
7 5 7 4 3  P A RI S  
 
F R A N C E  
Esti m at e d  D u r ati o n  of I n di vi d u al  S u bj e ct  P a rti ci p ati o n : 
T h e  d ur ati o n  of t h e  p arti ci p ati o n i n t h e st u d y f or  a n i n di vi d u al s u bj e ct  i n  C o h ort  1 is  e x p e ct e d t o  b e 
u p t o  1 7  d a ys ( + 1 5 -d a y s af et y f oll o w -u p) f or t h e  p h ar m a c o ki n eti c ( P K)  e v al u ati o n.  T h e  d ur ati o n  of 
p arti ci p ati o n i n t h e st u d y f or  a n i n di vi d u al s u bj e ct  i n  C o h ort  2 is  e x p e ct e d t o  b e 6  w e e ks f or t h e 
b as eli n e  p eri o d,  a n d  u p t o  1 7  w e e ks  of  d o u bl e -bli n d tr e at m e nt  wit h  Z X 0 0 8  or  pl a c e b o  i n t h e titr ati o n, 
m ai nt e n a n c e ,  a n d t a p er/tr a nsiti o n p eri o ds .  Eli gi bl e  p arti ci p a nts fr o m  b ot h  C o h ort  1  a n d  C o h ort  2  will 
b e  off er e d  e nr oll m e nt i n  a s e p ar at e  o p e n -l a b el e xt e nsi o n tri al .  S u bj e cts i n  C o h ort  1  w h o  c h oo s e t o 
e nr oll i n t h e s e p ar at e l o n g -t er m e xt e nsi o n tri al  will  p arti ci p at e i n  a tr a nsiti o n  p eri o d t h at  will l ast  u p 
t o  a  m a xi m u m  of  2 4  w e e ks. S u bj e cts i n  C o h ort  2  w h o  will  c o nti n u e i nt o  t h e o p e n -l a b el  e xt e nsi o n tri al 
will  p arti ci p at e i n  a tr a nsiti o n  p eri o d  of  1 4  d a ys . S u bj e cts i n  C o h ort  2  w h o  d o  n ot  p arti ci p at e i n t h e 
o p e n -l a b el  e xt e nsi o n tri al  will  u n d er g o  a t a p er  p eri o d  of  1 4  d a ys,  aft er  w hi c h t h e y  will  b e  off st u d y 
m e di c ati o n.  F or s u bj e cts  w h o  d o  n ot  e nr oll i n t h e s e p ar at e l o n g -t er m  e xt e nsi o n, t h er e  will  b e a 
f oll o w-u p  visit f or  c ar di o v a s c ul ar s af et y  m o nit ori n g  3-6  m o nt hs  aft er t h e l ast  d os e  of st u d y 
m e di c ati o n.  
O bj e cti v es:  
T h e  pri m ar y  effi c a c y  o bj e cti v e  of t his  t w o-c o h ort  st u d y is: 
o   T o  d e m o nstr at e t h at  Z X 0 0 8 is s u p eri or t o  pl a c e b o  as  a dj u n cti v e  t h er a p y i n t h e tr e at m e nt  of 
s y m pt o ms  of  Dr a v et s y n dr o m e  in  c hil dr e n  a n d  y o u n g  a d ults  b as e d  o n  c h a n g e i n t h e 
fr e q u e n c y  of  c o n v ulsi v e s ei z ur es  b et w e e n  b as eli n e  a n d t h e  c o m bi n e d  Titr ati o n  a n d 
M ai nt e n a n c e  P eri o ds ( T  +  M)  i n  C o h ort  2. 
T h e  k e y s e c o n d ar y  effi c a c y  o bj e cti v es  of t h e st u d y  ar e  r el at e d t o  C o h ort  2  a n d i n cl u d e: 
o   T o  d e m o nstr at e t h at  Z X 0 0 8 is s u p eri or t o  pl a c e b o  o n  t h e f oll o wi n g  e n d p oi nts: 
–   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥  5 0 % r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e 
s ei z ur e fr e q u e n c y.  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 2  of  1 9 4  
–   T h e l o n g est  c o n v ulsi v e s ei z ur e -fr e e i nt er v al. 
S e e  St atisti c al  M et h o ds ( S e cti o n  1 0. 5. 1. 3 ) f or  hi er ar c hi c al t esti n g  pr o c e d ur e. 
 
A d diti o n al s e c o n d ar y  effi c a c y  o bj e cti v es  of t h e st u d y  ( C o h ort  2) ar e:  
o   T o  d e m o nstr at e t h at  Z X 0 0 8  is s u p eri or t o  pl a c e b o  o n t h e f oll o wi n g  e n d p oi nts:  
–   T h e  n u m b er  of  c o n v ulsi v e s ei z ur e -fr e e  d a ys. 
–   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  ≥  2 5 %  or  ≥  7 5 % r e d u cti o ns fr o m  b as eli n e i n 
c o n v ulsi v e  s ei z ur e fr e q u e n c y.  
–   T h e  c h a n g e fr o m  b as eli n e i n  n o n -c o n v ulsi v e s ei z ur e fr e q u e n c y.  
–   T h e  c h a n g e fr o m  b as eli n e i n  c o n v ulsi v e  +  n o n -c o n v ulsi v e s ei z ur e fr e q u e n c y.  
–   T h e i n ci d e n c e  of  r es c u e  m e di c ati o n  us a g e. 
–   T h e i n ci d e n c e  of  h os pit ali z ati o n  t o tr e at s ei z ur es. 
–   T h e  i n ci d e n c e  of  st at us  e pil e pti c us ( S E). 
–   T h e  c h a n g e fr o m  b as eli n e i n  h e alt h -r el at e d q u alit y  of lif e ( H R Q O L)  m e as ur e d  usi n g  t h e 
P e di atri c  Q u alit y  of  Lif e I n v e nt or y ™  (P e ds Q L ) G e n eri c  C or e  S c al e.  
–   T h e  c h a n g e fr o m  b as eli n e i n  P e ds Q L  F a mil y I m p a ct  m o d ul e s c or e . 
–   C h a n g e fr o m  b as eli n e i n s u bj e cts’  q u alit y  of lif e  m e as ur e d  usi n g t h e  Q u alit y  of  Lif e i n 
C hil d h o o d  E pil e ps y  ( Q O L C E) 
–   T h e  c h a n g e fr o m  b as eli n e i n t h e  H R Q O L  of t h e  p ar e nt/ c ar e gi v er  usi n g t h e  st a n d ar di z e d 
m e as ur e  of  h e alt h st at us ( E Q -5 D -5 L ) s c al e. 
–   T h e  c h a n g e fr o m  b as eli n e  o n t h e i m p a cts  of t h e  c o n diti o n  o n  p ar e nts  a n d t h e f a mil y  usi n g 
t h e  P e ds Q L f a mil y i m p a ct  m o d ul e.  
–   Cli ni c al  Gl o b al I m pr essi o n  –  I m pr o v e m e nt ( C GI-I) r ati n g,  as  ass ess e d  b y t h e  pri n ci p al 
i n v esti g at or. 
–   C GI -I r ati n g,  as  ass ess e d  b y t h e  p ar e nt/ c ar e gi v er. 
 
T h e  P K  o bj e cti v es  of t his st u d y i n cl u d e:  
o   T o  ass ess t h e  P K  pr ofil e  of  Z X 0 0 8  a d mi nist er e d  as  a si n gl e  or al  d os e  wit h  cl o b a z a m ( C L B)  + 
v al pr o at e ( V P A)  a n d  wit h  C L B  +  V P A  +  stiri p e nt ol (S T P ) 
o   M o d el  P K  of  Z X 0 0 8 i n si n gl e  a n d  m ulti pl e  d os e r e gi m e ns  usi n g f e nfl ur a mi n e/ n or -
f e nfl ur a mi n e  c o n c e ntr ati o n-ti m e  d at a fr o m s u bj e cts i n  C o h orts  1  a n d  2 
 
E x pl or at or y  o bj e cti v es  of  t his st u d y ( C o h ort  2) i n cl u d e: 
o   T o  ass ess t h e  c h a n g e fr o m  b as eli n e i n  h e alt h  a n d s o ci al  c ar e r es o ur c e  us e .  T h es e  m e as ur es 
i n cl u de  pl a n n e d  a n d  u n pl a n n e d  h os pit al  visits,  us e  of  a m b ul a n c es,  g e n er al  p r a ctiti o n er ( G P) 
visits, s p e e c h  a n d l a n g u a g e t h er a p y  utili z ati o n ,  o c c u p ati o n al  a n d  p h ysi c al t h er a p y utili z ati o n . 
o   C h a n g e fr o m  b as eli n e i n sl e e p  q u alit y .  
o   C h a n g e fr o m  b as eli n e i n  m e alti m e  b e h a vi o r. 
o   Eff e ct  of st u d y  m e di c ati o n  o n sl e e pi n ess ( K ar oli ns k a  Sl e e pi n ess  S c al e) . 
o   Ass ess m e nt  of  a  Dr a v et  sy n dr o m e  c o m p osit e  e n d p oi nt , w hi c h  will  i n cl u de  c or e  o bj e cti v e ( e g , 
s ei z ur e fr e q u e n c y)  a n d s u bj e cti v e ( e g ,  b e h a vi or, sl e e pi n ess, et c ) p ati e nt -r el e v a nt  o ut c o m e 
m e as ur es .   
 
T h e s af e t y  o bj e cti v es  of t h e st u d y  ar e : 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 3  of  1 9 4  
o   C o h ort  1 :  T o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of  Z X 0 0 8  as  a si n gl e  d os e  w h e n  a d d e d t o 
st a n d ar d  of  c ar e tr e at m e nt f or  D r a v et s y n dr o m e (C L B  +  V P A;  C L B  +  V P A  +  S T P).  
o   C o h ort  2:  T o  c o m p ar e t h e s af et y  a n d t ol er a bilit y  of  Z X 0 0 8 t o  pl a c e b o  wit h r e g ar d t o  a d v ers e 
e v e nts ( A Es), l a b or at or y  p ar a m et ers,  p h ysi c al  e x a mi n ati o n,  n e ur ol o gi c al  e x a mi n ati o n,  vit al 
si g ns ( bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e),  el e ctr o c ar di o gr a ms 
( E C G),  e c h o c ar di o gr a ms ( E C H O),  b o d y  w ei g ht.  C o g niti v e f u n cti o n  will  b e  ass ess e d  usi n g 
t h e  c o g niti o n  d o m ai n s c or e  o n t h e  Q O L C E  a n d  a g e-a p pr o pri at e  v ersi o ns  of t h e  Bri ef  R ati n g 
I n v e nt or y  E x e c uti v e  F u n cti o n ( B RI E F). 
M et h o d ol o g y:  
T his is  a  m ulti c e nt er,  2 -c o h ort  tri al t o first a ss ess t h e P K  a n d  saf et y  p r ofil e  of a si n gl e  d os e  of  Z X 0 0 8 
(f e nfl ur a mi n e  h y dr o c hl ori d e) o r al sol uti o n  w h e n  a d d e d t o  a st a n d ar d tr e at m e nt r e gi m e n f or  Dr a v et 
s y n dr o m e (Z X 0 0 8  0 .2 m g/ k g  +  C L B  +  V P A;  Z X 0 0 8  0. 4  m g/ k g  +  C L B  +  V P A;  or  Z X 0 0 8  0. 2  m g/ k g 
+  C L B  +  V P A  +  S T P  [C o h ort  1 ]), foll o w e d  b y  a  ra n d o mi z e d,  d o u bl e -bli n d,  p l a c e b o-c o ntr oll e d 
p ar all el  g r o u p e v al u ati o n  of t h e  e ffi c a c y, saf et y,  a n d  tol er a bilit y  of  Z X 0 0 8  as  a dj u n cti v e  th er a p y  i n 
p e di atri c  a n d  y o u n g  a d ult s u bj e cts  wit h  D r a v et s y n dr o m e (C o h ort  2) . A p pr o xi m at el y  2 -3  sit es i n 
Fr a n c e  a n d t h e  N et h erl a n ds  will  e nr oll  i nt o C o h ort  1;  u p  t o  a p pr o xi m at el y  3 0 st u d y  sit es i n  Fr a n c e , 
t h e  N et h erl a n ds,  U nit e d  Ki n g d o m, C a n a d a , U nit e d  St at es,  S p ai n,  a n d  G er m a n y  will  e nr oll s u bj e cts 
f or  C o h ort  2.  
 
T his is  a  t w o-c o h ort  st u d y. S u bj e cts  will  o nl y  b e  all o w e d t o  p arti ci p at e i n  o n e  of t h e t w o  c o h orts. 
C o h ort  1  will  b e  e nr oll e d i n t h e  o p e n -l a b el si n gl e-d os e  P K  p h as e  of t h e st u d y  t o  e v al u at e p ot e nti al 
dr u g -dr u g  i nt er a cti o ns  b et w e e n Z X 0 0 8  a n d  C L B  +  V P A  a n d  b et w e e n  Z X 0 0 8  a n d  C L B  +  V P A  + 
S T P . T w e nt y s u bj e cts  will  b e  all o c at e d t o r e c ei v e  o n e  of t hr e e  d osi n g r e gi m e ns  1)  a si n gl e  d os e  of 
Z X 0 0 8  0. 2  m g/ k g  +  C L B + V P A [ N = 5],  2)  a si n gl e  d os e  of  Z X 0 0 8  0. 4  m g/ k g  +  C L B  + V P A  [ N = 5],  or 
3)  a si n gl e  d os e  of  Z X 0 0 8  0. 2  m g/ k g  +  C L B  +  V P A +  S T P [ N = 1 0].  All o c ati o n t o  e a c h tr e at m e nt 
gr o u p  will  b e str atifi e d  b y  a g e ( <  6  y e ar  of  a g e ; >  6  y e ars  of  a g e).  S u bj e cts  will  b e  c o nfi n e d t o t h e 
cli ni c al r es e ar c h  u nit ( C R U ) st arti n g  o n t h e m or ni n g  o f  d osi n g ( D a y  1)  a n d  will r e m ai n i n t h e  u nit 
t hr o u g h t h e  1 2-h o ur  p ost -d os e  bl o o d  dr a w.  Bl o o d s a m pl e  c oll e cti o ns f or  P K  ( 4  m L  p er s a m pl e) will 
b e  o bt ai n e d i n t h e  C R U  pri or t o  d osi n g ( pr e -d os e),  a n d  at  2,  4,  8,  a n d  1 2  h o urs  p ost -d os e . A fi n al 
bl o o d s a m pl e  f or  P K  a n al ysis  will  b e  p erf or m e d  o n  D a y  2 ( 2 4-3 6  h o urs  p ost -d os e) ,  a n d  a s ei z ur e 
di ar y  will  b e  pr o vi d e d . P ar e nts/ c ar e gi v ers  of s u bj e cts i n  C o h ort  1  will  us e  a  di ar y  d ail y t o r e c o r d t h e 
n u m b er/t y p e  of s ei z ur es  a n d  us e  of r es c u e  m e di c ati o n  u ntil  D a y  1 5 . S u b j e cts  will r et ur n t o t h e  cli ni c 
o n  D a y  1 5  a n d f oll o wi n g  c o m pl eti o n  of t his  P K  p orti o n  of t h e st u d y,  eli gi bl e s u bj e cts  will  b e  off er e d 
e nr oll m e nt i n  a s e p ar at e  o p e n -l a b el e xt e nsi o n tri al  a n d  e nt er e d i nt o  a tr a nsiti o n  p eri o d  w h er e t h e y  will 
r e c ei v e  a fi x e d  dos e  of  Z X 0 0 8  0. 2  m g/ k g/ d a y f or  u p t o  2 4  w e e ks . T h e  P K  a n d s af et y  d at a fr o m 
C o h ort  1  a n d  St u d y  Z X 0 0 8 -1 5 0 5  h a v e  b e e n  us e d t o  i nf or m t h e  d os e  of  Z X 0 0 8 t o  b e  us e d i n  C o h ort  2. 
F oll o w -u p  c ar di o v as c ul ar s af et y  ass ess m e nts, i n cl u di n g  E C G  a n d  E C H O ,  will  b e  p erf or m e d  
3 -6  m o nt hs f oll o wi n g t h e l ast  d os e  of st u d y  m e di c ati o n.  A s c h e d ul e  of  ass ess m e nts is  pr o vi d e d i n   
T a bl e  1 . 
P arti ci p a nts i n  C o h ort  2  will  b e  e nr oll e d i n  t h e m ulti c e nt er,  d o u bl e -bli n d,  p ar all el -gr o u p,  pl a c e b o -
c o ntr oll e d  p orti o n  of t h e st u d y  t o  ass ess t h e  effi c a c y  a n d s af et y  of  Z X 0 0 8 as  a dj u n cti v e t h er a p y  of 
s ei z ur es i n c hil dr e n  a n d  y o u n g  a d ults  wit h  D r a v et s y n dr o m e. T h e  6 -w e e k  B as eli n e  P eri o d  will  c o nsist 
of t h e  est a blis h m e nt  of i niti al  eli gi bilit y  d uri n g  a s cr e e ni n g  visit f oll o w e d  b y  a n  o bs er v ati o n  p eri o d 
w h er e s u bj e cts  will  b e  ass ess e d f or  b as eli n e s ei z ur e  a cti vit y  b as e d  o n r e c or di n gs  of  d ail y s ei z ur e 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 4  of  1 9 4  
a cti vit y  e nt er e d i nt o  a  di ar y.  U p o n  c o m pl eti o n  of t h e  B as eli n e  P eri o d, s u bj e cts  w h o  q u alif y f or t h e 
st u d y  will  b e r a n d o mi z e d ( 1: 1) i n  a  d o u bl e -bli n d  m a n n er t o r e c ei v e  Z X 0 0 8 ( at  a  d os e  of   
0. 5  m g/ k g / d a y; m a xi m u m  d os e  2 0  m g/ d a y)  or  pl a c e b o.  R a n d o mi z ati o n  will  b e str atifi e d  b y  a g e  gr o u p 
( <  6  y e ars,  ≥ 6  y e ars) t o  e ns ur e  b al a n c e  a cr oss tr e at m e nt  ar ms,  a n d  at l e ast  4 0 %  of s u bj e cts  will  b e i n 
e a c h  a g e  gr o u p.  Titr ati o n  will  o c c ur i n  3 st e ps st arti n g  wit h  a  0. 2  m g/ k g/ d a y  d os e  of  Z X 0 0 8 ( or 
pl a c e b o  e q ui v al e nt)  o n  St u d y  D a ys  1 -7, i n cr e as e d  t o  a  d os e  of  0. 4  m g/ k g/ d a y  o n  St u d y  D a ys  8-1 4, 
a n d t h e n i n cr e as e d  t o  a  d os e  of  0. 5  m g/ k g/ d a y  o n  St u d y  D a ys  1 5-2 1.  T h e  d ur ati o n  of t h e  Titr ati o n 
P eri o d  is 2 1  d a ys ,  a n d t h e  m a xi m u m  d ail y  d os e  at  a n y p oi nt is  2 0  m g/ d a y . F oll o wi n g titr ati o n, 
s u bj e cts  will  c o nti n u e tr e at m e nt  wit h t h e  assi g n e d  d os e  of  Z X 0 0 8  0 . 5 m g/ k g/ d a y  or  pl a c e b o  o v er  a 
1 2 -w e e k  M ai nt e n a n c e  P eri o d . T ot al tr e at m e nt ti m e fr o m t h e  b e gi n ni n g  of t h e  Titr ati o n  P eri o d 
t hr o u g h t h e  e n d  of t h e  M ai nt e n a n c e  P eri o d is  a  m a xi m u m  of 1 5  w e e ks .  At t h e  e n d  of t h e  M ai nt e n a n c e 
P eri o d ( or  e arl y  dis c o nti n u ati o n),  all s u bj e cts  will  e nt er  eit h er  a t a p er  or tr a nsiti o n  p eri o d  b as e d  o n 
w h et h er t h e y  e xit t h e st u d y  or  ar e  e nr oll e d i n t h e s e p ar at e l o n g -t er m  o p e n-l a b el e xt e nsi o n tri al , 
r es p e cti v el y. P K s a m pl es  will  b e  c oll e c t e d  d uri n g t h e  F oll o w-U p  visit  f or s u bj e cts  w h o  will  b e 
e nt eri n g t h e  o p e n -l a b el  e xt e nsi o n. A f oll o w -u p  E C G  a n d  E C H O  will  b e  p erf or m e d  3 -6  m o nt hs  aft er 
st u d y  dr u g  dis c o nti n u ati o n f or  e arl y t er mi n ati o n,  or f or t h os e s u bj e cts  w h o  c o m pl et e t h e st u d y  b ut  d o 
n ot  e nt er t h e  o p e n -l a b el e xt e nsi o n tri al  C o h ort  2  o nl y).  
 
P ar e nts/ c ar e gi v ers  of s u bj e cts i n  C o h ort  2  will  us e  a  di ar y  d ail y t o r e c or d t h e  n u m b er/t y p e  of s ei z ur es, 
d osi n g,  a n d  us e  of r es c u e  m e di c ati o n.  A s c h e d ul e  of  ass ess m e nts is  pr o vi d e d i n  T a bl e  2 . 
E xt e r n al I n di vi d u als  a n d  C o m mitt e es:   T h e  Z X 0 0 8  cli ni c al  pr o gr a m  will  e m pl o y  a n I n d e p e n d e nt 
D at a  a n d  S af et y  M o nit ori n g  C o m mitt e e (I D S M C) t h at  will  b e r es p o nsi bl e f or s af et y  o v ersi g ht . A 
s e p ar at e I nt er n ati o n al  P e di atri c  C ar di ol o g y  A d vis or y  B o ar d (I P C A B)  will  m o nit or t h e  c ar di a c s af et y 
of t h e  Z X 0 0 8  cli ni c al tri als.  E C Gs  a n d  D o p pl er  E C H Os  will  b e  c e ntr all y r e a d ( Bi o m e di c al  S yst e ms, 
I n c.)  a n d i nt er pr et e d  u n d er  bli n d e d  c o n diti o ns  usi n g  pr e-sp e cifi e d  crit eri a,  a n d if  n e c ess ar y,  wit h 
r e vi e w  b y t h e I P C A B. T h e I D S M C  will  b e i nf or m e d  of  t h e  d os e s el e ct e d f or  C o h ort  2. 
N u m b e r  of  S u bj e cts:   
C o h o rt  1:   A p pr o xi m at el y  2 5  s u bj e cts  will  b e s cr e e n e d  t o e ns ur e  1 8 -2 0 s u bj e cts  e nt er t h e st u d y  a n d 
c o m pl et e  all  P K  ass ess m e nts.  S u bj e cts  w h o  dis c o nti n u e  pri or t o  c o m pl eti o n  of  all st u d y -r el at e d 
pr o c e d ur es  m a y  b e r e pl a c e d.  
C o h o rt  2:   A p pr o xi m at el y  1 1 5  s u bj e cts  will  b e s cr e e n e d t o  r a n d o mi z e a p pr o xi m at el y  9 0  s u bj e cts. 
E a c h  cli ni c al sit e  will  n ot r a n d o mi z e  m or e t h a n  a  m a xi m u m  of  8 -1 0  s u bj e cts wit h o ut  pri or  c o ns e nt 
fr o m t h e S p o ns or.  S u bj e cts  w h o  dis c o nti n u e fr o m t h e  cli ni c al i n v esti g ati o n f or  a n y r e as o n  will  n ot  b e 
r e pl a c e d. 
I n cl usi o n  a n d  E x cl usi o n  C rit e ri a  
I n cl usi o n  C rit e ri a:  S u bj e cts  m ust  m e et  all  of t h e f oll o wi n g i n cl usi o n  crit eri a t o  b e  e nr oll e d i nt o t h e 
st u d y: 
1.   S u bj e ct is  m al e  or  n o n -pr e g n a nt,  n o n -l a ct ati n g f e m al e,  a g e  2 t o  1 8  y e ars, i n cl usi v e  as  of t h e 
d a y  of t h e  S cr e e ni n g  Visit.  F e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  m ust  n ot  b e  pr e g n a nt 
or  br e ast -f e e di n g.  F e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  m ust  h a v e a  n e g ati v e  uri n e 
pr e g n a n c y t est.  S u bj e cts  of  c hil d b e ari n g  or  c hil d -f at h eri n g  p ot e nti al  m ust  b e  willi n g t o  us e 
m e di c all y  a c c e pt a bl e f or ms  of  birt h  c o ntr ol ( s e e S e cti o n  4. 4 ), w hi c h i n cl u d es  a bsti n e n c e, 
w hil e  b ei n g tr e at e d  o n t his st u d y  a n d f or  9 0  d a ys  aft er t h e  d os e  of st u d y  dr u g.  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 5  of  1 9 4  
2.   S u bj e ct  m ust  h a v e  d o c u m e nt e d  m e di c al  hist or y t o s u p p ort  a  cli ni c al  di a g n osis  of  D r a v et 
s y n dr o m e,  w h er e  c o n v ulsi v e s ei z ur es  ar e  n ot c o m pl et el y  c o ntr oll e d  b y  c urr e nt  a nti e pil e pti c 
dr u gs  ( A E Ds). 
3.    S u bj e cts  m ust  m e et  all  of t h e f oll o wi n g  5  crit eri a:  
a.   O ns et  of s ei z ur es i n t h e first  y e ar  of lif e i n  a n  ot h er wis e  h e alt h y i nf a nt.   
b.   A  hist or y  of s ei z ur es t h at  ar e  eit h er  g e n er ali z e d t o ni c -cl o ni c  or  u nil at er al  cl o ni c  or 
bil at er al  cl o ni c,  a n d  ar e  pr ol o n g e d.  
c.   I niti al  d e v el o p m e nt is  n or m al. 
d.   Hist or y  of  n or m al  br ai n  m a g n eti c r es o n a n c e i m a gi n g ( M RI ) wit h o ut  c orti c al  br ai n 
m alf or m ati o n.  
e.   L a c k  of  alt er n ati v e  di a g n osis.  
4.   S u bj e cts  m ust  m e et  at l e ast  o n e  of t h e f o ll o wi n g  3  crit eri a: 
a.   E m er g e n c e  of  a n ot h er s ei z ur e t y p e, i n cl u di n g  m y o cl o ni c,  g e n er ali z e d t o ni c -cl o ni c, 
t o ni c,  at o ni c,  a bs e n c e  a n d/ or f o c al  h as  d e v el o p e d  aft er t h e first s ei z ur e t y p e. 
b.   Pr ol o n g e d  e x p os ur e t o  w ar m t e m p er at ur es i n d u c es s ei z ur es  a n d/ or s ei z ur es  a r e 
ass o ci at e d  wit h f e v ers  d u e t o ill n ess  or  v a c ci n es,  h ot  b at hs,  hi g h l e v els  of  a cti vit y 
a n d s u d d e n t e m p er at ur e  c h a n g es  a n d/ or s ei z ur es  ar e i n d u c e d  b y str o n g  n at ur al 
a n d/ or fl u or es c e nt li g hti n g,  as  w ell  as  c ert ai n  vis u al  p att er ns.   
c.   G e n eti c t est r es ults  c o n sist e nt  wit h  a  di a g n osis  of  D r a v et s y n dr o m e ( p at h o g e ni c, 
li k el y  p at h o g e ni c,  v ari a nt  of  u n k n o w n si g nifi c a n c e,  or i n c o n cl usi v e  b ut  u nli k el y t o 
s u p p ort  a n  alt er n ati v e  di a g n osis.)  
5.   S u bj e ct  m ust  h a v e  h a d  ≥  4  c o n v ulsi v e s ei z ur es (t o ni c -cl o ni c, t o ni c,  cl o ni c)  p er  4 -w e e k  p eri o d 
f or  1 2  w e e ks  pri or t o s cr e e ni n g,  b y  p ar e nt/ g u ar di a n r e p ort t o i n v esti g at or  or i n v esti g at or 
m e di c al  n ot es  [ C o h o rt  2  o nl y]. 
6.   All  m e di c ati o ns  or i nt er v e nti o ns f or  e pil e ps y (i n cl u di n g  k et o g e ni c  di et [ K D]  a n d  v a g al  n er v e 
sti m ul ati o n [ V N S]) m ust  b e  st a bl e f or  at l e ast  4  w e e ks  pri or t o  s cr e e ni n g  a n d  ar e  e x p e ct e d t o 
r e m ai n st a bl e t hr o u g h o ut t h e st u d y.  
7.   S u bj e ct  m ust  b e r e c ei vi n g  a t h er a p e uti c all y r el e v a nt  a n d st a bl e  d os e  of  C L B,  V P A ,  a n d  S T P 
f or  at l e ast  4  w e e ks  pri or t o s cr e e ni n g  a n d  ar e  e x p e ct e d t o r em ai n st a bl e t hr o u g h o ut t h e 
st u d y [ C o h o rt  2 o nl y ].  (I n s o m e  c as es, s u bj e cts  w h o  ar e  c o ntr ai n di c at e d f or  V P A  or  C L B 
m a y  b e  e nr oll e d i n  C o h ort  2.   S u bj e cts i n t h es e  c as es  m ust  b e r e c ei vi n g  a t h er a p e uti c all y 
r el e v a nt  a n d st a bl e  d os e  of  S T P  a n d  V P A [if c o ntr ai n di c at e d f or  C L B]  or  S T P  a n d  C L B [if 
c o ntr ai n di c at e d f or  V P A].   E a c h  s u bj e ct  m ust  b e r e vi e w e d  wit h t h e  M e di c al  M o nit or  a n d 
s p o ns or  b ef or e i niti ati n g s cr e e ni n g.   T h e  d e cisi o n t o  all o w  e nr oll m e nt  of t h es e s u bj e cts is  at 
t h e s ol e  dis cr eti o n  of t h e s p o ns or.) 
8.   S u bj e ct  m ust  b e r e c ei vi n g  a st a bl e  d os e  of  C L B  a n d  V P A ,  a d mi nist er e d t wi c e  d ail y (BI D ), t o 
b e  eli gi bl e f or  D os e  R e gi m e n  1  a n d  2  or  su bj e ct  m ust  b e r e c ei vi n g  a st a bl e  d os e  of  C L B , 
V P A,  a n d  S T P , a d mi nist er e d  BI D , t o  b e  eli gi bl e f or D os e  R e gi m e n  3  [ C o h ort  1  o nl y] . 
9.   S u bj e ct  a gr e es t o  pr o vi d e  a  b u c c al  s w a b f or  C Y P 2 D 6 ( c yt o c hr o m e  P 4 5 0  2 D 6) g e n ot y pi n g.  
1 0.  S u bj e ct  h as  b e e n i nf or m e d  of t h e  n at ur e  of t h e st u d y  a n d i nf or m e d  c o ns e nt  h as  b e e n 
o bt ai n e d fr o m t h e l e g all y r es p o nsi bl e  p ar e nt/ g u ar di a n.  
1 1.  S u bj e ct  h as  pr o vi d e d  ass e nt i n  a c c or d a n c e  wit h I nstit uti o n al  R e vi e w  B o ar d 
(I R B)/I n d e p e n d e nt Et hi cs  C o m mitt e e  (I E C) r e q uir e m e nts, if  c a p a bl e. 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 6  of  1 9 4  
1 2.  S u bj e ct’s  p ar e nt/ c ar e gi v er is  willi n g  a n d  a bl e t o  b e  c o m pli a nt  wit h  all st u d y r e q uir e m e nts  a n d 
visit s c h e d ul e.  S u bj e ct’s  p ar e nt/ c ar e gi v e r  m ust  als o  b e  willi n g  a n d  a bl e t o  b e  c o m pli a nt  wit h 
di ar y  c o m pl eti o n  a n d st u d y  dr u g  a c c o u nt a bilit y . 
 
E x cl usi o n  C rit e ri a:  S u bj e cts  m e eti n g  a n y  of t h e f oll o wi n g  e x cl usi o n  crit eri a  m ust  n ot  b e  e nr oll e d 
i nt o t h e st u d y: 
1.   S u bj e ct  h as  a  k n o w n  h y p ers e nsiti vit y t o  f e nfl ur a mi n e  or  a n y  of t h e  e x ci pi e nts i n t h e st u d y 
m e di c ati o n.  
2.   S u bj e ct  h as  p ul m o n ar y  art eri al  h y p ert e nsi o n.  
3.   S u bj e ct  h as  c urr e nt  or  p ast  hist or y  of  c ar di o v as c ul ar  or  c er e br o v as c ul ar  dis e as e, s u c h  as 
c ar di a c  v al v ul o p at h y,  m y o c ar di al i nf ar cti o n  or str o k e.  
4.   S u b j e ct  h as  c urr e nt  or r e c e nt  hist or y  of a n or e xi a  n er v os a,  b uli mi a,  or  d e pr essi o n  wit hi n t h e 
pri or  y e ar t h at r e q uir e d  m e di c al tr e at m e nt  or  ps y c h ol o gi c al tr e at m e nt f or  a  d ur ati o n  gr e at er 
t h a n  1  m o nt h. 
5.   S u bj e ct  h as  a  c urr e nt  or  p ast  hist or y  of  gl a u c o m a . 
6.   S u bj e ct  h as  m o d er at e  or s e v er e  h e p ati c i m p air m e nt.  
a.   As y m pt o m ati c s u bj e cts  wit h  mil d  h e p ati c i m p air m e nt ( as p ar tat e  a mi n otr a nsf er as e 
[ A S T]  a n d  al a ni n e  a mi n otr a nsf er as e [ A L T] <  2 x  t h e  u p p er li mit  of  n or m al (U L N ) 
a n d  n o  el e v ati o ns  of  g a m m a -gl ut a m yltr a nsf er as e [ G G T],  al k ali n e  p h os p h at as e,  or 
t ot al  bilir u bi n i n di c ati v e  of  m or e t h a n  mil d  h e p ati c i m p air m e nt), m a y  b e  e nt er e d i nt o 
t h e st u d y  aft er r e vi e w  a n d  a p pr o v al  b y t h e  M e di c al  M o nit or i n  c o nj u n cti o n  wit h t h e 
S p o ns or , i n  c o nsi d er ati o n  of  c o m or bi diti es  a n d  c o n c o mit a nt m e di c ati o ns  [C o h o rt  1 
o nl y ]. 
b.   As y m pt o m ati c s u bj e cts  wit h  mil d  h e p ati c i m p air m e nt ( el e v at e d li v er  e n z y m es  <  3 x 
U L N  a n d/ or  el e v at e d  bilir u bi n  <  2 x  U L N)  m a y  b e  e nt er e d i nt o t h e st u d y  aft er r e vi e w 
a n d  a p pr o v al  b y t h e  M e di c al  M o nit or i n  c o nj u n cti o n  wit h t h e  S p o n s or, i n 
c o nsi d er ati o n  of  c o m or bi diti es  a n d  c o n c o mit a nt  m e di c ati o ns  [ C o h o rt  2  o nl y]. 
7.   S u bj e ct is r e c ei vi n g  c o n c o mit a nt t h er a p y  wit h:  c e ntr all y -a cti n g  a n or e cti c  a g e nts;  m o n o a mi n e -
o xi d as e i n hi bit ors;  a n y  c e ntr all y -a cti n g  c o m p o u n d  wit h  cli ni c all y  a p pr e ci a bl e  a m o u nt  of 
s er ot o ni n  a g o nist  or  a nt a g o nist  pr o p erti es, i n cl u di n g s er ot o ni n r e u pt a k e i n hi biti o n;  tri pt a ns, 
at o m o x eti n e,  or  ot h er  c e ntr all y -a cti n g  n or a dr e n er gi c  a g o nist;  or  c y pr o h e pt a di n e  (s e e 
A p p e n di x  1 ). ( N ot e:  S h ort-t er m  m e di c ati o n r e q uir e m e nts  will  b e  h a n dl e d  o n  a  p er  c as e  b asis 
b y t h e  M e di c al  M o nit or.)  
8.   S u bj e ct is  c urr e ntl y r e c ei vi n g  or  h as r e c ei v e d  S T P  i n t h e  p ast  2 1  d a ys  pri or t o  S cr e e ni n g 
(o nl y  f o r  C o h o rt  1 s u bj e cts  all o c at e d t o  D os e  R e gi m e n  1  o r  2 ). 
9.   S u bj e ct is  c urr e ntl y  t a ki n g  car b a m a z e pi n e,  o x c ar b a z e pi n e ,  esli c ar b a z e pi n e,  p h e n o b ar bit al,  or 
p h e n yt oi n,  or  h as t a k e n  a n y  of t h es e  wit hi n t h e  p ast  3 0  d a ys  as  m ai nt e n a n c e t h er a p y.  
1 0.  S u bj e ct is  u n willi n g t o r efr ai n fr o m l ar g e  or  d ail y s er vi n gs  of  gr a p efr uits  a n d/ or  S e vill e 
or a n g es,  a n d t h e ir j ui c es  b e gi n ni n g  wit h t h e  B as eli n e  P eri o d  a n d t hr o u g h o ut t h e st u d y. 
1 1.  S u bj e ct  h as  p ositi v e r es ult  o n  uri n e t etr a h y dr o c a n n a bi n ol ( T H C)  P a n el  or  w h ol e  bl o o d 
c a n n a bi di ol ( C B D)  at t h e  S cr e e ni n g  Visit.  
1 2.  S u bj e ct  h as  p arti ci p at e d i n  a n ot h er  cli ni c al tri al  wit hi n  t h e  p ast  3 0  d a ys. 
1 3.  S u bj e ct is  c urr e ntl y r e c ei vi n g  a n i n v esti g ati o n al  pr o d u ct.  
1 4.  S u bj e ct is  u n willi n g  or  u n a bl e t o  c o m pl y  wit h s c h e d ul e d  visits,  dr u g  a d mi nistr ati o n  pl a n, 
l a b or at or y t ests,  ot h er st u d y  pr o c e d ur es,  a n d st u d y r estri cti o ns.  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 7  of  1 9 4  
1 5.  S u bj e ct  h as  a  cli ni c al l y si g nifi c a nt  c o n diti o n,  or  h as  h a d  cli ni c all y r el e v a nt s y m pt o ms  or  a 
cli ni c all y si g nifi c a nt ill n ess i n t h e  4  w e e ks  pri or t o t h e  S cr e e ni n g  Visit,  ot h er t h a n  e pil e ps y, 
t h at  w o ul d  n e g ati v el y i m p a ct st u d y  p arti ci p ati o n,  c oll e cti o n  of st u d y  d at a,  or  p os e  a ris k t o 
t h e s u bj e ct. 
 
R a n d o mi z ati o n  I n cl usi o n  C rit e ri a  [ C o h o rt  2]: S u bj e cts  m ust  m e et  all  of t h e i n cl usi o n  crit eri a 
a b o v e  pl us t h e f oll o wi n g  crit eri a, t o  b e r a n d o mi z e d  or  all o c at e d t o st u d y  m e di c ati o n : 
1.   S u bj e ct  h as  b e e n  a p pr o v e d f or st u d y i n cl usi o n  b y t h e  E pil e ps y  St u d y  C o ns orti u m.  
2.   S u bj e ct  d o es  n ot  h a v e  a  c ar di o v as c ul ar  or  c ar di o p ul m o n ar y  a b n or m alit y  b as e d  o n  E C H O, 
E C G  or  p h ysi c al  e x a mi n ati o n, i n cl u di n g  b ut  n ot li mit e d t o tr a c e  mitr al  or  a orti c  v al v e 
r e g ur git ati o n,  or si g ns  of  p ul m o n ar y  h y p ert e nsi o n,  a n d is a p pr o v e d f or  e ntr y  b y t h e  c e ntr al 
c ar di a c s af et y  r e a d er. 
3.   S u bj e ct  d e m o nstr at es  a st a bl e  b as eli n e  wit h  ≥  6  c o n v ulsi v e s ei z ur es  d uri n g t h e  6 -w e e k 
B as eli n e  P eri o d,  wit h  a  mi ni m u m  of  2 i n t h e first  3  w e e ks  a n d  2 i n t h e s e c o n d  3  w e e ks .  
4.   S u bj e ct’s  p ar e nt/ c ar e gi v er  h as  b e e n  c o m pli a nt  wit h  di ar y  c o m pl eti o n  d uri n g t h e  B as eli n e 
P eri o d, i n t h e  o pi ni o n  of t h e I n v esti g at or ( e g ,  at l e ast  9 0 %  c o m pli a n c e). 
St u d y  P r o d u ct,  D os e,  a n d  M o d e  of  A d mi nist r ati o n:  
Z X 0 0 8 is s u p pli e d  as  a n  or al s ol uti o n i n  c o n c e ntr ati o n s  of  1. 2 5,  2. 5,  a n d  5  m g/ m L.   
 
C o h o rt  1:  S u bj e cts  ar e t o  b e  d os e d  or all y  wit h  1  of  3  r e gi m e ns: 
•   R e gi m e n  1:   a si n gl e  d os e  of  Z X 0 0 8  0. 2  m g/ k g  +  C L B  + V P A  
•   R e gi m e n  2:  a si n gl e  d os e  of  Z X 0 0 8  0. 4  m g/ k g  +  C L B  +  V P A,  or   
•   R e gi m e n  3:  a si n gl e  d os e  of  Z X 0 0 8  0. 2  m g/ k g  +  C L B  +  V P A  +  S T P  
S u bj e cts  assi g n e d t o  R e gi m e n  1  or  2  will  b e  all o c at e d  t o tr e at m e nt ( usi n g  a str atifi e d r a n d o mi z ati o n 
b as e d  o n  a g e ) wit h  eit h er  Z X 0 0 8  0. 2  m g/ k g  or  Z X 0 0 8  0. 4  m g/ k g t o g et h er  wit h t h eir  us u al  d os e  of 
C L B  +  V P A.  Str atifi e d r a n d o mi z ati o n  will  e ns ur e t h at  b ot h  R e gi m e ns  1  a n d  2  h a v e  at l e ast  2  s u bj e cts 
<  6  y e ars  ol d  a n d  at l e ast  2 s u bj e ct s ≥  6  y e ars  ol d . S u bj e cts  assi g n e d t o  R e gi m e n  3  will r e c ei v e 
Z X 0 0 8  0. 2  m g/ k g  +  C L B  +  V P A  +  S T P.  At l e ast  5  s u bj e cts will  b e  all o c at e d t o  e a c h  pr e -d efi n e d  a g e 
gr o u p ( <  6  y e ars  ol d  a n d  ≥  6  y e ars  ol d) . 
B a c k gr o u n d  m e di c ati o ns :   O n t h e  d a y  pri or t o  d osi n g, t h e p ar e nt/ c ar e gi v er  will  b e r e mi n d e d  t o  bri n g 
t h e s u bj e ct’s us u al  e pil e ps y  m e di c ati o ns  (C L B  +  V P A  or  C L B  +  V P A  +  S T P)  t o t he  C R U  (i n 
a d diti o n t o  a n y  ot h er  p er mitt e d  e pil e ps y  m e di c ati o ns),  f or m or ni n g  a n d  e v e ni n g  a d mi nistr ati o n  o n t h e 
d a y  of  d osi n g.  
S u bj e cts  w h o  wis h t o  p arti ci p at e i n t h e  o p e n -l a b el e xt e nsi o n tri al ,  will e nt er t h e  tr a nsiti o n  p eri o d a n d  
will r e c ei v e  Z X 0 0 8  0. 2  m g/ k g/ d a y  t o g et h er  wit h t h eir  us u al  d os e  of  C L B  +  V P A  or  C L B  +  V P A  + 
S T P . St u d y  m e di c ati o n  will  b e  a d mi nist er e d t wi c e  a  d a y ( BI D) i n  e q u all y  di vi d e d  d os es  wit h f o o d.   
C o h o rt  2 :  S u bj e cts  will  b e r a n d o mi z e d t o r e c ei v e  Z X 0 0 8  (0. 5  m g/ k g/ d a y  wit h  a  m a xi m u m  d os e  
of  2 0  m g/ d a y ) or  pl a c e b o.  St u d y  m e di c ati o n  will  b e  a d mi nist er e d  BI D i n  e q u all y  di vi d e d  d os es 
wit h f o o d.   


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 8  of  1 9 4  
R ef e r e n c e  P r o d u ct,  D os e,  a n d  M o d e  of  A d mi nist r ati o n:  
C o h o rt  1:   n ot  a p pli c a bl e  
C o h o rt  2:   m at c hi n g  Z X 0 0 8  pl a c e b o is s u p pli e d  as  a n  or al s ol uti o n.   
D u r ati o n  of  T r e at m e nt:  
C o h o rt  1 :   All s u bj e cts  will r e c ei v e  a si n gl e  d os e  of st u d y  m e di c ati o n ( Z X 0 0 8  0.2  m g/ k g  +  C L B  
+ V P A  or  Z X 0 0 8  0. 4  m g/ k g  +  C L B  +  V P A  or  Z X 0 0 8  0. 2  m g/ k g  +  C L B  +  V P A  +  S T P)  i n t h e  P K 
e v al u ati o n  p orti o n  of t h e st u d y .  Aft er  c o m pl eti o n,  eli gi bl e s u bj e cts w h o  i nt e n d t o e nr oll i n t h e 
s e p ar at e o p e n -l a b el e xt e nsi o n tri al ,  will  e nt er  a tr a nsiti o n  p eri o d at  a fi x e d  d os e  of  Z X 0 0 8 
0. 2  m g/ k g/ d a y  f or  u p t o 2 4  a d diti o n al  w e e ks . F oll o w -u p  c ar di o v as c ul ar s af et y  ass ess m e nts, i n cl u di n g 
E C G  a n d  E C H O ,  will  b e  p erf or m e d  3-6  m o nt hs f oll o wi n g t h e l ast  d os e  of st u d y  m e di c ati o n.  
  
C o h o rt  2 :   All s u bj e cts  will r e c ei v e  Z X 0 0 8  or  m at c hi n g  pl a c e b o i n  a d diti o n t o t h eir st a bl e  A E Ds f or 
1 5  w e e ks  i n cl u di n g t h e titr ati o n  p eri o d t hr o u g h t o t h e  e n d  of t h e  M ai nt e n a n c e  P eri o d. Aft er 
c o m pl eti o n  of t h e  M ai nt e n a n c e  P eri o d,  eli gi bl e s u bj e cts  m a y  e nr oll i n t h e  o p e n -l a b el e xt e nsi o n tri al . 
S u bj e cts  w h o  d o  n ot  e nr oll i n t h e  o p e n -l a b el e xt e nsi o n tri al  will  u n d er g o  a  1 4 -d a y  t a p er  off  of st u d y 
m e di c ati o n ( d os es  will  b e  a d mi nist er e d i n  a  bli n d e d f as hi o n , a n d  will  b e  d e cr e as e d i n  4 -d a y  d os e 
st e ps). F or  s u bj e cts w h o  e nt er t h e  o p e n -l a b el e xt e nsi o n tri al , tr a nsiti o n will  o c c ur i n  7 -d a y  d os e st e ps  
o v er  1 4  d a ys .  F oll o w -u p  c ar di o v as c ul ar s af et y  ass ess m e nts, i n cl u di n g  E C G  a n d  E C H O,  will  b e 
p erf or m e d  3 t o  6  m o nt hs f oll o wi n g t h e l ast  d os e  of st u d y  m e di c ati o n.  
C rit e ri a f o r  E v al u ati o n:  
C o h o rt  1  
P h ar m a c o ki n eti cs : Bl o o d s a m pl es f or  P K  ass ess m e nt  of f e nfl ur a mi n e  a n d its  m et a b olit e 
( n orf e nfl ur a mi n e), S T P , C L B  a n d its  m et a b olit e ( n -d es m et h yl cl o b a z a m [ N -C L B]) ,  a n d v al pr oi c  a ci d  
( V P A) will  b e  o bt ai n e d fr o m s u bj e cts  a c c or di n g t o t h e s c h e d ul e i n T a bl e  1  ( a t ot al  of 6  s a m pl es  p er 
s u bj e ct).  
S af et y : P K  p orti o n  of t h e st u d y:   A Es,  p h ysi c al  e x a mi n ati o n,  vit al si g ns,  E C G,  cli ni c al l a b or at or y 
p ar a m et ers (st a n d ar d  h e m at ol o g y,  cli ni c al  c h e mistr y,  ur i n al ysis). Tr a nsiti o n  p eri o d:   A Es, l a b or at or y 
s af et y  p ar a m et ers ( h e m at ol o g y,  c h e mistr y,  uri n al ysis),  vit al si g ns ( bl o o d  pr ess ur e,  h e art r at e, 
t e m p er at ur e,  a n d r es pir at or y r at e),  p h ysi c al  e x a mi n ati o n,  n e ur ol o gi c al  e x a mi n ati o n,  1 2-l e a d  E C Gs, 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  2 9  of  1 9 4  
D o p pl er  E C H Os,  a n d  b o d y  w ei g ht.  C o g niti v e  F u n cti o n  will  b e  ass ess e d  usi n g t h e  c o g niti o n  d o m ai n 
s c or e  o n t h e  Q O L C E  a n d  a g e -a p pr o pri at e  v ersi o ns  of t h e  B RI E F.  
 
C o h o rt  2  
Effi c a c y:  
•   N u m b er  of s ei z ur es  b y t y p e  
•   C o n v ulsi v e s ei z ur e -fr e e i nt er v al 
•   Q O L C E t o  m e as ur e s u bj e ct’s  q u alit y  of lif e  
•   P e ds Q L  G e n eri c  C or e  S c al e  t o  m e as ur e  c h a n g es i n  H R Q O L  of t h e s u bj e ct 
•   H R Q O L  of  p ar e nt/ c ar e gi v er  usi n g t h e  E Q -5 D -5 L s c al e  
•   I m p a ct  of  c o n diti o n  o n  p ar e nt/ c ar e gi v er  usi n g  P e ds Q L F a mil y I m p a ct  M o d ul e  
•   D ur ati o n  of  pr ol o n g e d s ei z ur es (s ei z ur e t y p e t h at,  d u ri n g  b as eli n e,  h a d  d ur ati o n  > 2  mi n ut es)  
•   N u m b er  of  e pis o d es  of  S E  
•   N u m b er  of i nst a n c es  of r es c u e  m e di c ati o n  us e  a n d  n u m b er  of  d os es  
•   N u m b er  of i n p ati e nt  h os pit al  a d missi o ns  d u e t o  s ei z ur es 
•   C GI -I s c or e  ass ess e d  b y t h e  pri n ci p al i n v esti g at or   
•   C GI -I s c or e  ass ess e d  b y t h e  p ati e nt/ c ar e gi v er  
 
S af et y :  A Es, l a b or at or y s af et y  p ar a m et ers ( h e m at ol o g y,  c h e mistr y,  uri n al ysis),  vit al si g ns ( bl o o d 
pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e),  p h ysi c al  e x a mi n ati o n,  n e ur ol o gi c al 
e x a mi n ati o n,  1 2 -l e a d  E C Gs,  D o p pl er  E C H Os,  a n d  b o d y  w ei g ht. C o g niti v e  F u n cti o n  will  b e  ass ess e d 
usi n g t h e  c o g niti o n  d o m ai n s c or e  o n t h e  Q O L C E  a n d  a g e -a p pr o pri at e  v ersi o ns  of t h e  B RI E F . 
 
P h ar m a c o ki n eti cs :  F o ur  s e q u e nti al bl o o d s a m pl e s will  b e  c oll e ct e d  d uri n g  Visit  1 3  f or st e a d y-st at e 
P K .  F e nfl ur a mi n e / n or-f e nfl ur a mi n e  c o n c e ntr ati o n-ti m e  d at a fr o m s u bj e cts  e nr oll e d i n  C o h orts  1  a n d 
2  will  b e  us e d t o  m o d el  P K  of  Z X 0 0 8 i n si n gl e  a n d  m ulti pl e  d os e r e gi m e ns.  
 
E x pl or at or y:   
•   H e alt h  a n d s o ci al  c ar e r es o ur c e  us e i n cl u di n g  G P  visits, s p e e c h  a n d l a n g u a g e,  o c c u p ati o n al 
a n d  p h ysi c al t h er a p y, i n  a d diti o n t o  a c ut e  h os pit al  a n d i nstit uti o n al l e n gt h  of st a y, l oss  of 
w or k,  et c.  
•   C h a n g e i n sl e e p  q u alit y  ass ess e d  b y t h e  p ati e nt/ c ar e gi v er  
•   C h a n g e i n  m e al ti m e  b e h a vi or  ass ess e d  b y t h e  p ati e nt/ c ar e gi v er 
•   Sl e e pi n ess  ass ess e d  b y t h e  p ati e nt/ c ar e gi v er  usi n g t h e  K ar oli ns k a  Sl e e pi n ess  S c al e  
•   C o m p osit es  e n d p oi nts t h at  c o m bi n e  o bj e cti v e  a n d s u bj e cti v e  m e as ur es . 
S a m pl e  Si z e  D et e r mi n ati o n:  
N o f or m al  h y p ot h esis t ests  ar e  pl a n n e d f or t h e  P K  e n d p oi nts st u di e d i n  C o h ort  1.  T h us, t h e s a m pl e 
si z e f or  C o h ort  1 is  b as e d  o n  pr a cti c al  c o nsi d er ati o ns i n cl u di n g t h e  e x p e ct e d  a v ail a bilit y  of 
a p pr o pri at e s u bj e cts.  T h e  P K  d at a fr o m  C o h ort  1  will  b e  us e d i n  c o m bi n ati o n  wit h  p h ysi ol o gi c all y -
b as e d  P K ( P B P K)  m o d els t h at  ar e  b ei n g  d e v el o p e d  usi n g r o b ust  d at a fr o m  a d ults  a n d fr o m  e xisti n g 
P B P K  m o d els f or t h e  c o n c o mit a nt  m e di c ati o ns. I n t his  w a y, t h e  d at a fr o m  Z X 0 0 8 -1 5 0 4  wi ll  b e 
l e v er a g e d  wit h  e xisti n g  P K i nf or m ati o n  o n f e nfl ur a mi n e, S T P , C L B , a n d  V P A  t o  c o nfir m t h e 
e x p e ct ati o ns  d eri v e d fr o m t h e  m e c h a nis m -b as e d  P B P K  m o d els.  A n al ysis  of t h e  d at a i n t his  w a y 
all o ws f or t h e  c o nfir m ati o n  of t h e  a p pr o pri at e n ess  of t h e  e xt e nsi o n  o f t h e  P B P K  m o d el fr o m  a d ults t o 


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  3 0  of  1 9 4  
c hil dr e n  a n d  a r o b ust  ass ess m e nt  of t h e  p ot e nti al f or  a  dr u g -dr u g i nt er a cti o n  b et w e e n  Z X 0 0 8  a n d  S T P  
w hil e li miti n g  e x p os ur e t o  a s m all er  n u m b er  of  p ati e nts.  T h e  2 0 s u bj e cts t ar g et e d f or t h e  P K  p h as e  of 
t h e st u d y is  e x p e ct e d t o  b e s uffi ci e nt t o  all o w f or t h e  e xt e nsi o n  of t h e  P K i nf or m ati o n  g ai n e d i n t h e 
o n g oi n g  P K st u d y i n  a d ults  a n d  e xisti n g  P B P K  m o d els t o  p e di atri c  p ati e nts  wit h  Dr a v et s y n dr o m e.  
T h e s a m pl e si z e f or  C o h ort  2 is  b as e d  o n r es ults fr o m  St u d y  1,  t h e r a n d o mi ze d,  pl a c e b o -c o ntr oll e d 
st u dy  i n s u bj e cts  wit h  Dr a v et s y n dr o m e s p o ns or e d  b y  Z o g e ni x . T h e st a n d ar d  d e vi ati o n ( S D)  of t h e 
p er c e nt a g e  c h a n g e i n s ei z ur e fr e q u e n c y fr o m  b as eli n e t o  t h e e n d  of st u d y ( D a y  9 9)  w as  5 0 % f or t h e 
0. 8  m g/ k g/ d a y  gr o u p  a n d  6 9 % f or t h e  0. 2  m g/ k g/ d a y  gr o u p . F or  t h e s a m pl e si z e  c al c ul ati o n f or 
C o h ort  2 , t h e  S D is  ass u m e d t o  b e i nt er m e di at e  b et w e e n t h e  S Ds  o bs er v e d i n t h e  hi g h  a n d l o w  d os e 
gr o u ps i n  St u d y  1.  Ass u mi n g  a n  S D  of  5 8,  a n d  u si n g  a t w o -si d e d t est  at t h e  α = 0. 0 5 si g nifi c a n c e l e v el, 
a s a m pl e si z e  of  4 5  s u bj e cts  p er tr e at m e nt  gr o u p  aff or ds  9 0 %  p o w er t o  d et e ct  a  diff er e n c e i n  m e a n 
c h a n g e  i n s ei z ur e fr e q u e n c y fr o m  b as eli n e  of  4 0  p er c e nt a g e  p oi nts.  T h us, t h e t ot al s a m pl e si z e f or 
C o h ort  2 is  pl a n n e d t o  b e  a p pr o xi m at el y  9 0  s u bj e cts (4 5  p er  ar m).  
St atis ti c al  M et h o ds: 
Effi c a c y  
Effi c a c y  a n al ys es  will  b e  p erf or m e d  o nl y  o n s u bj e cts  e nr oll e d i n  C o h ort  2.  T h e  pri m ar y  effi c a c y 
e n d p oi nt is t h e  c h a n g e i n t h e  m e a n  c o n v ulsi v e s ei z ur e fr e q u e n c y ( M C S F)  p er  2 8  d a ys  d uri n g t h e   
T  +  M  p eri o ds  c o m p ar e d  wit h  B as eli n e.  T h e  M C S F  will  b e  c al c ul at e d fr o m  all  a v ail a bl e  d at a 
c oll e ct e d  d uri n g t h e  B as eli n e  a n d tr e at m e nt  p eri o ds.  T h e  pri m ar y  e n d p oi nt  will  b e  a n al y z e d  usi n g  a n 
a n al ysis  of  c o v ari a n c e ( A N C O V A)  m o d el  wit h tr e at m e nt  gr o u p ( Z X 0 0 8  or  pl a c e b o)  a n d  a g e  gr o u p   
( <  6  y e ars,  ≥ 6  y e ars)  as f a ct ors,  a n d  wit h  b as eli n e fr e q u e n c y  as  a  c o v ari at e.  T h e  pri m ar y  a n al ysis  will 
c o m p ar e t h e  Z X 0 0 8  gr o u p t o t h e  pl a c e b o  gr o u p  usi n g  a t w o -si d e d t est  at t h e  al p h a = 0. 0 5 l e v el  of 
si g nifi c a n c e.  T h e  pri m ar y  e n d p oi nt  will  als o  b e  a n al y z e d  usi n g  a  n o n p a r a m etri c  m et h o d  a n d if 
n or m alit y  ass u m pti o ns  ar e  n ot  m et, t h e r es ults  of t h e  n o n p ar a m etri c  a n al ysis  will  b e  us e d f or 
e v al u ati o n  of t h e  pri m ar y  e n d p oi nt.  A n  a d diti o n al  a n al ysis  will  b e  p erf or m e d t o  ass ess t h e s e nsiti vit y 
of t h e  pri m ar y  a n al ysis t o  c h a n g es i n  c o n c o mit a nt  A E D  m e di c ati o ns t h at  m a y  o c c ur  d uri n g t h e  c o urs e 
of t h e tri al.  S p e cifi c all y, t h e  pri m ar y  a n al ysis  will  b e r e p e at e d  wit h  a f a ct or  a d d e d t o i n di c at e  w h et h er 
a s u bj e ct  h a d  a  c h a n g e i n  c o n c o mit a nt  A E D  m e di c ati o n  d uri n g t h e  T  +  M  p eri o d.  


Z o g e ni x I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N ) 2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  3 1  of  1 9 4  
S af et y   
All s af et y  d at a f or  C o h ort  2  will  b e  a p pr o pri at el y  a n al y z e d  b y tr e at m e nt  gr o u p.  T h e  n u m b er  a n d 
p er c e nt a g e  of s u bj e cts  wit h  A Es  will  b e  dis pl a y e d  b y  b o d y s yst e m  a n d  pr ef err e d t er m  usi n g t h e 
M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es ( M e d D R A).  S u m m ari es i n  t er ms  of s e v erit y  a n d 
r el ati o ns hi p t o st u d y  dr u g  will  als o  b e  pr o vi d e d.  A d v ers e e v e nts  of  sp e ci al  int er est  ( A E SI)  a n d 
seri o us  A Es ( S A Es)  will  b e s u m m ari z e d s e p ar at el y i n  a si mil ar  m a n n er.  L a b or at or y t ests,  vit al si g ns, 
p h ysi c al  e x a mi n ati o ns,  n e ur ol o gi c al  e x a mi n ati o ns,  E C G,  D o p pl er  E C H O , C ol u m bi a -S ui ci d e  S e v erit y 
R ati n g  S c al e  (C -S S R S ),  T a n n er  St a gi n g r es ults,  et c,  will  b e s u m m ari z e d  a p pr o pri at el y,  b y tr e at m e nt. 
A n  a d diti o n al  A E s u m m ar y  will  b e  pr o d u c e d f or  all s u bj e cts i n  C o h ort  1.  
 
P h ar m a c o ki n eti cs  
All  d at a fr o m  C o h ort  1  will  b e  e v al u at e d  usi n g  p o p ul ati o n  P K  a n al ysis  m et h o ds , w hi c h  will  b e 
d es cri b e d i n  d et ail i n  a s e p ar at e  P K  a n al ysis  pl a n.  W hil e t h e  a p pr o a c h es  will  b e si mil ar f or  all 
a n al yt es  of i nt er est (f e nfl ur a mi n e/ n orf e nfl ur a mi n e,  C L B / n-d es m et h yl cl o b a z a m,  V P A ,  a n d S T P ), t h e y 
will  b e t ail or e d t o t h e  a v ail a bilit y  of  pr e vi o us  P K i nf or m ati o n  a n d/ or  e xisti n g  P K  m o d els.  S u m m ar y 
st atisti cs  will  b e  pr es e nt e d  b y tr e at m e nt  gr o u p  a n d s a m pli n g ti m e.  Tr e at m e nt  gr o u ps  will  b e 
c o m p ar e d  usi n g  g e o m etri c  m e a n r ati os  w h er e  a p pr o pri at e.   


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
 P a g e  3 2  of  1 9 4  
T a bl e  1 .  
S c h e d ul e  of  Ass ess m e nts   
 
  
  
( H o u rs  r el ati v e t o  a d mi nist r ati o n  of st u d y  m e di c ati o n)   
 
 
  
 
St u d y  Ass ess m e nts  
S c r e e ni n g  
 
 
D a y  1  
D a y  2   
  
T r a nsi ti o n  P e ri o d 
E O S/
E T  
C a r di a c  
F oll o w -
u p  
Visit  n u m b e r  
1   
2  
3  
4  
5  
P h o n e  
6,  8,  1 0,  1 2 , 
1 4,  1 6  
7,  9,  1 1, 
1 3,  1 5  
1 7   
1 8,  1 9  
St u d y  D a y  
-1 4  t o -2   
– 1  
P r e d os e 
0  
2   
4   
8   
1 2   
2 4 -3 6   
1 5 a 
2 9,  5 7,  8 5, 
1 1 3 , 1 4 1, 
1 6 9  
4 3,  7 1,  9 9, 
1 2 7 ,  1 5 5 
1 8 3   
3 -6  m os  p ost 
l ast  d os e 
I nf or m e d  C o ns e nt 
X   
  
  
  
  
  
 
 
  
  
  
  
 
I n cl usi o n/  E x cl usi o n 
X   
X   
  
  
  
  
 
 
  
  
  
  
 
M e di c al  Hist or y  
X   
X   
  
  
  
  
 
 
  
  
  
  
 
D e m o gr a p hi cs  
X   
  
  
  
  
  
 
 
  
  
  
  
 
C o m pl et e  n e ur ol o gi c al  hist or y  a n d  e x a mi n ati o n   
X   
  
  
  
  
  
 
 
  
  
  
X   
 
N e ur ol o gi c al  e x a mi n ati o n ,  a b br e vi at e d 
  
  
  
  
  
  
 
 
X   
  
X   
  
 
E pil e ps y  hist or y  
X   
  
  
  
  
  
 
 
  
  
  
  
 
E pil e ps y  st at us ( n u m b er/t y p e/ d ur ati o n s ei z ur es  p er 
m o nt h)  
X   
  
  
  
  
  
 
 
X  
  
X   
X   
 
P h ysi c al  E x a mi n ati o n ,  c o m pl et e 
X   
X b  
  
  
  
  
 
 
  
  
  
X   
 
P h ysi c al  E x a mi n ati o n ,  a b br e vi at e d 
  
  
  
  
  
  
 
 
X   
  
X   
  
 
Pri or  m e di c ati o ns  
X   
  
  
  
  
  
 
 
  
  
  
  
 
B o d y  W ei g ht,  H ei g ht,  B MI  
X   
X c  
  
  
  
  
 
 
  
  
X   
X   
 
1 2 -l e a d  E C G 
X   
  
  
  
  
  
 
 
  
  
X d  
X   
 
E c h o c ar di o gr a m  
X   
  
  
  
  
  
 
 
 
  
X d 
X   
 
Uri n e  Pr e g n a n c y  T est  
X   
X   
  
  
  
  
 
 
X   
  
X   
X   
 
Cli ni c al  L a b or at or y  T est s  
X   
X e  
  
  
  
  
 
 
  
  
X   
X   
 
W h ol e  bl o o d  C B D  
X   
X e  
  
  
  
  
 
 
  
  
X   
X   
 
Uri n e  T H C  p a n el  
X   
X e  
  
  
  
  
 
 
  
  
X   
X   
 
B u c c al s w a b  f or  C Y P 2 D 6  g e n ot y pi n g 
X   
  
  
  
  
  
 
 
  
  
  
  
 
E pil e ps y  G e n ot y p e  P a n el  
X k  
  
  
  
  
  
 
 
  
  
  
  
 
Vit al  Si g ns f 
X   
X   
X   
X   
  
X   
 
X  
  
  
X   
X   
 
St u d y  Dr u g  A d mi nistr ati o n  
  
  
X   
  
  
  
 
 
X  
  
 
P K  S a m pli n g g 
  
  
X   
X   
X   
X   
X   
X  
  
  
  
  
 
Dis p e ns e  S ei z ur e  Di ar y  
  
  
  
  
  
  
 
X  
X   
  
X   
  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
 P a g e  3 3  of  1 9 4  
T a bl e  1.   C o h o rt  1:  S c h e d ul e  of  Ass ess m e nts  ( c o nti n u e d) 
 
  
 
( H o u rs  r el ati v e t o  a d mi nist r ati o n  of st u d y 
m e di c ati o n)  
 
 
  
 
St u d y  Ass ess m e nts  
S c r e e ni n g  
 
 
D a y  1  
D a y  2   
  
T r a nsi ti o n  P e ri o d 
E O S/
E T  
C a r di a c  
F oll o w -
u p  
Visit  n u m b e r  
1   
2  
3  
4  
5  
P h o n e  
6,  8,  1 0,  1 2 , 
1 4,  1 6  
7,  9,  1 1, 
1 3,  1 5  
1 7   
1 8,  1 9  
St u d y  D a y  
-1 4  t o -2  
–
1  
P r e -
D os e,  0  
2   
4   
8   
1 2   
2 4 -3 6   
1 5 a 
2 9,  5 7,  8 5, 
1 1 3 ,  1 4 1, 
1 6 9  
4 3,  7 1,  9 9, 
1 2 7 ,  1 5 5 
1 8 3   
3 -6  m os  p ost 
l ast  d os e 
R e vi e w  S ei z ur e  Di ar y  
  
  
  
  
  
  
 
 
X   
X   
X   
X   
 
St u d y  M e di c ati o n  
  
  
  
  
  
  
 
 
D   
R   
C/ R/ D   
C/ R   
 
C o n c o mit a nt  M e di c ati o ns  
X   
---------------------------------------------------------------------------------X h----------------------------------------------------------- 
A d v er s e  E v e nts  
  
------------------------------------------------------------------- X ----------------------------------------------------------   
X
i 
A d v er s e  E v e nts  of  S p e ci al I nt er est  
  
  
  
  
  
  
  
----------------------X ------------------------  
X  
P E Ds Q L  G e n eri c  C or e  S c al e  
  
  
  
  
  
  
  
X   
  
X   
X   
 
P e ds Q L  F a mil y I m p a ct  M o d ul e   
  
  
  
  
  
  
  
X   
  
X   
X   
 
Sl e e p  q u alit y  a n d  m e alti m e  b e h a vi or  q u esti o ns  
  
  
  
  
  
  
  
X   
  
X   
X   
 
K ar oli ns k a  Sl e e pi n ess  S c al e  
  
  
  
  
  
  
  
X   
  
X   
X   
 
B RI E F  
  
  
  
  
  
  
  
X   
  
X   
X   
 
Q O L C E  
  
  
  
  
  
  
  
X   
  
X   
X   
 
H e alt h c ar e  utili z ati o n  q u esti o ns  
  
  
  
  
  
  
  
X   
X   
X   
X   
 
C GI -I ( ass ess e d  b y  p ar e nt/ c ar e gi v er) 
  
  
  
  
  
  
  
  
  
X   
X   
 
C GI -I ( ass ess e d  b y  pri n ci p al i n v esti g at or) 
  
  
  
  
  
  
  
  
  
X   
X   
 
E Q -5 D -5 L ( Q o L  of  p ar e nt/ c ar e gi v er)  
  
  
  
  
  
  
  
X   
  
X   
X   
 
T a n n er  St a gi n g (f or s u bj e cts  >  7  y e ars  ol d)  
  
  
  
  
  
  
  
X   
  
X l  
X   
 
C -S S R S  
  
  
  
  
  
  
  
X   
  
X j  
X   
 
Pl as m a s a m pl e f or  b a c k gr o u n d  A E D  
  
  
  
  
  
  
  
X   
  
X j  
X   
 
A E D = a nti e pil e pti c  dr u g;  B MI = b o d y  m ass i n d e x;  B RI E F = B e h a vi or  R ati n g I n v e nt or y  of  E x e c uti v e  F u n cti o n;  C = C oll e ct;  C B D = c a n n a bi di ol;  ; C GI -I = Cli ni c al  Gl o b al I m pr essi o ns –  I m pr o v e m e nt; C -S S R S + C ol u m bi a  S ui ci d e  S e v erit y  R ati n g  S c al e; 
C Y P 2 D 6 = c yt o c hr o m e  P  4 5 0  2 D 6;  D = Dis p e ns e;  E C G = el e ctr o c ar di o gr a m;  E C H O = e c h o c ar di o gr a m;  E O S = e n d  of st u d y;  E T = e arl y t er mi n ati o n;  E Q -5 D -5 L =st a n d ar di z e d  m e as ur e  of  h e alt h st at us;  m os = m o nt hs;  P e ds Q L = P e di atri c  Q u alit y  of  Lif e 
I n v e nt or y; P K = p h ar m a c o ki n eti cs;  Q o L = q u alit y  of lif e;  Q O L C E = Q u alit y  of  Lif e i n  C hil d h o o d  E pil e ps y;  R = R e vi e w ;  T H C =t etr a h y dr o c a n n a bi n ol 
1.   
D a y  1 5  +  1.  F or  all s u bj e cts i n cl u di n g t h os e  w h o  dis c o nti n u e d  e arl y fr o m t h e st u d y,  
2.   
S y m pt o m -dir e ct e d  p h ysi c al  e x a mi n ati o n  p erf or m e d  at t h e i n v esti g at or’s  dis cr eti o n  
3.   
W ei g ht  a n d  B MI  o nl y  
4.   
T h e  W e e k  6  E C H O  m ust  b e  p erf or m e d  a n y ti m e  b et w e e n  St u d y  D a y  4 5  a n d  St u d y  D a y  6 9.  T h e  W e e k  1 2  E C H O  m ust  b e  p erf or m e d  a n y ti m e  b et w e e n  St u d y  D a y  8 7  a n d  St u d y  D a y  1 1 1; if  a s u bj e ct  dis c o nti n u es  e arl y fr o m t h e st u d y, t h e  E C H O 
s h o ul d  b e s c h e d ul e d  as s o o n  as  pr a cti c al.  If t h e  W e e k  6  or  W e e k  1 2  E C H O  w as  c o m pl et e d  ≤ 3 0  d a ys  pri or t o  e arl y t er mi n ati o n, t h e  Visit  1 7  E C H O  will  n ot  b e  p erf or m e d  pr o vi d e d t h e  p ar e nt/ g u ar di a n  a gr e es t o  bri n g t h e  s u bj e ct t o t h e 
cli ni c f or t h e  c ar di a c f oll o w -u p  visit.  
5.   
T h es e  ar e  b as eli n e  as s ess m e nts  a n d r es ults  will  n ot  b e  a v ail a bl e  pri or t o  d osi n g.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
 P a g e  3 4  of  1 9 4  
6.   
Or al t e m p er at ur e,  bl o o d  pr ess ur e,  h e art r at e  a n d r es pir at or y r at e . 
7.   
P K  dr a ws t a k e  pr e c e d e n c e  o v er  ot h er st u d y  pr o c e d ur es.  
8.   
R e c or d  all  c o n c o mit a nt  m e di c ati o ns.  
9.   
C oll e ct  a d v ers e  e v e nts  of s p e ci al i nt e r est  o nl y 
1 0.   Visits  7,  9,  a n d  1 1 ( D a ys  4 3,  7 1,  a n d  9 9, r es p e cti v el y)  o nl y  
1 1.   M a n d at or y  o n e ti m e  c oll e cti o n  a n y ti m e  d uri n g  or  aft er s cr e e ni n g  
1 2.   Visit  1 1 ( D a y  9 9)  o nl y . 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
 P a g e  3 5  of  1 9 4  
T a bl e  2 . C o h o rt  2:  S c h e d ul e  of  Ass ess m e nts  
 
B as eli n e  P e ri o d a 
Tit r ati o n  +  M ai nt e n a n c e  P e ri o d  
 
E O S/  
E T b  
 
F oll o w -
u p  
C a r di a c  
F oll o w -
u p c 
 
St u d y  Ass ess m e nts  
 
S c r e e ni n g  
 
R a n d o m -
i z ati o n 
 
 
Tit r ati o n  P e ri o d  
 
M ai nt e n a n c e  P e ri o d  
Visit  N u m b e r  
1   
2  
( P h o n e) 
3   
  
4   
( P h o n e 
o r 
Cli ni c ) 
5  
 
6   
7   
( P h o n e) 
8   
9   
( P h o n e) 
1 0   
1 1  
( P h o n e) 
1 2   
1 3   
 
1 4  
St u d y  D a y  
--4 3 t o  -4 2 
o r  
4 2 t o  -4 1  
-2 1    
-1   
1   
8    
1 5   
2 2   
3 6   
5 0   
6 4   
7 8   
9 2   
1 0 6   
1 2 0  
3 -6  m os  p ost 
l ast st u d y 
d r u g  d os e  
I nf or m e d  C o ns e nt (s u bj e ct  a n d  p ar e nt) 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
I nf or m e d  C o ns e nt ( E Q-5 D -5 L  Q o L  of 
p ar e nt/ c ar e gi v er)  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
I n cl usi o n/ E x cl usi o n Crit eri a  
X   
  
X   
  
  
  
  
  
  
  
  
  
  
  
 
D e m o gr a p hi cs  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
M e di c al/ N e ur ol o gi c al  Hist or y  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
E pil e ps y  hist or y  & st at us  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
C oll e ct r etr os p e cti v e s ei z ur e  di ar y  d at a  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Pri or  M e di c ati o n  
X   
  
X   
  
  
  
  
  
  
  
  
  
  
  
 
P h ysi c al  E x a mi n ati o n,  c o m pl et e  
X   
  
X   
  
  
  
  
  
  
  
  
  
X   
  
X c 
P h ysi c al  E x a mi n ati o n,  a b br e vi at e d   
  
  
  
  
  
X   
X   
  
X   
  
X   
  
  
  
X c 
N e ur ol o gi c al  E x a mi n ati o n,  c o m pl et e  
X   
  
  
  
  
  
  
  
  
  
  
  
X   
  
 
N e ur ol o gi c al  E x a mi n ati o n,  a b br e vi at e d  
  
  
X   
  
  
X   
X   
  
  
  
  
  
  
  
 
Vit al si g ns  
X   
  
X   
  
  
X   
X   
  
X   
  
X   
  
X   
  
 
W ei g ht,  H ei g ht,  B MI  
X   
  
X   
  
  
X   
X   
  
X   
  
X   
  
X   
  
 
1 2 -l e a d  E C G 
X   
  
X   
  
  
  
  
  
X   
  
  
  
X   
  
X c 
D o p pl er  E C H O  
X  
  
  
  
  
  
  
X d  
  
  
  
X d  
  
X c 
Uri n e  pr e g n a n c y t est e 
X   
  
X   
  
  
  
X   
  
X   
  
X   
  
X   
  
 
Cli ni c al l a b or at or y  e v al u ati o n 
( h e m at ol o g y/ cli ni c al  c h e mistr y/ uri n al ysis,  et c) 
X   
  
X   
  
  
  
X   
  
X   
  
X   
  
X   
  
 
Pl as m a s a m pl e f or  Z X 0 0 8  P K  
  
  
  
  
  
  
  
  
  
  
  
  
  
X f  
 
Pl as m a s a m pl e f or  b a c k gr o u n d  A E Ds  
  
  
X g  
  
  
  
X g  
  
X g  
  
  
  
X g  
  
 
B u c c al s w a b  f or  C Y P 2 D 6 g e n ot y pi n g  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Uri n e  T H C  P a n el/ W h ol e  bl o o d  C B D  
X   
  
X   
  
  
  
X   
  
X   
  
X   
  
X   
  
 
T a n n er  St a gi n g (f or s u bj e cts  >  7  y e ars  ol d)   
  
  
X   
  
  
  
  
  
  
  
  
  
X   
  
 
S u bj e ct  Di ar y  
D  
R  
C/ R/ D  
 
R  
C/ R/ D   
C/ R/ D  
R  
C/ R/ D  
R  
C/ R/ D  
R  
C/ R/ D h 
C/ R  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
 P a g e  3 6  of  1 9 4  
T a bl e  2 .   C o h o rt  2:  S c h e d ul e  of  Ass ess m e nts ( c o nti n u e d)  
 
B as eli n e  P e ri o d a 
Tit r ati o n  +  M ai nt e n a n c e  P e ri o d  
 
E O S/  
E T b  
 
F oll o w -
u p  
C a r di a c  
F oll o w -
u p c 
 
St u d y  Ass ess m e nts  
 
S c r e e ni n g  
 
R a n d o m -
i z ati o n 
 
Tit r ati o n  P e ri o d  
 
M ai nt e n a n c e  P e ri o d  
Visit  N u m b e r  
1   
2  
( P h o n e) 
3   
  
4   
( P h o n e 
o r 
Cli ni c ) 
5  
 
6  
 
7  
( P h o n e) 
8   
9   
( P h o n e) 
1 0   
1 1  
( P h o n e) 
1 2   
1 3   
 
1 4  
St u d y  D a y  
-4 3 t o  -4 2 
o r  
-4 2 t o  -4 1  
-2 1    
-1   
1   
8   
1 5   
2 2   
3 6   
5 0   
6 4   
7 8   
9 2   
1 0 6   
1 2 0  
3 -6  m os 
p ost l ast 
st u d y  d r u g 
d os e  
E pil e ps y  g e n ot y p e  p a n el  
X l  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
St u d y  M e di c ati o n  
  
 
D  
 
R i 
C/ R/ D   
C/ R/ D  
R  
C/ R/ D  
R  
C/ R/ D  
R  
C/ R/ D h 
C/ R  
 
C -S S R S  
X   
  
X   
  
  
  
X   
  
X   
  
X   
  
X   
  
 
C GI -I ( ass ess e d  b y  p ar e nt/ c ar e gi v er) 
  
  
  
  
  
X   
X   
  
X   
  
X   
  
X   
  
 
C GI -I ( ass ess e d  b y  pri n ci p al i n v esti g at or)  
  
  
  
  
  
X   
X   
  
X   
  
X   
  
X   
  
 
Sl e e p  q u alit y  &  m e alti m e  b e h a vi or  
q u esti o ns  
  
  
  
  
  
  
X   
  
X   
  
X   
  
X   
  
 
K ar oli ns k a  Sl e e pi n ess  S c al e  
  
  
X   
  
  
  
X   
  
X   
  
X   
  
X   
  
 
B RI E F  
  
  
X   
  
  
  
  
  
X   
  
  
  
X   
  
 
Q O L C E  
  
  
X   
  
  
  
  
  
X   
  
  
  
X   
  
 
H e alt h c ar e  utili z ati o n  q u esti o ns  
X   
  
X   
  
  
X   
  
X   
  
X   
  
X   
X   
  
 
P E Ds Q L  G e n eri c  C or e  S c al e  
  
  
X   
  
  
  
  
  
X   
  
  
  
X   
  
 
P e ds Q L  F a mil y I m p a ct  M o d ul e   
  
  
X   
  
  
  
  
  
X   
  
  
  
X   
  
 
E Q -5 D -5 L ( Q o L  of  p ar e nt/ c ar e gi v er)  
  
  
X   
  
  
  
  
  
  
  
  
  
X   
  
 
R a n d o mi z e s u bj e ct  
  
  
X   
  
  
  
  
  
  
  
  
  
  
  
 
First  D a y  of  St u d y  Dr u g  A d mi nistr ati o n   
  
  
  
X j  
 
 
  
 
O p e n -l a b el  c o ns e nt f or m 
 
X  
 
D ail y  Di ar y  C o m pl eti o n   
 
X  
 
C o n c o mit a nt  M e di c ati o ns  
  
  
 
X  
 
A d v er s e  e v e nts  
X  
X  
 
A d v er s e  e v e nts  of s p e ci al i nt er est  
X  
X  
X k 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
 P a g e  3 7  of  1 9 4  
T a bl e  2 .   C o h o rt  2:  S c h e d ul e  of  Ass ess m e nts ( c o nti n u e d)  
 
B as eli n e  P e ri o d a 
Tit r ati o n  +  M ai nt e n a n c e  P e ri o d  
 
E O S/  
E T b  
 
F oll o w
-u p  
C a r di a c  
F oll o w -
u p c 
 
St u d y  Ass ess m e nts  
 
S c r e e ni n g  
 
R a n d o m -
i z ati o n 
 
 
Tit r ati o n  P e ri o d *  
 
M ai nt e n a n c e  P e ri o d  
Visit  N u m b e r  
1   
2  
( P h o n e) 
3   
  
4   
( P h o n e 
o r 
Cli ni c ) 
5  
 
6  
 
7  
( P h o n e) 
8   
9   
( P h o n e) 
1 0   
1 1  
( P h o n e) 
1 2   
1 3   
 
1 4  
St u d y  D a y  
-4 3 t o  -4 2 
o r   
-4 2 t o  -4 1  
-2 1    
-1   
1   
8   
1 5   
2 2   
3 6   
5 0   
6 4   
7 8   
9 2   
1 0 6   
T B D  
3 -6  m os  
p ost l ast 
st u d y 
d r u g  d os e  
A E D = a nti e pil e pti c  dr u g;  B MI = b o d y  m ass i n d e x;  B RI E F = B e h a vi or  R ati n g I n v e nt or y  of  E x e c uti v e  F u n cti o n;  C = C oll e ct;  C B D = c a n n a bi di o l;  C Y P 2 D 6 = c yt o c hr o m e  P  4 5 0  2 D 6;  D = Dis p e ns e;  E C G = el e ctr o c ar di o gr a m; E C H O = e c h o c ar di o gr a m; 
E O S = e n d  of st u d y;  E T = e arl y t er mi n ati o n;  E Q -5 D -5 L =st a n d ar di z e d  m e as ur e  of  h e alt h st at us;  m os = m o nt hs;  P K = p h ar m a c o ki n eti c s;  Q o L = q u alit y  of lif e;  Q O L C E = Q u alit y  of  Lif e i n  C hil d h o o d  E pil e ps y;  R = R e vi e w ; T H C =t etr a h y dr o c a n n a bi n ol  
a:   
T h e  B as eli n e  P eri o d is  c o m pris e d  of t h e i niti al s cr e e ni n g f or t h e st u d y  a n d t h e  ass ess m e nt  of  b as eli n e s ei z ur e  a cti vit y r e c or d e d  d ail y i n t h e  di ar y.  T h e  pr o c e d ur es t o  b e  c o m pl et e d  at t h e  S cr e e ni n g  visit  m a y  b e  c o m pl et e d i n  a si n gl e  d a y  or 
s plit s o t h at t h e y  ar e  c o m pl et e d  o v er t h e  2 -d a y  p eri o d (i. e.,  D a ys  -4 3 t o  - 4 2  or  D a ys  -4 2 t o  -4 1).  
b:   
S u bj e cts  w h o  ar e  dis c o nti n u e d  e arl y  a n d t h os e  w h o  c o m pl et e t h e st u d y  a n d  c h o os e  n ot t o  e nr oll i n t h e s e p ar at e  o p e n -l a b el  e xt e nsi o n  will  b e t a p er e d  off st u d y  m e di c ati o n  o v er a  2 -w e e k  p eri o d . S u bj e cts  w h o  c h o os e t o  c o nti n u e i n t h e s e p ar at e 
o p e n -l a b el e xt e nsi o n tri al  will  u n d er g o  a  2 -w e e k tr a nsiti o n  p eri o d  pri or t o  e nr oll m e nt.  
c:   
F oll o w -u p  E C G,  E C H O,  a n d  p h ysi c al  e x a mi n ati o n  will  b e  p erf or m e d  3 -6  m o nt hs  aft er  e arl y t er mi n ati o n,  or f or t h os e s u bj e cts  w h o  c o m pl et e t h e st u d y  b ut  d o  n ot  e nt er t h e  o p e n -l a b el e xt e nsi o n tri al  (s e e S e cti o n  6. 2. 6 ). 
d:   
T h e  Visit  8  E C H O  m ust  b e  p erf or m e d  a n y ti m e  b et w e e n  St u d y  D a y  4 0  a n d  St u d y  D a y  5 4.  T h e  Visit  1 2  E C H O  m ust  b e  p erf or m e d  a n y ti m e  b et w e e n  St u d y  D a y  9 0  a n d  St u d y  D a y  1 1 3; if  a s u bj e ct  dis c o nti n u es  e arl y fr o m t h e st u d y, t h e 
E C H O s h o ul d  b e s c h e d ul e d  as s o o n  as  pr a cti c al . If t h e  St u d y  D a y  4 3  E C H O  w as  c o m pl et e d  ≤ 3 0  d a ys  pri or t o  e arl y t er mi n ati o n, t h e  Visit  1 2  E C H O  will  n ot b e  p erf or m e d  pr o vi d e d t h e  p ar e nt/ g u ar di a n  a gr e es t o  bri n g t h e s u bj e ct t o t h e  cli ni c 
f or t h e  c ar di a c f oll o w-u p  visit.  
e:   
F e m al es  of  c hil d -b e ari n g  p ot e nti al  
f:  
Pl as m a s a m pl e f or  P K  ass ess m e nt  will  b e  c o n d u ct e d  pri or t o t h e  d os e  at t h e  F oll o w -u p  visit  a n d  1,  2,  a n d  4 -6  h o urs  aft er  d os e  a d mi nistr ati o n  f or  S u bj e cts  c o nti n ui n g i nt o t h e  o p e n-l a b el  e xt e nsi o n tri al. 
g:   
Pl as m a s a m pl e f or  ass ess m e nt  of  b a c k gr o u n d  A E D(s)  will  b e  c o n d u ct e d  pri or t o t h e  d os e  of  A E D(s)  at  Visits  3,  6,  8  a n d  1 2.  
h:   
St u d y  dr u g/ di ar y  dis p e ns e d f or t h e tr a nsiti o n f or s u bj e cts  e nt eri n g t h e  o p e n -l a b el e xt e nsi o n tri al  a n d f or t a p eri n g f or s u bj e cts  e xiti n g t h e st u d y.  
i:  
Sit e  p ers o n n el  will r e vi e w st u d y  m e di c ati o n  d osi n g  pr o c e d ur e (titr ati o n)  wit h  p ar e nt/ c ar e gi v er.  
j:  
St u d y  dr u g  a d mi nistr ati o n  b e gi ns i n t h e  m or ni n g  of  St u d y  D a y  1.  
k:   
O nl y  a d v ers e  e v e nts r el at e d t o  c ar di a c s af et y  will  b e  c oll e ct e d  at t his  visit.  
l:  
M a n d at or y  o n e ti m e  c oll e cti o n  a n y ti m e  d uri n g  or  aft er s cr e e ni n g  a n d  b ef or e  Visit  1 0 .   


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  3 8  of  1 9 4  
1.   
I N T R O D U C TI O N 
1. 1   
B A C K G R O U N D  I N F O R M A TI O N  O N I N DI C A TI O N  S T U DI E D  
Z X 0 0 8  (f e nfl ur a mi n e  h y dr o c hl ori d e) is  u n d er  cli ni c al  d e v el o p m e nt f or t h e a dj u n cti v e  tr e at m e nt 
of  p ati e nts  wit h  Dr a v et s y n dr o m e . 
Dr a v et s y n dr o m e ,  als o  k n o w n  as s e v er e  m y o cl o ni c  e pil e ps y  of i nf a n c y ( S M EI), is  a r ar e  a n d 
s e v er e f or m  of  e pil e ps y first  d es cri b e d  b y  C h arl ott e  Dr a v et i n  1 9 7 8 (Dr a v et  1 9 7 8 ).   T h e 
c o n diti o n  m ost  c o m m o nl y  a p p e ars  d uri n g t h e first  y e ar  of lif e  as fr e q u e nt f e bril e s ei z ur es.   As 
t h e  c o n diti o n  pr o gr ess es,  ot h er t y p es  of s ei z ur es t y pi c all y  o c c ur, i n cl u di n g  m y o cl o ni c s ei z ur es 
a n d st at us  e pil e pti c us  ( S E) (Dr a v et  1 9 7 8 ).   F oll o wi n g t h e  a p p e ar a n c e  of t h es e s ei z ur es,  aff e ct e d 
c hil dr e n  d e v el o p s e v er al  c o -m or bi d  c o n diti o ns i n cl u di n g  ps y c h o m ot or r e gr essi o n,  at a xi a, sl e e p 
dist ur b a n c e,  a n d  c o g niti v e i m p air m e nt.  I nt ell e ct u al i m p air m e nt  b e gi ns t o  b e c o m e  a p p ar e nt 
ar o u n d  a g e  2  y e ars  d u e t o l a c k  of i nt ell e ct u al/ b e h a vi or al  pr o gr essi o n.   C hil dr e n  wit h  Dr a v et 
s y n dr o m e oft e n  h a v e  a l a c k  of  c o or di n ati o n,  p o or  d e v el o p m e nt  of l a n g u a g e,  h y p er a cti vit y,  a n d 
diffi c ult y r el ati n g t o  ot h ers ( Dr a v et  1 9 7 8 ; H urst  1 9 9 0 ).   T h e  d e gr e e  of  c o g niti v e i m p air m e nt 
a p p e ars t o  c orr el at e,  at l e ast i n  p art,  wit h t h e fr e q u e n c y  of s ei z ur es,  a n d  mi g ht  b e  a r es ult  of 
r e p e at e d  c er e br al  h y p o xi a.   C hil dr e n  wit h D r a v et s y n dr o m e als o  e n c o u nt er  a  hi g h er i n ci d e n c e 
of  su d d e n  u n e x p e ct e d  d e at h  in  e pil e ps y  ( S U D E P; N as h ef  2 0 1 2 ) t h a n  ot h er  p o p ul ati o ns  wit h 
e pil e ps y.  I n dir e ct  e vi d e n c e  h as li n k e d  S U D E P t o s e v er al  p ossi bl e  eti ol o gi es, i n cl u di n g s ei z ur e -
i n d u c e d  a p n e a,  p ul m o n ar y  e d e m a,  d ysr e g ul ati o n  of  c er e br al  cir c ul ati o n, a n d  c ar di a c 
arr h yt h mi as ( S h or v o n  2 0 1 1 ),  alt h o u g h t h e  a ct u al  eti ol o g y r e m ai ns  u n k n o w n  a n d ot h er 
m e c h a nis ms  h a v e  n ot  b e e n r ul e d  o ut.   T h e  v ast  m aj orit y  of  p ati e nts  w h o s ur vi v e t o  a d ult h o o d 
ar e  w h oll y  d e p e n d e nt  o n  ar o u n d -t h e-cl o c k  c ar e gi v ers  a n d  e v e nt u all y li v e i n i nstit uti o n al  c ar e 
h o m es.   
1. 1. 1   
E xisti n g  T r e at m e nt f o r  D r a v et  S y n d r o m e  
Dr a v et s y n dr o m e  is  a  hi g hl y tr e at m e nt-r esist a nt  a n d r efr a ct or y  e pil e ps y s y n dr o m e.  
Est a blis h m e nt  of  a s ei z ur e -fr e e  c o n diti o n i n  aff e ct e d  c hil dr e n,  e v e n wit h  a nti c o n v uls a nt  dr u g  
p ol y p h ar m a c y , is e xtr e m el y r ar e, si n c e  all s ei z ur e t y p es i n  Dr a v et s y n dr o m e  a p p e ar t o  b e  dr u g 
r esist a nt,  wit h  mi ni m al i m pr o v e m e nt  o n  c urr e ntl y  a v ail a bl e a nti c o n v uls a nt  dr u g t h er a pi es 
(Dr a v et  2 0 0 0 ; Dr a v et  2 0 0 5 ).   M or e o v er,  cl assi c  a nti c o n v uls a nt  m e di c ati o ns  w h os e  m e c h a nis m 
is  vi a s o di u m  c h a n n el  bl o c k a d e, s u c h  as  p h e n yt oi n  a n d  c ar b a m a z e pi n e, i n cr e as e t h es e 
c hil dr e n’s s ei z ur e fr e q u e n c y  a n d s e v erit y.  
T o  d at e,  o nl y  o n e tr e at m e nt,  Di a c o mit ® (stiri p e nt ol) is  a p pr o v e d i n  E ur o p e , C a n a d a , J a p a n,  a n d 
A ustr ali a  as  a dj u n cti v e t h er a p y i n  p ati e nts  wit h  S M EI  (Dr a v et s y n dr o m e ), a n d  m ust  b e  c o -
a d mi nist er e d  wit h  cl o b a z a m ( C L B ) a n d  v al pr o at e ( V P A ).  Stiri p e nt ol ( S T P ) h as  n ot  b e e n 
a p pr o v e d f or  us e i n t h e  U nit e d  St at es  of  A m eri c a ,  b ut is  a v ail a bl e  u n d er  c o m p assi o n at e  us e 
pr ot o c ols  at  c ert ai n  cli ni c al sit es .   


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  3 9  of  1 9 4  
T h e r es ults  of  a n  o nli n e  p ar e nt -r e p ort e d s ur v e y t o  c oll e ct i nf or m ati o n  o n t h e  d e m o gr a p hi cs, 
cli ni c al  c h ar a ct eristi cs  a n d  us e  of  a nti e pil e p ti c  m e di c ati o ns  b y  E ur o p e a n  p ati e nts  wit h D r a v et 
s y n dr o m e w as r e c e ntl y r e p ort e d ( Ar as  2 0 1 5 ).   T h e s ur v e y t o o k  pl a c e fr o m  M a y t o J u n e  2 0 1 4 
a n d i n cl u d e d t w o  h u n dr e d s e v e nt y -f o ur  p ati e nts fr o m  1 5  E ur o p e a n  c o u ntri es.  M ost  p ati e nts 
w er e  4 -8  y e ars  ol d,  a n d  9 0 %  h a d  c o nfir m e d  m ut ati o ns i n  S C N 1 A .  T h eir  e pil e ps y  w as 
c h ar a ct eri z e d  b y  m ulti pl e s ei z ur e t y p es,  a n d  4 5 %  of t h e  p o p ul ati o n r e p ort e d  m or e t h a n  4 t o ni c -
cl o ni c s ei z ur es  p er  m o nt h.   I n s pit e  of t h e  a v ail a bilit y  of  a n  arra y  of  a nti e pil e pti c  m e di c ati o ns, 
t h e  m ost  c o m m o n dr u g  c o m bi n ati o n  w as  C L B , V P A ,  a n d S T P ,  wit h  4 2 %  of t h e  p ati e nts 
c urr e ntl y t a ki n g  S T P .   
D es pit e tr e at m e nt  wit h  m ulti pl e  a nti e pil e pti c  m e di c ati o ns,  e m er g e n c y r o o m  a d missi o ns f or  S E 
w er e  c o m m o n  d uri n g t h e  pr e vi o us  1 2  m o nt hs.  I n  b ot h t h e t ot al  p o p ul ati o n  a n d t h e 
s u b p o p ul ati o n  wit h  > 4 t o ni c -cl o ni c s ei z ur es  p er  m o nt h,  a p pr o xi m at el y  o n e -t hir d  of t h e  p ati e nts 
h a d  o n e  or  m or e  c o nti n u o us,  u nr e mitti n g s ei z ur e s r e q uiri n g  e m er g e n c y r o o m  a d missi o n.  
T w e nt y -ei g ht  p ati e n ts ( 1 0 %) r e p ort e d  4  or  m or e  e m er g e n c y r o o m  a d missi o ns  wit h s o m e 
r e p orti n g  as  m a n y  as  3 0  a d missi o ns f or S E .  I n  a d diti o n t o s e v er e  e pil e ps y wit h  m ulti pl e s ei z ur e 
t y p es, r es p o n d e nts r e p ort e d s e v er al  c o-m or bi diti es t h at  e xt e n d e d  b e y o n d  s ei z ur es, i n cl u di n g 
sl e e p  dist ur b a n c es,  m ot or i m p air m e nt,  a n d  a b n or m al s o ci ali z ati o n.   T h er ef or e, t h er e r e m ai ns  a 
n e e d  f or  n e w  m e di c ati o ns t h at  pr o vi d e  b ett er s ei z ur e  c o ntr ol, as  w ell  as  pr es er v e  or i m pr o v e t h e 
b e h a vi or al  a n d  c o g niti v e  c o m p o n e nts  of  D r a v et s y n dr o me . 
F or  o v er  2 7  y e ars, f e nfl ur a mi n e  h as  b e e n  us e d  as  a n  u nli c e ns e d  m e di ci n e i n  B el gi u m  at 
2  a c a d e mi c  m e di c al  c e nt ers,  c urr e ntl y  usi n g  a n  a p pr o v e d  pr ot o c ol  u n d er  a  B el gi u m  R o y al 
D e cr e e ( g o v er n m e nt  a p pr o v e d  pr os p e cti v e  o bs er v ati o n tri al ) f or t h e a dj u n cti v e  tr e at m e nt  of 
D r a v et s y n dr o m e i n  1 9  p ati e nts; t h e  effi c a c y  a n d s af et y  of t his t h er a p e uti c  a p pr o a c h  h a v e  b e e n 
p u blis h e d i n  a  p e er r e vi e w e d j o ur n al  (C e ul e m a ns  2 0 1 2 ; C e ul e m a ns  2 0 1 6 )  a n d r e p ort e d t o  b e 
f a v or a bl e. A c c or di n gl y, t h er e r e m ai ns  a n  u n m et  n e e d f or  a n  a p pr o v e d tr e at m e nt f or  c hil dr e n 
wit h  D r a v et s y n dr o m e. 
1. 1. 2   
Ot h e r  A nti e pil e pti c  M e di c ati o ns  
E ur o p e a n  U ni o n , U nit e d  St at es  of  A m eri c a ( U S A ),  C a n a d a,  a n d  A ustr ali a a p pr o v e d  a nti -
e pil e pti c  dr u g  (A E Ds ) pr o d u cts i n cl u d e  V P A , t o pir a m at e,  c ar b a m a z e pi n e,  o x c ar b a z e pi n e, 
l a m otri gi n e,  b e n z o di a z e pi n es,  p h e n o b ar bit al,  p ot assi u m  br o mi d e,  et h os u xi mi d e,  p h e n yt oi n,  a n d 
vi g a b atri n.   T h e tr e at m e nt  of  Dr a v et s y n dr o m e  fr e q u e ntl y r e q uir es  a  c o m bi n ati o n  of t w o  or 
t hr e e  of t h es e  c o m p o u n ds,  b ut  wit h  c o nti n u e d s u b o pti m al s ei z ur e  c o ntr ol.  It  c a n n ot  b e  ass u m e d 
t h at  b e c a us e  a tr e at m e nt  h as  b e e n s h o w n t o  b e  eff e cti v e i n  c o m m o n s ei z ur e t y p es, t h at it  will  b e 
eff e cti v e i n  D r a v et s y n dr o m e.   I n f a ct, s o m e c o m m o nl y  us e d  A E Ds  wit h  a  s o di u m  c h a n n el 
m e c h a nis m  of  a cti o n, s u c h  as  c ar b a m a z e pi n e,  o x c ar b a z e pi n e,  p h e n yt oi n,  a n d l a m otri gi n e,  c a n 
w ors e n s ei z ur es i n  D r a v et s y n dr o m e. 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 0  of  1 9 4  
A r e vi e w  of t h e tr e at m e nt  m o d aliti es  us e d f or  D r a v et s y n dr o m e h as  b e e n  p u blis h e d  b y  C hir o n 
a n d  D ul a c ( C hir o n  a n d  D ul a c  2 0 1 1 ).   T his r e vi e w i n di c at es t h at V P A  is  c o m m o nl y  us e d  as  a 
first-li n e  a g e nt t o  pr e v e nt t h e r e c urr e n c e  of f e bril e s ei z ur es  a n d  or al/ n as al/r e ct al  b e n z o di a z e pi n e 
is  us e d f or  a n y l o n g-l asti n g s ei z ur es.   H o w e v er, t h e  a ut h ors  c o m m e nt t h at t h es e  a g e nts  ar e  m ost 
oft e n i ns uffi ci e nt.   T h es e  a ut h or  e x p erts st at e t h at l a m otri gi n e,  c ar b a m a z e pi n e,  a n d  hi g h  d os es 
of i ntr a v e n o us  p h e n o b ar bit al s h o ul d  b e  a v oi d e d  b e c a us e t h e y  m a y  w ors e n s ei z ur es  a n d t h at  
t o pir a m at e, l e v etir a c et a m  a n d  br o mi d e  m a y  pr o vi d e s u bst a nti al  effi c a c y  as  a dj u n cti v e t h er a p y 
f or s o m e  p ati e nts.   T h e  a ut h ors  c o m m e nt t h at t h er e  ar e  n o tri als t o  v ali d at e t h e i m pr essi o n  of 
a n y  eff e ct.  
1. 2   
B A C K G R O U N D I N F O R M A TI O N  O N  S T U D Y  P R O D U C T  
Z o g e ni x  h as  d e v el o p e d  a n  or al s ol uti o n  f or m ul ati o n  of f e nfl ur a mi n e  h y dr o c hl ori d e,  Z X 0 0 8, f or 
t h e  a dj u n cti v e tr e at m e nt  of s ei z ur es i n D r a v et s y n dr o m e. I n  a d diti o n, t h e  eff e cts  of  Z X 0 0 8  o n  a 
c o m p osit e  of s y m pt o ms t h at  n e g ati v el y i m p a ct  q u alit y  of lif e  a n d i nt ell e ct u al  d e v el o p m e nt  will 
b e  e x pl or e d.   F e nfl ur a mi n e is  a n  a m p h et a mi n e  a n al o g u e t h at  w as  a p pr o v e d i n  a l ar g e  n u m b er  of 
c o u ntri es  a n d  wi d el y  pr es cri b e d  as  a n  a p p etit e s u p pr ess a nt f or t h e tr e at m e nt  of  a d ult  o b esit y.    
Pr o d u cts  c o nt ai ni n g f e nfl ur a mi n e  a n d  t h e D -e n a nti o m er  w er e  wit h dr a w n fr o m t h e  m ar k et  
gl o b all y  aft er r e p orts  of  h e art  v al v e  dis e as e  a n d  p ul m o n ar y  h y p ert e nsi o n  i n t h e l at e  1 9 9 0’s 
(C o n n oll y  1 9 9 7 ; C D C  1 9 9 7 ; W o n g  1 9 9 8 ).  W hil e t h e ris k/ b e n efit r el ati o ns hi p f or f e nfl ur a mi n e 
is t h us  c o nsi d er e d  u nf a v or a bl e f or t h e tr e at m e nt  of  o b esit y i n  a d ults,  est a blis hi n g s ei z ur e 
c o ntr ol i n  D r a v et s y n dr o m e or  a n y  of t h e  c at astr o p hi c  c hil d h o o d  e pil e psi es  mi g ht l e a d t o  a 
m or e  a c c e pt a bl e ris k/ b e n efit  pr ofil e f or f e nfl ur a mi n e,  es p e ci all y if l o w er  d os es  c a n  b e  us e d 
s u c c essf ull y.  
As  a r es ult  of t his  pr e vi o us  e xt e nsi v e  us e  of f e nfl ur a mi n e, t h er e is  a  l ar g e b o d y  of i nf or m ati o n 
i n t h e  p u bli c  d o m ai n  c o n c er ni n g its  p h ar m a c ol o g y, t o xi c ol o g y  a n d  us e i n t h e tr e at m e nt  of 
o b esit y ( Z X 0 0 8 I B  2 0 1 6 ).   T h er e is  als o  a l ar g e  b o d y  of i nf or m ati o n  c o n c er ni n g its  cli ni c al 
s af et y  pr ofil e.  
1. 3   
P R E C LI NI C A L  D A T A  
T h e  p h ar m a c o ki n eti cs  ( P K) of f e nfl ur a mi n e,  n orf e nfl ur a mi n e  a n d t h eir r es p e cti v e is o m ers  h as 
b e e n st u di e d i n  mi c e, r ats,  d o gs  a n d  h u m a ns.  T h e  P K  i n  h u m a ns  diff ers fr o m t h at  of  ot h er 
s p e ci es,  wit h  a l o n g er  d ur ati o n  of  e x p os ur e t o  b ot h t h e  p ar e nt  a n d t h e  m et a b olit e.  I n  vitr o 
m et a b olis m st u di es  h a v e s h o w n t h at t h er e  ar e l ar g e s p e ci es  diff er e n c es i n  P K  a n d  m et a b olis m 
of f e nfl ur a mi n e  aft er  or al  a d mi nistr ati o n. I n  h u m a ns, f e nfl ur a mi n e is  m et a b oli z e d t o  pri m aril y 
n orf e nfl ur a mi n e.  C Y P 1 A 2,  C Y P 2 B 6,  a n d  C Y P 2 D 6  a p p e ar t o  b e t h e  pr e d o mi n a nt  C Y P 
(c yt o c hr o m e  P 4 5 0)  e n z y m es t h at  m et a b oli z e f e nfl ur a mi n e t o  n orf e nfl ur a mi n e.  C Y P 2 C 9 , 
C Y P 2 C 1 9  a n d  C Y P 3 A 4  als o  a p p e ar t o  b e i n v ol v e d,  b ut t o  a l ess er  d e gr e e . T h er e is  als o s o m e 
c o ntri b uti o n  of r e n al  cl e ar a n c e t o t h e  eli mi n ati o n  of  d e xf e nfl ur a mi n e ( 8 %  - 1 6 %)  a n d  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 1  of  1 9 4  
n or d e xf e nfl ur mi n e  ( 7 % - 8 %) fr o m t h e  b o d y.  B e c a us e f e nfl ur a mi n e  a n d its  a cti v e  m et a b olit e 
n orf e nfl ur a mi n e  h a v e  m ulti pl e  p at h w a ys  of  eli mi n ati o n, i nt erf er e n c e  wit h  a si n gl e  p at h w a y is 
u nli k el y t o  c a us e  a si g nifi c a nt  c h a n g e i n f e nfl ur a mi n e’s  cl e ar a n c e t h o u g h t h e  pr o b a bilit y  of  a n 
i nt er a cti o n i n cr e as es if  m ulti pl e  eli mi n ati o n  m e c h a nis ms  ar e  aff e ct e d si m ult a n e o usl y. 
W hil e i n  vitr o st u di es s h o w e d t h at  b ot h f e nfl ur a mi n e  a n d  n orf e nfl ur a mi n e  c a us e  w e a k 
i n hi biti o n  of  C Y P 2 D 6  a n d f e nfl ur a mi n e  c a us es  w e a k i n d u cti o n  of  C Y P 3 A 4  a n d  C Y P 2 B 6, 
f urt h er  a n al ysis  b as e d  o n t h e F o o d  a n d  Dr u g  A d mi nistr ati o n’s ( F D A’s ) m e c h a nisti c st ati c 
m o d el s h o ws t h at f e nfl ur a mi n e  a n d its  m aj or  m et a b olit e  n orf e nfl ur a mi n e  ar e  u nli k el y t o  alt er 
t h e P K  of s u bstr at es  of t h es e  C Y P 4 5 0  e n z y m es i n t h e r a n g e  of  Z X 0 0 8  d os es t h at  will  b e 
a d mi nist er e d i n t his st u d y.  
A  G o o d  L a b or at or y  Pr a cti c e  d os e -r a n g e-fi n di n g j u v e nil e t o xi c ol o g y  a n d t o xi co ki n eti c  st u d y, 
w hi c h i n cl u d e d  a  3 -w e e k r e p e at  d os e  m ai n st u d y,  a n d  hist o p at h ol o g y  of  h e art  v al v es  a n d  ot h er 
k e y  or g a ns, f o u n d  n o  eff e ct  o n  h e art  v al v es  or  ot h er  or g a ns.   
B as e d  o n  cli ni c al si g ns  a n d  d e cr e as e d  b o d y  w ei g ht  g ai n, t h e  n o -o bs er v e d -a d v ers e -eff e ct -l e v el 
f or t his st u d y  w as  1 2 m g/ k g/ d a y.  T his is  esti m at e d t o  b e  e q ui v al e nt t o  a  h u m a n  d os e  of  1. 9 4 
m g/ k g/ d a y  b as e d  o n  b o d y s urf a c e  ar e a,  a n d  pr o vi d es  a s af et y f a ct or  of  a p pr o xi m at el y  2. 4 f or 
t h e s er u m l e v els  of  Z X 0 0 8 t h at  ar e  a nti c i p at e d i n t his st u d y. 
F urt h er  d et ails  o n t h e  pr e cli ni c al  d at a  of  Z X 0 0 8  ar e  a v ail a bl e i n t h e  I n v esti g at or’s  Br o c h ur e 
(Z X 0 0 8 I B  2 0 1 6 ). T h e  c urr e nt  v ersi o n is  a v ail a bl e i n  t h e I n v esti g at or  St u d y  Fil e.  
1. 4   
B A C K G R O U N D I N F O R M A TI O N  O N  R E F E R E N C E  P R O D U C T  
N ot  a p pli c a bl e.  
1. 5   
R A TI O N A L E  F O R  C U R R E N T  S T U D Y  
T h er e is  o nl y  o n e tr e at m e nt  a p pr o v e d f or  a dj u n cti v e tr e at m e nt  of s ei z ur es i n  c hil dr e n  wit h 
Dr a v et s y n dr o m e  i n  E ur o p e (i e, S T P ),  a n d it is  a d mi nist er e d i n  c o nj u n cti o n  wit h t w o  ot h er 
a nti e pil e pti c  dr u gs,  V P A  a n d  C L B.   F urt h er, t h e r e c e nt s ur v e y  c o n d u ct e d  b y  Ar as  a n d 
c oll e a g u es ( Ar as  2 0 1 5 ) r e v e al e d t h at i n s pit e  of t h e  a v ail a bilit y  of  a n  arr a y  of  a nti e pil e pti c 
m e di c ati o ns, t h e  m ost  c o m m o n  dr u g  c o m bi n ati o n  w as  C L B,  V P A,  a n d  S T P,  wit h  4 2 %  of t h e 
p ati e nts  c urr e ntl y t a ki n g  S T P.   S T P i n hi bits s e v er al  C Y P 4 5 0  e n z y m es,  a n d  dr u g -dr u g 
i nt er a cti o ns  wit h  S T P  will  n e e d t o  b e  e v al u at e d f or  a n y  n e w  dr u gs li k el y t o  b e  c o-a d mi nist er e d 
wit h it.   T h e  p ot e nti al f or  a  dr u g -dr u g i nt er a c ti o n  of  S T P  wit h f e nfl ur a mi n e  n e e ds t o  b e 
c ar ef ull y t a k e n i nt o  a c c o u nt  b y  a dj usti n g t h e  d os e(s)  of  eit h er f e nfl ur a mi n e,  a n ot h er 
a nti e pil e pti c  m e di c ati o n,  or t h e  c o m bi n e d  a nti e pil e pti c  dr u gs  as t h e  P K i nt er a cti o ns  mi g ht 
aff e ct  effi c a c y  a n d t ol er a bilit y.  T hi s  p ot e nti al i nt er a cti o n  will  b e  e x pl or e d i n  C o h ort  1  of t his 
st u d y.  Gi v e n t h at  S T P  a cts  as  a n i n hi bit or  of  C Y P 3 A 4,  C Y P 1 A 2  a n d i n  p arti c ul ar  C Y P 2 C 1 9, 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 2  of  1 9 4  
i n vi v o  i n  e pil e pti c  p ati e nts, it is li k el y t h at t h e  d os e  of f e nfl ur a mi n e  will  n e e d t o  b e  at t h e l o w er 
e n d  of t h e  d os e r a n g e  of t h e  d os es  us e d i n t h e  B el gi a n st u d y  cit e d  a b o v e ( d os es r a n g e d fr o m 
0. 1 2  –  0. 9  m g/ k g/ d a y i n t his s eri es).   S u bj e cts i n  C o h ort  1 ( R e gi m e n  3)  will  b e  d os e d  wit h 
0. 2  m g/ k g  of  Z X 0 0 8 t o  e v al u at e t h e  P K  a n d s af et y  pr ofil e  of  a si n gl e  d os e  w h e n  a d d e d t o t h e 
s u bj e cts’  us u al r e gi m e n  of  S T P/ V P A/ C L B.   T h e  d at a f or t his  C o h ort  h as  i nf or me d  t h e  d osi n g 
f or  C o h ort  2.  M or e o v er,  bl o o d s a m pl es f or  p o p ul ati o n  P K  will  b e  c oll e ct e d fr o m  C o h ort  2,  a n d 
t h e f e nfl ur a mi n e/n or -f e nfl ur a mi n e c o n c e ntr ati o n -ti m e  d at a fr o m s u bj e cts  e nr oll e d i n C o h orts  1 
a n d  2  will  b e  us e d t o  m o d el  P K  of  Z X 0 0 8 i n si n gl e  a n d  m ulti pl e  d os e r e gi m e ns.  
T h e  effi c a c y  a n d s af et y  of  Z X 0 0 8  as  a dj u n cti v e t h er a p y  a d d e d t o t h e  S T P r e gi m e n f or  s ei z ur es 
i n  c hil dr e n  a n d  y o u n g  a d ults  wit h Dr a v et s y n dr o m e  will  b e  e v al u at e d i n  C o h ort  2.   A r e c e nt 
st u d y  p u blis h e d  b y  Ar as  a n d  c oll e a g u es  (Ar as  2 0 1 5 ) o n  2 7 4  c hil dr e n  wit h  Dr a v et s y n dr o m e 
fr o m  1 5 E ur o p e a n  c o u ntri es, f o u n d t h at t h eir  e pil e ps y  w as  c h ar a ct eri z e d  b y s e v er al  diff er e nt 
t y p es of s ei z ur es,  a n d  4 5 %  h a d si g nifi c a nt r esi d u al t o ni c -cl o ni c s ei z ur es  d es pit e t a ki n g  a n  arr a y 
of  a nti e pil e pti c  m e di c ati o ns .   T h e m ost  c o m m o n  dr u g  c o m bi n ati o n  i n t h es e  p ati e nts w as  C L B , 
V P A ,  a n d S T P ,  wit h  4 2 %  of t h e  p ati e nts  c urr e ntl y t a ki n g S T P .  A c c or di n gl y, t h er e r e m ai ns  a 
si g nifi c a nt  u n m et  n e e d f or  ot h er  a dj u n cti v e tr e at m e nts f or  c hil dr e n  a n d  a d ults  wit h  Dr a v et 
s y n dr o m e.  
1. 6   
RI S K -B E N E FI T  A S S E S S M E N T  
It is t h e  S p o ns or’s  p ositi o n t h at f e nfl ur a mi n e  m a y  b e  a n i m p ort a nt  n e w t h er a p e uti c f or  c hil dr e n 
wit h  Dr a v et s y n d r o m e  a n d t h at it  c a n  b e s af el y st u di e d i n  p ati e nts  wit h  Dr a v et s y n dr o me  gi v e n 
pr o p er st u d y  d esi g ns ( e g,  i n cl u di n g r e g ul ar  e c h o c ar di o gr a p hi c  e v al u ati o ns)  a n d t h e  us e  of 
i n d e p e n d e nt s af et y  m o nit ori n g  c o m mitt e es, r es ulti n g i n  a f a v or a bl e  b e n efit t o ris k r ati o f or t h e 
pr o p os e d i n di c ati o n  at t h e  pr o p os e d  d os es.   A d diti o n all y, f e nfl ur a mi n e  w as  a d mi nist er e d t o 
o v er  5 0 0  c hil dr e n  wit h  n e ur o b e h a vi or al  c o n diti o ns, i n cl u di n g  a utis m  a n d  att e nti o n  d efi cit 
h y p er a cti vit y  dis or d er ,  wit h  g o o d s af et y  a n d t ol er a bilit y,  m ost  oft e n  at  a  1  m g/ k g  d os e.   
Dr a v et  S y n dr o m e is  a r ar e,  d e v ast ati n g  e pil e pti c  e n c e p h al o p at h y.   T h e  c o n diti o n is  m ar k e d  b y 
fr e q u e nt  a n d  m ulti pl e s ei z ur e t y p es, i n cl u di n g S E ,  w hi c h  b e gi n i n t h e first  y e ar  of lif e  a n d 
r e m ai n  p h ar m a c or esist a nt t o  c urr e ntl y  a v ail a bl e  a nti e pil e pti c  dr u gs (C hir o n  2 0 1 1 ).   T h e 
fr e q u e nt  pr ol o n g e d s ei z ur e  a cti vit y  a n d  e pis o d es  of S E  i n  Dr a v et s y n dr o m e  p ati e nts,  u n a b at e d 
b y t h e l ar g el y i n eff e cti v e  a v ail a bl e tr e at m e nts, is  b eli e v e d t o r es ult i n  br ai n i nj ur y,  a n d 
i m p air m e nt  of  ps y c h o m ot or,  b e h a vi or al,  a n d  n e ur ol o gi c al  d e v el o p m e nt (Dr a v et  2 0 1 1 ).   
T h e  m ort al it y ris k is  hi g h  a n d  c hil d h o o d  d e at h is fr e q u e ntl y  c a us e d  b y  S U D E P.  T h e  esti m at e d 
m e a n  a n n u al r at e  of  S U D E P i n  Dr a v et  S y n dr o m e is  0. 6 % , w hi c h is si g nifi c a ntl y  hi g h er t h a n 
t h at r e p ort e d i n t h e  g e n er al  p o p ul ati o n  of  p ati e nts  wit h  e pil e ps y ( <  0. 1 %;  a n d  a  m ortalit y r at e  of 
1 0 %  t o  1 5 %  d uri n g  c hil d h o o d  a n d  a d ol es c e n c e (S kl u z a c h e k  2 0 1 1 ).    


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 3  of  1 9 4  
A  gr o u p i n  B el gi u m  b e g a n tr e ati n g  Dr a v et s y n dr o m e  p ati e nts  wit h f e nfl ur a mi n e  u n d er  a 
g o v er n m e nt  c o m p assi o n at e  us e  pr o gr a m ( B el gi a n  R o y al  D e cr e e ) i n  2 0 0 2.  I n  2 0 1 2 t h es e 
i n v esti g at ors r e p ort e d  o n t h e  us e  of f e nfl ur a mi n e i n  1 2  p ati e nts tr e at e d  u ntil  2 0 1 0.   E x p os ur e 
d ur ati o n t o f e nfl ur a mi n e r a n g e d fr o m  1 – 1 9  y e ars.  S e v e n  of t h e  Dr a v et s y n dr o m e  p ati e nts  w h o 
w er e still r e c ei vi n g f e nfl ur a mi n e tr e at m e nt  at t h e ti m e  of t h e l ast  visit  h a d  b e e n s ei z ur e -fr e e f or 
at l e ast  1  y e ar. I n t ot al,  p ati e nts  h a d  b e e n s ei z ur e -fr e e f or  a  m e a n  of  6  y e ars,  7  m o nt hs  
( 1-1 9  y e ars).   F e nfl ur a mi n e  w as  g e n er all y  w ell t ol er at e d.   N o  p ati e nt  e x hi bit e d  a n y 
c ar di o v as c ul ar s y m pt o m at o l o g y.   R e g ul ar  c ar di o v as c ul ar f oll o w-u p,  w hi c h i n cl u d e d 
el e ctr o c ar di o gr a ms ( E C Gs ) a n d  e c h o c ar di o gr a ms  ( E C H Os), s h o w e d  n o  c as es  of  p ul m o n ar y 
h y p ert e nsi o n.   A sli g ht t hi c k e ni n g  of  1  or  2  h e art  v al v es  w as  d e m o nstr at e d i n  2  p ati e nts 
( P ati e nts  2  a n d  1 0)  b ut t h es e  c h a n g es  w er e st a bl e  a n d  c o nsi d er e d  n ot  cli ni c all y si g nifi c a nt.  
P ati e nt  2  h a d  b e e n  o n  5  m g  t wi c e  d ail y (BI D ) f or  2  y e ars  a n d  P ati e nt  1 0  o n  2 0  m g o n c e  d ail y  
f or  1 1  y e ars.   
A s e c o n d  m or e r e c e nt  eff e cti v e n ess  a n d t ol er a bilit y  ass ess m e nt  of t his  c o h ort i n c l u d e d  visit 
d at a fr o m  2 0 1 0 t hr o u g h t h e  e n d  of  2 0 1 4, i e,  5  y e ars  of  d at a.    M or e t h a n  8 0 %  of  p ati e nts  h a d  a 
≥ 7 5 % r e d u cti o n i n s ei z ur e fr e q u e n c y i n r es p o ns e t o  f e nfl ur a mi n e  e a c h  y e ar  of t h e  5-y e ar 
e v al u ati o n.   D uri n g t his  5 -y e ar  o bs er v ati o n  p eri o d,  3  p ati e nt s  w er e s ei z ur e-fr e e f or  all  5  y e ars 
a n d  5  p ati e nts  w er e s ei z ur e -fr e e f or  2-4  y e ars; i n  all,  2 9  of  5 8 ( 5 0 %)  p ati e nt -tr e at m e nt  y e ars 
w er e s ei z ur e -fr e e.  I n t his  2 0 1 0 t o  2 0 1 4  p eri o d,  5  p ati e nts  h a d tr a nsi e nt,  mil d  c ar di a c  v al v e 
t hi c k e ni n g r e p ort e d  o n  e c h o c ar di o gr a p h y  at  o nl y  o n e  e x a mi n ati o n  w hi c h  w er e  n o l o n g er 
o bs er v e d i n  all s u bs e q u e nt st u di es.   O n e  p ati e nt  h a d  v al v e t hi c k e ni n g s e e n i n t h e first  4  y e ars 
b ut  w as  n ot f o u n d  at t h e  m ost r e c e nt f oll o w -u p  e c h o c ar di o gr a m.   T w o  p ati e nts  h a d  mil d  v al v e 
t hi c k e ni n g  n ote d  o n t h eir l ast  e c h o c ar di o gr a p h y,  b ut  wit h o ut  a n y  cli ni c al s y m pt o ms; ( a c c or di n g 
t o t h e i n v esti g at ors, t h es e r e m ai n st a bl e).  At  n o  p oi nt  w as  cli ni c all y si g nifi c a nt  v al v e t hi c k e ni n g 
o bs er v e d  wit h f e nfl ur a mi n e  n or  w er e t h er e  a n y si g ns  of  p ul m o n ar y  h y p ert e nsi o n.   N o  p ati e nts 
h a v e  dis c o nti n u e d tr e at m e nt  as  a r es ult  of  a n y  c ar di o v as c ul ar  A Es.  
A t hir d r e c e nt  a n al ysis  w as  c o n d u ct e d t h at i n cl u d e d  7  a d diti o n al  p ati e nts ( 5  m al es  a n d 
2  f e m al es)  w h o  w er e  e nr oll e d  aft er  2 0 1 0,  wit h  d at a t hr o u g h  M ar c h  2 0 1 5 (C e ul e m a ns  2 0 1 5 ).  
T h e  m e di a n st arti n g f e nfl ur a mi n e  d os e  w as  1 0  m g  p er  d a y.   M e a n tr e at m e nt  d ur ati o n  w as  2 2 
m o nt hs.  T h e  m e a n s ei z ur e fr e q u e n c y i n t h es e  7  p ati e nts  pri or t o i niti ati o n  of f e nfl ur a mi n e  w as 
1 1. 4  p er  m o nt h (r a n g e  0. 4 t o  3 9. 7)  a n d  at  6  m o nt hs  aft er st arti n g f e nfl ur a mi n e t h er e  w as  a 
dr a m ati c  d e cr e as e  wit h  a  m e a n  of  2. 6 s ei z ur es  p er  m o nt h (r a n g e  0 -6) s ei z ur es  p er  m o nt h.   E v er y 
p ati e nt’s  e c h o c ar di o gr a p hi c  e x a mi n ati o ns  w hi c h  w er e  n or m al  at  b as eli n e,  c o nti n u e d t o  b e 
n or m al  at  e v er y  p ost -tr e at m e nt  ass ess m e nt  wit h o ut  a n y si g ns  of  v al v ul o p at h y,  p ul m o n ar y 
h y p ert e nsi o n  or  a n y  ot h er  c ar di o v as c ul ar  a b n or m alit y.   
T h e  dr a m ati c l o n g -t er m  pr os p e cti v e  eff e cti v e n ess  d at a  d es cri b e d  a b o v e  of t h e  B el gi a n  c o h ort  of 
Dr a v et s y n dr o m e  p ati e nts  w h o  h a v e  n o w  b e e n s u c c essf ull y tr e at e d  wit h f e nfl ur a mi n e, i n s o m e 
c as es, f or  o v er  2 5  y e ars,  wit h o ut  a n y si g ns  of  cli ni c all y si g nifi c a nt  v al v ul o p at h y  or r e p orts  of 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 4  of  1 9 4  
p ul m o n ar y  h y p ert e nsi o n, str o n gl y s u p p orts t h e  p ot e nti al  b e n efit  o ut w ei g hs t h e ris k i n t his 
p arti c ul ar  p a ti e nt  p o p ul ati o n.   
T h e  a p pr o xi m at e  v ol u m e  of  bl o o d ( 6 3. 4  m L)  pl a n n e d f or  c oll e cti o n fr o m  C o h ort  1  u p t o  D a y 
1 5  pr es e nts  n o  u n d u e ris k t o t h e s u bj e cts,  a n d  will  pr o vi d e  us ef ul i nf or m ati o n  o n t h e  P K  pr ofil e 
of t h es e  a nti e pil e pti c  m e di c ati o ns  w h e n  Z X 0 0 8 is  a d d e d t o tr e at m e nt  wit h  C L B  +  V P A  or  wit h 
C L B  +  V P A  +  S T P.   As  n ot e d  a b o v e, t h e  d os e  of  Z X 0 0 8 t o  b e  us e d i n  C o h ort  1  will  b e  at t h e 
l o w  e n d  of t h e  d os e r a n g e f or s u bj e cts  w h o  ar e r e c ei vi n g  S T P/ V P A/ C L B t o  mi ni mi z e  p ot e nti al 
si d e  eff e cts  ass o ci at e d  wit h t h e  c o m bi n ati o n .   
T h e  0. 5  m g/ k g / d a y, wit h  a  m a xi m u m  2 0  m g/ d a y  d os e  of  Z X 0 0 8 t o  b e  a d mi nist er e d  f or  C o h ort 
2  h as  b e e n  i nf or m e d b y  ass ess m e nt  of  P K  a n d s af et y  d at a  d eri v e d fr o m  C o h ort  1.   T h e 
I n d e p e n d e nt  D at a  a n d  S af et y  M o nit ori n g  C o m mitt e e (I D SM C ) h as  b e e n  pr o vi d e d  wit h  t h e 
s af et y  a n d  P K  d at a fr o m  C o h ort  1  a n d  h a v e  v ali d at e d  t h e m et h o d ol o g y f or t h e  0. 5  m g/ k g / d a y 
d os e s el e ct e d f or  C o h ort  2.   B as e d  o n  pr e vi o us  w or k  wit h  Z X 0 0 8 i n t his  p o p ul ati o n, 
f e nfl ur a mi n e s h o ul d  pr o vi d e s uffi ci e nt  a nti-e pil e pti c s u p p or t f or  a s ust ai n e d  p eri o d  of ti m e 
d uri n g t h e st u d y.   
T h e s af et y  m o nit ori n g  pr a cti c es  e m pl o y e d  b y t his  pr ot o c ol, i n cl u di n g  e xt e nsi v e  c ar di o v as c ul ar 
m o nit ori n g,  ar e  a d e q u at e t o  pr ot e ct t h e s u bj e cts’ s af et y  a n d s h o ul d  d et e ct  e x p e ct e d  a n d 
u n e x p e ct e d tr e at m e nt -e m er g e nt  a d v ers e  e v e nts.  
T h e  a v ail a bl e i nf or m ati o n s u g g ests t h at t h e  pr es e nt  cli ni c al st u d y  h as  a n  a c c e pt a bl e ris k -b e n efit 
r ati o. 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 5  of  1 9 4  
2.   
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  
2. 1   
P RI M A R Y  E F FI C A C Y  O B J E C TI V E  
T h e  pri m ar y  effi c a c y  o bj e cti v e  of t his  m ulti c e nt er  t w o-c o h ort  st u d y is: 
•   T o  d e m o nstr at e t h at  Z X 0 0 8 is s u p eri or t o  pl a c e b o  as  a dj u n cti v e t h er a p y  i n t h e 
tr e at m e nt  of s y m pt o ms of  Dr a v et s y n dr o m e i n  c hil dr e n  a n d  y o u n g  a d ult s b as e d 
o n  c h a n g e i n t h e fr e q u e n c y  of  c o n v ulsi v e s ei z ur es  b et w e e n  b as eli n e  a n d t h e 
c o m bi n e d  Titr ati o n  a n d  M ai nt e n a n c e  P eri o ds ( T  +  M)  i n  C o h ort  2. 
2. 2   
K E Y  S E C O N D A R Y  E F FI C A C Y  O B J E C TI V E S  
T h e  k e y s e c o n d ar y  effi c a c y  o bj e cti v es  of t h e st u d y  ar e  r el at e d t o t h e  d o u bl e-bli n d,  pl a c e b o -
c o ntr oll e d  p art  of t h e st u d y ( C o h ort  2)  a n d i n cl u d e : 
•   T o  d e m o nstr at e t h at  Z X 0 0 8  is s u p eri or t o  pl a c e b o  o n t h e f oll o wi n g  e n d p oi nts:  
o   
T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥  5 0 % r e d u cti o n fr o m  b as eli n e 
i n  c o n v ulsi v e s ei z ur e fr e q u e n c y. 
o   
T h e l o n g est  c o n v ulsi v e s ei z ur e -fr e e i nt er v al. 
S e e  St atisti c al  M et h o ds ( S e cti o n  1 0. 5. 1. 3 ) f or  hi er ar c hi c al t esti n g  pr o c e d ur e. 
2. 3   
A D DI TI O N A L  S E C O N D A R Y  E F FI C A C Y  O B J E C TI V E S  
A d diti o n al  s e c o n d ar y  effi c a c y  o bj e cti v es  of t h e st u d y  ( Co h ort  2 ) ar e:  
•   T o  d e m o nstr at e t h at  Z X 0 0 8  is s u p eri or t o  pl a c e b o  o n t h e f oll o wi n g  e n d p oi nts:  
o   
T h e  n u m b er  of  c o n v ulsi v e s ei z ur e -fr e e  d a ys. 
o   
T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  ≥  2 5 %  or  ≥  7 5 %  r e d u cti o ns fr o m 
b as eli n e i n  c o n v ulsi v e s ei z ur e fr e q u e n c y.  
o   
T h e  c h a n g e fr o m  b as eli n e i n  n o n -c o n v ulsi v e s ei z ur e fr e q u e n c y.  
o   
T h e  c h a n g e fr o m  b as eli n e i n  c o n v ulsi v e  +  n o n -c o n v ulsi v e s ei z ur e 
fr e q u e n c y 
o   
T h e i n ci d e n c e  of r es c u e  m e di c ati o n  us a g e  
o   
T h e i n ci d e n c e  of  h os p it ali z ati o n t o tr e at s ei z ur es 
o   
T h e i n ci d e n c e  of  S E  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 6  of  1 9 4  
o   
T h e  c h a n g e fr o m  b as eli n e i n  h e alt h -r el at e d q u alit y  of lif e ( H R Q O L) 
m e as ur e d  usi n g t h e  P e di atri c  Q u alit y  of  Lif e I n v e nt or y ™  ( P e ds Q L) 
G e n eri c  C or e  S c al e  
o   
T h e  c h a n g e fr o m  b as eli n e i n  P e ds Q L  F a mil y I m p a ct  m o d ul e  s c or e 
o   
C h a n g e fr o m  b as eli n e  i n s u bj e cts’  q u alit y  of lif e  m e as ur e d  usi n g t h e 
Q u alit y  of  Lif e i n  C hil d h o o d  E pil e ps y  (Q O L C E ) 
o   
T h e  c h a n g e fr o m  b as eli n e i n t h e  H R Q O L  of t h e  p ar e nt/ c ar e gi v er  usi n g t h e 
st a n d ar di z e d  m e as ur e  of  h e alt h st at us ( E Q -5 D -5 L ) s c al e 
o   
T h e  c h a n g e fr o m  b as eli n e  o n t h e i m p a ct s of  t h e  c o n diti o n  o n  p ar e nts  a n d 
t h e f a mil y  usi n g t h e  P e ds Q L f a mil y i m p a ct  m o d ul e.  
o   
Cli ni c al  Gl o b al I m pr essi o n  –  I m pr o v e m e nt ( C GI-I) r ati n g,  as  ass ess e d  b y 
t h e  pri n ci p al i n v esti g at or 
o   
C GI -I r ati n g,  as  ass ess e d  b y t h e  par e nt/ c ar e gi v er  
T h e s af et y  o bj e cti v e s  of t h e st u d y  ar e: 
•   T o  e v al u at e t h e s af et y  a n d t ol er a bilit y  of  Z X 0 0 8  a d mi nist er e d  as  a si n gl e  or al  d os e  
w h e n  a d d e d t o st a n d ar d  of  c ar e tr e at m e nt f or  Dr a v et s y n dr o m e ( C L B  +  V P A;  C L B  + 
V P A  +  S T P)  ( C o h ort  1) 
•   T o  c o m p ar e t h e  s af et y  a n d t ol er a bilit y  of  Z X 0 0 8 t o  pl a c e b o  wit h r e g ar d t o  A Es , 
l a b or at or y  p ar a m et ers,  p h ysi c al  e x a mi n ati o n, n e ur ol o gi c al  e x a mi n ati o n,  vit al si g ns 
( bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e),  E C Gs, E C H Os , a n d  b o d y 
w ei g ht ,  a n d  ass ess m e nt of  c o g niti v e f u n cti o n  ( C o h ort  2). 
T h e  P K  o bj e cti v e s of t h e st u d y  ar e : 
•   T o  ass ess  t h e P K  pr ofil e  of  Z X 0 0 8  a d mi nist er e d  as  a si n gl e  or al  d os e  wit h  C L B  +  V P A 
or  wit h  C L B  +  V P A  +  S T P  i n s u bj e cts  a g es  2-1 8  y e ars  of  a g e  wit h  D r a v et s y n dr o m e 
(C o h ort  1 ). 
•   M o d el  P K  of  Z X 0 0 8 i n si n gl e  a n d  m ulti pl e  d os e r e gi m e ns  usi n g f e nfl ur a mi n e/ n or -
f e nfl ur a mi n e  c o n c e ntr ati o n-ti m e  d at a fr o m s u bj e cts i n  C o h orts  1  a n d  2. 
2. 4   
E X P L O R A T O R Y  O B J E C TI V E  
E x pl or at or y  o bj e cti v es  of t his st u d y  [ C o h ort 1  a n d  2  will  b e  e v al u at e d s e p ar at el y ] i n cl u d e: 
•   T h e  c h a n g e fr o m  b as eli n e i n  h e alt h  a n d s o ci al  c ar e r es o ur c e  us e i n cl u di n g  pl a n n e d  a n d 
u n pl a n n e d  h os pit al  visits,  us e  of  a m b ul a n c es,  g e n er al  pr a ctiti o n er ( G P ) visits, s p e e c h 
a n d l a n g u a g e t h er a p y  utili z ati o n ,  o c c u p ati o n al  a n d  p h ysi c al t h er a p y utili z ati o n.  
•   C h a n g e fr o m  b as eli n e i n sl e e p  q u alit y.   


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 7  of  1 9 4  
•   C h a n g e fr o m  b as eli n e i n  m e alti m e  b e h a vi or.  
•   Eff e ct  of st u d y  m e di c ati o n  o n sl e e pi n ess ( K ar oli ns k a  Sl e e pi n ess  S c al e).  
•   Ass ess m e nt  of  a  Dr a v et s y n dr o m e  c o m p osit e  e n d p oi nt i n cl u di n g s ei z ur e fr e q u e n c y  a n d 
s e v erit y  a n d s u bj e cti v e  p ati e nt -r el e v a nt  o ut c o m e  m e as ur es ( e g,  b e h a vi or, sl e e pi n ess, 
et c)  usi n g  d at a fr o m t h e  c oll e ct e d r ati n g s c al es  will  b e  p erf or m e d.  
2. 5   
S T U D Y  E N D P OI N T S  
2. 5. 1   
Effi c a c y  E n d p oi nts  (C o h o rt  2  o nl y ) 
T h e  effi c a c y  e n d p oi nts  of t h e st u d y  ar e:  
•   N u m b er  of s ei z ur es  b y t y p e  
•   C o n v ulsi v e s ei z ur e -fr e e i nt er v al 
•   N u m b er  of i nst a n c es  of r es c u e  m e di c ati o n  us e  a n d  n u m b er  of  d os es  
•   N u m b er  of  i n p ati e nt  h os pit al  a d missi o ns d u e t o s ei z ur es  
•   D ur ati o n  of  pr ol o n g e d s ei z ur es (s ei z ur e t y p e t h at,  d uri n g  b as eli n e,  h a d  d ur ati o n   
>  2  mi n ut es)  
•   N u m b er  of  e pis o d es  of  S E  
•   Q O L C E t o  m e as ur e  c h a n g es i n  q u alit y  of lif e  of t h e s u bj e ct  
•   H R Q O L  b as e d  o n t h e  P e d Q L  G e n eri c  C or e  S c al e  
•   H R Q O L  of t h e  p ar e nt/ c ar e gi v er  usi n g t h e  E Q -5 D -5 L s c al e  
•   I m p a ct  of t h e  c o n diti o n  o n  p ar e nts  an d t h e f a mil y  usi n g t h e  P e ds Q L  F a mil y  I m p a ct 
M o d ul e.  
2. 5. 2   
S af et y  E n d p oi nts  
T h e s af et y  e n d p oi nts  of t h e st u d y  ar e:  
•   A Es  
•   L a b or at or y s af et y ( h e m at ol o g y,  c h e mistr y,  uri n al ysis)  
•   Vit al si g ns ( bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e)  
•   P h ysi c al  e x a mi n ati o n  
•   N e ur ol o gi c al  e x a mi n ati o n  
•   1 2 -l e a d  E C Gs 
•   D o p pl er  E C H O s 
•   B o d y  w ei g ht  
•   C o g niti v e  F u n cti o n  will  b e  ass ess e d  usi n g t h e  c o g niti o n  d o m ai n s c or e  o n t h e  Q O L C E 
a n d  a g e -a p pr o pri at e  v ersi o ns  of t h e  B RI E F   


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 8  of  1 9 4  
2. 5. 3   
P h a r m a c o ki n eti c  E n d p oi nts  
T h e  P K  e n d p oi nts  of t h e st u d y  ar e:  
•   P K  d at a  f or  all  a n al yt es (f e nfl ur a mi n e,  n orf e nfl ur a mi n e, C L B , 
n -d es m et h yl cl o b a z a m  (N -C L B ), V P A ,  a n d S T P ) f or  C o h ort  1 will  b e  us e d f or 
P K  m o d eli n g  
•   P K s a m pli n g f or  Z X 0 0 8  will  b e  p erf or m e d  o n s u bj e cts i n  C o h ort  2. 
F e nfl ur a mi n e/ n or -f e nfl ur a mi n e  c o n c e ntr ati o n-ti m e  d at a fr o m s u bj e ct  e nr oll e d i n 
C o h orts  1  a n d  2  will  b e  us e d  t o  m o d el  P K  of  Z X 0 0 8 i n si n gl e  a n d  m ulti pl e  d os e 
r e gi m e ns 
2. 5. 4   
E x pl o r at o r y  E n d p oi nts  
T h e  e x pl or at or y  e n d p oi nts  of t h e st u d y  ar e:  
•   H e alt h  a n d s o ci al  c ar e r es o ur c e  us e i n cl u di n g  G P  visits, s p e e c h  a n d l a n g u a g e, 
o c c u p ati o n al  a n d  p h ysi c al t h er a p y, i n  a d diti o n t o  a c ut e  h os pit al  a n d i nstit uti o n al l e n gt h 
of st a y, l oss  of  w or k,  et c.  
•   C h a n g e i n sl e e p  q u alit y  ass ess e d  b y t h e  p ati e nt/ c ar e gi v er  
•   C h a n g e i n  m e alti m e  b e h a vi or  ass ess e d  b y t h e  p ati e nt/ c ar e gi v er  
•   Sl e e pi n ess  ass ess e d  b y t h e  p ati e nt/ c ar e gi v er  usi n g t h e K ar oli ns k a  Sl e e pi n ess  S c al e  
•   C o m p osit es  e n d p oi nts t h at  c o m bi n e  o bj e cti v e  a n d s u bj e cti v e  m e as ur es  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  4 9  of  1 9 4  
3.   
I N V E S TI G A TI O N A L  P L A N  
3. 1   
O V E R A L L  S T U D Y  D E SI G N  A N D  P L A N  
T his is  a  m ulti c e nt er,  t w o-c o h ort tri al t o  ass ess t h e  P K  a n d s af et y  p r ofil e  of a si n gl e  d os e  of 
Z X 0 0 8 (f e nfl ur a mi n e  h y dr o c hl ori d e)  or al s ol uti o n  w h e n  a d d e d t o  D r a v et s y n dr o m e tr e at m e nt 
r e gi m e n  c o nt ai ni n g  V P A  a n d  C L B,  wit h  or  wit h o ut  S T P (C o h ort  1), f oll o w e d  b y  a r a n d o mi z e d, 
d o u bl e -bl i n d,  pl a c e b o-c o ntr oll e d  p ar all el  gr o u p  e v al u ati o n  of t h e  effi c a c y, s af et y,  a n d 
t ol er a bilit y  of Z X 0 0 8  as  a dj u n cti v e t h er a p y  f or s ei z ur es i n  c hil dr e n  a n d  y o u n g  a d ults  wit h 
D r a v et s y n dr o m e ( C o h ort  2).   P K  a n d s af et y  d at a fr o m  C o h ort  1 fr o m  13  s u bj e cts h a v e  b e e n 
c oll e ct e d  a n d  e v al u at e d  t o g et h er  wit h  d at a fr o m  St u d y  Z X 0 0 8-1 5 0 5 ( h e alt h y  v ol u nt e er  dr u g -
dr u g i nt er a cti o n st u d y)  a n d  h as  i nf or me d  t h e  d os e  of  Z X 0 0 8 0. 5  m g/ k g / d a y,  m a xi m u m  2 0 
m g/ d a y , t o  b e  us e d i n  C o h ort  2.  T h e  c urr e nt  A m e n d m e nt  of t his  pr ot o c ol  d efi n es t h e  d os e f or 
C o h ort  2.  A p pr o xi m at el y  2 -3 sit es i n  Fr a n c e  a n d t h e  N et h erl a n ds  will  b e i n v ol v e d i n t h e  P K 
p orti o n  of t h e tri al ( C o h ort  1).   U p t o  a p pr o xi m at el y  3 0  st u d y sit es i n C a n a d a,  Fr a n c e , 
G er m a n y,  N et h erl a n ds ,  U nit e d  Ki n g d o m, S p ai n,  a n d t h e  U nit e d  St at es  will  e nr oll  p arti ci p a nts 
f or C o h ort  2 . 
C o h o rt  1:   S u bj e cts  will  att e n d t h e  cli ni c al r es e ar c h  u nit ( C R U ) f or  a s cr e e ni n g  visit  u p t o 1 4  
d a ys  b ef or e  d osi n g.  Eli gi bl e s u bj e cts  will  r et ur n t o C R U  o n  St u d y  D a y  – 1  f or  a n  o ut p ati e nt 
visit.   I n cl usi o n  a n d  e x cl usi o n  crit eri a  will  b e  c o nfir m e d,  a n d p h ysi c al  e x a m,  m e di c al  hist or y, 
b o d y  w ei g ht/ b o d y  m ass i n d e x ( B MI ),  vit al si g ns,  uri n e  pr e g n a n c y t est, uri n e 
t etr a h y dr o c a n n a bi n ol (T H C ), a n d  w h ol e  bl o o d  c a n n a bi n ol ( C B D ) will  b e  o bt ai n e d.   T h e  s u bj e ct 
will  b e  dis c h ar g e d fr o m t h e  u nit  or  all o w e d t o st a y  o v er ni g ht,  as r e q uir e d.  Aft er  di n n er  a n d  a 
li g ht s n a c k  pri or t o  b e dti m e, s u bj e cts  will  b e f ast e d  u ntil t h e  n e xt  m or ni n g.  O n t h e f oll o wi n g 
d a y ( St u d y  D a y  1),  a  p ar e nt/ c ar e gi v er  will  bri n g t h e  f ast ed  s u bj e ct t o t h e  C R U  b et w e e n  6  A M 
a n d  7  A M.  
F oll o wi n g  b l o o d  c oll e cti o n f or  cli ni c al l a bs,  a n d  vit al si g n  m e as ur e m e nts a n d  w ei g ht , s u bj e cts 
will  b e  gi v e n  a li g ht, l o w f at  br e a kf ast, f oll o w e d  b y  a d mi nistr ati o n  of t h eir  us u al  e pil e ps y 
m e di c ati o ns.   B as e d  o n t h e  assi g n e d tr e at m e nt  all o c ati o n ,  e a c h s u bj e ct  will t h e n r e c ei v e t h e 
a p pr o pri at e  d os e  of  st u d y  m e di c ati o n ( Z X 0 0 8). S u bj e cts r e c ei vi n g  C L B  a n d  V A  at s cr e e ni n g 
will  b e str atifi e d  b y  a g e  gr o u p ( <  6  y e ars  of  a g e;  ≥  6  of  a g e)  a n d r a n d o ml y  all o c at e d t o  D osi n g 
R e gi m e n  1 ( Z X 0 0 8  0. 2  m g/ k g  +  C L B  +  V P A)  or  R e gi m e n  2 ( Z X 0 0 8  0. 4 m g/ k g  +  C L B  +  V P A). 
At l e ast t w o s u bj e cts fr o m  e a c h  pr e -s p e cifi e d  a g e  gr o u p  ar e t o  b e  assi g n e d t o  R e gi m e n  1 ; a n d  at 
l e ast  2 s u bj e cts fr o m  e a c h  gr o u p  ar e t o  b e  assi g n e d t o  R e gi m e n 2.   S u bj e cts  r e c ei vi n g  C L B  a n d 
V A  a n d  S T P  at s cr e e ni n g,  will  b e  assi g n e d t o  R e gi m e n  3 ( Z X 0 0 8  0. 2  m g/ k g  +  C L B  +  V P A  + 
S T P).   A p pr o xi m at el y  5 s u bj e cts fr o m  e a c h  a g e  gr o u p ( <  6  y e ars;  ≥  6  y e ars) s h o ul d  b e  e nr oll e d  
i n  d osi n g  R e gi m e n  3. D et ails f or  e a c h r e gi m e n  ar e s h o w n  i n T a bl e  3 . 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 0  of  1 9 4  
T a bl e  3 . C o h o rt  1  D osi n g  R e gi m e ns  
D osi n g  R e gi m e n   
D osi n g  o n  D a y  1   
D os e  of  Z X 0 0 8  
A g e  St r atifi c ati o n  
# 1  
C L B  +  V P A  +  Z X 0 0 8   
0. 2  m g/ k g   
[ n = 5];  at l e ast  2 s u bj e cts  p er  a g e  gr o u p  
( < 6  a n d  >  6  y e ars)  
# 2  
C L B  +  V P A  +  Z X 0 0 8   
0. 4  m g/ k g   
[ n = 5];  at l e ast  2 s u bj e cts  p er  a g e  gr o u p  
( < 6  a n d  >  6  y e ars)  
# 3   
C L B  +  V P A  +  S T P  +  Z X 0 0 8   
0. 2  m g/ k g   
[ n = 1 0]; t ot al  of  5 s u bj e cts  p er  a g e  gr o u p  
 ( < 6  a n d  >  6  y e ars)  
 
Bl o o d s a m pl es f or  P K  ass ess m e nt  will  b e  o bt ai n e d fr o m  all s u bj e cts  t hr o u g h  1 2-h o urs  p ost -
d os e.   Aft er t h e l ast  St u d y  D a y  1  bl o o d  dr a w ( 1 2  h o urs  p ost -d os e), s u bj e cts  will  b e  dis c h ar g e d. 
T w e nt y -f o ur t o t hirt y-si x h o urs f oll o wi n g  d osi n g t h e  s u bj e cts will r et ur n t o t h e r es e ar c h  u nit f or 
ass ess m e nt  of  vit al si g ns ,  a fi n al  P K s a m pl e a n d t o r e c or d  a n y  a d v ers e  e v e nts t h at  m a y  h a v e 
o c c urr e d  si n c e l e a vi n g t h e  C R U.  A s ei z ur e  di ar y  will  b e  pr o vi d e d t o r e c or d s ei z ur e  a cti vit y 
b et w e e n  St u d y  D a y  2  a n d t h e f oll o w -u p s af et y  visit ( St u d y  D a y  1 5).   O n  St u d y  D a y  1 5, 
s u bj e cts a n d/ or  c ar e gi v ers  will  r et ur n t o t h e  C R U f or f oll o w-u p , i n cl u di n g r e vi e w  of  di ar y  d at a. 
At t h e  c o n cl usi o n  of t his  p orti o n  of t h e st u d y,  eli gi bl e s u bj e cts fr o m  C o h ort  1  will  b e  off er e d 
e nr oll m e nt i n  a s e p ar at e  o p e n -l a b el e xt e nsi o n tri al  a n d  if t h e y  c h oo s e t o  d o s o, t h e y will  b e gi n 
tr a nsiti o ni n g t o st u d y  m e di c ati o n ( Z X 0 0 8,  0. 2  m g/ k g/ d a y), s af et y  a n d di ar y  d at a  will  c o nti n u e 
t o  b e  c a pt ur e d  a n d t h e  e x pl or at or y  c o m p osit e  e n d p oi nt  c o m p o n e nts  will  b e  a d mi nist er e d  pri or 
t o  c o m m e n c e m e nt  of tr a nsiti o n al tr e at m e nt. T h e  d ur ati o n  of t h e tr a nsiti o n  p eri o d  will  n ot 
e x c e e d  2 4  w e e ks.   S u bj e cts  m a y  e nr oll i n t h e  s e p ar at e  o p e n -l a b el e xt e nsi o n tri al  w h e n t h e  d os e 
f or  C o h ort  2  h as  b e en s el e ct e d.  A s c h e d ul e  of  ass ess m e nts is  pr o vi d e d i n  T a bl e  1 . 
F or  C o h ort  1 s u bj e cts,  a  f oll o w-u p  E C H O ,  E C G,  a n d s y m pt o m-dir e ct e d  p h ysi c al  e x a mi n ati o n  
will  b e  p erf or m e d  3 -6  m o nt hs  aft er st u d y  dr u g  dis c o nti n u ati o n  wit h  e arl y t er mi n ati o n . 
C o h o rt  2:   A  6 -w e e k  B as eli n e  P eri o d  will  c o nsist  of t h e  est a blis h m e nt  of i niti al  eli gi bilit y 
d uri n g  a s cr e e ni n g  visit f oll o w e d  b y  a n  o bs er v ati o n  p eri o d  w h er e s u bj e cts  will  b e  ass ess e d f or 
b as eli n e s ei z ur e  a cti vit y  b as e d  o n r e c or di n gs  of  d ail y s ei z ur e  a cti vit y  e nt er e d i nt o  a  di ar y.  
U p o n  c o m pl eti o n  of t h e  B as eli n e  P eri o d, s u bj e cts  w h o  q u alif y f or t h e st u d y  will  b e r a n d o mi z e d 
( 1: 1) i n  a  d o u bl e-bli n d  m a n n er t o r e c ei v e  Z X 0 0 8  (at  a  d os e  of  0. 5  m g/ k g/ d a y , m a xi m u m  2 0  
m g/ d a y ) or  pl a c e b o.   R a n d o mi z ati o n  wil l  b e str atifi e d  b y  a g e gr o u p ( <  6  y e ars,  ≥  6  y e ars) t o 
e ns ur e  b al a n c e  a cr oss tr e at m e nt  ar ms,  a n d  at l e ast  4 0 %  of s u bj e cts  will  b e i n  e a c h  a g e  gr o u p. 
All s u bj e cts  will  b e titr at e d t o t h eir r a n d o mi z e d  d os e  d uri n g t h e  Titr ati o n  P eri o d . T itr ati o n will 
o c c ur i n  3 st e ps  st arti n g  wit h a  0. 2  m g/ k g/ d a y  d os e  of  Z X 0 0 8  ( or  pl a c e b o  e q ui v al e nt)  o n  St u d y 
D a ys  1 -7, i n cr e as e d  t o  a  d os e  of  0. 4  m g/ k g/ d a y  o n  St u d y D a y  8 -1 4,  a n d t h e n i n cr e as e d  t o  a 
d os e  of  0. 5  m g/ k g/ d a y  o n  St u d y  D a ys  1 5 -2 1; t h e  m a xi m u m  d ail y  d os e  at  a n y  p oi nt is  2 0 
m g/ d a y.  T h e  d ur ati o n  of t h e titr ati o n  p eri o d  will  b e  2 1  d a ys . 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 1  of  1 9 4  
F oll o wi n g titr ati o n s u bj e cts  will  c o nti n u e tr e at m e nt  at t h eir r a n d o ml y  assi g n e d  d os e  of  Z X 0 0 8 
0. 5  m g/ k g/ d a y  ( m a xi m u m  2 0  m g/ d a y) or  pl a c e b o  o v er  a  1 2 -w e e k  M ai nt e n a n c e  P eri o d.  T ot al 
tr e at m e nt ti m e fr o m t he  b e gi n ni n g  of t h e  Titr ati o n  P eri o d t hr o u g h t h e  e n d  of t h e  M ai nt e n a n c e 
P eri o d  is a  m a xi m u m  of  1 5  w e e ks . P ar e nts/ c ar e gi v ers  will  us e  a  di ar y  d ail y t o r e c or d t h e 
n u m b er/t y p e  of s ei z ur es,  d osi n g,  a n d  us e  of r es c u e  m e di c ati o n.   A s c h e d ul e  of  ass ess m e nts is 
pr o vi d e d i n  T a bl e  2 . 
At t h e  e n d  of t h e  M ai nt e n a n c e  P eri o d ( or  e arl y  dis c o nti n u ati o n), s u bj e cts  w h o  will  n ot  b e 
e nt eri n g t h e  o p e n -l a b el  e xt e nsi o n will  u n d er g o  a t a p er  of  1 4  d a ys ,  aft er  w hi c h t h e y  will  b e  off 
st u d y  m e di c ati o n.  S u bj e cts  w h o  will  b e  e nr oll e d i n t h e s e p ar at e  o p e n -l a b el e xt e nsi o n tri al  will 
e nt er  a  1 4 -d a y  tr a nsiti o n  p eri o d.    
F or  C o h ort  2 s u bj e cts,  a  f oll o w-u p  E C H O ,  E C G,  a n d  p ossi bl y  p h ysi c al  e x a mi n ati o n will  b e 
p erf or m e d  3 -6  m o nt hs  aft er  st u d y  dr u g  dis c o nti n u ati o n  wit h  e arl y t er mi n ati o n,  or f or t h os e 
s u bj e cts  w h o  c o m pl et e t h e st u d y  b ut  d o  n ot  e nt er t h e  o p e n -l a b el e xt e nsi o n tri al . 
3. 2   
N U M B E R  O F  S U B J E C T S  
C o h o rt  1:   A p pr o xi m at el y  2 5 s u bj e cts  will  b e s cr e e n e d t o  o bt ai n  1 8 -2 0  s u bj e cts  w h o c o m pl et e 
all  P K  ass ess m e nts.  Dr o p o uts  will  b e r e pl a c e d.  
C o h o rt  2:   A p pr o xi m at el y  1 1 5  s u bj e cts  will  b e s cr e e n e d t o   r a n d o mi z e  a p pr o xi m at el y9 0  
s u bj e cts . E a c h  cli ni c al sit e  will  n ot r a n d o mi z e  m or e t h a n  a  m a xi m u m  of  8 -1 0  s u bj e cts wit h o ut 
pri or  c o ns e nt fr o m t h e  S p o ns or . 
3. 3   
S T U D Y  D U R A TI O N  
C o h o rt  1:   F or t h e  P K  p orti o n  of t h e st u d y, t h e  d ur ati o n  of  p arti ci p ati o n f or  a n i n di vi d u al 
s u bj e ct is  e x p e ct e d t o  b e  u p  t o 3 2  d a ys:  
•   S cr e e ni n g  –  1 4  d a ys  (T h e  s cr e e ni n g  p eri o d  m a y  b e  e xt e n d e d t o  e ns ur e  all s cr e e ni n g 
r es ults  ar e r e vi e w e d f or  eli gi bilit y  pri or t o  d osi n g.) 
•   D a y  -1  C R U  o ut p ati e nt  visit  –  1  d a y  
•   D osi n g/ P K s a m pli n g  –  2  d a y s 
•   A E f oll o w -u p  –  1 5  d a ys  
•   I n  a d diti o n, t h e s u bj e ct  m a y  e nt er  a tr a nsiti o n  p eri o d  u ntil  e nr ol m e nt i nt o t h e  o p e n-l a b el 
e xt e nsi o n tri al ,  n ot t o  e x c e e d 1 6 8  d a ys  ( 2 4  w e e ks) 
•   C ar di a c  F oll o w -u p ( E C G  a n d  E C H O)  –  3 -6  m o nt hs  aft er st u d y  dr u g  dis c o nti n u ati o n f or 
e arl y t er mi n ati o n.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 2  of  1 9 4  
C o h o rt  2:   T h e  d ur ati o n  of  p arti ci p ati o n i n  t h e st u d y f or  a n i n di vi d u al s u bj e ct is 1 5  w e e ks  of 
d o u bl e  bli n d t h er a p y ( T  +  M;  n ot i n cl u di n g tr a nsiti o n  or t a p er) ,  pl us f oll o w-u p s af et y  visit  3 t o 
6  m o nt hs  aft er t h e l ast  d os e : 
•   B as eli n e  P eri o d  –  6  w e e ks  
•   T  +  M  P eri o d  –  2 1  d a ys  +  1 2  w e e ks  
•   Tr a nsiti o n f or s u bj e cts  c o nti n ui n g i nt o  o p e n -l a b el  e xt e nsi o n tri al –  1 4  d a ys  
•   T a p er f or s u bj e cts  n ot  c o nti n ui n g i nt o  o p e n -l a b el e xt e nsi o n tri al  –  1 4  d a ys,  aft er  w hi c h 
t h e y  will  b e  off st u d y  m e di c ati o n 
•   P ost -D osi n g  F oll o w -u p  Visit  –  1 4  d a ys  aft er st u d y  c o m pl eti o n  or  e arl y t er mi n ati o n  
•   C ar di a c  F oll o w -u p ( E C G  a n d  E C H O)  –  3 -6  m o nt hs  aft er st u d y  dr u g  dis c o nti n u ati o n f or 
e arl y t er mi n ati o n  or f or s u bj e cts  w h o  c o m pl et e t h e st u d y  b ut  d o  n ot  e nr oll i n t h e  o p e n -
l a b el e xt e nsi o n tri al  
3. 4   
N U M B E R  O F  S T U D Y  C E N T E R S  
T w o t o t hr e e r es e ar c h  c e nt ers i n  Fr a n c e  a n d t h e  N et h erl a n ds  will  e nr oll  p arti ci p a nts f or 
C o h ort  1 .  U p t o  a p pr o xi m at el y  3 0  r es e ar c h  c e nt ers i n C a n a d a,  Fr a n c e , G er m a n y,  t h e 
N et h erl a n ds ,  U nit e d  Ki n g d o m, S p ai n,  a n d  t h e  U nit e d  St at es will  e nr oll s u bj e cts f or  C o h ort  2.   
A d diti o n al st u d y  c e nt ers  or  c o u ntri es  m a y  b e  a d d e d if  e nr oll m e nt  c a n n ot  b e  c o m pl et e d i n  a 
ti m el y  m a n n er. 
3. 5   
R A TI O N A L E  F O R  S T U D Y  D E SI G N  A N D  C H OI C E  O F  T R E A T M E N T   
It is r e c o g ni z e d t h at  p erf or mi n g  cli ni c al st u di es in  y o u n g  c hil dr e n  or i n s u bj e cts  wit h r e d u c e d 
c o g niti v e  c a p a cit y  pr es e nts  p arti c ul ar  pr a cti c al  a n d  et hi c al iss u es.   M e eti n g t h e  o bj e cti v es  of t h e 
st u d y r e q uir e  e v al u ati o n i n t h e  p ati e nt  p o p ul ati o n, i e ,  e v al u ati o n  of  P K  a n d  effi c a c y  a n d s af et y 
e n d p oi nts i n  c hil d re n  wit h  Dr a v et s y n dr o m e.  G i v e n t h e s eri o us n ess  of  Dr a v et s y n dr o m e, wit h 
o ns et  of s ei z ur es  b ef or e t w o  y e ars  of  a g e,  a n d t h e  p ossi bl e  c o ns e q u e n c es  of  c urr e nt tr e at m e nt 
li mit ati o ns, th e  us e  of  c hil dr e n  wit h  D r a v et s y n dr o m e i n t his st u d y is  c o nsi d er e d 
j ustifi e d.  R es ults fr o m  a  p ar e nt -r e p ort e d s ur v e y  o n  a nti e pil e pti c  m e di c ati o n  us e i n t h e 
E ur o p e a n  p o p ul ati o n  wit h  D r a v et s y n dr o m e d e m o nstr at e  t h at m a n y  c hil dr e n  wit h  Dr a v et 
s y n dr o m e ar e st ill  h a vi n g s ei z ur es  d es pit e  c o m bi n ati o n tr e at m e nt  wit h st a n d ar d  of  c ar e  a g e nts 
(C L B  +  V P A  or  S T P  +  C L B  +  V P A ); m or e o v er,  m ost  c o nti n u e t o  h a v e  ot h er  si g nifi c a nt 
n e ur ol o gi c al  a n d  b e h a vi or al  c o m or bi diti es.  A d di n g  a  m e di c ati o n  wit h  a  diff er e nt  m e c h a nis m  of 
a c ti o n t o  e xisti n g tr e at m e nt i n cr e as es t h e li k eli h o o d  of a  m e a ni n gf ul  cli ni c al r es p o ns e.   Z X 0 0 8 
(f e nfl ur a mi n e  h y dr o c hl ori d e),  a n  a n al o g u e  of  a m p h et a mi n e t h at i n cre as es  e xtr as y n a pti c 
s er ot o ni n, h as  b e e n s h o w n t o  h a v e  a  p ositi v e  cli ni c al  o ut c o m e  as  a n  a d d -o n t r e at m e nt f or 
D r a v et s y n dr o m e i n  a  c as e s eri es  of  p ati e nts f oll o w e d f or  m or e t h a n t w o  d e c a d es. 
C urr e nt st a n d ar d  of  c ar e f or  p ati e nts  wit h  D r a v et s y n dr o m e i n t h e E ur o p e a n  U ni o n  i n cl u d es 
tr e at m e nt  wit h  a  c o m bi n ati o n  of  a nti e pil e pti c  m e di c ati o ns,  m ost  c o m m o nl y V P A , C L B , 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 3  of  1 9 4  
t o pir a m at e, l e v etir a c et a m,  a n d S T P .  S T P  (t o g et h er  wit h C L B  a n d  V P A ), t h e  o nl y  dr u g 
s p e cifi c all y  a p pr o v e d f or t his i n di c ati o n, is  wi d el y  pr es cri b e d  b y  p e di atri c  e pil e ps y  p h ysi ci a ns 
f or t h eir p ati e nts  wit h  Dr a v et s y n dr o m e.  S T P  is  a  p ot e nt i n hi bit or  of s e v er al  C Y P 4 5 0 
is o e n z y m es, i n cl u di n g  C Y P 2 D 6,  a n d  w h e n  us e d i n  c o m bi n ati o n  wit h  ot h er  a nti e pil e pti c 
m e di c ati o ns  m a y i n cr e as e  t h eir  pl as m a l e v els  a n d  h e n c e i n cr e as e si d e  eff e cts.  A c k n o wl e d gi n g 
t h at a n  a dj u n cti v e  a nti e pil e ps y  m e di c at i o n  m ar k et e d i n  E ur o p e is li k el y t o  b e t a k e n  b y  p ati e nts 
als o t a ki n g  S T P ,  a n d t h at i n hi biti o n  of  C Y P 2 D 6 is li k el y t o i n cr e as e l e v els  of  Z X 0 0 8, t his st u d y 
f o c us es first  o n  e v al u ati n g t h e  P K  a n d s af et y  pr ofil e  of l o w d os es  of  Z X 0 0 8  w h e n  a d mi nist er e d 
wit h   a  st a n d ar d tr e at m e nt r e gi m e n ( C L B  +  V P A  or  C B A  +  V P A  +  S T P) i n  o n e  c o h ort, t h us 
est a blis hi n g t h e  d os e  of  Z X 0 0 8  t h at  pr o d u c es s er u m l e v els  w h e n  gi v e n  wit h  S T P t h at  ar e 
si mil ar t o  eff e cti v e  d os es fr o m t h e  B el gi a n  e x p eri m e nt  (C e ul e m a ns  2 0 1 2 ). B as e d  o n  d at a fr o m 
1 3  p ati e nts i n  C o h ort  1,  a n d  d at a fr o m  St u d y  Z X 0 0 8 -1 5 0 5 t h e  0. 5  m g/ k g/ d a y ( m a xi m u m   
2 0  m g/ d a y)  Z X 0 0 8  d os e  w as  d et er mi n e d  as t h e t ar g et  d os e f or t h e s e c o n d  c o h ort  b as e d  o n 
m at c hi n g t h e  e x p os ur e  (A U C)  of f e nfl ur a mi n e  at  0. 8  m g/ k g/ d a y ( m a xi m u m  3 0  m g/ d a y)  wit h o ut 
S T P/ C L B/ V L P.  T h e  a n al ysis l e v er a g e d  p h ysi ol o gi c all y -b as e d  p h ar m a c o ki n eti cs ( P B P K) 
m o d els f or  Z X 0 0 8,  C L B,  V L P,  a n d  S T P.   P K  a n d s af et y  d at a fr o m  C o h ort  1,  a n d  d at a fr o m 
St u d y  Z X 0 0 8 -1 5 0 5  w er e  e v al u at e d  usi n g t h e  m o d el t o  q u a ntif y t h e  e xt e nt  of t h e  P K i nt er a cti o n 
b et w e e n f e nfl ur a mi n e  a n d t h e  c o m bi n ati o n  of  C B A  +  V P A  +  S T P.  T h e  0. 5  m g/ k g/ d a y  Z X 0 0 8 
d os e ( m a xi m u m  2 0  m g/ d a y) f or  C o h ort  2  w as s el e ct e d  wit h t h e  g o al  of  m ai nt ai ni n g  m e a n 
p ati e nt  P K  e x p os ur es  wit hi n  1 0 %  of t h at  w hi c h is  e x p e ct e d i n  p ati e nts r e c ei vi n g  0. 8  m g/ k g 
( m a xi m u m  3 0  m g/ d a y) i n t h e  a bs e n c e  of i nt er a cti n g  A E Ds.  D at a fr o m  St u d y  Z X 0 0 8-1 5 0 5 
s h o w e d t h at f e nfl ur a mi n e  d o es  n ot  h a v e  a si g nifi c a nt  eff e ct  o n t h e  P K  of t h e  c o n c o mit a nt 
m e di c ati o ns ( S T P/ C L B/ V L P).  
T h e  g o al  o f  d os e s el e cti o n  w as t o  pr e di ct t h e  dr u g i nt er a cti o n  o n f e nfl ur a mi n e f or s u bj e cts 
t a ki n g  S T P/ C L B/ V L P t o g et h er.   T h e  mi ni m u m  n u m b er  of s u bj e cts r e q uir e d t o  pr o vi d e  a n 
a d e q u at e  ass ess m e nt  of t h e  m e a n r es ult f or t h e  p ur p os es  of s el e cti n g t h e  C o h ort  2  d os e  w as  
d efi n e d  as  1 0  s u bj e cts fr o m  all  d os e r e gi m e ns  c o m bi n e d;  d at a fr o m  1 3 s u bj e cts  w er e  a v ail a bl e 
at t h e ti m e  of  m a ki n g  a  d os e  d e cisi o n.   T e n  of t h e  1 3 s u bj e cts i n t h e  C o h ort  1  d at a s et  w er e i n 
R e gi m e n  3 , i e, t h e y  w er e t a ki n g  all t hr e e  c o n c o mit a nt  m e di c ati o ns r e q uir e d  b y t h e  pr ot o c ol i n 
C o h ort  2.     
A  P B P K  m o d el s yst e m  h as  b e e n  d e v el o p e d i n  or d er t o  q u a ntif y t h e  p ot e nti al i m p a ct  of  S T P, 
C L B,  a n d  V P A  o n t h e  P K  of f e nfl ur a mi n e.  T h e  m o d el s yst e m  h as  b e e n  q u alifi e d  usi n g  d at a 
fr o m  St u d y  Z X 0 0 8-1 5 0 5  a n d  w as s h o w n t o  r e pli c at e t h e  a d ult  d at a  w ell (i. e., t h e si m ul at e d r ati o 
of f e nfl ur a mi n e  ar e a  u n d er t h e  c o n c e ntr ati o n -ti m e  c ur v e [A U C ] w h e n  a d mi nist er e d  al o n e t o t h e 
f e nfl ur a mi n e  A U C  wit h  c o m bi n ati o n t h er a p y  w er e  v er y si mil ar t o t h e  o bs er v e d f e nfl ur a mi n e 
A U C r ati os fr o m  S t u d y  Z X 0 0 8-1 5 0 5).  
T h e  m o d el s yst e m  w as t h e n  m o difi e d f or  a p pli c ati o n t o  c hil dr e n.  T h e  d at a fr o m  C o h ort  1  of 
Z X 0 0 8 -1 5 0 4  w as  us e d t o  q u alif y t h e  m o d el s yst e m i n  c hil dr e n  a g e d  2 -1 8  y e ars  wit h  Dr a v et 
s y n dr o m e.  T his  w as  a c c o m plis h e d  b y si m ul ati n g  c o n c e ntr ati o n -ti m e  pr ofil es  usi n g t h e 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 4  of  1 9 4  
d e m o gr a p hi c  c h ar a ct eristi cs  a n d  c o n c o mit a nt  m e di c ati o n  d os a g es fr o m t h e  1 3 s u bj e cts i n cl u d e d 
i n t h e i nt eri m  a n al ysis. I n  e a c h  c as e,  p ati e nt-s p e cifi c  d at a  w er e  us e d, i n  c o m bi n ati o n  wit h 
e m piri c al  esti m at es  of  v ari a bilit y i n  m o d el  p ar a m et ers, t o  g e n er at e  a  m e di a n  a n d  9 0 % 
pr e di cti o n i nt er v al f or  dr u g  c o n c e ntr ati o ns  o v er ti m e  aft er t h e  a d mi nistr ati o n  of t h e si n gl e  d os e 
of  Z X 0 0 8.  T h e  p ati e nt -s p e cifi c  d at a  w er e:  1)  d osi n g  hist ori es f or  Z X 0 0 8,  S T P,  a n d  C L B, 
i n cl u di n g  d os e, i nt er v al,  a n d ti mi n g  of  d os es r el ati v e t o t h e  P K s a m pli n g ti m es,  a n d  2)  p ati e nt 
d e m o gr a p hi c f a ct ors s u c h  as  a g e, s e x,  h ei g ht,  a n d  w ei g ht.  T h e  o bs er v e d f e nfl ur a mi n e  a n d 
n orf e nfl ur a mi n e  c o n c e ntr ati o ns  w er e t h e n  c o m p ar e d t o t h e  pr e di cti o ns  a cr oss  all  p ati e nts, 
str atifi e d  b y t r e at m e nt  wit h  or  wit h o ut stiri p e nt ol.  
Usi n g t h e  m o difi e d  P B P K  m o d el s yst e m, si m ul ati o ns  w er e  c o n d u ct e d t o  esti m at e  dr u g 
e x p os ur e ( A U C)  aft er  a d mi nistr ati o n  of  Z X 0 0 8 i n  a  h y p ot h eti c al  p o p ul ati o n  of  c hil dr e n 
( n = 1 0 0 0)  a g e d  2-1 8  y e ars  wit h  h ei g ht  a n d  w ei g ht  a p pr o pri at e f or t h eir  a g e  a n d s e x ( 5 0 % 
f e m al e).  E x p os ur e  esti m at es  w er e  g e n er at e d  ass u mi n g  all s u bj e cts  w er e r e c ei vi n g  S T P  a n d 
C L B  at  d os es  of  5 0 0  a n d  5  m g  BI D, r es p e cti v el y.   T h es e r e pr es e nt  a n  esti m at e  of t h e  d os es i n 
C o h ort  1 f or  S T P  a n d  C L B.   T his  w as  c o m p ar e d  a g ai nst  a r ef er e n c e  Z X 0 0 8  d os e  of   
0. 8  m g/ k g/ d a y  wit h  a  m a xi m u m  d os e  of  3 0  m g/ d a y t o i d e ntif y  a n  a p pr o pri at e  m at c hi n g  d os e.  
B as e d  u p o n t h e  pr e di ct e d  eff e cts  of  c o n c o mit a nt  stiri p e nt ol a n d  cl o b a z a m , t h e  d os e t h at  b est 
m at c h e d t h e  e x p os ur e f or t h e r e f er e n c e  d os e (i e, 0. 8  m g/ k g/ d a y  wit h  a  m a xi m u m  of  3 0  m g/ d a y, 
i n t h e  a bs e n c e  of stiri p e nt ol or  cl o b a z a m )  w as  0. 5  m g/ k g/ d a y  wit h  a  m a xi m u m  d os e  of  
2 0  m g/ d a y.   B ot h t h e  m g/ k g  a n d  m a xi m u m  d os e  w er e  m o difi e d t o  e ns ur e t h e  b est  m at c h  of 
e x p os ur e i n  y o u n g  c hil dr e n ( 0. 5  m g/ k g/ d a y)  as  w ell  as t o  e ns ur e t h at i n di vi d u al  ol d er  p ati e nts 
di d  n ot  h a v e  e x c ursi o ns i n  e x p os ur e ( 2 0  m g/ d a y).   Fi g ur es  1 A  a n d  B  s h o ws b o x  a n d  w his k er 
pl ot s of t h e  pr e di ct e d st e a d y -st at e  e x p os ur e  as  a f u n cti o n  of  a g e.  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 5  of  1 9 4  
Fi g u r e  1 A:  F e nfl u r a mi n e  0. 8  m g/ k g/ d a y,  m a xi m u m  3 0  m g/ d a y,  n o  S T P  o r  C L B;  a n d 
Fi g u r e  1 B:  F e nfl u r a mi n e  0. 5  m g/ k g/ d a y,  m a xi m u m  2 0  m g/ d a y,  S T P  1 0 0 0  m g/ d a y,  C L B  1 0 
m g/ d a y  
 
B o x  a n d  w his k er  pl ots:  b o x r e pr es e nts  2 5t h  –  7 5t h i nt er q u artil e r a n g e  (I Q R), li n e i n  mi d dl e  of 
t h e  b o x r e pr es e nts t h e  m e di a n,  v erti c al li n es ( w his k ers)  a b o v e  a n d  b el o w  b o x  ar e  +  a n d - 1. 5 
ti m es t h e I Q R,  d ots  b e y o n d t h e  w his k ers  ar e  o utsi d e t h at r a n g e.  R e vi e w  of s af et y  d at a fr o m t h e 
1 3 s u bj e cts i n st u d y  Z X 0 0 8 -1 5 0 4 t h at  c o ntri b ut e d t o t h e  d os e  d e cisi o n s h o ws  Z X 0 0 8  h as  b e e n 
w ell t ol er at e d.  B as e d  o n t h e  pr e di ct e d  e x p os ur es, t h e s af et y  pr ofil e f or  0. 5  m g/ k g/ d a y  Z X 0 0 8 
( m a xi m u m  2 0  m g/ d a y) i n  c o m bi n ati o n  wit h  S T P/ C L B/ V P A is  e x p e ct e d t o  b e si mil ar t o  0. 8 
m g/ k g/ d a y  Z X 0 0 8.  
D os e s el e cti o n  i nf or m ati o n f or  C o h ort  2 w as  s h ar e d  wit h a n d  v ali d at e d  b y  t h e I D S M C ( w hi c h 
i n cl u d es  a  n e ur ol o gist, p e di atri c  e pil e pt ol o gist,  g e n er al  p e di atri ci a n,  a n d  p e di atri c  c ar di ol o gist) 
a n d i n d e p e n d e nt st atisti ci a n . T h e  d e cisi o n  o n  d os e s el e cti o n f or  C o h ort  2  w as  c o m m u ni c at e d  b y 
n otifi c ati o n  wit h t h e  u p d at e d  pr ot o c ol, i nf or m e d  c o ns e nt  d o c u m e nt,  a n d s c h e d ul e  of 
ass ess m e nts t o t h e  Et hi cs  C o m mitt e es,  C o m p et e nt  A ut h orit y,  a n d I n v esti g at ors.   Tr ai ni n g  o n 
t h e  u p d at e d pr ot o c ol  will  b e  pr o vi d e d t o t h e i n v esti g ati v e sit es.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 6  of  1 9 4  
F or  b ot h  c o h orts, str atif yi n g t h e r a n d o mi z ati o n  or  all o c ati o n  b y  a g e  gr o u p is  c o nsi d er e d 
a p pr o pri at e  b e c a us e t h e fr e q u e n c y  a n d s e v erit y  of  m aj or s ei z ur es  c a n  b e  hi g h er i n  y o u n g er 
s u bj e cts.  T h e t w o str at a i n t h e st u d y  will  b e s u bj e cts  a g e d  b el o w  6  y e ars  a n d s u bj e cts  ≥  6  y e ars. 
T h e st u d y  d esi g n  f or  C o h ort  2 h as i n c or p or at e d  a titr ati o n  p eri o d t o  e ns ur e  s u bj e cts h a v e 
a d e q u at e ti m e t o  a c cli m at e t o t h eir  d os e  of  Z X 0 0 8.   F oll o wi n g t h e  Titr ati o n  P eri o d, s u bj e cts 
will  e nt er  a  1 2 -w e e k  M ai nt e n a n c e  P eri o d  w h er e t h e y  will  c o nti n u e  o n t h eir r a n d o mi z e d  d os e 
f or t h e r e m ai n d er  of t h e st u d y.  T h e  1 2-w e e k  d ur ati o n  of t h e  M ai nt e n a n c e  P eri o d is i n  k e e pi n g 
wit h t h e  c urr e nt st a n d ar d st u d y  d ur ati o n f or  e v al u ati n g t h e  effi c a c y  of  c hr o ni c  m e di c ati o ns. 
Gi v e n t h e i n di vi d u al  v ari a bilit y i n s ei z ur e fr e q u e n c y  a n d s ei z ur e t y p e i n t his  p ati e nt  p o p ul ati o n, 
t h e  pri m ar y  e n d p oi nt,  w hi c h s e e ks t o  c o m p ar e  a n  a p pr o pri at e  b as eli n e  of  c o n v ulsi v e s ei z ur e 
fr e q u e n c y t o t h e  c o n v ulsi v e s ei z ur e fr e q u e n c y f oll o wi n g tr e at m e nt, is  a n  a p pr o pri at e  pri m ar y 
e n d p oi nt f or  effi c a c y i n t his  p o p ul ati o n.   T h e  pri m ar y  e n d p oi nt  c o nsi d ers  o nl y  c o n v ulsi v e 
s ei z ur es t o i m pr o v e  a c c ur a c y  of t h e  m e as ur e.   S e c o n d ar y  e n d p oi nts  will  e v al u at e  all s ei z ur e 
t y p es. 
S u bj e cts  will r e c ei v e i n v esti g ati o n al  m e di ci n al  pr o d u ct ( Z X 0 0 8  or  pl a c e b o) i n  a d diti o n t o t h eir 
e xisti n g  a nti e pil e pti c  m e di c ati o ns  at t h eir st a bl e  d os es t hr o u g h o ut t h e  e ntir e st u d y.   T h us, 
s u bj e cts r e c ei vi n g  pl a c e b o  will  n ot  b e  d e ni e d  a cti v e t h er a p y; t h e y  will  c o nti n u e t o r e c ei v e t h eir 
e xisti n g  m e di c ati o ns  at t h e  e x a ct s a m e  d os a g es  t hr o u g h o ut t h e  e ntir e st u d y.  As t h e  pri n ci p al 
st u d y  m e as ur e m e nt ( c o n v ulsi v e s ei z ur es)  mi g ht  b e  c o nsi d er e d s u bj e cti v e,  a  d o u bl e -bli n d st u d y 
d esi g n  will  pr e v e nt s u bj e cti v e  bi as.  U p o n st u d y  c o m pl eti o n,  eli gi bl e s u bj e cts fr o m  b ot h 
C o h orts  1  a n d  2  w h o  mi g ht  d eri v e  a d diti o n al  b e n efit fr o m  o n g oi n g tr e at m e nt  wit h f e nfl ur a mi n e 
will  b e  a bl e t o r e c ei v e  Z X 0 0 8 i n  a n  o p e n -l a b el e xt e nsi o n tri al  f or  1  a d diti o n al  y e ar  of tr e at m e nt, 
wit h  a d diti o n al  e xt e nsi o ns if s af et y  a n d  effi c a c y  ar e  d et er mi n e d  a n d t h e  m e di c ati o n is  n ot 
a v ail a bl e f or  pr es cri pti o n i n t h eir  c o u ntr y . 
3. 6   
P R E M A T U R E  T E R MI N A TI O N  O F  S T U D Y  
T h e  S p o ns or  c a n t er mi n at e t h e st u d y  pr e m at ur el y  at  a n y ti m e f or  m e di c al  or  et hi c al r e as o ns  at 
i n di vi d u al  or at  all st u d y sit es.  T h e i n v esti g at or  will  b e  n otifi e d i n  writi n g,  o utli ni n g t h e r e as o ns 
f or t h e t er mi n ati o n. I nstr u cti o ns  will  b e  pr o vi d e d if  ass ess m e nts  b e y o n d t h os e  d es cri b e d i n t h e 
st u d y  pr ot o c ol  n e e d t o  b e  c o n d u ct e d.   
If t h e st u d y is t er mi n at e d  pr e m at ur el y f or  a n y r e as o n, t h e i n v esti g at or s h o ul d  pr o m ptl y i nf or m 
t h e s ubj e cts  p arti ci p ati n g  at  his  or  h er st u d y sit e  a n d s h o ul d  e ns ur e t h at  a p pr o pri at e  alt er n ati v e 
t h er a p y is  a v ail a bl e  a n d t h at E n d -of -St u d y  pr o c e d ur es  ar e  c o n d u ct e d,  as  d es cri b e d i n 
S e cti o n  6. 1. 5 , S e cti o n  6. 2. 5. 1 0 ,  a n d S e cti o n  6. 2. 5. 1 1 . 
All st u d y  m at eri als  i n cl u di n g i n v esti g ati o n al  m e di ci n al  pr o d u ct (I M P) a n d  c o m pl et e d,  p arti all y 
c o m pl et e d,  a n d  bl a n k  d o c u m e nt ati o n , e x c e pt  d o c u m e nts  n e e d e d f or  ar c hi vi n g r e q uir e m e nts, 
will  b e r et ur n e d t o t h e  S p o ns or .  T h e st u d y  m o nit or  will  e ns ur e t h at  a n y  o utst a n di n g  d at a 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 7  of  1 9 4  
cl arifi c ati o n iss u es  a n d  q u eri es  ar e r es ol v e d,  a n d t h at  all st u d y r e c or ds  at t h e st u d y sit e  ar e 
c o m pl et e.  
I n  a c c or d a n c e  wit h  a p pli c a bl e r e g ul at or y r e q uir e m e nts, t h e S p o ns or  will  pr o m ptl y i nf or m t h e 
c o m p et e nt r e g ul at or y  a ut h oriti es  of t h e t er mi n ati o n  a n d its r e as o n(s),  a n d t h e i n v esti g at or  or 
S p o ns or  will  pr o m ptl y i nf or m t h e  I n d e p e n d e nt  Et hi cs  C o m mitt e e (I E C)/I nstit uti o n al  R e vi e w 
B o ar d ( I R B). 
3. 7   
S T U D Y  M O NI T O RI N G  P R O C E D U R E S  
3. 7. 1   
I n d e p e n d e nt  D at a  a n d  S af et y  M o nit o ri n g  C o m mitt e e  
T h e I D S M C is  a n i n d e p e n d e nt  a d vis or y  b o d y t h at  m o nit ors  p arti ci p a nt s af et y,  d at a  q u alit y  a n d 
pr o gr ess  of  t h e  cli ni c al tri al. T h e I D S M C  c h art er  will  o utli n e t h e r ol es  a n d r es p o nsi biliti es  of 
t h e  c o m mitt e e  a n d  g ui d e its  op er ati o ns  a n d fr e q u e n c y  of  m e eti n gs.   T h e I D S M C  will  c o nsist  of 
i n di vi d u als  e xt er n al t o t h e S p o ns or  w h o  h a v e r el e v a nt  cli ni c al tri al  e x p ertis e  a n d  e x p eri e n c e i n  
s af et y  ass ess m e nt; i nt er n ati o n al  m e m b ers  of t h e I D S M C i n cl u d e  a  p e di atri c  n e ur ol o gist, 
p e di atri c  c ar di ol o gist,  g e n er al  p e di atri ci a n,  p e di atri c  e pil e pt ol o gist,  a n d  a st atisti ci a n.  
At r e g ul arl y  d efi n e d i nt er v als, t h e I D S M C  will  c o n v e n e t o r e vi e w  a n d  m o nit or  st u d y  pr o gr ess, 
A Es  a n d  s eri o us  a d v ers e  e v e nts ( S A Es ), ot h er  m e as ur es  of s af et y s u c h  as  E C Gs  or  E C H Os,  a n d 
effi c a c y  d at a  as  di ct at e d  b y t h e  c h art er .   
T h e  I DS M C  will:  
•   B e r es p o nsi bl e f or  pr o vi di n g r e c o m m e n d ati o ns t o  t h e S p o ns or  s urr o u n di n g st u d y 
c o n d u ct  m att ers t h at  aff e ct s af et y.  
•   R e vi e w s af et y  d at a  at  a d  h o c ti m e  p oi nts  a n d i d e ntif y if si g nifi c a nt  s af et y  c o n c er ns  aris e 
d uri n g t h e st u d y.  
•   R e vi e w  P K  d at a  a n d  a n y  ot h er  d at a t h at  m a y  aff e ct s u bj e ct  c o nti n u ati o n.  
•   M a k e r e c o m m e n d ati o ns r e g ar di n g  t h e  c o nti n u ati o n, s us p e nsi o n,  or t er mi n ati o n  of t h e 
st u d y. 
•   B e i nf or m e d  of t h e  d os e s el e cti o n f or  C o h ort  2.   
3. 7. 2   
I nt e r n ati o n al  P e di at ri c  C a r di a c  A d vis o r y  B o a r d (I P C A B)  
T h e  I nt er n ati o n al  P e di atri c  C ar di a c  A d vis or y  B o ar d (I P C A B) is  a n  a d vis or y  b o d y t o t h e 
S p o ns or  t h at  m o nit ors  c ar di a c s af et y  of t h e  Z X 0 0 8  cli ni c al tri als  a n d  pr o vi d es  a d vi c e t o t h e 
I DS M C .  T h e I P C A B  c h arter  o utli n es t h e r ol es  a n d r es p o nsi biliti es  of t h e  c o m mitt e e  a n d  g ui d e 
its  o p er ati o ns,  a n d r e vi e ws i n di vi d u al s u bj e ct  c as es.   T h e I P C A B  c o nsists  of i n di vi d u als 
e xt er n al t o t h e  S p o ns or  w h o  h a v e r el e v a nt  e x p eri e n c e i n  c ar di ol o g y,  p e di atri c  c ar di ol o g y,  a n d 
e c h o c ar di o gr a p h y.   T h e I P C A B  will  a d vis e  t h e S p o ns or  a n d t h e I D S M C  o n t h e  c ar di a c s af et y 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 8  of  1 9 4  
m o nit ori n g  pl a n, i n cl u di n g  al ert  crit eri a  a n d  d e cisi o n  p at h w a y  f or s u bj e ct  m a n a g e m e nt r el ati v e 
t o  c ar di a c s af et y i n t h e  cli ni c al st u di es  of  Z X 0 0 8.   
All  E C H O  e x a mi n ati o ns  p erf or m e d t hr o u g h o ut t h e tri al  will  b e s e nt t o  a n  e x p eri e n c e d  p e di atri c 
c ar di ol o gist  c e ntr al r e a d er ( Bi o m e di c al  S yst e ms, I n c.) ;  d uri n g t h e  d o u bl e-bli n d  p h as e  of t h e 
st u d y, t h e  c e ntr al r e a d er  will  b e  bli n d e d  as t o  e a c h s u bj e ct’s tr e at m e nt .  If t h e  c e ntr al r e a d er 
cl assifi es  a s u bj e ct  as  h a vi n g  m et  a  pr e -d efi n e d t hr es h ol d  v al u e i n di c ati v e  of  p ot e nti al  c ar di a c 
v al v ul o p at h y  or  p ul m o n ar y  h y p ert e nsi o n,  or  a n y  ot h er  u n e x p e ct e d  c ar di a c  A E , t h e  c as e  will 
t h e n  b e s e nt f or s e c o n d ar y  a dj u di c ati o n  b y  o n e  or  m or e  m e m b ers of t h e I P C A B  a c c or di n g t o t h e 
pr o c e d ur es  o utli n e d i n t h e I P C A B  m a n u al.  I n  a d diti o n,  m e m b er s of t h e I P C A B  will  p erf or m 
a u dits  of  E C H Os  d e e m e d  n or m al  b y t h e  c e ntr al  c ar di a c  r e a d er. 
4.   
S E L E C TI O N  O F  S T U D Y  P O P U L A TI O N  
T h e st u d y  p o p ul ati o n  will  b e s el e ct e d  o n t h e  b asis  of  t h e i n cl usi o n  a n d  e x cl usi o n  crit eri a 
d es cri b e d i n t h e s e cti o ns  b el o w.  B ef or e  e v al u ati n g t h es e  crit eri a  a n d  d e ci di n g  o n t h e  eli gi bilit y 
of s u bj e cts t o  p arti ci p at e i n t h e st u d y, it is i m p ort a nt t h at t h e i n v esti g at or  is f a mili ar wit h t h e 
s af et y  pr ofil e  of Z X 0 0 8  b y r ef erri n g t o t h e  I n v esti g at or’s  Br o c h ur e ( 2 0 16 ),  as s u p pli e d  b y t h e 
S p o ns or . 
4. 1   
I N C L U SI O N  C RI T E RI A   
S u bj e cts  m ust  m e et  all  of t h e f oll o wi n g i n cl usi o n  crit eri a  t o b e  e nr oll e d i nt o t h e st u d y:  
1.   S u bj e ct is  m al e  or  n o n -pr e g n a nt,  n o n -l a ct ati n g f e m al e,  a g e  2 t o  1 8  y e ars, i n cl usi v e  as  of 
t h e  d a y  of t h e  S cr e e ni n g  Visit.   F e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  m ust  n ot  b e 
pr e g n a nt  or  br e ast -f e e di n g.  F e m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  m ust  h a v e a 
n e g ati v e  uri n e  pr e g n a n c y t est.  S u bj e cts  of  c hil d b e ari n g  or  c hil d -f at h eri n g  p ot e nti al  m ust 
b e  willi n g t o  us e  m e di c all y  a c c e pt a bl e f or ms  of  birt h  c o ntr ol (s e e  S e cti o n  4. 4 ),  w hi c h 
i n cl u d es  a bsti n e n c e,  w hil e  b ei n g tr e at e d  o n t his st u d y  a n d f or  9 0  d a ys  aft er t h e  d os e  of 
st u d y  dr u g.  
2.   S u bj e ct  m ust  h a v e  d o c u m e nt e d  m e di c al  hist or y t o s u p p ort  a  cli ni c al  di a g n osis  of  D r a v et 
s y n dr o m e,  w h er e  c o n v ulsi v e s ei z ur es  ar e  n ot  c o m pl etel y  c o ntr oll e d  b y  c urr e nt 
a nti e pil e pti c  dr u gs.  
3.    S u bj e cts  m ust  m e et  all  of t h e f oll o wi n g  5  crit eri a:  
a.   O ns et  of s ei z ur es i n t h e first  y e ar  of lif e i n  a n  ot h er wis e  h e alt h y i nf a nt.   
b.   A  hist or y  of s ei z ur es t h at  ar e  eit h er  g e n er ali z e d t o ni c -cl o ni c  or  u nil at er al  cl o ni c 
or  bil at er al  cl o ni c,  a n d  ar e  pr ol o n g e d.  
c.   I niti al  d e v el o p m e nt is  n or m al. 
d.   Hist or y  of  n or m al  br ai n  m a g n eti c r es o n a n c e i m a gi n g ( M RI ) wit h o ut  c orti c al 
br ai n  m alf or m ati o n.  
e.   L a c k  of  alt er n ati v e  di a g n osis.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  5 9  of  1 9 4  
4.   S u bj e cts  m ust  m e et  at l e ast  o n e  of t h e f oll o wi n g  3  crit eri a:  
a.   E m er g e n c e  of  a n ot h er s ei z ur e t y p e, i n cl u di n g  m y o cl o ni c,  g e n er ali z e d t o ni c -
cl o ni c, t o ni c,  at o ni c,  a bs e n c e  a n d/ or f o c al  h as  d e v el o p e d  aft er t h e first s ei z ur e 
t y p e. 
b.   Pr ol o n g e d  e x p os ur e t o  w ar m t e m p er at ur es i n d u c es s ei z ur es  a n d/ or s ei z ur es  ar e 
ass o ci a t e d  wit h f e v ers  d u e t o ill n ess  or  v a c ci n es,  h ot  b at hs,  hi g h l e v els  of 
a cti vit y  a n d s u d d e n t e m p er at ur e  c h a n g es  a n d/ or s ei z ur es  ar e i n d u c e d  b y str o n g 
n at ur al  a n d/ or fl u or es c e nt li g hti n g,  as  w ell  as  c ert ai n  vis u al  p att er ns.   
c.   G e n eti c t est r es ults  c o nsist e nt  wi t h  a  di a g n osis  of Dr a v et s y n dr o m e  ( p at h o g e ni c, 
li k el y  p at h o g e ni c,  v ari a nt  of  u n k n o w n si g nifi c a n c e,  or i n c o n cl usi v e  b ut  u nli k el y 
t o s u p p ort  a n  alt er n ati v e  di a g n osis.) 
5.   S u bj e ct  m ust  h a v e  h a d  ≥  4  c o n v ulsi v e s ei z ur es (t o ni c -cl o ni c, t o ni c,  cl o ni c)  p er  4 -w e e k 
p er i o d f or  1 2  w e e ks  pri or t o s cr e e ni n g,  b y  p ar e nt/ g u ar di a n r e p ort t o i n v esti g at or  or 
i n v esti g at or  m e di c al  n ot es (C o h o rt  2  o nl y ). 
6.   All  m e di c ati o ns  or i nt er v e nti o ns f or  e pil e ps y (i n cl u di n g  k et o g e ni c  di et [ K D]  a n d  v a g al 
n er v e sti m ul ati o n [ V N S])  m ust  b e st a bl e f or  at l e ast  4  w e e ks  pri or t o s cr e e ni n g  a n d  ar e 
e x p e ct e d t o r e m ai n st a bl e t hr o u g h o ut t h e st u d y.    
7.   S u bj e ct  m ust  b e r e c ei vi n g  a t h er a p e uti c all y r el e v a nt  a n d st a bl e  d os e  of  C L B,  V P,  a n d 
S T P f or  at l e ast  4  w e e ks  pri or t o s cr e e ni n g  a n d  ar e  e x p e ct e d t o r e m ai n st a bl e t hr o u g h o ut 
t h e st u d y (C o h o rt  2  o nl y ).  (I n s o m e  c as es, s u bj e cts  w h o  ar e  c o ntr ai n di c at e d f or  V P A 
or  C L B  m a y  b e  e nr oll e d i n  C o h ort  2.   S u bj e cts i n t h es e  c as es  m ust  b e r e c ei vi n g  a 
t h er a p e uti c all y r el e v a nt  a n d st a bl e  d os e  of  S T P  a n d  V P A [if  c o ntr ai n di c at e d for  C L B] 
or  S T P  a n d  C L B [if  c o ntr ai n di c at e d f or  V P A].   E a c h s u bj e ct  m ust  b e r e vi e w e d  wit h t h e 
M e di c al  M o nit or  a n d s p o ns or  b ef or e i niti ati n g s cr e e ni n g.   T h e  d e cisi o n t o  all o w 
e nr oll m e nt  of t h es e s u bj e cts is  at t h e s ol e  dis cr eti o n  of t h e s p o ns or.)  
8.   S u bj e ct  m us t  b e r e c ei vi n g  a st a bl e  d os e  of  C L B  a n d  V P A,  a d mi nist er e d BI D , t o  b e 
eli gi bl e f or  D os e  R e gi m e n  1  a n d  2  or s u bj e ct  m ust  b e r e c ei vi n g  a st a bl e  d os e  of  C L B, 
V P A,  a n d  S T P,  a d mi nist er e d  BI D , t o  b e  eli gi bl e f or  D os e  R e gi m e n  3 (C o h o rt  1  o nl y ). 
9.   S u bj e ct  a gr e es t o  pr o vi d e  a  b u c c al  s w a b f or  C Y P 2 D 6 ( c yt o c hr o m e  P 4 5 0  2 D 6) 
g e n ot y p e/ p h e n ot y p e.  
1 0.  S u bj e ct  h as  b e e n i nf or m e d  of t h e  n at ur e  of t h e st u d y  a n d i nf or m e d  c o ns e nt  h as  b e e n 
o bt ai n e d fr o m t h e l e g all y r es p o nsi bl e  p ar e nt/ g u ar di a n.  
1 1.  S u bj e ct  h as  pr o vi d e d  ass e nt i n  a c c or d a n c e  wit h I R B/ I E C r e q uir e m e nts, if  c a p a bl e. 
1 2.  S u bj e ct’s  p ar e nt/ c ar e gi v er is  willi n g  a n d  a bl e t o  b e  c o m pli a nt  wit h  all st u d y 
r e q uir e m e nts  a n d  visit s c h e d ul e. S u bj e ct’s  p ar e nt/ c ar e gi v er  m ust  als o  b e  willi n g  a n d 
a bl e t o  b e  c o m pli a nt  wit h  di ar y  c o m pl eti o n  a n d st u d y  dr u g  a c c o u nt a bilit y.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 0  of  1 9 4  
4. 2   
E X C L U SI O N  C RI T E RI A  
S u bj e cts  m e eti n g  a n y  of t h e f oll o wi n g  e x cl usi o n  crit eri a  m ust  n ot  b e  e nr oll e d i nt o t h e st u d y:  
1.   S u bj e ct  h as  a  k n o w n  h y p ers e nsiti vit y t o f e nfl ur a mi n e  or  a n y  of t h e  e x ci pi e nts i n t h e 
st u d y  m e di c ati o n.  
2.   S u b j e ct  h as  p ul m o n ar y  art eri al  h y p ert e nsi o n. 
3.   S u bj e ct  h as  c urr e nt  or  p ast  hist or y  of  c ar di o v as c ul ar  or  c er e br o v as c ul ar  dis e as e, s u c h  as 
c ar di a c  v al v ul o p at h y,  m y o c ar di al i nf ar cti o n  or str o k e.  
4.   S u bj e ct  h as  c urr e nt  or r e c e nt  hist or y  of  a n or e xi a  n er v os a ,  b uli mi a, o r  d e pr essi o n  wit hi n 
t h e  pri or  y e ar t h at r e q uir e d  m e di c al tr e at m e nt  or  ps y c h ol o gi c al tr e at m e nt f or  a  d ur ati o n 
gr e at er t h a n  1  m o nt h.  
5.   S u bj e ct  h as  a  c urr e nt  or  p ast  hist or y  of  gl a u c o m a.  
6.  S u bj e ct  h as  m o d er at e  or s e v er e  h e p ati c i m p air m e nt.  
a.   As y m pt o m ati c s u bj e cts  wit h  mil d  h e p ati c i m p air m e nt ( as p ar tat e  a mi n otr a nsf er as e 
[ A S T]  a n d  al a ni n e  a mi n otr a nsf er as e [ A L T]  < 2 x t h e  u p p er li mit  of  n or m al ( U L N) 
a n d  n o  el e v ati o ns  of  g a m m a -gl ut a m yltr a nsf er as e  [G G T ],  al k ali n e  p h os p h at as e,  or 
t ot al  bilir u bi n i n di c ati v e  of  m or e t h a n  mil d  h e p ati c i m p air m e nt)  m a y  b e  e nt er e d i nt o 
t h e st u d y  aft er r e vi e w  a n d  a p pr o v al  b y t h e  M e di c al  M o nit or i n  c o nj u n cti o n  wit h t h e 
S p o ns or , i n  c o nsi d er ati o n  of  c o m or bi diti es  a n d  c o n c o mit a nt  m e di c ati o ns (C o h o rt  1 
o nl y ). 
b.  As y m pt o m ati c s u bj e cts  wit h  mil d  h e p ati c i m p air m e nt ( el e v at e d li v er  e n z y m es  <  3 x 
t h e  U L N  a n d/ or  el e v at e d  bilir u bi n <  2 x  U L N)  m a y  b e  e nt er e d i nt o  t h e st u d y  aft er 
r e vi e w  a n d  a p pr o v al  b y t h e  M e di c al  M o nit or i n  c o nj u n cti o n  wit h t h e S p o ns or , i n 
c o nsi d er ati o n  of  c o m or bi diti es  a n d  c o n c o mit a nt  m e di c ati o ns  (C o h o rt  2  o nl y ). 
7.   S u bj e ct is r e c ei vi n g  c o n c o mit a nt  t h er a p y  wit h:  c e ntr all y-a cti n g  a n or e cti c  a g e nts; 
m o n o a mi n e -o xi d as e i n hi bit ors;  a n y  c e ntr all y -a cti n g  c o m p o u n d  wit h  cli ni c all y 
a p pr e ci a bl e  a m o u nt  of s er ot o ni n  a g o nist  or  a nt a g o nist  pr o p erti es, i n cl u di n g s er ot o ni n 
r e u pt a k e i n hi biti o n; tri pt a ns, at o m o x eti n e,  or  ot h er  c e ntr all y -a cti n g  n or a dr e n er gi c 
a g o nist;  or  c y pr o h e pt a di n e (s e e  A p p e n di x  1 ). ( N ot e:  S h ort-t er m  m e di c ati o n 
r e q uir e m e nts  will  b e  h a n dl e d  o n  a  p er  c as e  b asis  b y t h e  M e di c al  M o nit or.) 
8.   S u bj e ct is  c urr e ntl y r e c ei vi n g  or  h as r e c ei v e d  S T P  i n t h e  p ast  2 1  d a ys  pri or t o  S cr e e ni n g 
(o nl y f o r  C o h o rt  1 s u bj e cts  a ll o c at e d t o  D os e  R e gi m e n  1  o r  2). 
9.   S u bj e ct is  c urr e ntl y t a ki n g  c ar b a m a z e pi n e,  o x c ar b a z e pi n e , esli c ar b a z e pi n e, 
p h e n o b ar bit al,  or  p h e n yt oi n,  or  h as t a k e n  a n y  of t h es e  wit hi n t h e  p ast  3 0  d a ys,  as 
m ai nt e n a n c e t h er a p y.  
1 0.  S u bj e ct is  u n willi n g t o r efr ai n fr o m  l ar g e  or  d ail y s er vi n gs  of  gr a p efr uits a n d/ or  S e vill e 
or a n g es,  a n d t h eir j ui c es  b e gi n ni n g  wit h t h e  B as eli n e  P eri o d  a n d t hr o u g h o ut t h e  st u d y.  
1 1.  S u bj e ct  h as  p ositi v e r es ult  o n  uri n e  T H C  P a n el  or  w h ol e  bl o o d  C B D  at t h e  S cr e e ni n g 
Visit.  
1 2.  S u bj e ct  h as  p arti ci p at e d i n  a n ot h er  cli ni c al tri al  wit hi n t h e  p ast  3 0  d a ys.  
1 3.  S u bj e ct is  c urr e ntl y r e c ei vi n g  a n i n v esti g ati o n al  pr o d u ct.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 1  of  1 9 4  
1 4.  S u bj e ct is  u n willi n g  or  u n a bl e t o  c o m pl y  wit h s c h e d ul e d  visits,  dr u g  a d mi nistr ati o n 
pl a n, l a b or at or y t ests,  ot h er st u d y  pr o c e d ur es,  a n d st u d y r estri cti o ns.  
1 5.   S u bj e ct  h as  a  cli ni c all y si g nifi c a nt  c o n diti o n,  or  h as  h a d  cli ni c all y r el e v a nt s y m pt o ms 
or  a  cli ni c all y si g nifi c a nt ill n es s i n t h e  4  w e e ks  pri or t o t h e  S cr e e ni n g  Visit,  ot h er t h a n 
e pil e ps y, t h at  w o ul d  n e g ati v el y i m p a ct st u d y  p arti ci p ati o n,  c oll e cti o n  of st u d y  d at a,  or 
p os e  a ris k t o t h e s u bj e ct.  
4. 3   
R A N D O MI Z A TI O N  I N C L U SI O N  C RI T E RI A  –  C O H O R T  2   
S u bj e cts  m ust  m e et  all  of t h e i n cl us i o n  crit eri a  a b o v e  pl us t h e f oll o wi n g  crit eri a, t o  b e 
r a n d o mi z e d ( C o h ort  2): 
1.   S u bj e ct  h as  b e e n  a p pr o v e d f or st u d y i n cl usi o n  b y t h e  E pil e ps y  St u d y  C o ns orti u m.  
2.   S u bj e ct  d o es  n ot  h a v e  a  c ar di o v as c ul ar  or  c ar di o p ul m o n ar y  a b n or m alit y  b as e d  o n 
E C H O,  E C G  or  p h ysi c a l  e x a mi n ati o n, i n cl u di n g  b ut  n ot li mit e d t o tr a c e mitr al  or  a orti c 
v al v e r e g ur git ati o n  or si g ns  of  p ul m o n ar y  h y p ert e nsi o n,  a n d is  a p pr o v e d f or  e ntr y  b y t h e 
c e ntr al  c ar di a c  r e a d er. 
3.   S u bj e ct  d e m o nstr at es  a st a bl e  b as eli n e  wit h  ≥  6  c o n v ulsi v e s ei z ur es  d uri n g t h e  6 -w e e k 
B as eli n e  P eri o d ,  wit h  a  mi ni m u m  of  2 i n t h e first  3  w e e ks  a n d  2 i n t h e s e c o n d t hr e e  w e e ks. 
4.   S u bj e ct’s  p ar e nt/ c ar e gi v er  h as  b e e n  c o m pli a nt  wit h  di ar y  c o m pl eti o n  d uri n g t h e 
B as eli n e  P eri o d, i n t h e  o pi ni o n  of t h e  i n v esti g at or ( e g,  at l e ast  9 0 %  c o m pli a nt). 
4. 4   
S U B J E C T S  O F  R E P R O D U C TI V E  P O T E N TI A L  
M al e s u bj e cts  w h o  ar e s e x u all y  a cti v e  wit h  a  p art n er  of  c hil d -b e ari n g  p ot e nti al  m ust  us e,  wit h 
t h eir  p art n er, a  c o n d o m  pl us  a n  a p pr o v e d  m et h o d  of  hi g hl y  a c c e pt a bl e  c o ntr a c e pti o n  fr o m t h e 
ti m e  of i nf or m ed  c o ns e nt  u ntil  9 0  d a ys  aft er  l ast  d os e  of st u d y  dr u g. 
T h e f oll o wi n g  m et h o ds  ar e  a c c e pt a bl e : 
•   C o m bi n e d ( estr o g e n  a n d  pr o g es t o g e n  c o nt ai ni n g)  h or m o n al  c o ntr a c e pti o n  ass o ci at e d  wit h 
i n hi biti o n  of  o v ul ati o n:  
−   or al   
−   i ntr a v a gi n al  
−   tr a ns d er m al  
•   Pr o g est o g e n -o nl y  h or m o n al  c o ntr a c e pti o n  ass o ci at e d  wit h i n hi biti o n  of  o v ul ati o n:  
−   or al   
−   i nj e ct a bl e  
−   i m pl a nt a bl e i ntr a ut eri n e  d e vi c e 
−   i ntr a ut eri n e  h or m o n e-r el e asi n g s yst e m 
•   S ur gi c al st erili z ati o n ( v as e ct o m y  or  bil at er al t u b al  o c cl usi o n)  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 2  of  1 9 4  
F e m al e s u bj e cts  w h o  ar e  n ot  of  c hil d -b e ari n g  p ot e nti al  d o  n ot  n e e d t o  us e  a n y  m et h o ds  of 
c o ntr a c e pti o n.  A  w o m a n is  c o nsi d er e d  of  c hil d b e ari n g  p ot e nti al,  u nl ess t h e y  ar e  at l e ast  2  y e ars 
p ost -m e n o p a us al  or  p er m a n e ntl y st eril e.  P er m a n e nt st erili z ati o n  m et h o ds i n cl u d e  h yst er e ct o m y, 
bil at er al s al pi n g e ct o m y  a n d  bil at er al  o o p h or e ct o m y.  
F e m al e s u bj e cts  w h o  ar e s e x u all y  a cti v e  a n d  ar e  of  c hil d -b e ari n g  p ot e nti al  m ust  us e,  wit h t h eir 
p art n er,  a n  a p pr o v e d  m et h o d  of  hi g hl y  eff e cti v e  c o ntr a c e pti o n fr o m t h e ti m e  of i nf or m e d 
c o ns e nt  u nti l 9 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g . 
T h e f oll o wi n g  m et h o ds  ar e  a c c e pt a bl e:  
•   C o m bi n e d ( estr o g e n  a n d  pr o g est o g e n  c o nt ai ni n g)  h or m o n al  c o ntr a c e pti o n  ass o ci at e d  wit h 
i n hi biti o n  of  o v ul ati o n a n d  a  b arri er  m et h o d (i e,  c o n d o m f or  m al e  p art n er) :  
−   or al   
−   i ntr a v a gi n al  
−   tr a ns d er m al  
•   Pr o g est o g e n -o nl y   h or m o n al   c o ntr a c e pti o n   ass o ci at e d   wit h  i n hi biti o n   of   o v ul ati o n   a n d   a  
b arri er  m et h o d (i e,  c o n d o m f or  m al e  p art n er)  
−   or al   
−   i nj e ct a bl e  
−   i m pl a nt a bl e i ntr a ut eri n e  d e vi c e 
−   i ntr a ut eri n e  h or m o n e-r el e asi n g s yst e m 
•   S ur gi c al  st erili zati o n ( v as e ct o m y  or  bil at er al t u b al  o c cl usi o n)  
Alt er n ati v el y, tr u e  a bsti n e n c e is  a c c e pt a bl e  w h e n it is i n li n e  wit h t h e s u bj e ct’s  pr ef err e d  a n d 
us u al lif est yl e. If  a s u bj e ct is  us u all y  n ot s e x u all y  a cti v e  b ut  b e c o m es  a cti v e, t h e y,  wit h t h eir 
p art n er , t h e y  m ust  c o m pl y  wit h t h e  c o ntr a c e pti v e r e q uir e m e nts  d et ail e d  a b o v e. 
4. 4. 1   S p e r m  a n d  E g g  D o n ati o n  
M al e s u bj e cts s h o ul d  n ot  d o n at e s p er m  a n d f e m al e s u bj e cts s h o ul d r efr ai n fr o m  e g g  d o n ati o n 
f or t h e  d ur ati o n  of t h e st u d y  a n d f or  at l e ast  9 0 d a ys  aft er t h e l ast  d a y  of st u d y  m e di c ati o n 
a d mi nistr ati o n.  
4. 4. 2   P r e g n a n c y  
S u bj e cts  will  b e i nstr u ct e d t h at if t h e y/t h eir  p art n er  b e c o m e  pr e g n a nt  d uri n g t h e st u d y t his 
s h o ul d  b e r e p ort e d t o t h e i n v esti g at or.  T h e i n v esti g at or s h o ul d  als o  b e  n otifi e d  of  pr e g n a n c y 
o c c urri n g  d uri n g t h e  st u d y  b ut  c o nfir m e d  aft er  c o m pl eti o n  of t h e st u d y. I n t h e  e v e nt t h at  a 
s u bj e ct/s u bj e ct’s  p art n er is s u bs e q u e ntl y f o u n d t o  b e  pr e g n a nt  aft er t h e  s u bj e ct is i n cl u d e d i n 
t h e st u d y, t h e n  c o ns e nt  will  b e s o u g ht fr o m t h e  p art n er  a n d, if  gr a nt e d,  a n y  pr e g n a n c y  will  b e 
f oll o w e d  a n d t h e st at us  of  m ot h er  a n d/ or  c hil d  will  b e r e p ort e d t o t h e S p o ns or  aft er  d eli v er y. 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 3  of  1 9 4  
A n y s u bj e ct r e p orti n g  a  pr e g n a n c y  d uri n g t h e st u d y  will  b e  wit h dr a w n fr o m t h e st u d y  a n d 
s h o ul d  c o m pl et e t h e t a p er s c h e d ul e . 
4. 5   
R E M O V A L  O F  S U B J E C T S  F R O M  T H E R A P Y  O R  A S S E S S M E N T  
W hil e s u bj e cts  ar e  e n c o ur a g e d t o  c o m pl et e  all st u d y  e v al u ati o ns, s u bj e cts  m a y  v ol u nt aril y 
wit h dr a w fr o m t h e st u d y f or  a n y r e as o n  at  a n y ti m e.  T h e y  m a y  b e  c o nsi d er e d  wit h dr a w n if t h e y 
f ail t o r et ur n f or  visits,  or  b e c o m e l ost t o f oll o w-u p f or  a n y  ot h er r e as o n.   
If  pr e m at ur e  wit h dr a w al  o c c urs f or  a n y r e as o n, t h e i n v esti g at or  m ust  m a k e  a  g e n ui n e  eff ort t o 
d et er mi n e t h e  pri m ar y r e as o n f or  a s u bj e ct’s  pr e m at ur e  wit h dr a w al fr o m t h e st u d y  a n d r e c or d 
t his i nf or m ati o n  o n t h e el e ctr o ni c  c as e r e p ort f or m ( e C R F ).  All s u bj e cts w h o  wit h dr a w fr o m t h e 
st u d y  wit h  a n  o n g oi n g  A E  m ust  b e f oll o w e d  u ntil t h e  e v e nt is r es ol v e d  or  d e e m e d st a bl e.  If  a 
s u bj e ct wit h dr a ws  pr e m at ur el y  aft er  d osi n g,  all  d at a t o  b e  c oll e ct e d  pri or t o  dis c h ar g e fr o m t h e 
cli ni c al sit e s h o ul d  b e  c oll e ct e d  at t h e ti m e  of  pr e m at ur e  dis c o nti n u ati o n  or  at t h e s c h e d ul e d 
dis c h ar g e.    
F or s u bj e cts  w h o  ar e l ost t o f oll o w -u p (i e, t h os e s u bj e cts  w h os e st at us is  u n cl e ar  b e c a us e t h e y 
f ail e d t o  a p p e ar f or st u d y  visits  wit h o ut st ati n g  a n i nt e nti o n t o  wit h dr a w), t h e i n v esti g at or 
s h o ul d s h o w  " d u e  dili g e n c e "  b y  d o c u m e nti n g i n t h e s o ur c e  d o c u m e nts t h e st e ps t a k e n t o 
c o nt a ct t h e  s u bj e ct ( e g,  d at es  of t el e ph o n e  c alls, r e gist er e d l ett ers).   
S u bj e cts  m ust  b e  dis c o nti n u e d fr o m t h e st u d y f or t h e f oll o wi n g r e as o ns, if  d e e m e d  a p pr o pri at e 
b y t h e  S p o ns or  or i n v esti g at or:   
1.  D e v el o p m e nt  of  si g ns  or s y m pt o ms i n di c ati v e  of  c ar di a c  v al v ul o p at h y  or r e g ur git ati o n 
( mitr al,  a orti c, tri c us pi d,  p ul m o n ar y  v al v es), or  p ul m o n ar y  h y p ert e nsi o n f or  w hi c h 
I D S M C, i n  c o ns ult ati o n  wit h t h e I P C A B, t h e  c e ntr al  c ar di a c r e a d er, a n d  t h e i n v esti g at or 
b eli e v e t h e  b e n efit  of  c o nti n u e d  p arti ci p ati o n  d o es  n ot  o ut w ei g h t h e ris k . 
2.  S u bj e ct is f o u n d t o  h a v e  e nt er e d t h e  cli ni c al i n v esti g ati o n i n  vi ol ati o n  of t h e  pr ot o c ol . 
3.  S u bj e ct r e q uir es  or st arts  usi n g  t h e  us e  of  a n  u n a c c e pt a bl e  or  c o ntr ai n di c at e d 
c o n c o mit a nt  m e di c ati o n . 
4.  S u b j e ct’s  c o n diti o n  c h a n g es  aft er  e nt eri n g t h e  cli ni c al i n v esti g ati o n s o t h at t h e s u bj e ct  n o 
l o n g er  m e ets t h e i n cl usi o n  crit eri a  or  d e v el o ps  a n y  of t h e  e x cl usi o n  crit eri a. 
5.  S u bj e ct is  n o n c o m pli a nt  wit h  pr o c e d ur es s et f ort h i n t h e  pr ot o c ol i n  a n  o n g oi n g  or 
r e p eat e d  m a n n er . 
6.  S u bj e ct  e x p eri e n c es  a n  A E t h at  w arr a nts  wit h dr a w al fr o m t h e  cli ni c al i n v esti g ati o n . 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 4  of  1 9 4  
7.  Cli ni c all y si g nifi c a nt  w ors e ni n g  of s ei z ur es , j u d g e d  b y i n v esti g at or or s u bj e ct / c ar e gi v er 
s u c h t h at tr e at m e nt  o utsi d e  of t h e  pr ot o c ol  a n d  ot h er t h a n  Z X 0 0 8  is ass u m e d t o  b e i n t h e 
s u bj e ct’s  b est i nt er est.  Fr e q u e nt  or i n cr e as e d  us e  of r es c u e  m e di c ati o n  m a y  b e  c o nsi d er e d 
i n di c ati v e  of  w ors e ni n g. 
8.  A n  “ a ct u al s ui ci d e  att e m pt ”  as  cl assifi e d  b y t h e  C ol u m bi a -S ui ci d e  S e v erit y  R ati n g  S c al e 
( C-S S R S) . 
9.  It is t h e i n v esti g at or’s  o pi ni o n t h at it is  n ot i n t h e s u bj e ct’s  b est i nt er est t o  c o nti n u e i n t h e 
st u d y.  
1 0.  S u bj e ct is f o u n d t o  b e  pr e g n a nt  w hil e  o n st u d y.   
Dis c o nti n u ati o n  d e cisi o ns  will  b e  m a d e  at  e a c h  p arti ci p ati n g sit e  b y t h e  sit e i n v esti g at or,  e x c e pt 
t h at  dis c o nti n u ati o ns  d u e t o  d e v el o p m e nt  of  c ar di o v as c ul ar  or  c ar di o p ul m o n ar y  c o m pli c ati o ns 
ar e t o  b e  m a d e  b y t h e I D S M C  wit h i n p ut fr o m t h e I P C A B  a n d t h e i n v esti g at or .   
If f e asi bl e, t h e  pr o c ess  of  dis c o nti n u ati o n s h o ul d  b e  dis c uss e d  wit h t h e  M e di c al  M o nit or.  T h e 
d e cisi o ns r e g ar di n g t h e  dis c o nti n u ati o n  of t h e i n v esti g ati o n al t h er a p y,  w h et h er t h e st u d y 
m e di c ati o n s h o ul d  b e st o p p e d i m m e di at el y  or t a p er e d s h o ul d  b e  dis c uss e d  wit h t h e  M e di c al 
M o nit or,  b ut fi n al  d e cisi o ns  a b o ut t h e  pr o c ess  will r e m ai n  at t h e  dis cr eti o n  of t h e sit e  pri n c i p al 
in v esti g at or.   
S u bj e cts  w h o  ar e  dis c o nti n u e d fr o m t h e  cli ni c al i n v esti g ati o n  ( C o h ort  2) f or  a n y r e as o n  will  n ot 
b e r e pl a c e d.  
S u bj e cts  m a y  wit h dr a w t h eir  c o ns e nt t o  p arti ci p at e i n t h e st u d y  at  a n y ti m e  wit h o ut  h a vi n g t o 
j ustif y t h e r e as o n f or  d oi n g s o. T h e  d e cisi o n t o  wit h dr a w  c o ns e nt  a n d  dis c o nti n u e  p arti ci p ati o n 
i n t h e st u d y  will  n ot  pr ej u di c e t h e s u bj e ct’s f ut ur e  m e di c al tr e at m e nt i n  a n y  w a y. S u bj e cts  m ust 
b e  dis c o nti n u e d fr o m r e c ei vi n g  Z X 0 0 8  a n d/ or  p arti ci p ati n g i n  a n y f urt h er st u d y  pr o c e d ur es 
u n d er  t h e f oll o wi n g  cir c u mst a n c es: 
•   T h e s u bj e ct  or  t h e s u bj e ct’s l e g all y  a ut h ori z e d r e pr es e nt ati v e  wis h es t o  dis c o nti n u e 
p arti ci p ati o n i n t h e st u d y.  
•   T h e i n v esti g at or  a d vis es t h at t h e s u bj e ct’s s af et y  or  w ell -b ei n g  c o ul d  b e 
c o m pr o mis e d  b y f urt h er  p arti ci p ati o n i n  t h e st u d y. 
•   T h e  S p o ns or  r e q u ests t h at  a s u bj e ct  dis c o nti n u es  p arti ci p ati o n i n t h e st u d y ( e g,  d u e 
t o s us pi ci o n  of fr a u d,  m ulti pl e e nr oll m e nts  i n  cli ni c al st u di es, l a c k  of  c o m pli a n c e, 
et c).  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 5  of  1 9 4  
T h e I D S M C  m a y r e q u est t h at t h e st u d y  b e t er mi n at e d  aft er r e vi e w  of  t h e s af et y i nf or m ati o n at 
a n y ti m e  d uri n g t h e st u d y .  T h e  I DS M C  will r e vi e w t h e  d at a f or t h e  d e v el o p m e nt  of  h e art  v al v e 
dis e as e  a n d  p ul m o n ar y  h y p ert e nsi o n  as t h e y  o c c ur  o n  a  c as e -b y -c as e  b asis  a n d  at r e g ul ar 
m e eti n gs.    
I n t h e  e v e nt t h at t h e st u d y is t er min at e d  pr e m at ur el y t h e n t h e  pr o c e d ur e f or t er mi n ati o n s h o ul d 
b e f oll o w e d  as  d es cri b e d i n  S e cti o n  3. 6 . C o n c er n f or t h e i nt er ests  of t h e s u bj e ct  will  al w a ys 
pr e v ail  o v er t h e i nt er ests  of t h e st u d y.  
T h e r e as o n f or,  a n d  d at e  of  dis c o nti n u ati o n fr o m  p arti ci p ati o n i n t h e st u d y  m ust  b e r e c or d e d i n 
d et ail i n t h e  e C R F  a n d i n t h e s u bj e ct’s  m e di c al r e c or ds ( e g,  A E s, l a c k  of  c o m pli a n c e, l ost t o 
f oll o w-u p,  et c).  If  p ossi bl e, t h e s u bj e ct/s u bj e ct’s l e g al r e pr es e nt ati v e s h o ul d  c o nfir m  his 
d e cisi o n i n  writi n g.  
T h e i n v esti g at or  will  att e m pt t o  c o m pl et e  all  pr o c e d ur es  us u all y r e q ui r e d  at t h e  en d  of t h e st u d y 
at t h e ti m e  w h e n t h e s u bj e ct’s  p arti ci p ati o n i n t h e st u d y is  d is c o nti n u e d  or  as  cl os e  as  p ossi bl e 
t o t h at ti m e. S p e cifi c  pr o c e d ur es r e q uir e d  ar e  d es cri b e d i n  S e cti o n  6. 1. 5 , S e cti o n  6. 2. 5. 1 0 , a n d  
S e cti o n  6. 2. 5. 1 1 . As f ar  as  p ossi bl e,  a  c o m pl et e fi n al  e x a mi n ati o n  m ust  b e  p erf or m e d  o n  all 
s ubj e cts  w h o  d o  n ot  c o m pl et e t h e st u d y  a c c or di n g t o t h e st u d y  pr ot o c ol.   
D at a  c oll e ct e d  u ntil t h e ti m e  a s u bj e ct  dis c o nti n u es  p arti ci p ati o n i n t h e st u d y  will  b e  h a n dl e d i n 
t h e s a m e  m a n n er  as  d at a f or s u bj e cts  c o m pl eti n g t h e st u d y.  W h er e  p ossi bl e, f urt h er i nf or m ati o n 
will  b e  c oll e ct e d if  a n y  A Es  ar e  e x p eri e n c e d  b y  a s u bj e ct  aft er  dis c o nti n ui n g  p arti ci p ati o n i n t h e 
st u d y.  
4. 6   
T E R MI N A TI O N  O F  T H E  C LI NI C A L  S T U D Y  
If t h e i n v esti g at or, t h e S p o ns or , t h e  M e di c al  M o nit or,  or t h e I DS M C  b e c o m es  a w ar e  of 
c o n diti o ns  or  e v e nts t h at s u g g est  a  p ossi bl e  h a z ar d t o  s u bj e cts if t h e  cli ni c al st u d y  c o nti n u es, 
t h e n t h e  cli ni c al st u d y  m a y  b e t er mi n at e d.  T h e  cli ni c al st u d y  m a y  b e t er mi n at e d  at t h e 
S p o ns or ’s  dis cr eti o n at  a n y ti m e  als o i n t h e  a bs e n c e  o f s u c h  a fi n di n g. 
C o n diti o ns t h at  m a y  w arr a nt t er mi n ati o n  of t h e  cli ni c al st u d y i n cl u d e,  b ut  ar e  n ot li mit e d t o:  
•   T h e  dis c o v er y  of  a n  u n e x p e ct e d, r el e v a nt,  or  u n a c c e pt a bl e ris k t o t h e  s u bj e cts e nr oll e d i n 
t h e  cli ni c al st u d y. 
•   F ail ur e t o  e nr oll  s u bj e cts at t h e r e q uir e d r at e . 
•   A  d e cisi o n  of t h e  S p o ns or  t o s us p e n d  or  dis c o nti n u e  d e v el o p m e nt  of Z X 0 0 8 .   


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 6  of  1 9 4  
4. 7   
R E P L A C E M E N T  O F  S U B J E C T S  
A p pr o xi m at el y  2 5  s u bj e cts will  b e  s cr e e n e d f or C o h ort  1 t o  e ns ur e t h at  s u bj e cts  e nt er t h e st u d y 
a n d  c o m pl et e  all  P K  ass ess m e nts ;  parti ci p a n ts  w h o  dis c o nti n u e  pri or t o  c o m pl eti o n  of  all st u d y-
r el at e d  pr o c e d ur es  m a y b e r e pl a c e d.   A p pr o xi m at el y  1 1 5  s u bj e cts  will  b e s cr e e n e d f or  C o h ort  2 
t o r a n d o mi z e a p pr o xi m at el y  9 0  s u bj e cts i nt o t h e  T +  M  P eri o d ; ra n d o mi z e d s u bj e cts  will  n ot  b e 
r e pl a c e d. 
4. 8   
E LI GI BI LI T Y  F O R  E X T E N SI O N  T RI A L  
S u bj e cts fr o m  C o h ort  1  w h o  c o m pl et e t h e  P K  p orti o n  of t h is st u d y or  su bj e cts fr o m  C o h ort  2 
w h o  c o m pl et e t h e  1 2 -w e e k  M ai nt e n a n c e  P eri o d  of t his  st u d y  will  b e  eli gi bl e t o  e nr ol i n  a 
pl a n n e d, s e p ar at e,  o p e n -l a b el  e xt e nsi o n tri al  of  Z X 0 0 8 if t h e y  m e et I n cl usi o n/ E x cl usi o n  crit eri a 
f or t h at st u d y ar e  d e e m e d  eli gi bl e  f or  c o nti n u e d  p arti ci p ati o n i n  a tri al  of f e nfl ur a mi n e.  C o h ort 
1 s u bj e cts  m ust  h a v e t ol e r at e d t h e I M P  a n d t h e I n v esti g at or  als o  m ust f e el t h at t h e s u bj e ct 
w o ul d  b e n efit fr o m l o n g t er m t h er a p y  wit h  Z X 0 0 8 f or  ot h er  m ulti pl e s ei z ur e t y p es,  e g ,  p att er n 
s e nsiti vit y,  p h ot os e nsiti vit y, s e v er e  a bs e n c es,  n o ct ur n al s ei z ur es, s e v er e  m y o cl o n us  w hi c h  ar e 
n ot  m a n a g e d  wit h  c urr e nt t h er a p y.   S u bj e cts fr o m  C o h ort  1  m a y  n ot  e nt er t h e  s e p ar at e,  o p e n -
l a b el e xt e nsi o n tri al  u ntil t h e  d os e f or  C o h ort  2  h as  b e e n s el e ct e d.  
T h os e s u bj e cts  w h o  d o  n ot  c o m pl et e t h e  P K  p h as e  or t h e  1 2 -w e e k  M ai nt e n a n c e  P eri o d  of t h e 
st u d y  ma y,  o n  a  c as e -b y -c as e  b asis,  b e  eli gi bl e f or  e ntr a n c e i nt o t h e s e p ar at e  o p e n -l a b el 
e xt e nsi o n tri al  aft er  c o nsi d er ati o n  of t h e  cir c u mst a n c es  of t h e  e arl y t er mi n ati o n  a n d t h e 
p ot e nti al  b e n efit -ris k  of  c o nti n u e d  p arti ci p ati o n i n  a  Z X 0 0 8 tri al.  T h e  d e cisi o n  w h et h er t o 
p er mit  o p e n -l a b el e xt e nsi o n tri al  p arti ci p ati o n r esi d es s ol el y  wit h t h e  S p o ns or ,  w h o  m a y  c o ns ult 
wit h t h e sit e i n v esti g at or, t h e I P C A B  a n d/ or t h e I D S M C.    
5.   
I N V E S TI G A TI O N A L  M E DI CI N A L  P R O D U C T I N F O R M A TI O N  
Z X 0 0 8 / m at c hi n g  pl a c e b o will  b e  a d mi nist er e d i n t h e  c urr e nt st u d y . A  bri ef  d es cri pti o n  of t h e 
Z X 0 0 8  pr o d u ct  is pr o vi d e d  b el o w  (T a bl e  4 ). 
T a bl e  4 . I n v esti g ati o n al  M e di ci n al  P r o d u ct  –  Z X 0 0 8  
 
St u d y  P r o d u ct  
S u bst a n c e  C o d e  
Z X 0 0 8   
A cti v e  S u bst a n c e (I N N)  
F e nfl ur a mi n e  h y dr o c hl ori d e  
Tr a d e  N a m e  
N ot  a p pli c a bl e  
F or m ul ati o n (i n cl u di n g  d os a g e f or m  a n d str e n gt h)   
S ol uti o n  1. 2 5,  2. 5 ,  a n d  5 m g/ m L  
R o ut e/ M o d e  of  A d mi nistr ati o n   
Or al  
M a n uf a ct ur er  
P CI  P h ar m a  S er vi c es  o n  b e h alf  of  Z o g e ni x 
I nt er n ati o n al Li mit e d  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 7  of  1 9 4  
T h e I M P(s)  will  b e  a d mi nist er e d  b y t h e  or al r o ut e.  
B a c k gr o u n d  m e di c ati o ns  ( C o h ort  1):   O n t h e  d a y  pri or t o  d osi n g ( D a y -1) t h e  p ar e nts/ c ar e gi v ers 
will  b e r e mi n d e d t o  bri n g t h e s u bj e ct’s  us u al  e pil e ps y  m e di c ati o ns ( C L B  +  V P A  or  C L B  +  V P A 
+  S T P)  a n d  a n y  ot h er  e pil e ps y  m e di c ati o ns t h e  p ati e nt  m a y  b e t a ki n g , t o t h e  C R U  o n t h e  d a y  of 
d osi n g ( D a y  1) f or  A M  a n d  P M  a d mi nistr ati o n ,  as  a p pli c a bl e. 
5. 1   
I D E N TI T Y  O F I N V E S TI GA TI O N A L  M E DI CI N A L  P R O D U C T  
Z X 0 0 8  dr u g  pr o d u ct is  a n  or al  a q u e o us  s ol uti o n  of f e nfl ur a mi n e  h y dr o c hl ori d e  b uff er e d t o  p H  5 
a n d  pr o vi d e d  i n c o n c e ntr ati o ns  of  1. 2 5  m g/ m L,  2. 5  m g/ m L ,  a n d 5  m g/ m L . T h e  e x ci pi e nts 
s el e ct e d  h a v e  b e e n a p pr o v e d f or  us e i n t h e f or m u l ati o ns  of  c urr e ntl y  m ar k et e d dr u g  pr o d u cts 
a n d  ar e  c o nsi d er e d t o  b e s af e.  T h e s ol uti o n f or m ul ati o ns  will  b e s uit a bl y fl a v or e d  a n d  c ol or e d, 
a n d  will  c o nt ai n  pr es er v ati v es  a n d  a t hi c k e ni n g  a g e nt.   T h e  pr o d u ct is s u g ar fr e e  a n d i s i nt e n d e d 
t o  b e  c o m p ati bl e  wit h  a K D . 
T h e f or m ul ati o n  will  b e  pr o vi d e d i n  b ottl es  wit h t a m p er -e vi d e nt,  c hil d -r esist a nt  c a ps.  T h e 
cli ni c al tri als  m at eri al  will  b e s u p pli e d i n  1  b ottl e si z e  wit h  n o mi n al fill  v ol u m e  of  1 2 0  m L.  
M at c hi n g  pl a c e b o  f or  C o h ort  2 als o  will  b e  pr o vi d e d.   D os es t o  b e st u di e d i n cl u d e  0. 2  m g/ k g  
a n d  0. 4  m g/ k g  f or  C o h ort  1 d uri n g t h e  P K  p orti o n  of t h e st u d y ; s u bj e cts  will r e c ei v e  Z X 0 0 8  at  a 
fi x e d  d os e  of  0. 2  m g/ k g/ d a y i n t h e  C o h ort  1 tr a nsiti o n  p eri o d.   Dosi n g f or  C o h ort  2  w as 
i nf or m e d b as e d  o n  e v al u ati o n  of  C o h ort  1  a n d  St u d y  Z X 0 0 8 -1 5 0 5  d at a,  a n d  assi g n e d  t o  b e  0.5  
m g/ k g/ d a y  a n d  n o  m or e t h a n  2 0  m g/ d a y.   
If t h e p ar e nt/ c ar e gi v er  f or  C o h ort  2 is  u n a bl e t o  a d mi nist er t h e f ull  d os e  d u e t o s pill a g e ( e g, 
d os e  w as s pill e d  d uri n g  m e as uri n g, s u bj e ct s pit  d os e  o ut  d uri n g  a d mi nistr ati o n) ,  h e/s h e s h o ul d 
att e m pt t o  gi v e t h e f ull  d os e  n oti n g t h e  e xtr a  a m o u nt  us e d t o f ulfill t h e  d os e.   C a r e  m ust  b e 
t a k e n  n ot t o  o v e r d os e.  If t h e  a m o u nt s pill e d is  n ot  k n o w n, t h e p ar e nt/ c ar e gi v er s h o ul d  n ot 
gi v e  a d diti o n a l  m e di c ati o n t o  a v oi d  p ot e nti al  o v er d os e. 
5. 1. 1   
P a c k a gi n g  a n d  L a b eli n g  
T h e  Z X 0 0 8  pr o d u ct  will  b e  p a c k a g e d  a n d l a b el e d  a c c or di n g t o  c urr e nt I nt er n ati o n al  C o nf er e n c e 
o n  H ar m o ni z ati o n (I C H),  G o o d  M a n uf a ct uri n g  Pr a cti c es ( G M P ), a n d  G o o d  Cli ni c al  Pr a cti c es 
(G C P ) g ui d eli n es,  a n d  n ati o n al l e g al r e q uir e m e nts.  
D osi n g  dir e cti o ns f or t h e  pr o d u ct  c a n  b e f o u n d i n t h e I M P  h a n dli n g i nstr u cti o ns f or t h e st u d y 
s u bj e cts  a n d f or t h e i n v esti g at or.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 8  of  1 9 4  
5. 2   
D E S C RI P TI O N  O F  R E F E R E N C E  T R E A T M E N T,  C O M P A R A T O R, 
A N D/ O R  P L A C E B O  
Pl a c e b o  s ol uti o n is i d e nti c al i n  as p e ct  a n d  c o m p ositi o n t o Z X 0 0 8  a n d  is c o m p os e d  of i d e nti c al 
i n gr e di e nts us e d i n t h e  Z X 0 0 8  f or m ul ati o n,  e x c e pt t h at it  d o es n ot  c o nt ai n t h e  a cti v e  i n gr e di e nt, 
f e nfl ur a mi n e  h y dr o c hl ori d e.  
N o  c o m p ar at ors  or r ef er e n c e tr e at m e nts  will  b e  us e d.  
5. 2. 1   
P a c k a gi n g  a n d  L a b eli n g  
Pl a c e b o s ol uti o n  will  b e  p a c k a g e d i n  a n i d e nti c al  m a n n er t o  Z X 0 0 8.   T h e  m at c hi n g  pl a c e b o  
pr o d u ct  will  b e  p a c k a g e d  a n d l a b el e d  a c c or di n g t o  c urr e nt  I C H, G M P , a n d  G C P  g ui d eli n es,  a n d 
n ati o n al l e g al r e q uir e m e nts.  
D osi n g  dir e cti o ns f or  t h e  pr o d u ct  c a n  b e f o u n d i n t h e I M P  h a n dli n g i nstr u cti o ns f or t h e st u d y 
s u bj e cts  a n d f or t h e i n v esti g at or.  
5. 3   
S HI P M E N T  A N D  S T O R A G E  
I M P will  b e s u p pli e d t o t h e st u d y sit es  b y t h e  S p o ns or  or  its d el e g at e.  
All I M P  will  b e tr a ns p ort e d, r e c ei v e d, st or e d,  a n d  h a n dl e d stri ctl y i n  a c c or d a n c e  wit h t h e 
c o nt ai n er  or  pr o d u ct l a b el, t h e i nstr u cti o ns s u p pli e d t o t h e r es e ar c h sit e  a n d its  d esi g n at e d 
p h ar m a c y, t h e sit e’s st a n d ar d  o p er ati n g  pr o c e d ur es,  a n d  a p pli c a bl e r e g u l ati o ns.  I M P m ust  b e 
st or e d s e p ar at el y fr o m  n or m al  h os pit al  or  pr a cti c e i n v e nt ori es, i n  a l o c k e d f a cilit y  wit h  a c c ess 
li mit e d t o t h e i n v esti g at or  a n d  a ut h ori z e d  p ers o n n el.  T h e i n v esti g at or  m ust  e ns ur e t h at t h e I M P 
is  dis p e ns e d  o nl y t o s u bj e cts  e nr oll e d i n t his st u d y  a c c or di n g t o t his st u d y  pr ot o c ol. 
A p pr o pri at e st or a g e t e m p er at ur e  a n d tr a ns p ort ati o n  c o n diti o ns  will  b e  m ai nt ai n e d f or t h e st u d y 
dr u g fr o m t h e  p oi nt  of  m a n uf a ct ur e  u p t o  d eli v er y  of t h e st u d y  dr u g.  St u d y  m e di c ati o n  m ust  b e 
st or e d  at 1 5 -2 5° C  wit h  e x c ursi o ns  of  5 -3 0° C  p er mitt e d ;  d o  n ot fr e e z e. 
St or a g e  a n d  h a n dli n g i nstr u cti o ns  of t h e  I M P m ai nt ai n e d  at t h e s u bj e ct’s  h o m e  ar e  d es cri b e d i n 
t h e s u bj e ct’s I M P  h a n dli n g i nstr u cti o ns. 
All  u n us e d  I M P will  b e s a v e d  b y t h e sit e f or fi n al  dis p ositi o n  a c c or di n g t o t h e  S p o ns or ’s 
dir e cti v e.   
5. 4   
I M P A C C O U N T A BI LI T Y  
T h e i n v esti g at or  or  d el e g at e  will  c o nfir m r e c ei pt  of  all s hi p m e nts  of  t h e I M P i n  writi n g  usi n g 
t h e r e c ei pt f or m(s)  pr o vi d e d  b y t h e S p o ns or  or  v e n d or . 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  6 9  of  1 9 4  
F or  b ot h  c o h orts ,  assi g n m e nt  of  I M P t o t h e s u bj e ct  will  b e  h a n dl e d t hr o u g h  a n i nt er a cti v e  v oi c e 
r a n d o mi z ati o n (I V R) or  I nt er a cti v e  W e b  Res p o ns e ( I W R) pl atf or m .   T h e i n v esti g at or  or 
d el e g at e  will  b e r e q uir e d t o r e gist er t h e s u bj e ct t hr o u g h I V R /I W R a n d  all st u d y  m e di c ati o n  will 
b e  assi g n e d t o  t h e s u bj e ct t hr o u g h t h e I V R/I W R.   T h e I V R/I W R will  als o  m ai nt ai n  a l o g  of  all 
r e c ei v e d  a n d  dis p e ns e d  m e di c ati o n. 
All s u p pli es  m ust  b e  a c c o u nt e d f or t hr o u g h o ut t h e st u d y  usi n g t h e  st u d y d r u g a c c o u nt a bilit y 
f or m.  At t h e  e n d  of t h e st u d y, t h e  d at e d  a n d si g n ed ( b y  t h e i n v esti g at or  or  d el e g at e, e g , 
p h ar m a cist)  ori gi n al  dr u g  a c c o u nt a bilit y f or m  m ust  b e r et ai n e d  at t h e st u d y sit e  as  v erifi c ati o n 
of fi n al  dr u g  a c c o u nt a bilit y.  
R e c or ds f or t h e  d eli v er y  of  t h e I M P t o t h e st u d y sit e, t h e i n v e nt or y  at t h e st u d y sit e, t h e  us e  b y 
e a c h s u bj e ct  ( us e  b y s u bj e ct  will  b e  d o c u m e nt e d i n t h e s u bj e ct di ar y ),  a n d t h e  d estr u cti o n  or 
ret ur n  of  t h e I M P t o t h e S p o ns or  m ust  b e  m ai nt ai n e d  b y t h e  in v esti g at or ( or  d el e g at e).  T h e 
r e c or ds  will i n cl u d e  d at es,  q u a ntiti es,  b at c h  n u m b ers,  a n d  uni q u e  c o d e  n u m b ers  assi g n e d t o  t h e 
I M P a n d  t o t h e s u bj e cts.  T h e in v esti g at or  m ust  m ai nt ai n r e c or ds  d o c u m e nti n g t h at s u bj e cts 
w er e  pr o vi d e d  wit h  t h e d os es  of  t h e I M P s p e cifi e d i n t his st u d y  pr ot o c ol.  F urt h er m or e, t h e 
i n v esti g at or  m ust r e c o n cil e  all I M Ps r e cei v e d fr o m t h e  S p o ns or .  T h e i n v esti g at or  m ust  pr o vi d e 
r e as o ns f or  a n y  dis cr e p a n ci es i n dr u g  a c c o u nt a bilit y.  F or ms  will  b e  pr o vi d e d  b y t h e  S p o ns or  t o 
e ns ur e st a n d ar di z e d  a n d  c o m pl et e  dr u g  a c c o u nt a bilit y.  
5. 5   
T R E A T M E N T  A D MI NI S T R A TI O N  
5. 5. 1   
  C o h o rt  1:   R a n d o mi z ati o n  
F or  C o h ort  1,  p arti ci p a nts i n  R e gi m e n  1  a n d  R e gi m e n  2  will  b e r a n d o mi z e d t o  o p e n -l a b el 
tr e at m e nt, str atifi e d  b y  a g e.   A r a n d o miz ati o n s c h e d ul e  will  b e  pr o d u c e d f or  t h es e t w o r e gi m e ns 
a n d  pr o vi d e d t o t h e sit es.   S u bj e cts  w h o  e nt er t h e st u d y  o n  C L B  +  V P A  wil l  b e r a n d o mi z e d t o 
tr e at m e nt  wit h  a si n gl e  d os e  of  Z X 0 0 8  0.2  m g/ k g  a d d e d t o t h eir  us u al  d os e  of  C L B  +  V P A  
(R e gi m e n  1)  or  a si n gl e  d os e  of  Z X 0 0 8  0. 4  m g/ k g  a d d e d t o t h eir  us u al  d os e  of  C L B  +  V P A  
(R e gi m e n  2).   R a n d o mi z ati o n  will  b e str atifi e d  b y  a g e  e ns ur e  t h at  b ot h  R e gi m e ns  1  an d  2  h a v e 
at l e ast  2 s u bj e cts  <  6  y e ar s  ol d  a n d  at l e ast  2 s u bj e cts  ≥  6  y e ars  ol d.  S u bj e cts  w h o  e nt er  t h e 
st u d y  o n  S T P  + C L B  +  V P A  will  b e  assi g n e d t o  R e gi m e n  3 ( Z X 0 0 8  0. 2  m g/ k g  +  C L B  +  V P A 
+  S T P ). 
5. 5. 2   
C o h o rt  2:   R a n d o mi z ati o n  
F or s u bj e ct s  w h o  e nt er  C o h ort  2,  u p o n  c o m pl eti o n  of t h e  B as eli n e  P eri o d, s u bj e cts  w h o  q u alif y 
f or t h e st u d y  will  b e r a n d o mi z e d ( 1: 1) i n  a  d o u bl e-bli n d  m a n n er t o r e c ei v e  eit h er tr e at m e nt  wit h  
Z X 0 0 8  (0. 5  m g/ k g/ d a y , 2 0  m g / d a y  m a xi m u m) or  pl a c e b o.  T h e  r a n d o mi z ati o n  will  b e str atifi e d 
b y  a g e ( <  6  y e ars,  ≥  6  y e ars)  t o  e ns ur e  b al a n c e  a cr oss tr e at m e nt  ar ms,  a n d  at l e ast  4 0 %  of 
s u bj e cts  will  b e i n  e a c h  a g e  gr o u p .  S u bj e cts  will  b e  assi g n e d  a r a n d o mi z ati o n  n u m b er  b y t h e 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 0  of  1 9 4  
I V R/I W R s yst e m  u p o n  c o nfir m ati o n t h at t h e s u bj e ct  q u alifi es f or  e nr oll m e nt i n t h e  Titr ati o n 
P eri o d.  O n c e  a r a n d o mi z ati o n  n u m b er is  assi g n e d t o  a s u bj e ct, t h e sit e  will r e c or d t h e s u bj e ct’s  
i niti als  a n d i d e ntifi c ati o n n u m b er  o n t h e  c orr es p o n di n g st u d y  d r u g  b ottl es.  E a c h  b ottl e  will 
c o nt ai n t h e  assi g n e d tr e at m e nt ( Z X 0 0 8  or  pl a c e b o).  Z X 0 0 8  a n d  pl a c e b o  will  b e i d e nti c al, t h us 
r e n d eri n g t h e st u d y  dr u g  a n d  pl a c e b o i n disti n g uis h a bl e.  F or  e a c h I M P b ottl e  a n d r a n d o mi z ati o n 
n u m b er  assi g n e d, t h e f oll o wi n g i nf or m at i o n  will  b e r e c or d e d  o n t h e  dr u g  a c c o u nt a bilit y f or m: 
s u bj e ct i niti als,  u ni q u e  b ottl e  n u m b er,  d at e  e a c h  b ottl e is  assi g n e d,  a n d  dr u g  us e d  a n d  u n us e d 
d uri n g t h e st u d y.  
5. 5. 3   
C o h o rt  2:   Tit r ati o n  P e ri o d  
T h e i n v esti g at or ( or  d el e g at e)  will  dis p e ns e  I M P o nl y t o s u bj e cts i n cl u d e d i n t his st u d y 
f oll o wi n g t h e  pr o c e d ur es s et  o ut i n t his st u d y  pr ot o c ol. 
St u d y  m e di c ati o n  will  b e  a d mi nist er e d  as  e q u al  d os es  BI D  i n t h e  m or ni n g  a n d i n t h e  e v e ni n g 
a p pr o xi m at el y  1 2  h o urs  a p art ,  wit h f o o d.  E a c h  d os e s h o ul d  b e s e p ar at e d  b y  a  mi n i m u m  of  8 
h o urs  a n d  a  m a xi m u m  of  1 2  h o urs.   A  miss e d  d os e  of st u d y  m e di c ati o n  m a y  b e t a k e n l at er  u p t o 
8  h o urs  b ef or e t h e  n e xt s c h e d ul e d  d os e;  ot h er wis e, t h e  miss e d  d os e s h o ul d  n ot  b e  gi v e n. 
A d mi nistr ati o n  of t h e I M P  will  b e  b as e d  o n t h e  r a n d o mi z e d  d os e  a nd  s u bj e ct’s  w ei g ht at  Visit  3 
(St u d y  D a y  -1).   At  Visit  8 ( D a y  5 0 ), if t h e s u bj e ct’s  w ei g ht  h as  c h a n g e d ± 2 5 %  of t h e  w ei g ht  at 
D a y -1, t h e I M P  d os e  will  b e r e c al c ul at e d . S u bj e cts  will  b e  d os e d  usi n g t h e  or al  d osi n g s yri n g e 
pr o vi d e d.  
T h e  assi g n e d  0. 5  m g/ k g/ d a y  ( m a xi m u m  2 0  m g/ d a y) d os e f or  C o h ort  2  w as  i nf or m e d b as e d  o n 
P K  a n d s af et y  d at a fr o m  C o h ort  1,  w h er e si n gl e  d os es  of  0. 2  a n d  0. 4  m g/ k g  t o g et h er  wit h  d at a 
fr o m  St u d y  Z X 0 0 8-1 5 0 5  w er e  e v al u at e d.  I n  or d er t o  m a xi mi z e t ol er a bilit y, t h e  d os e f or  e a c h 
su bj e ct  will  b e titr at e d  t o 0. 5  m g/ k g/ d a y .  All s u bj e cts  will st art  wit h  a  d os e  of  Z X 0 0 8  
0. 2  m g/ k g/ d a y ( or  pl a c e b o  e q ui v al e nt),  a d mi nist er e d i n  di vi d e d  d os es  BI D ( m a xi m u m   
2 0  m g/ d a y)  o n  St u d y  D a ys  1 -7.  T h e  d os e  will  b e i n cr e as e d t o  Z X 0 0 8  0. 4  m g/ k g/ d a y ( or  p l a c e b o 
e q ui v al e nt)  a d mi nist er e d i n  di vi d e d  d os es  BI D ( m a xi m u m  2 0  m g/ d a y)  o n  S t u d y  D a ys  8-1 4.  T h e 
d os e  of  Z X 0 0 8  will  b e i n cr e as e d t o  0. 5  m g/ k g/ d a y ( or  pl a c e b o  e q ui v al e nt)  a d mi nist er e d i n 
di vi d e d  d os es  BI D ( m a xi m u m : 2 0  m g/ d a y)  o n  St u d y  D a ys  1 5 -2 1 .  T h e titr a ti o n  al g orit h m is 
s h o w n i n T a bl e  5 .  S e e  S e cti o n  5. 6  for  m or e i nf or m ati o n  a b o ut t h e  v ol u m e  of  Z X 0 0 8  or  pl a c e b o 
t o  b e  ad mi nist er e d.  
T a bl e  5 . Tit r ati o n  Al g o rit h m  
 
R a n d o mi z e d  D os e  
Tit r ati o n  St e p  1   
St u d y  D a y s 1 -7  
Tit r ati o n  St e p  2  
St u d y  D a ys  8 -1 4  
Tit r ati o n  St e p  3  
St u d y  D a ys  1 5 -2 1  
Z X 0 0 8  0. 5  m g/ k g/ d a y   
Z X 0 0 8   
0. 2  m g/ k g/ d a y  
Z X 0 0 8  
0. 4  m g/ k g/ d a y  
Z X 0 0 8  
0. 5  m g/ k g/ d a y  
Pl a c e b o  
Pl a c e b o  
Pl a c e b o  
Pl a c e b o  
N ot e:  m a xi m u m  d ail y  d os e  of  Z X 0 0 8 is  2 0  m g; t h e  d osi n g r e gi m e n f or  all  d os es is  BI D  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 1  of  1 9 4  
5. 5. 4   
C o h o rt  2:   M ai nt e n a n c e  P e ri o d  
Aft er  c o m pl eti o n  of t h e  Titr ati o n  P eri o d,  s u bj e cts will  e nt er t h e  M ai nt e n a n c e  P eri o d  a n d 
c o nti n u e t o  r e c ei v e t h e r a n d o mi z e d 0. 5  m g/ k g/ d a y  ( m a xi m u m  2 0  m g/ d a y) d os e  of  Z X 0 0 8  or 
pl a c e b o  a n d  b e tr e at e d f or  a n  a d diti o n al  1 2  w e e ks  o n st a bl e  d os a g e .  St u d y  m e di c ati o n  will 
c o nti n u e t o  b e  a d mi nist er e d  BI D i n t h e  m o r ni n g  a n d i n t h e  e v e ni n g, a p pr o xi m at el y  1 2  h o urs 
a p art ,  wit h f o o d. E a c h  d os e s h o ul d  b e s e p ar at e d  b y  a  mi ni m u m  of  8  h o urs  a n d  a  m a xi m u m  of 
1 2  h o urs.   A  miss e d  d os e  of st u d y  m e di c ati o n  m a y  b e t a k e n l at er  u p t o  8  h o urs  b ef or e t h e  n e xt 
s c h e d ul e d  d os e;  ot h er wis e, t h e  miss e d  d os e s h o ul d  n ot  b e  gi v e n.   
5. 5. 5   
C o h o rt  2:   T a p e r  P e ri o d  
S u bj e cts  w h o  c o m pl et e  all  of t h e  M ai nt e n a n c e  P eri o d  a n d  will  n ot  b e  c o nti n ui n g i nt o t h e  o p e n -
l a b el  e xt e nsi o n tri al, a n d s u bj e cts  w h o  dis c o nti n u e fr o m t h e st u d y  e arl y,  will  b e t a p er e d  off  of 
st u d y  m e di c ati o n o v er  8  d a ys  a n d  will r e c ei v e  n o st u d y  dr u g  d uri n g t h e fi n al  6  d a ys  of t h e t a p er 
p eri o d.  St u d y  dr u g  a d mi nistr ati o n  will  n ot  b e r es u m e d  aft er  c o m pl eti o n  of t h e t a p er  p eri o d .  T h e 
t a p er  al g orit h m is s h o w n i n T a bl e  6 .  
T a bl e  6 .   T a p e r  Al g o rit h m  
 
 
 
R a n d o mi z e d  D os e  
T a p e r  St e p  1   
D a y s 1 -4  aft e r st u d y 
c o m pl eti o n  o r  e a rl y 
t e r mi n ati o n 
T a p e r  St e p  2  
D a y s 5 -8  aft e r st u d y 
c o m pl eti o n  o r  e a rl y 
t e r mi n ati o n 
T a p e r  St e p  3  
D a ys  9 -1 4  aft e r st u d y 
c o m pl eti o n  o r  e a rl y 
t e r mi n ati o n 
Z X 0 0 8  0. 5  m g/ k g/ d a y   
Z X 0 0 8  0. 4  m g/ k g/ d a y   
Z X 0 0 8  0. 2  m g/ k g/ d a y   
N o st u d y  dr u g 
a d mi nistr ati o n  
Pl a c e b o  
Pl a c e b o  
Pl a c e b o  
N o st u d y  dr u g 
a d mi nistr ati o n  
N ot e:   m a xi m u m  d ail y  d os e  of  Z X 0 0 8 is  2 0  m g  
St u d y  m e di c ati o n  will  c o nti n u e t o  b e  a d mi nist er e d  as  e q u al  d os es  BI D i n t h e  m or ni n g  a n d i n 
t h e  e v e ni n g  a p pr o xi m at el y  1 2  h o urs  a p art,  wit h f o o d.   E a c h  d os e s h o ul d  b e s e p ar at e d  b y  a 
mi ni m u m  of  8  h o urs  a n d  a  m a xi m u m  of  1 2  h o urs.   A  miss e d  d os e  of st u d y  m e di c ati o n  m a y  b e 
t a k e n l at er  u p t o  8  h o urs  b ef or e t h e  n e xt s c h e d ul e d  d os e;  ot h er wis e, t h e  miss e d  d os e s h o ul d  n ot 
b e  gi v e n. I M P  will  b e  a d mi nist er e d  usi n g t h e  or al  d osi n g s yri n g e  pr o vi d e d.  
5. 5. 6   
C o h o rt  1:   T r a nsiti o n  P e ri o d  
F or  C o h ort  1,  p arti ci p a nts  w h o  c h o os e  t o e nt er t h e  o p e n -l a b el e xt e nsi o n tri al  will  b e gi n  a 
tr a nsiti o n  p eri o d  o n  St u d y  D a y  1 5.   All s u bj e cts  will r e c ei v e  a d os e  of  Z X 0 0 8  0 .2  m g/ k g / d a y 
a d d e d t o t h eir  us u al  A E D r e gi m e n .  St u d y  m e di c ati o n  will  b e  a d mi nist er e d  as  e q u al  d os es  BI D 
i n t h e  m or ni n g  a n d i n t h e  e v e ni n g  a p pr o xi m at el y 1 2  h o urs  a p art,  wit h f o o d.   E a c h  d os e s h o ul d 
b e s e p ar at e d  b y  a  mi ni m u m  of  8  h o urs  a n d  a  m a xi m u m  of  1 2  h o urs.   A  miss e d  d os e  of st u d y 
m e di c ati o n  m a y  b e t a k e n l at er  u p t o  8  h o urs  b ef or e t h e  n e xt s c h e d ul e d  d os e;  ot h er wis e, t h e 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 2  of  1 9 4  
miss e d  d os e s h o ul d  n ot  b e  gi v e n .  St u d y  m e di c ati o n  will  b e  a d mi nist er e d  usi n g t h e  or al  d osi n g 
s yri n g e  pr o vi d e d.   T his  d os e  of  Z X 0 0 8  0. 2  m g/ k g/ d a y  will  c o nti n u e  u ntil  t h e  d os e f or  C o h ort  2 
h as  b e e n  c h os e n  a n d t h e s u bj e ct is  e nt er e d  i nt o t h e s e p ar at e o p e n -l a b el e xt e nsi o n tri al . 
5. 5. 7   
C o h o rt  2:   T r a nsiti o n  P e ri o d  
S u bj e cts  w h o  c o m pl et e t h e  M ai nt e n a n c e  P eri o d  a n d  will  b e  c o nti n ui n g i nt o t h e  o p e n -l a b el 
e xt e nsi o n tri al  will  b e tr a nsiti o n e d fr o m  d o u bl e -bli n d st u d y  m e di c ati o n t o  o p e n -l a b el  Z X 0 0 8 
(d e pi ct e d i n  T a bl e  7 ).  St u d y  m e di c ati o n  will  b e  a d mi nist er e d  as  e q u al  d os es  BI D i n t h e 
m or ni n g  a n d i n t h e  e v e ni n g  a p pr o xi m at el y  1 2  h o urs  a p art,  wit h f o o d.   E a c h  d os e s h o ul d  b e 
s e p ar at e d  b y  a  mi ni m u m  of  8  h o urs  a n d  a  m a xi m u m  of  1 2  h o urs.   A  miss e d  d os e  of st u d y 
m e di c ati o n  m a y  b e t a k e n l at er  u p t o  8  h o urs  b ef or e t h e  n e xt s c h e d ul e d  d os e;  ot h er wis e, t h e 
miss e d  d os e s h o ul d  n ot  b e  gi v e n.  St u d y  m e di c ati o n  will  b e  a d mi nist er e d  usi n g t h e  or al  d osi n g 
s yri n g e  pr o vi d e d.  
T h is tr a nsiti o n is r e q uir e d i n  or d er t o  m ai nt ai n t h e  bli n d.  All  s u bj e cts  e nt eri n g t h e  o p e n -l a b el 
e xt e nsi o n tri al  will  b e tr a nsiti o n e d fr o m t h eir  bli n d e d  d ail y  d os e ( pl a c e b o,  or  0. 5  m g/ k g/ d a y 
[ m a xi m u m  2 0  m g/ d a y] d os e  of  Z X 0 0 8 ) t o t h e  0. 2  m g/ k g/ d a y Z X 0 0 8  d os e  d uri n g t h e i nt er v al 
b et w e e n  Visits  1 2  a n d  1 3 ,  wit h o ut  br e a ki n g t h e  bli n d. S u bj e cts i n t h e  Z X 0 0 8  ar m  will tr a nsiti o n 
t o  0. 4  m g/ k g/ d a y  d os e  o n  D a ys  1-7,  a n d t h e n tr a nsiti o n t o  a  d os e  of  0. 2  m g/ k g/ d a y  o n  D a ys  8 -
1 4  d uri n g t h e tr a nsiti o n  p eri o d.  S u bj e cts i n t h e  pl a c e b o  ar m  will  h a v e  a titr ati o n st e p fr o m 
pl a c e b o t o  0. 2  m g/ k g/ d a y  a n d t h e n  will  c o m m e n c e t a ki n g st u d y  m e di c ati o n  as  p er t h e  o p e n -
l a b el  e xt e nsi o n tri al ( 0. 2  m g/ k g/ d a y).  All s u bj e cts  will r e c ei v e  Z X 0 0 8  
0. 2  m g/ k g/ d a y f or t h e l ast tr a nsiti o n st e p i n t h ei r r es p e cti v e  d os e  gr o u p. A  n e w  b ottl e  of I M P 
will  b e st art e d  b y t h e s u bj e ct  at  e a c h l e v el  of t h e tr a nsiti o n st e p.   S e e  S e cti o n  5. 6  f or  m or e 
i nf or m ati o n  a b o ut t h e  v ol u m e  of  Z X 0 0 8  or  pl a c e b o t o  b e  a d mi nist er e d.  
T a bl e  7 .   T r a nsiti o n  Al g o rit h m  
R a n d o mi z e d  D os e  
S el e ct e d f o r  C o h o rt  2  
 St e p  1   
D a y s 1 -7  aft e r st u d y  c o m pl eti o n   
 St e p  2  
D a ys  8 -1 4  aft e r st u d y  c o m pl eti o n   
Z X 0 0 8  0. 5  m g/ k g/ d a y  
Z X 0 0 8  0. 4  m g/ k g/ d a y  
Z X 0 0 8  0. 2  m g/ k g/ d a y  
Pl a c e b o  
Pl a c e b o  
Z X 0 0 8  0. 2  m g/ k g/ d a y  
N ot e:   m a xi m u m  d ail y  d os e  of  Z X 0 0 8 is  2 0  m g  
 
5. 6   
B LI N DI N G  ( C O H O R T  2) 
At t h e  e n d  of t h e  B as eli n e  P eri o d, s u bj e cts  w h o  q u alif y t o  e nt er t h e  d o u bl e -bli n d  p orti o n  of t h e 
st u d y will  b e r a n d o mi z e d t o r e c ei v e  Z X 0 0 8 ( 0. 5  m g/ k g/ d a y , m a xi m u m  d os e  2 0  m g/ d a y),  or 
pl a c e b o  a n d  assi g n e d  a r a n d o mi z ati o n  n u m b er  b y t h e I V R/I W R s yst e m . O n c e  a r a n d o mi z ati o n 
n u m b er is  assi g n e d t o  a s u bj e ct, t h e sit e  will r e c or d t h e s u bj e ct’s i niti als  o n t h e  c or r es p o n di n g 
st u d y  dr u g l a b els.  E a c h  b ottl e  will  c o nt ai n t h e  assi g n e d tr e at m e nt ( Z X 0 0 8  or  pl a c e b o)  a n d t h e 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 3  of  1 9 4  
Z X 0 0 8  a n d  pl a c e b o s ol uti o ns  will  b e i d e nti c al.   
T h e I V R/I W R  s yst e m  will i nstr u ct sit e  p ers o n n el t o t h e  v ol u m e  of  or al s ol uti o n t o  b e 
a d mi nist er e d  b as e d  o n t h at s u bj e ct’s  w ei g ht. ( D os e  will  b e r e c al c ul at e d  b y t h e s yst e m  o n c e  at 
t h e  mi d p oi nt  of t h e st u d y.)  D uri n g t h e  Titr ati o n,  M ai nt e n a n c e, T a p er/ Tr a nsiti o n  P eri o ds, t h e 
s u bj e cts  a n d st u d y  p ers o n n el (i n v esti g at ors,  cli ni c al  st aff,  p ers o n n el i n v ol v e d i n  d at a  c oll e cti o n 
a n d  a n al ysis, t h e  M e di c al  M o nit or,  a n d t h e  S p o ns or )  will  b e  bli n d e d t o t h e tr e at m e nt  all o c ati o n. 
If a n  i n v esti g at or f e els t h e  bli n d s h o ul d  b e  br o k e n,  h e/s h e s h o ul d  e n d e a v or t o  dis c uss  wit h t h e 
M e di c al  M o nit or  or  S p o ns or ’s  M e di c al  R e pr es e nt ati v e i n  c o nsi d er ati o n  of t h e  n at ur e  of t h e 
e m er g e n c y  a n d t h e  a v ail a bilit y  of t h e  M e di c al  M o nit or  or  S p o ns or ’s  M e di c al  R e pr es e nt ati v e 
t h at t h e  bli n d s h o ul d  o nl y  b e  br o k e n i n t h e  e v e nt t h e  k n o wl e d g e  of  w h et h er t h e s u bj e ct is  o n 
a cti v e st u d y  m e di c ati o n  v ers us  pl a c e b o is  n e e d e d t o  d et er mi n e  c o urs e  of  m e di c al tr e at m e nt f or 
a n  A E  or  S A E ; t h at t h e s u bj e ct  will  b e  dis c o nti n u e d fr o m t h e  cli ni c al tri al  u p o n  br e a ki n g  of t h e 
bli n d;  a n d t h at t h e  d e cisi o n  w h et h er t h e s u bj e ct  c a n  e nt er t h e  s e p ar at e o p e n -l a b el e xt e nsi o n tri al  
will r est  wit h t h e  S p o ns or if t h e s u bj e ct  e xit e d  St u d y  Z X 0 0 8 -1 5 0 4  pri or t o  c o m pl eti o n.  
5. 7   
P RI O R  A N D  C O N C O MI T A N T  M E DI C A TI O N S  
All  m e di c ati o ns  ta k e n  b y  a s u bj e ct  d uri n g t h e  S cr e e ni n g  a n d  B as eli n e  S ei z ur e  Ass ess m e nt 
P eri o d s ar e r e g ar d e d  as  pri or t h er a p y  a n d  m ust  b e  d o c u m e nt e d i n t h e  e C R F.  Si g nifi c a nt  
m e di c ati o ns ( e g,  a nti bi oti cs) t a k e n  wit hi n  3 0  d a ys  pri or t o t h e  S cr e e ni n g  visit s h o ul d  als o  b e 
c a pt ur e d.  All  pri or  a n d  c o n c o mit a nt  A E Ds  will  b e  c oll e ct e d i n t h e  C R F.  
All  m e di c at i o ns t a k e n  b y  a s u bj e ct aft er  t h e first  a d mi nistr ati o n  of I M P ar e r e g ar d e d  as 
c o n c o mit a nt  m e di c ati o n s a n d  m ust  b e  d o c u m e nt e d i n t h e  e C R F , i n cl u di n g  o v er-t h e-c o u nt er 
m e di c ati o n,  h er b al , a n d  vit a mi n /s u p pl e m e nt pr e p ar ati o ns . S u bj e cts  ar e r e q uir e d t o t a k e  at l e ast 
o n e  c o n c o mit a nt  A E D  d uri n g t h e st u d y.   All s u bj e cts  will  c o nti n u e t o r e c ei v e t h eir  e xisti n g 
A E D (s) wit h t h e s a m e  d os es  t hr o u g h o ut t h e st u d y.   E v er y  eff ort s h o ul d  b e  m a d e t o  e ns ur e t h at 
t h e r e gi m e n  of e xisti n g  m e di c ati o ns r e m ai ns st a bl e  d uri n g t h e st u d y ;  a n y  c h a n g es  m ust  b e 
dis c uss e d  wit h t h e  S p o ns or  pri or t o i m pl e m e nt ati o n.  If  a  c h a n g e is  n e c ess ar y t o  m a n a g e  a n  A E, 
t his  m ust  b e  dis c uss e d  wit h t h e S p o ns or  as s o o n  as  p ossi bl e  aft er  i m pl e m e nt ati o n if  n ot  b ef or e 
i m pl e m e nt ati o n.  N o n-st u d y  m e di c ati o ns  a n d  t h er a pi es t h at  ar e  c o nsi d er e d  n e c ess ar y f or t h e 
s u bj e ct’s  w elf ar e  a n d  will  n ot i nt erf er e  wit h t h e r es p o ns e t o t h e st u d y  m e di c ati o n  m a y  b e  gi v e n 
at t h e  dis cr eti o n  of t h e i n v esti g at or , i nf or mi n g t h e  M e di c al  M o nit or  as s o o n  as  p ossi bl e. 
It s h o ul d  b e  n ot e d f or a n y s u bj e ct r e c ei vi n g  h y p o gl y c e mi c  a g e nts, t h e i n v esti g at or s h o ul d 
c o nsi d er  di a b eti c  m e di c ati o n  c h a n g es i n t h e s etti n g  of  w ei g ht l oss  a n d  h y p o gl y c e mi a.    
5. 7. 1   
V a g al  N e r v e  Sti m ul a ti o n 
S u bj e cts r e c ei vi n g tr e at m e nt  wit h  a  V N S  m a y  b e i n cl u d e d  i n t h e st u d y as l o n g  as t h e  V N S  h as 
b e e n i n  pl a c e f or  at l e ast  6  m o nt hs  pri or t o  e ntr y i nt o t h e st u d y, t h e  V N S  b att er y is  n ot  d u e f or 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 4  of  1 9 4  
r e pl a c e m e nt  d uri n g t h e st u d y,  a n d sti m ul ati o n  p ar a m et ers  h a v e  b e e n  k e pt  c o nst a nt f or 4  w e e ks  
pri or t o s cr e e ni n g  a n d  m ust r e m ai n s o t hr o u g h o ut t h e st u d y .  T h e s u bj e ct’s  us e  of  V N S  will  b e 
r e c or d e d i n t h e e C R F.    
5. 7. 2   
K et o g e ni c  Di et  
A d h er e n c e t o t h e  K D ,  or  a  m o difi e d  v ersi o n  of  K D, is  p er mitt e d  d uri n g t h e st u d y if t h e  di et ar y 
h a bits  w er e i niti at e d  m or e t h a n  4  w e e ks  pri or t o  S cr e e ni n g  a n d r e m ai n st a bl e t hr o u g h o ut t h e 
st u d y.  T h e s u bj e ct’s  us e  of  K D  will  b e r e c or d e d i n t h e  e C R F.  
5. 7. 3   
R es c u e  M e di c ati o n f o r  S ei z u r es  
T h e s u bj e ct's  us u al  or  pr es cri b e d r e gi m e n  a n d fr e q u e n c y  of r es c u e t h er a p y f or s ei z ur es s h o ul d 
b e  e nt er e d i nt o t h e  pri or  a n d  or  c o n c o mit a nt  m e di c ati o n s s e cti o ns  of t h e  e C R F.    
Us e  of r es c u e  m e di c ati o n is  p er mitt e d  d uri n g t h e st u d y  a n d s h o ul d  b e r e c or d e d  o n t h e  e C R F  
( d a y,  m e di c ati o n[s],  d os e[s])  a n d i n t h e  di ar y ( d a y, ti m efr a m e  ass o ci at e d  wit h s ei z ur e  e pis o d es).  
R e p e at e d  a d mi nistr ati o ns  wit hi n t h e s a m e  e pis o d e  s h o ul d b e r e c or d e d s e p ar at el y.  
5. 7. 4   
P r o hi bit e d  C o n c o mit a nt  m e di c ati o ns  a n d  F o o d  
Al c o h ol i n  all f or ms ( wi n e,  b e er, li q u ors)  a n d  a m o u nts  is  pr o hi bit e d  d uri n g t h e st u d y. T h e 
f oll o wi n g  c o n c o mit a nt  m e di c ati o ns/f o o ds ar e  pr o hi b it e d  d uri n g t h e  cli ni c al tri al: 
•   A E Ds:   P h e n yt oi n,  c ar b a m a z e pi n e,  o x c ar b a z e pi n e,  esli c ar b a z e pi n e, 
r eti g a bi n e/e z o g a bi n e ,  or  p h e n o b ar bit al 
•   F el b a m at e is  pr o hi bit e d  as  a  c o n c o mit a nt  m e di c ati o n  u nl ess  t h e s u bj e ct  h as  b e e n  o n 
f el b a m at e f or  at l e ast  1 8  m o nt hs pri or t o s cr e e ni n g , h as st a bl e  li v er f u n cti o n a n d 
h e m at ol o g y l a b or at or y t ests , a n d t h e  d os e is  e x p e ct e d t o r e m ai n  c o nst a nt t hr o u g h o ut t h e 
st u d y.  
•   A n y  c e ntr all y -a cti n g  m e di c ati o n  wit h  cli ni c all y  a p pr e ci a bl e  a m o u nt  of s er ot o ni n  a g o nist 
or  a nt a g o nist  a cti vit y, i n cl u di n g  i mi pr a mi n e,  m o n o a mi ne  o xi d as e i n hi bit ors,  s er ot o ni n-
r e u pt a k e i n hi bit ors or  mi x e d  n or e pi n e p hri n e/s er ot o ni n r e u pt a k e i n hi bit ors , v orti o x eti n e , 
c y pr o h e pt a di n e,  or  a n y  of t h e tri pt a ns (f or  mi gr ai n e) . 
•   Dr u gs t h at i n cr e as e  c ar di o v as c ul ar ris k:   at o m o x eti n e  a n d t h os e  wit h  n or a dr e n er g i c 
r e u pt a k e  pr o p erti es 
•   Dr u gs i nt e n d e d t o f a cilit at e  w ei g ht l oss  
•   Ot h er:   a n y f or m  of  m arij u a n a,  T H C  a n d  d eri v ati v es (i n cl u di n g  E pi di ol e x ®)  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 5  of  1 9 4  
•   A list  of  m e di c ati o ns/f o o ds  t h at ar e  t o  b e  a v oi d e d  as  o n g oi n g  m e di c ati o ns  or f or  c hr o ni c 
us e if i niti at e d  d uri n g t h e st u d y  fr o m t h e ti m e  of si g ni n g t h e i nf or m e d  c o ns e nt f or m 
(I C F) u ntil t h e  e n d -of -st u d y  visit ( or  e arl y t er mi n ati o n)  is  pr o vi d e d i n A p p e n di x  1 .  If 
m e di c al  n e c essit y r e q uir es s h ort -t er m  us e  of  o n e  or  m or e  of t h es e  m e di c ati o ns  d uri n g 
t h e  c o urs e  of t h e st u d y,  pl e as e  c o nt a ct t h e  M e di c al  M o nit or f or  a p pr o v al.  T h e  us e  of 
di a z e p a m  or  mi d a z ol a m  as r es c u e  m e di c ati o n  d o es  n ot r e q uir e  M e di c al  M o nit or 
a p pr o v al  pri or t o  us e.  
5. 8   
T R E A T M E N T  C O M P LI A N C E  
E a c h s u bj e ct  or  p ar e nt /c ar e gi v er  will r e c or d t h e  d os e ,  d osi n g fr e q u e n c y  a n d I M P c o ns u m pti o n 
i n t h e s u bj e ct’s di ar y . S u bj e cts  will  bri n g t h eir  us e d ,  p arti all y  us e d,  a n d  u n us e d I M P t o  e v er y 
st u d y  visit.   Tr e at m e nt  c o m pli a n c e  will  b e  m o nit or e d  b y  m e as uri n g t h e  v ol u m e  of I M P i n t h es e 
b ottl es  a n d  c o m p ari n g t o t h e  dis p e ns ati o n l o g  a n d  di ar y  r e c or ds.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 6  of  1 9 4  
6.   
VI SI T  S C H E D U L E  
F or  b ot h  C o h orts, s t u d y  pr o c e d ur es  will  b e  c o n d u ct e d  a c c or di n g t o t h e  S c h e d ul e  of 
Ass ess m e nts i n  T a bl e  1  a n d  T a bl e  2 .  Ti m e  wi n d o ws f or  tr a nsiti o n p eri o d  ass ess m e nts  i n 
C o h ort  1  a n d  all  ass ess m e nts i n  C o h ort  2  ar e  d et ail e d i n  T a bl e  8  a n d  T a bl e  9 , r es p e cti v el y. N ot e 
t h at f or  C o h ort  1 t h e s cr e e ni n g  p eri o d  m a y  b e  e xt e n d e d t o  e ns ur e  all s cr e e ni n g r es ults  ar e 
r e vi e w e d f or  eli gi bilit y  pri or t o  d osi n g. 
T a bl e  8 . C o h o rt  1 : Ti m e  Wi n d o ws f o r  Ass ess m e nts  D u ri n g t h e  T r a nsiti o n  P e ri o d  
T r a nsiti o n  P e ri o d  Visit /  P r o c e d u r e  
Ti m e  wi n d o w ( r el ati v e t o s c h e d ul e d  visit /  p r o c e d u r e)  
Visit  6  ( P h o n e;  D a y 2 9 ) 
±  3  d a ys  
Visit  7  ( Cli ni c;  D a y 4 3 ) 
±  4  d a ys  
Visit  8 ( P h o n e:  D a y  5 7 ) 
±  3  d a ys  
Visit  9  ( Cli ni c;  D a y 7 1 ) 
±  4  d a ys  
Visit  1 0  ( P h o n e:  D a y 8 5 ) 
±  3  d a ys  
Visit  1 1  ( Cli ni c;  D a y 9 9 )  
±  4  d a ys  
Visit  1 2  ( P h o n e:  D a y 1 1 3 ) 
±  3  d a ys  
Visit  1 3  ( Cli ni c;  D a y 1 2 7 ) 
±  4  d a ys  
Visit  1 4  ( P h o n e:  D a y 1 4 1)  
±  3  d a ys  
Visit  1 5  ( Cli ni c:  D a y 1 5 5 ) 
±  4  d a ys  
Visit  1 6  ( P h o n e:  D a y 1 6 9)  
±  3  d a ys  
Visit  1 7  ( Cli ni c:  D a y 1 8 3 ) 
±  4  d a ys  
Visit s 1 8  a n d  1 9  ( E C H O  cli ni c;  3-6  m o nt hs  aft er 
l ast  d os e) 
±  3 0  d a ys  
Bl o o d  c oll e cti o n f or  A E D  c o n c e ntr ati o n   
Pri or t o  m or ni n g  d os e  of  A E D  m e di c ati o n  
A E D = a nti e pil e pti c  dr u g (s);  E C H O = e c h o c ar di o gr a m  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 7  of  1 9 4  
T a bl e  9 . C o h o rt  2:  Ti m e  Wi n d o ws f o r  Ass ess m e nts  
Visit /  P r o c e d u r e  
Ti m e  wi n d o w ( r el ati v e t o s c h e d ul e d  visit /  p r o c e d u r e)  
Visit  1 ( Cli ni c;  D a y  -4 3 t o  -4 2,  or  -4 2 t o  -4 1 : 
S cr e e ni n g)   
N ot  a p pli c a bl e  
Visit  2 ( P h o n e;  D a y  -2 1 ) 
±  3  d a ys  
Visit  3 ( Cli ni c;  D a y  -1;  R a n d o mi z ati o n)   
+  4  d a ys  
Visit  4  (Cli ni c :  D a y 8)  
+  4  d a ys  
Visit  5 ( Cli ni c;  D a y  1 5 ) 
+  4  d a ys  
Visit  6 ( Cli ni c;  D a y  2 2 ) 
+  4  d a ys  
Visit  7 ( P h o n e:  D a y  3 6 ) 
±  4  d a ys  
Visit  8 ( Cli ni c;  D a y  5 0 )  
±  4  d a ys  
Visit  9 ( P h o n e:  D a y  6 4 ) 
±  4  d a ys  
Visit  1 0 ( Cli ni c;  D a y  7 8 ) 
±  4  d a ys  
Visit  1 1 ( P h o n e:  D a y  9 2)  
±  4  d a ys  
Visit  1 2 ( Cli ni c:  D a y  1 0 6 ) 
±  4  d a ys  
Visit  1 3 ( Cli ni c ;  D a y 1 2 0 ; p ost -d osi n g ) 
±  4  d a ys  
Visit  1 4  ( E C H O  cli ni c;  3-6  m o nt hs  aft er l ast 
d os e)  
±  3 0  d a ys  
Bl o o d  c oll e cti o n f or  Z X 0 0 8  P K  
±  1 5  mi n ut e s  
Bl o o d  c oll e cti o n f or  A E D  c o n c e ntr ati o n   
P ri or t o  m or ni n g  d os e  of A E D  m e di c ati o n  
A E D = a nti e pil e pti c  dr u g (s);  E C H O = e c h o c ar di o gr a m;  P K  =  p h ar m a c o ki n eti cs  
6. 1   
C O H O R T  1:   S T U D Y  P R O C E D U R E S  
6. 1. 1   
S c r e e ni n g ( U p  t o 1 4  d a ys  p ri o r t o  d osi n g)  
S cr e e ni n g is t h e  pr e d et er mi n e d s eri es  of  pr o c e d ur es  wit h  w hi c h  e a c h i n v esti g at or s el e cts  a n 
a p pr o pri at e  a n d r e pr es e nt ati v e s a m pl e  of s u bj e cts f or  e nr oll m e nt i nt o t h e st u d y .   S u bj e cts  will 
att e n d t h e  cli ni c al  u nit f or  a s cr e e ni n g  visit  u p t o  1 4  d a ys  pri or t o  d osi n g.  T h e  s cr e e ni n g  p eri o d 
m a y  b e  e xt e n d e d t o  e ns ur e  all s cr e e ni n g r es ults  ar e r e vi e w e d f or  eli gi bilit y  pri or t o  d osi n g.  
S el e ct s cr e e ni n g  d at a  will  b e  e nt er e d i nt o t h e  e C R F.  
Writt e n i nf or m e d  p ar e nt al  or  g u ar di a n  c o ns e nt  a n d  ass e nt  of  mi n ors (if t h e s u bj e ct is  c a p a bl e  of 
pr o vi di n g  ass e nt)  m ust  b e  o bt ai n e d  b ef or e  a s u bj e ct  c a n st art  a n y  of t h e s cr e e ni n g  pr o c e d ur es. 
T h e  pr o c e d ur e(s) f or  o bt ai ni n g  writt e n i nf or m e d  c o ns e nt  a n d  ass e nt  of  mi n or (if t h e s u bj e ct is 
c a p a bl e  of  pr o vi di n g  ass e nt)  ar e  d es cri b e d i n  S e cti o n  1 1. 2 . 
T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d  d uri n g t h e  S cr e e ni n g  visit,  w hi c h  m a y  b e s plit i nt o 
t w o  visits: 
•   O bt ai n  writt e n i nf or m e d  c o ns e nt f or t h e st u d y  
•   R e vi e w i n cl usi o n  a n d  e x cl usi o n  crit eri a  
•   R e c or d  d e m o gr a p hi c i nf or m ati o n  
•   R e c or d  m e di c al,  n e ur ol o gi c al,  a n d  e pil e ps y  hist or y  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 8  of  1 9 4  
•   R e c or d  c urr e nt  e pil e ps y st at us ( n u m b er/t y p e/ d ur ati o n s ei z ur es  p er  m o nt h)   
•   R e c or d  pri or  m e di c ati o ns  
•   C o m pl et e  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht,  w ei g ht,  a n d  c al c u l ati o n  of  B MI 
•   C o m pl et e  n e ur ol o gi c al  e x a mi n ati o n  
•   1 2 -l e a d  el e ctr o c ar di o gr a m 
•   D o p pl er  E C H O   
•   Vit al si g ns  (bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e ) 
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e ari n g  p ot e nti al  
•   L a b or at or y  e v al u ati o n (s er u m  c h e mistr y,  h e m at ol o g y,  uri n al ysis , t ests  of  gr o wt h  a n d 
pr e c o ci o us  p u b ert y,  c o a g ul ati o n ) 
•   Uri n e  T H C  p a n el  
•   W h ol e  bl o o d  C B D  
•   O bt ai n  bl o o d s a m pl e f or  e pil e ps y  g e n ot y p e  p a n el  
•   O bt ai n  b u c c al  s w a b f or  C Y P 2 D 6  g e n ot y p e/p h e n ot y p e  c h ar a ct eri z ati o n.  
 
O nl y  eli gi bl e s u bj e cts  as s p e cifi e d  b y t h e i n cl usi o n  a n d  e x cl usi o n  crit eri a  wit h  a n i n d e p e n d e ntl y 
c o nfir m e d  di a g n osis  of  D r a v et s y n dr o m e b y t h e  E pil e ps y  St u d y  C o ns orti u m  will  b e  e nr oll e d 
i nt o t h e st u d y.  
Aft er  e nr oll m e nt i nt o t h e st u d y,  e a c h s u bj e ct  will  b e iss u e d  a  “ S u bj e ct  C ar d ”  c o nt ai ni n g 
i nf or m ati o n  a b o ut t h e s u bj e ct’s  p arti ci p ati o n i n t h e st u d y.   T h e s u bj e ct  or  p ar e nt/ c ar e gi v er  will 
b e  a d vis e d t o r et ai n t his  c ar d  o n  his  p ers o n f or t h e  e ntir e  d ur ati o n  of t h e st u d y s o t h at t h e 
i n v esti g at or  or t h e S p o ns or  c a n  b e  c o nt a ct e d i n  c a s e  of  e m er g e n c y.  
If  a s u bj e ct  d o es  n ot  m e et  all i n cl usi o n/ e x cl usi o n  crit eri a  at t h e ti m e  of t h e  S cr e e ni n g  Visit, t h e 
s u bj e ct  m a y  b e r es cr e e ne d l at er t o  d et er mi n e  eli gi bilit y,  u p o n  a p pr o v al fr o m t h e  M e di c al 
M o nit or.    
6. 1. 2   
S T U D Y  D A Y  -1   
O n  t h e d a y  pri or t o  d osi n g, s u bj e cts  will r et ur n t o t h e  C R U f or  a n  o ut p ati e nt  visit . T h e i d e ntit y 
of t h e s u bj e cts  will  b e  c o nfir m e d  at  a d missi o n  a n d  at  pr e -d os e. I n  a d diti o n, t h e  o n g oi n g 
eli gi bilit y  of s u bj e cts  will  b e r e -ass ess e d i n cl u di n g: r e vi e w  of i n cl usi o n  a n d  e x cl usi o n  crit e ri a, 
a n y  u p d at es t o s cr e e ni n g  m e di c al  hist or y, s y m pt o m -d eri v e d  p h ysi c al  e x a m ( at t h e i n v esti g at or’s 
dis cr eti o n),  w ei g ht  a n d  B MI,  uri n e  pr e g n a n c y t est f or s u bj e cts  of  c hil d b e ari n g  p ot e nti al , vit al 
si g ns a n d  cli ni c al l a bs ,  w h ol e  bl o o d  C B D  a n d  uri n e  T H C  will b e  c oll e ct e d . T h es e  ar e  b as eli n e 
l a b  ass ess m e nts  a n d r es ults  will  n ot  b e  a v ail a bl e  pri or t o  d osi n g.  A d v ers e  e v e nts  a n d 
c o n c o mit a nt  m e di c ati o ns  will  b e r e c or d e d.  S u bj e cts  will  b e  dis c h ar g e d fr o m t h e  C R U  or 
p er mitt e d t o st a y  o v er ni g ht,  as  n e e d e d .   F oll o wi n g di n n er  a n d  a li g ht  e v e ni n g s n a c k, s u bj e cts 
will  b e r e q uir e d t o f ast  o v er ni g ht (f or  at l e ast  1 0  h o urs).  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  7 9  of  1 9 4  
6. 1. 3   
S T U D Y  D A Y  1   
O n t h e  m or ni n g  of  t h e  n e xt  d a y, St u d y  D a y  1, s u bj e cts  will r et ur n t o t h e  C R U  b et w e e n  6: 0 0 
A M  a n d  7: 0 0  A M.  Pri or t o  d osi n g, t h e i d e ntit y  of  t h e s u bj e ct  will  b e r e c o nfir m e d,  vit al si g ns 
will  b e  ass ess e d .  S u bj e cts  will t h e n  b e  pr o vi d e d  wit h  a li g ht, l o w f at  br e a kf ast.  F oll o wi n g 
br e a kf ast, s u bj e cts  will  c o nti n u e t o f ast f or  a p pr o xi m at el y  4  h o urs  p ost -d os e  at  w hi c h ti m e 
l u n c h  will  b e  pr o vi d e d.   Wat er  will  n ot  b e r estri ct e d.   O n e  h o ur  or l ess  pri or t o  d osi n g , a  bl o o d 
s a m pl e f or  P K  ass ess m e nt  will  b e  o bt ai n e d fr o m  all s u bj e cts  (bl o o d  s a m pl es will  b e  o bt ai n e d 
vi a i n d w elli n g  c at h et er).   S u bj e cts  will t h e n t a k e t h eir  us u al  e pil e ps y  m e di c ati o ns.  B as e d  o n t h e 
tr e at m e nt  all o c ati o n,  e a c h s u bj e ct  will t h e n r e c ei v e t h eir  assi g n e d d os e  of  st u d y  m e di c ati o n 
( Z X 0 0 8). 
W it h  a d mi nistr ati o n  of t a bl ets/ c a ps ul es, s u bj e cts  will  b e  gi v e n  w at er i m m e di at el y f oll o wi n g 
or al  a d mi nistr ati o n.  W h e n s u bj e cts  ar e  a d mi nist er e d  a n  o r al s ol uti o n, t h e  d osi n g  v ess el  will  b e 
ri ns e d t wi c e  wit h  w at er  a n d t h e su bj e cts  will  c o ns u m e t h e ri ns e s ol uti o ns i m m e di at el y  aft er 
d osi n g.   T h e  e x a ct ti m e  of  d osi n g  will  b e  d e ci d e d  b as e d  o n l o gisti cs  a n d  will  b e  d o c u m e nt e d i n 
t h e s o ur c e  w or k b o o k.   D uri n g d osi n g, s u bj e cts  will  b e  o bs er v e d  b y st u d y st aff t o  e ns ur e t h e 
t a bl et/ c a ps ul e/s ol uti o n  h as  b e e n s w all o w e d.   M o ut h  a n d  h a n d  c h e c ks  will  b e  c o n d u ct e d  aft er 
d osi n g t o  e ns ur e t h at  all  m e di c ati o ns  h a v e  b e e n i n g est e d.  
F o ur  m L  bl o o d s a m pl es f or  P K  ass ess m e nt  will  b e  c oll e ct e d  at  2  h o urs,  4  h o urs,  8  h o urs,  a n d 
1 2  h o urs  p ost -d os e,  aft er  vit al si g ns  ar e  p erf or m e d.   Vit al si g ns  will  b e  p erf or m e d  at  2  a n d 
8  h o urs  p ost -d os e.   A n  e v e ni n g  m e al  will  b e  pr o vi d e d  at  a p pr o xi m at el y  9  h o urs  p ost -d os e  a n d 
a n  e v e ni n g s n a c k  at  a p pr o xi m at el y  1 2  h o urs  p ost -d os e . A p pr o xi m at el y  1 2  h o urs  p ost -d os e,  aft er 
t h e  1 2-h o ur  P K s a m pl e  h as  b e e n  c oll e ct e d,  s u bj e cts  will t a k e t h e  P M  d os e  of t h eir  us u al 
e pil e ps y  m e di c ati o ns.  R e p ort e d  or  o bs er v e d  a d v ers e  e v e nts  a n d  a n y  c o n c o mit a nt  m e di c ati o ns 
will  b e r e c or d e d,  a n d t h e s u bj e ct  will  b e  dis c h ar g e d fr o m t h e  C R U  or  p er mitt e d t o st a y 
o v er ni g ht, if r e q uir e d.  
6. 1. 4   
S T U D Y  D A Y  2   
T w e nt y -f o ur t o 3 6  h o urs  p ost -d os e, s u bj e cts  will r et ur n t o t h e  C R U f or  a fi n al  P K s a m pl e.   A  4 -
m L  bl o o d s a m pl e f or  P K  ass ess m e nt  will  b e  c oll e ct e d ,  a n d t h e ti m e r e c or d e d, aft er  vit al si g ns 
ar e  p erf or m e d.   R e p ort e d  or  o bs er v e d  a d v ers e  e v e nts  a n d  a n y  c o n c o mit a nt  m e di c ati o ns  will  b e 
r e c or d e d.  A s ei z ur e  di ar y  will  b e  pr o vi d e d  s o t h at  p ar e nts  c a n r e c or d  a n y sei z ur e  a cti vit y  t h at 
o c c ur s b et w e e n  t h e St u d y  D a y  2  a n d t h e  St u d y  D a y  1 5  visit.   
6. 1. 5   
S T U D Y  D A Y  1 5  
All  s u bj e cts will r et ur n t o t h e  C R U  o n  D a y  1 5.   T h e f oll o wi n g  will  b e r e c or d e d/ p erf or m e d:  
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n) fr o m  di ar y si n c e  pr e vi o us  visit  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 0  of  1 9 4  
•   A b br e vi at e d  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht  a n d  w ei g ht,  a n d  c al c ul ati o n  of  B MI  
•   A b br e vi at e d  n e ur ol o gi c al  e x a mi n ati o n  
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e ari n g  p ot e nti al  
•   R e c or d  c urr e nt  e pil e ps y st at us ( n u m b er/t y p e/ d ur ati o n s ei z u r es  p er  m o nt h) 
•   T a n n er  St a gi n g f or s u bj e cts  >  7  y e ars  of  a g e ( A p p e n di x  5 ) 
•   C oll e ct  pl as m a s a m pl e f or  b a c k gr o u n d  A E D  P K  e v al u ati o n  pri or t o t h e    m or ni n g  d os e 
of st u d y  m e di c ati o n(s)  
•   C oll e ct  a n d r e vi e w  di ar y  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e  di ar y  
•   A Es  
•   A d v ers e  e v e nts  of s p e ci al i nt er est ( A E SI ) 
•   C o n c o mit a nt  m e di c ati o ns  
•   A d mi nist er  h e alt h c ar e  utili z ati o n  q u esti o ns  
•   C -S S R S  C hil dr e n’s  B as eli n e/ S cr e e ni n g  Ass ess m e nt ( A p p e n di x  2 ) 
•   P e ds Q L  G e n eri c  C or e  S c al e  
•   B RI E F ( A p p e n di x  3 ) 
•   Q O L C E f or s u bj e cts  ≥ 5  y e ars  of  a g e ( A p p e n di x  4 ) 
•   P ar e nt/ C ar e gi v er  q u alit y  of lif e  (Q o L ) usi n g t h e  E Q -5 D -5 L s c al e ( A p p e n di x  7 ) 
•   P e ds Q L  F a mil y I m p a ct  M o d ul e ( A p p e n di x  6 ) 
•   Sl e e p  q u alit y  a n d  m e alti m e  b e h a vi or  q u esti o ns  
•   K ar oli ns k a  Sl e e pi n ess  S c al e   
•   Dis p e ns e st u d y  m e di c ati o n  
S u bj e cts  w h o  will  e nt er t h e  o p e n -l a b el e xt e nsi o n tri al  will  b e tr a nsiti o n e d t o  Z X 0 0 8  
( 0. 2 m g/ k g/ d a y) ,  a n d  will b e  dis p e n s e d st u d y  m e di c ati o n t o  b e gi n  t a ki n g t h e  n e xt  m or ni n g i n 
a c c or d a n c e  wit h t h e st u d y  pr ot o c ol ; s e e  S e cti o n 6. 1. 6 .  
6. 1. 6   
T r a nsiti o n  P e ri o d  
S u bj e cts  w h o  c o m pl et e  D a y  1 5  a cti viti es  will  e nt er  a tr a nsiti o n  p eri o d  w h er e t h e y  will r e c ei v e 
o p e n -l a b el Z X 0 0 8 ( 0. 2  m g/ k g/ d a y) .   S u bj e cts  will h a v e  e v er y -2 -w e e k  p h o n e  visits  a n d  will 
att e n d  e v er y -4 -w e e k  cli ni c  visits  u ntil t h e  d os e f or  C o h ort  2  h as  b e e n s el e ct e d  a n d t h e  o p e n -
l a b el e xt e nsi o n tri al  is o p e n f or  e nr oll m e nt .   T h e  n u m b er  of  p h o n e  a n d  cli ni c  visits  will  b e 
d et er mi n e d  b as e d  o n t h e  s el e cti o n  of t h e  d os e f or  C o h ort  2  a n d t h e  a v ail a bilit y  of t h e  o p e n -l a b el 
e xt e nsi o n tri al  n ot t o  e x c e e d  2 4  w e e ks.   
6. 1. 6. 1   
P h o n e  Visit s 6,  8 ,  1 0,  1 2,  1 4,  a n d  1 6 (St u d y  D a ys  2 9,  5 7,  8 5,  1 1 3 ,  1 4 1,  a n d  1 6 9) 
Sit e  p ers o n n el  will  c o nt a ct t h e s u bj e ct  vi a t el e p h o n e  o n  St u d y  D a ys  2 9,  5 7,  8 5,  1 1 3 ,  1 4 1,  a n d 
1 6 9  a n d r e c or d t h e f oll o wi n g:  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 1  of  1 9 4  
•   A Es  
•   A E SI  
•   C o n c o mit a nt  m e di c ati o ns  
•   H e alt h c ar e  utili z ati o n  q u esti o ns  
I n  a d diti o n, sit e  p ers o n n el  will r e vi e w st u d y  m e di c ati o n  d osi n g  pr o c e d ur e  a n d t h e  di ar y  e ntri es 
wit h t h e  p ar e nt/ c ar e gi v er.  
6. 1. 6. 2   
Cli ni c  Visit s 7,  9,  1 1,  1 3 ,  a n d  1 5 (St u d y  D a ys  4 3,  7 1,  9 9,  1 2 7 ,  a n d  1 5 5) 
S u bj e cts  will r e p ort t o t h e  cli ni c i n t h e  m or ni n g  of  St u d y  D a ys  4 3,  7 1,  9 9,  1 2 7 ,  a n d  1 5 5.  
S u bj e cts s h o ul d  n ot t a k e t h eir  m or ni n g  d os e(s)  of st u d y  m e di c ati o n  a n d  A E D  m e di c ati o n  pri or 
t o r e p orti n g t o t h e  cli ni c.   T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d: 
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n) fr o m  di ar y si n c e  pr e vi o us  visit   
•   R e c or d  c o n c o mit a nt  m e di c ati o ns  
•   A b br e vi at e d  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht  a n d  w ei g ht,  a n d  c al c ul ati o n  of  B MI  
•   A b br e vi at e d  n e ur ol o gi c al  e x a mi n ati o n  
•   V it al si g ns (b l o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e) 
•   1 2 -l e a d  el e ctr o c ar di o gr a m ( a c c or di n g t o t h e  E C H O s c h e d ul e  b el o w) 
•   D o p pl er  E C H O ( this  m ust  b e  o bt ai n e d  aft er  6  a n d  1 2  w e e ks  o n st u d y  m e di c ati o n; f or 
t h e  6-w e e k  ass ess m e nt,  a n y ti m e  b et w e e n  St u d y  D a y  4 5  a n d  St u d y  D a y  6 9 ,  a n d f or t h e 
1 2 -w e e k  ass ess m e nt,  a n y ti m e  b et w e e n  St u d y  D a y  8 7  a n d  St u d y  D a y  1 1 1 ) 
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e ari n g  p ot e nti al  
•   L a b or at or y  e v al u ati o n (s er u m  c h e mistr y  a n d  h e m at ol o g y,  a n d  uri n al ysis ; n ot e 
l ut ei ni zi n g  h or m o n e (L H ), f olli cl e sti m ul ati n g  h or m o n e (F S H ),  estr a di ol, t est ost er o n e, 
i ns uli n-li k e  gr o wt h f a ct or-1 ( I G F-1 ), gr o wt h  h or m o n e ( G H ),  a n d  c o a g ul ati o n will  o nl y 
b e  c oll e ct e d  o n  D a ys  7 1,  1 2 7,  a n d  1 9 3 ) 
•   Uri n e  T H C  p a n el  
•   W h ol e  bl o o d  C B D  
•   C oll e ct  pl as m a s a m pl e f or  b a c k gr o u n d  A E D  P K  e v al u ati o n  pri or t o t h e    m or ni n g  d os e 
of st u d y  m e di c ati o n(s)  ( Visits  7,  9,  a n d  1 1 [ D a ys  4 3,  7 1,  9 9, r es p e cti v el y]  o nl y) 
•   T a n n er  St a gi n g f or s u bj e cts  >  7  y e ars  of  a g e  ( Visit  1 1 [ D a y  9 9]  o nl y) (A p p e n di x  5 ) 
•   C oll e ct  a n d r e vi e w  di ar y  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e  di ar y  
•   A d mi nist er  h e alt h c ar e  utili z ati o n  q u esti o ns  
•   P ar e nt/ C ar e gi v er  Q o L  usi n g t h e  E Q -5 D -5 L s c al e ( A p p e n di x  7 ) 
•   C -S S R S  C hil dr e n’s  Si n c e  L ast  Visit  Ass ess m e nt ( A p p e n di x  2 ) 
•   P e ds Q L  G e n eri c  C or e  S c al e ( A p p e n di x  6 ) 
•   B RI E F ( A p p e n di x  3 ) 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 2  of  1 9 4  
•   Q O L C E  (A p p e n di x  4 ) 
•   P e ds Q L  F a mil y I m p a ct  M o d ul e  (A p p e n di x  6 ) 
•   C GI -I ( ass ess e d  b y  p ar e nt/ c ar e gi v er) 
•   C GI -I ( ass ess e d  b y i n v esti g at or) 
•   A d mi nist er sl e e p  q u alit y  a n d  m e al ti m e  b e h a vi or  q u esti o ns 
•   K ar oli ns k a  Sl e e pi n ess  S c al e ( A p p e n di x  8 ) 
•   R e c or d  A Es  
•   R e c or d  A E SI  
•   C oll e ct  us e d,  p arti all y  us e d  a n d  u n us e d st u d y  m e di c ati o n;  p erf or m  dr u g  a c c o u nt a bilit y 
a n d r e vi e w  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e st u d y  m e di c ati o n  
6. 1. 6. 3   
Cli ni c  Visit  1 7  ( D a y 1 8 3 ):   E n d  of  St u d y/ E a rl y  T e r mi n ati o n 
F or  C o h ort  1, t h e  E n d -of -St u d y  p arti ci p ati o n f or  a n i n di vi d u al s u bj e ct  o c c urs  aft er  t h e  d os e  of 
I M P  h as  b e e n s el e ct e d f or  C o h ort  2  a n d t h e s e p ar at e, l o n g-t er m e xt e nsi o n tri al  is  o p e n f or 
e nr oll m e nt . 
T h e  E n d -of -St u d y  visit  m a y  als o  o c c ur if t h e s u bj e ct  wit h dr a ws  p arti ci p ati o n fr o m t h e st u d y  or 
t h e S p o ns or  t er mi n at es t h e st u d y.  If t h e s u bje ct  wit h dr a ws  p arti ci p ati o n fr o m t h e st u d y, t h e y 
m a y  o n  a  c as e -b y -c as e  b asis,  b e  eli gi bl e f or  e ntr a n c e i nt o t h e s e p ar at e  o p e n -l a b el e xt e nsi o n tri al  
aft er  c o nsi d er ati o n  of t h e  cir c u mst a n c es  of t h e  e arl y t er mi n ati o n  a n d t h e  p ot e nti al  b e n efit -ris k 
of  c o nti n u e d  p arti ci p ati o n i n  a  Z X 0 0 8 tri al.   T h e  d e cisi o n  w h et h er t o  p er mit  o p e n -l a b el 
e xt e nsi o n tri al  p arti ci p ati o n r esi d es s ol el y  wit h t h e  S p o ns or ,  w h o  m a y  c o ns ult  wit h t h e sit e 
i n v esti g at or.  If t h e S p o ns or  t er mi n at es t h e st u d y  e arl y, t h e s u bj e ct  m a y  or  m a y  n ot  be  off er e d 
e nr oll m e nt i nt o t h e  o p e n -l a b el  e xt e nsi o n,  d e p e n di n g  o n t h e r e as o n f or t er mi n ati o n. 
S u bj e cts  will  visit t h e  cli ni c f or t h e  E n d -of -St u d y  visit if  o n e t h e f oll o wi n g  e v e nts  o c c ur:  
1.   T h e s u bj e ct  wit h dr a ws  or is  wit h dr a w n fr o m  p arti ci p ati o n i n t h e st u d y.  
2.   T h e  S p o ns or  t er mi n at es t h e st u d y. 
3.   T h e s u bj e ct  c o m pl et es  all st u d y r el at e d  visits  a n d  pr o c e d ur es.  
T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d:  
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n) fr o m  di ar y si n c e  pr e vi o us  visit   
•   R e c or d  c o n c o mit a nt  m e di c ati o ns  
•   C o m pl et e  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht  a n d  w ei g ht,  a n d  c al c ul ati o n  of  B MI  
•   C o m pl et e  n e ur ol o gi c al  e x a mi n ati o n  
•   V it al si g ns (bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e ) 
•   1 2 -l e a d  el e ctr o c ar di o gr a m 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 3  of  1 9 4  
•   D o p pl er  E C H O ( m ust  b e  p er f or m e d  a n y ti m e  b et w e e n  D a y 1 7 0  a n d  Visit  1 7 ; if s u bj e ct 
t er mi n at es  e arl y fr o m t h e st u d y, t h e  E C H O s h o ul d  b e s c h e d ul e d  as s o o n  as  pr a cti c al. If 
t h e  D a y 5 7  or  D a y  9 9  E C H O  w as  c o m pl et e d  ≤ 3 0  d a ys  pri or t o  e arl y t er mi n ati o n, t h e 
Visit  1 7  E C H O  will  n ot  b e  p erf o r m e d  pr o vi d e d t h e  p ar e nt/ g u ar di a n  a gr e es t o  bri n g t h e 
s u bj e ct t o t h e  cli ni c f or t h e  c ar di a c f oll o w -u p  visit (s e e  T a bl e  1 0 ). 
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e ari n g  p ot e nti al  
•   L a b or at or y  e v al u ati o n (s er u m  c h e mistr y  a n d  h e m at ol o g y,  a n d  uri n al ysis)  
•   Uri n e  T H C  p a n el  
•   W h ol e  bl o o d  C B D  
•   C oll e ct  pl as m a s a m pl e f or  b a c k gr o u n d  A E D  P K  e v al u ati o n  pri or t o t h e  m or ni n g  d os e  of 
st u d y  m e di c ati o n(s)  
•   T a n n er  St a gi n g f or s u bj e cts  >  7  y e ars  of  a g e ( A p p e n di x  5 ) 
•   C oll e ct  a n d r e vi e w  di ar y  wit h  p ar e nt/ c ar e gi v er  
•   C -S S R S  C hil dr e n’s  Si n c e  L ast  Visit  Ass ess m e nt ( A p p e n di x  2 ) 
•   C GI -I ( ass ess e d  b y  p ar e nt/ c ar e gi v er) 
•   C GI -I ( ass ess e d  b y i n v esti g at or)  
•   H e alt h c ar e  utili z ati o n  q u esti o ns  
•   D r a v et s y n dr o m e o ut c o m e s m e as ur es  
•   Sl e e p  q u alit y  a n d  m e al ti m e  b e h a vi or  q u esti o ns  
•   K ar oli ns k a  Sl e e pi n ess  S c al e ( A p p e n di x  8 ) 
•   P e ds Q L  G e n eri c  C or e  S c al e ( A p p e n di x  6 ) 
•   B RI E F ( A p p e n di x  3 ) 
•   Q O L C E ( A p p e n di x  4 ) 
•   P ar e nt/ C ar e gi v er  Q o L  usi n g t h e  E Q -5 D -5 L s c al e ( A p p e n di x  7 ) 
•   P e ds Q L  F a mil y I m p a ct  M o d ul e  (A p p e n di x  6 ) 
•   R e c or d  A Es  
•   R e c or d  A E SI  
•   C oll e ct  us e d,  p arti all y  us e d  a n d  u n us e d st u d y  m e di c ati o n;  p erf or m  dr u g  a c c o u nt a bilit y 
a n d r e vi e w  wit h  p ar e nt/ c ar e gi v er  
I nf or m e d  c o ns e nt f or t h e  o p e n-l a b el e xt e nsi o n tri al  m ust  b e si g n e d  at  Visit  1 7 . 
6. 2   
C O H O R T  2 :  S T U D Y  P R O C E D U R E S  
6. 2. 1   
B A S E LI N E  P E RI O D ( S T U D Y  D A Y  -4 2  T O  S T U D Y  D A Y  -1)  
T h e  B as eli n e  P eri o d  of t h e st u d y  e n c o m p ass es  t h e s cr e e ni n g  a cti viti es t h at  will  o c c ur  o n St u d y 
D a y  -4 2  as  w ell  as t h e  o bs er v ati o n  p eri o d  w h er e s u bj e cts  will  b e  ass ess e d f or  b as eli n e s ei z ur e 
a cti vit y  b as e d  o n r e c or di n gs  of  d ail y s ei z ur e  a cti vit y  e nt er e d i nt o  a  di ar y.    


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 4  of  1 9 4  
6. 2. 2   
S C R E E NI N G,  C LI NI C  VI SI T  1 ( S T U D Y  D A Y  -4 2  A N D  S T U D Y  D A Y  -4 1)  
S cr e e ni n g is t h e  pr e d et er mi n e d s eri es  of  pr o c e d ur es  wit h  w hi c h  e a c h i n v esti g at or s el e cts  a n 
a p pr o pri at e  a n d r e pr es e nt ati v e s a m pl e  of s u bj e cts f or  e nr oll m e nt i nt o  t h e st u d y. S el e ct 
scr e e n i n g d at a  will  b e  d o c u m e nt e d  i n t h e I V R/I W R a n d  e C R F.   
Writt e n i nf or m e d  p ar e nt al  or  g u ar di a n  c o ns e nt  a n d  ass e nt  of  mi n ors  (if t h e s u bj e ct is c a p a bl e  of 
pr o vi di n g  ass e nt)  m ust  b e  o bt ai n e d  b ef or e  a s u bj e ct  c a n st art  a n y  of t h e s cr e e ni n g  pr o c e d ur es. 
T h e  pr o c e d ur e(s) f or  o bt ai ni n g  writt e n i nf or m e d  c o ns e nt  a n d  ass e nt  of  mi n or (if t h e s u bj e ct is 
c a p a bl e  of  pr o vi di n g  ass e nt)  ar e  d es cri b e d i n  S e cti o n  1 1. 2 . 
T h e  S cr e e ni n g  visit  will  o c c ur  o n  St u d y  D a y  -4 2;  h o w e v er, t h e  pr o c e d ur es  m a y  b e s plit  o v er 
2  c o ns e c uti v e  d a ys ( e g , St u d y  D a y  -4 3  a n d  St u d y  D a y  -4 2 , or  St u d y  D a y -4 2  a n d  St u d y  D a y  -4 1). 
S plitti n g t h e  visit  pr o c e d ur es  a cr oss  2  n o ns e q u e nti al  d a ys r e q uir es t h e  a p pr o v al  of t h e  M e di c al 
M o nit or.  T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d f or  all s u bj e cts  b ef or e t h e st art  of s ei z ur e 
a cti vit y  o bs er v ati o n:  
•   O bt ai n  writt e n  i nf or m e d  c o ns e nt f or t h e st u d y 
•   O bt ai n  writt e n i nf or m e d  c o ns e nt fr o m  p ar e nt/ c ar e gi v er t o  c oll e ct  E Q -5 D -5 L  r ati n gs  of 
p ar e nt/ c ar e gi v er s y m pt o ms  a n d  q u alit y  of lif e  
•   R e vi e w i n cl usi o n  a n d  e x cl usi o n  crit eri a  
•   R e c or d  d e m o gr a p hi c  i nf or m ati o n 
•   R e c or d  m e di c al,  n e ur ol o gi c al,  a n d  e pil e ps y  hist or y  
•   R e c or d  c urr e nt  e pil e ps y st at us ( n u m b er/t y p e / d ur ati o n s ei z ur es  p er  m o nt h )  
•   C oll e ct  p ast  6  m o nt hs  ( or  a v ail a bl e  d ur ati o n) of  p ar e nt/ c ar e gi v er  s ei z ur e  di ar y  d at a if 
a v ail a bl e (s cr e e n s h ots  of  c ell  p h o n es  ar e  a c c e pt a bl e,  as  ar e  p h ot o c o pi es  of  p a p er  di ari es 
or  pri nt  o uts)  a n d  pl a c e i n s o ur c e fil e  
•   A d mi nist er  h e alt h c ar e  utili z ati o n  q u esti o ns  
•   A d mi nist er  D r a v et s y n dr o m e o ut c o m e s  m e as ur es  
•   R e c or d  pri or  m e di c ati o ns   
•   C o m pl et e  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht , w ei g ht ,  a n d  c al c ul ati o n  of  B MI 
•   C o m pl et e  n e ur ol o gi c al  e x a mi n ati o n  
•   1 2 -l e a d E C G  
•   D o p pl er  E C H O  (t his  m a y  b e  o bt ai n e d  a n y ti m e  b et w e e n D a y  -4 2  a n d  D a y  -2 1 ) 
•   V it al si g ns (bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e ) 
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e ari n g  p ot e nti al  
•   L a b or at or y  e v al u ati o n (s er u m  c h e mistr y , h e m at ol o g y,  uri n al ysis ,  et c) 
•   U ri n e  T H C  p a n el 
•   W h ol e  bl o o d  C B D  
•   O bt ai n  bl o o d s a m pl e f or  e pil e ps y  g e n ot y p e  p a n el  ( o n e  bl o o d s a m pl e  dr a w n  b et w e e n 
s cr e e ni n g  a n d  Visit 1 0)  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 5  of  1 9 4  
•   O bt ai n  b u c c al  s w a b f or  C Y P 2 D 6  g e n ot y p e/ p h e n ot y p e 
•   C -S S R S  C hil dr e n’s  B as eli n e/ S cr e e ni n g  Ass ess m e nt ( A p p e n di x  2 ) 
•   I nstr u ct p ar e nt/ c ar e gi v er  o n  us e  of  di ar y  
•   Dis p e ns e  di ar y  ( aft er  a b o v e  pr o c e d ur es  h a v e  b e e n  c o n cl u d e d) 
•   R e c or d  A Es  
•   R e c or d  A E SI s 
O nl y  eli gi bl e s u bj e cts  as s p e cifi e d  b y t h e i n cl usi o n  a n d  e x cl usi o n  crit eri a  wit h  a n i n d e p e n d e ntl y 
c o nfir m e d  di a g n osis  of  D r a v et s y n dr o m e b y t h e  E pil e ps y  St u d y  C o ns orti u m  will  b e  e nr oll e d i nt o 
t h e st u d y.  
Aft er   e nr oll m e nt  i nt o  t h e  st u d y,   e a c h  s u bj e ct   will   b e  iss u e d   a   “ S u bj e ct   C ar d ”   c o nt ai ni n g  
i nf or m ati o n  a b o ut t h e s u bj e ct’s  p arti ci p ati o n i n t h e st u d y.   T h e s u bj e ct  or p ar e nt/ c ar e gi v er  will 
b e   a d vis e d  t o  r et ai n  t his   c ar d   o n   his   p ers o n  f or  t h e   e ntir e   d ur ati o n   of  t h e  st u d y s o  t h at  t h e  
in v esti g at or  or t h e  S p o ns or  c a n  b e  c o nt a ct e d i n  c as e  of  e m er g e n c y.  
I n  c ert ai n  cir c u mst a n c es t h e S p o ns or  m a y  all o w s u bj e cts  w h o  di d  n ot  m e et  all i n cl usi o n/ e x cl usi o n 
crit eri a   at  t h e  ti m e   of  t h e   S cr e e ni n g   Visit  t o   h a v e  t h e  s cr e e ni n g   p eri o d   e xt e n d e d,   or  t o   b e  
r es cr e e ne d  f or  eli gi bilit y. I n  all  c as es t h e i n v esti g at or s h o ul d  c o ns ult  wit h t h e  M e di c al  M o nit or. 
D e cisi o ns  w h et h er t o  p er mit r es cr e e ni n g r esi d es s ol el y  wit h t h e  S p o ns or .  
T h e  d e cisi o n  w h et h er t o  p er mit  e xt e n d e d s cr e e ni n g  or r es cr e e ni n g  c a n  b e i nfl u e n c e d  b y  m a n y 
f act ors i n di vi d u al t o t h at s u bj e ct  c as e.  S o m e  g e n er al  pri n ci pl es  a p pl y:  
1.   If   b as eli n e  s ei z ur e  s cr e e ni n g  is   e xt e n d e d   or  t h e  s u bj e ct  is   dis c o nti n u e d   a n d  t h e n  
r es cr e e n e d, t h e s cr e e ni n g  p eri o d f or  est a blis hi n g t h e  b as eli n e s ei z ur e fr e q u e n c y  will  b e 
t h e i m m e di at e  6 w e e ks  b ef or e t h e r a n d o mi z ati o n  visit.  
2.   S u bj e cts  w h o  ar e f o u n d t o  b e  o n  a  pr o hi bit e d  m e di c ati o n  at t h e s cr e e ni n g  visit  m a y  b e 
w e a n e d  off  of t h at  m e di c ati o n  pr o vi d e d:  
a.   D e cisi o ns t o  wit h dr a w  a  dis all o w e d  c o n c o mit a nt  m e di c ati o n  m ust  b e  m a d e  wit h 
t h e  a gr e e m e nt  of t h e  pr es cri bi n g  p h ysi ci a n. 
b.   If t h e  m e di c ati o n  h as  a nti e pil e pti c  pr o p erti es,  a  w as h-o ut  of  at l e ast  5  h alf -li v es 
m ust  b e  c o m pl et e d  b ef or e  c oll e cti o n  of  b as eli n e s ei z ur e  d at a.   
c.   If  a  d e cisi o n  h as  b e e n  m a d e t o  w e a n  off  of  a  m e di c ati o n  wit h o ut  a nti e pil e pti c 
pr o p erti es  a n d t h e  w as h -o ut  p eri o d ( at l e ast  5  h alf -li v es) is  e x p e ct e d t o  b e s h ort er 
t h a n  5  w e e ks, t h e n t h e s u bj e ct  m a y r e m ai n i n s cr e e ni n g  a n d  c h art s ei z ur es  usi n g 
t h e s ei z ur e  di ar y. 
6. 2. 3   
P H O N E  VI SI T  2 ( S T U D Y  D A Y  -2 1)  
Sit e  p ers o n n el  will  c o nt a ct t h e s u bj e ct  vi a  t el e p h o n e  o n St u d y  D a y  -2 1  a n d r e c or d t h e 
f oll o wi n g: 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 6  of  1 9 4  
•   A Es  
•   A E SI  
•   C o n c o mit a nt  m e di c ati o ns  
I n  a d diti o n, sit e  p ers o n n el  will r e vi e w t h e  di ar y  e ntri es  wit h t h e p ar e nt/ c ar e gi v er.  
6. 2. 4   
C LI NI C  VI SI T  3 ( S T U D Y  D A Y  -1):  R A N D O MI Z A TI O N  
T his  p eri o d is i nt e n d e d t o  e ns ur e t h at s u bj e cts  m e et t h e st u d y  e ntr y  crit eri a  a n d  c o nfir m t h e y 
h a v e  e x p eri e n c e d  ≥  6  c o n v ulsi v e  s ei z ur es d uri n g t h e  6 -w e e k  B as eli n e  P eri o d ,  wit h  at l e ast  2 
s ei z ur es i n  e a c h 3 -w e e k  h alf  of t h e  B as eli n e  P eri o d .  S u bj e cts  m ust  h a v e  at l e ast  4 2  d a ys  of 
pr os p e cti v e  di ar y  d at a  at  Visit  3.  S u bj e cts  will r e p ort t o t h e  cli ni c i n t h e  m or ni n g  o n  St u d y   
D a y  -1 t o  all o w f or  pl as m a s a m pl e  c oll e cti o n f or  A E D  P K  e v al u ati o n  pri or t o t h e  m or ni n g  d os e 
of t h es e  m e di c ati o ns.  S u bj e cts s h o ul d  n ot t a k e t h eir  m or ni n g  d os e(s)  of  A E D  m e di c ati o n  pri or 
t o r e p orti n g t o t h e  cli ni c. 
T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d  o n  St u d y  D a y  -1 : 
•   R e vi e w i n cl usi o n  a n d  e x cl usi o n  crit eri a  
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n) fr o m  di ar y si n c e  pr e vi o us  visit  
a n d  c al c ul at e  t h e  n u m b er  of  c o n v ulsi v e s ei z ur es  d uri n g t h e first  3  w e e ks, t h e s e c o n d  3 
w e e ks,  a n d  o v er t h e f ull  6 -w e e k s  of t h e o bs er v ati o n  p eri o d.  
•   R e c or d  pri or  m e di c ati o ns si n c e  pr e vi o us  visit  
•   C o m pl et e  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht  a n d  w ei g ht ,  a n d  c al c ul ati o n  of  B MI 
•   A b br e vi at e d  n e ur ol o gi c al  e x a mi n ati o n  
•   Vit al si g ns  (bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e ) 
•   1 2 -l e a d  EC G  
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e ari n g  p ot e nti al  
•   L a b or at or y  e v al u ati o n (s er u m  c h e mistr y,  a n d  h e m at ol o g y,  a n d  uri n al ysis)  
•   C oll e ct  pl as m a s a m pl e f or  b a c k gr o u n d  A E D  P K  e v al u ati o n  pri or t o t h e  m or ni n g  d os e  of 
st u d y  m e di c ati o n(s)  
•   Uri n e  T H C  p a n el  
•   W h ol e  bl o o d  C B D  
•   T a n n er  St a gi n g  f or s u bj e cts >  7  y e ars  of  a g e  (A p p e n di x  5 ) 
•   C oll e ct  a n d r e vi e w  di ar y  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e  di ar y  
•   C -S S R S  C hil dr e n’s  Si n c e  L ast  Visit  Ass ess m e nt ( A p p e n di x  2 ) 
•   H e alt h c ar e  utili z ati o n  q u esti o ns  
•   P e ds Q L  G e n eri c  C or e  S c al e  (A p p e n di x  6 ) 
•   B RI E F  (A p p e n di x  3 ) 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 7  of  1 9 4  
•   Q O L C E  (A p p e n di x  4 ) 
•   P ar e nt/ C ar e gi v er  Q o L  usi n g t h e  E Q -5 D -5 L s c al e ( A p p e n di x  7 ) 
•   P e ds Q L  F a mil y I m p a ct  M o d ul e  (A p p e n di x  6 ) 
•   K ar oli ns k a  Sl e e pi n ess  S c al e   
•   R e c or d  A Es  
•   R e c or d  A E SI  
•   W h e n  eli gi bilit y f or t h e  Titr ati o n  P eri o d is  c o nfir m e d, r a n d o mi z e ( bli n d e d) s u bj e ct t o 
tr e at m e nt  assi g n m e nt ( Z X 0 0 8  or  pl a c e b o) 
•   Dis p e ns e st u d y  m e di c ati o n  (If  a d mi nistr ati o n  of t h e first  d os e  of st u d y m e di c ati o n 
o c c urs i n t h e  cli ni c, t h e  n e xt  d os e s h o ul d  b e  at l e ast  8  h o urs l at er  or t h e f oll o wi n g 
m or ni n g.  T h e  d os e  o n t h e f oll o wi n g  m or ni n g  will  c o u nt  as  St u d y  D a y  1 .) 
6. 2. 5   
TI T R A TI O N  A N D  M AI N T E N A N C E  P E RI O D S  
6. 2. 5. 1   
Tit r ati o n  P e ri o d:  D a y  1  
S u bj e cts  will  t a k e t h eir first d os e  of st u d y  m e di c ati o n  i n t h e  m or ni n g  of St u d y  D a y  1.   St u d y 
D a y  1 is  c o nsi d er e d t h e first  d a y  of  d osi n g,  e v e n  f or t h e s u bj e cts t h at r e c ei v e d  a n i n-cli ni c  d os e 
o n  S t u d y  D a y -1.  
6. 2. 5. 2   
P h o n e  o r  Cli ni c  Visit  4 ( Tit r ati o n  P e ri o d : D a y  8 )  
Sit e  p ers o n n el  will  c o nt a ct t h e s u bj e ct  vi a t el e p h o n e  or t h e s u bj e ct  c a n  b e r e vi e w e d i n t h e  cli ni c  
o n  Titr ati o n  P eri o d  D a y  8  a n d r e c or d t h e f oll o wi n g:  
•   A Es  
•   A E SI  
•   C o n c o mit a nt  m e di c ati o ns  
I n  a d diti o n, sit e  p ers o n n el will  r e vi e w st u d y  m e di c ati o n  d osi n g  pr o c e d ur e  a n d  t h e di ar y  e ntri es 
wit h t h e  p ar e nt/ c ar e gi v er.  
6. 2. 5. 3   
Cli ni c  Visit  5  ( Tit r ati o n  P e ri o d: D a y  1 5 ) 
S u bj e cts  will r e p ort t o t h e  cli ni c i n t h e  m or ni n g  o n  Titr ati o n  P eri o d  D a y  1 5.   T h e f oll o wi n g 
pr o c e d ur es  will  b e  p erf or m e d:  
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n)  fr o m  di ar y si n c e  pr e vi o us  visit  
•   R e c or d  c o n c o mit a nt  m e di c ati o ns  
•   A b br e vi at e d  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht  a n d  w ei g ht,  a n d  c al c ul ati o n  of  B MI  
•   A b br e vi at e d  n e ur ol o gi c al  e x a mi n ati o n  
•   Vit al si g ns ( bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y  r at e ) 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 8  of  1 9 4  
•   C oll e ct  a n d r e vi e w  di ar y  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e  di ar y  
•   C GI -I ( ass ess e d  b y  p ar e nt/ c ar e gi v er) 
•   C GI -I ( ass ess e d  b y i n v esti g at or) 
•   H e alt h c ar e r es o ur c e  utili z ati o n  q u esti o ns  
•   R e c or d  A Es  
•   R e c or d  A E SI  
•   C oll e ct  us e d,  p arti all y  us e d  a n d  u n us e d st u d y  m e di c ati o n;  p erf or m  dr u g  a c c o u nt a bilit y 
a n d r e vi e w  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e st u d y  m e di c ati o n  
6. 2. 5. 4   
Cli ni c  Visit  6  (M ai nt e n a n c e  P e ri o d : D a y  2 2)   
S u bj e cts  will r e p ort t o t h e  c li ni c i n t h e  m or ni n g o n  M ai nt e n a n c e  P eri o d  D a y  2 2 .  S u bj e cts 
s h o ul d  n ot t a k e t h eir  m or ni n g  d os e(s)  of  A E D  m e di c ati o n  pri or t o r e p orti n g t o t h e  cli ni c.   T h e 
f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d: 
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e / d ur ati o n) fr o m di ar y  si n c e  pr e vi o us  visit   
•   R e c or d  c o n c o mit a nt  m e di c ati o ns  
•   A b br e vi at e d  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht  a n d  w ei g ht ,  a n d  c al c ul ati o n  of  B MI 
•   A b br e vi at e d  n e ur ol o gi c al  e x a mi n ati o n  
•   V it al si g ns (bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e ) 
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e a ri n g  p ot e nti al 
•   L a b or at or y  e v al u ati o n (s er u m  c h e mistr y  a n d  h e m at ol o g y,  a n d  uri n al ysis)  
•   Uri n e  T H C  p a n el  
•   W h ol e  bl o o d  C B D  
•   C oll e ct  pl as m a s a m pl e f or  b a c k gr o u n d  A E D  P K  e v al u ati o n  pri or t o t h e  m or ni n g  d os e  of 
st u d y  m e di c ati o n(s)  
•   C oll e ct  a n d r e vi e w  di ar y  wit h  p ar e nt/ c ar e gi v er  
•   A d mi nist er sl e e p  q u alit y  a n d  m e alti m e  b e h a vi or  q u esti o ns  
•   A d mi nist er  K ar oli ns k a  Sl e e p i n ess S c al e ( A p p e n di x  8 ) 
•   Dis p e ns e  di ar y  
•   C -S S R S  C hil dr e n’s  Si n c e  L ast  Visit  Ass ess m e nt ( A p p e n di x  2 ) 
•   C GI -I ( ass ess e d  b y  p ar e nt/ c ar e gi v er) 
•   C GI -I ( ass ess e d  b y i n v esti g at or) 
•   R e c or d  A Es  
•   R e c or d  A E SI  
•   C oll e ct  us e d,  p arti all y  us e d  a n d  u n us e d st u d y  m e di c ati o n;  p erf or m  dr u g  a c c o u nt a bilit y  
a n d r e vi e w  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e st u d y  m e di c ati o n  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  8 9  of  1 9 4  
6. 2. 5. 5   
P h o n e  Visit  7  (M ai nt e n a n c e  P e ri o d : D a y  3 6 ) 
Sit e  p ers o n n el  will  c o nt a ct t h e s u bj e ct  vi a t el e p h o n e  o n  M ai nt e n a n c e  P eri o d  D a y  3 6  a n d r e c or d 
t h e f oll o wi n g: 
•   A Es  
•   A E SI  
•   C o n c o mit a nt  m e di c ati o ns  
•   H e alt h c ar e  utili z ati o n  q u esti o ns  
I n  a d diti o n, sit e  p ers o n n el  will r e vi e w st u d y m e di c ati o n  d osi n g  pr o c e d ur e  a n d t h e  di ar y  e ntri es 
wit h t h e  p ar e nt/ c ar e gi v er.  
6. 2. 5. 6   
Cli ni c  Visit  8  ( M ai nt e n a n c e  P e ri o d: D a y  5 0 ) 
S u bj e cts  will r e p ort t o t h e  cli ni c  i n t h e  m or ni n g o n  M ai nt e n a n c e  P eri o d  D a y  5 0 .   S u bj e cts 
s h o ul d  n ot t a k e t h eir  m or ni n g  d os e (s) of st u d y  m e di c ati o n  a n d  A E D  m e di c ati o n  pri or t o 
r e p orti n g t o t h e  cli ni c.   T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d: 
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n) fr o m  di ar y si n c e  pr e vi o us  visit   
•   R e c or d  c o n c o mit a nt  m e di c ati o ns  
•   A b br e vi at e d  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht  a n d  w ei g ht ,  a n d  c al c ul ati o n  of  B MI 
( N ot e: if t h e s u bj e ct’s  w ei g ht is ± 2 5 %  of t h e  w ei g ht  at  D a y  -1, t h e I M P  d os e  will  b e 
r e c al c ul at e d)   
•   V it al si g ns (bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e ) 
•   1 2 -l e a d E C G  
•   D o p pl er  E C H O (t his  m ust  b e  o bt ai n e d  a n y ti m e  b et w e e n  D a y  4 0  a n d  D a y  5 4 ) 
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e ari n g  p ot e nti al  
•   L a b or at or y  e v al u ati o n (s er u m  c h e mistr y  a n d  h e m at ol o g y,  a n d  uri n al ysis)  
•   Uri n e  T H C  p a n el  
•   W h ol e  bl o o d  C B D  
•    C oll e ct  pl as m a s a m pl e f or  b a c k gr o u n d  A E D  P K  e v al u ati o n  pri or t o t h e  m or ni n g  d os e  of 
st u d y  m e di c ati o n(s)  
•   C oll e ct  a n d r e vi e w  di ar y  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e  di ar y  
•   C -S S R S  C hil dr e n’s  Si n c e  L ast  Visit  Ass ess m e nt ( A p p e n di x  2 ) 
•   P e ds Q L  G e n eri c  C or e  S c al e  (A p p e n di x  6 ) 
•   B RI E F  (A p p e n di x  3 ) 
•   Q O L C E  (A p p e n di x  4 ) 
•   P e ds Q L  F a mil y I m p a ct  M o d ul e ( A p p e n di x  6 ) 
•   C GI -I ( ass ess e d  b y  p ar e nt/ c ar e gi v er) 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 0  of  1 9 4  
•   C GI -I ( ass ess e d  b y i n v esti g at or) 
•   A d mi nist er s l e e p q u alit y  a n d  m e al ti m e  b e h a vi or q u esti o ns  
•   K ar oli ns k a  Sl e e p i n ess S c al e  (A p p e n di x  8 ) 
•   R e c or d  A Es  
•   R e c or d  A E SI  
•   C oll e ct  us e d,  p arti all y  us e d  a n d  u n us e d st u d y  m e di c ati o n;  p erf or m  dr u g  a c c o u nt a bil it y 
a n d r e vi e w  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e st u d y  m e di c ati o n  
6. 2. 5. 7   
P h o n e  Visit  9  (M ai nt e n a n c e  P e ri o d : D a y  6 4 ) 
Sit e  p ers o n n el  will  c o nt a ct t h e s u bj e ct  vi a t el e p h o n e  o n  M ai nt e n a n c e  P eri o d  D a y  6 4  a n d r e c or d 
t h e f oll o wi n g: 
•   A Es  
•   A E SI  
•   C o n c o mit a nt  m e di c ati o ns  
•   H e alt h c ar e  utili z ati o n  q u esti o ns  
I n  a d diti o n, sit e  p ers o n n el  will r e vi e w st u d y  m e di c ati o n  d osi n g  pr o c e d ur e  a n d t h e  di ar y  e ntri es 
wit h t h e  p ar e nt/ c ar e gi v er.  
6. 2. 5. 8   
Cli ni c  Visit  1 0 ( M ai nt e n a n c e  P e ri o d  D a y : 7 8 ) 
S u bj e cts  will r e p ort t o t h e  cli ni c  o n  M ai nt e n a n c e  P eri o d  D a y  7 8 .  T h e f oll o wi n g  pr o c e d ur es  will 
b e  p erf or m e d:  
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n) fr o m  di ar y si n c e  pr e vi o us  visit   
•   R e c or d  c o n c o mit a nt  m e di c ati o ns  
•   A b br e vi at e d  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht  a n d  w ei g ht ,  a n d  c al c ul ati o n  of  B MI 
•   V it al si g ns (bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e ) 
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e ari n g  p ot e nti al  
•   L a b or at or y  e v al u ati o n (s er u m  c h e mistr y  a n d  h e m at ol o g y,  a n d  uri n al ysis)  
•   Uri n e  T H C  p a n el  
•   W h ol e  bl o o d  C B D  
•   C oll e ct  a n d r e v i e w  di ar y  wit h p ar e nt/ c ar e gi v er  
•   Dis p e ns e  di ar y  
•   C -S S R S  C hil dr e n’s  Si n c e  L ast  Visit  Ass ess m e nt ( A p p e n di x  2 ) 
•   C GI -I ( ass ess e d  b y  p ar e nt/ c ar e gi v er) 
•   C GI -I ( ass ess e d  b y i n v esti g at or) 
•   A d mi nist er sl e e p  q u alit y  a n d  m e alti m e  b e h a vi o r q u esti o ns  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 1  of  1 9 4  
•   K ar oli ns k a  Sl e e p i n ess S c al e ( A p p e n di x  8 ) 
•   R e c or d  A Es  
•   R e c or d  A E SI  
•   C oll e ct  us e d,  p arti all y  us e d  a n d  u n us e d st u d y  m e di c ati o n;  p erf or m  dr u g  a c c o u nt a bilit y 
a n d r e vi e w  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e st u d y  m e di c ati o n  
At  Cli ni c  Visit  1 0,  c o m pli a nt s u bj e cts  w h o  h a v e t ol er at e d I M P s h o ul d  b e  pr es e nt e d  wit h t h e 
I C F f or t h e  o p e n-l a b el e xt e nsi o n tri al .  I nf or m e d  c o ns e nt f or t h e  o p e n-l a b el e xt e nsi o n tri al  m ust 
b e si g n e d  at  Visit  1 2  or  e arli er i n  or d er t o  e nt er t h e  o p e n -l a b el e xt e nsi o n tri al . 
6. 2. 5. 9   
P h o n e  Visit  1 1 ( M ai nt e n a n c e  P e ri o d : D a y  9 2 ) 
Sit e  p ers o n n el  will  c o nt a ct t h e s u bj e ct  vi a t el e p h o n e  o n  M ai nt e n a n c e  P eri o d  D a y  9 2  a n d r e c or d 
t h e f oll o wi n g: 
•   A Es  
•   A E SI  
•   C o n c o mit a nt  M e di c ati o ns  
•   H e alt h c ar e  utili z ati o n  q u esti o ns  
I n  a d diti o n, sit e  p ers o n n el will  r e vi e w st u d y  m e di c ati o n  d osi n g  pr o c e d ur e  a n d  t h e  di ar y\e ntri es 
wit h t h e  p ar e nt/ c ar e gi v er.   
6. 2. 5. 1 0   
Cli ni c  Visit  1 2 ( E n d  of  St u d y/ E a rl y  T e r mi n ati o n : D a y  1 0 6 ) 
T h e  E n d -of -S t u d y  p arti ci p ati o n f or  a n i n di vi d u al s u bj e ct  o c c urs  aft er h e /s h e h as r e c ei v e d  I M P 
f or 1 2  w e e ks i n t h e  M ai nt e n a n c e  P eri o d . At  t h e  E n d-of -St u d y  visit , t h e s u bj e ct m a y  e nr oll i nt o 
t h e s e p ar at e e xt e nsi o n tri al  if t h e y  h a v e  c o m pl et e d  1 2  w e e ks of tr e at m e nt  i n t h e  M ai nt e n a n c e 
P eri o d .  Ot h er  cir c u mst a n c es f or  p arti ci p ati o n i n t h e  e xt e nsi o n tri al  ar e  d es cri b e d i n  S e cti o n  4. 8 . 
T h e  E n d -of -S t u d y visit  m a y  als o  o c c ur if t h e s u bj e ct  wit h dr a ws  p arti ci p ati o n fr o m t h e st u d y  or 
t h e S p o ns or  t er mi n at es t h e st u d y.  If t h e s u bj e ct  wit h dr a ws  p arti ci p ati o n fr o m t h e st u d y, t h e y 
m a y  o n  a  c as e -b y -c as e  b asis,  b e  eli gi bl e f or  e ntr a n c e i nt o t h e s e p ar at e  o p e n -l a b el e xt e nsi o n tri al  
aft er  c o nsi d er ati o n  of t h e  cir c u mst a n c es  of t h e  e arl y t er mi n ati o n  a n d t h e  p ot e nti al  b e n efit -ris k 
of  c o nti n u e d  p arti ci p ati o n i n  a  Z X 0 0 8 tri al.   T h e  d e cisi o n  w h et h er t o  p er mit  o p e n -l a b el 
e xt e nsi o n tri al  p arti ci p ati o n r esi d es s ol el y  wit h t h e  S p o ns or ,  w h o  m a y  c o ns ult  wit h t h e sit e 
i n v esti g at or.  If t h e S p o ns or  t er mi n at es t h e st u d y  e arl y, t h e s u bj e ct  m a y  or  m a y  n ot b e  off er e d 
e nr oll m e nt  i nt o t h e  o p e n-l a b el  e xt e nsi on,  d e p e n di n g  o n t h e r e as o n f or t er mi n ati o n.  
S u bj e cts  will  visit  t h e  cli ni c f or t h e  E n d-of -St u d y  v isit if o n e t h e f oll o wi n g  e v e nts  o c c ur : 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 2  of  1 9 4  
•   T h e s u bj e ct  wit h dr a ws  or is  wit h dr a w n  fr o m  p arti ci p ati o n i n t h e st u d y. 
•   T h e  S p o ns or  t er mi n at es t h e st u d y. 
•   T h e s u bj e ct  c o m pl et es  all st u d y r el at e d  visits  a n d  pr o c e d ur es.  
T h e f oll o wi n g  pr o c e d ur es  will  b e  p erf or m e d:  
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n) fr o m  di ar y si n c e  pr e vi o us  visit   
•   R e c or d  c o n c o mit a nt  m e di c ati o ns  
•   C o m pl et e  p h ysi c al  e x a mi n ati o n, i n cl u di n g  h ei g ht  a n d  w ei g ht ,  a n d  c al c ul ati o n  of  B MI 
•   C o m pl et e  n e ur ol o gi c al  e x a mi n ati o n  
•   V it al si g ns (bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e ) 
•   1 2 -l e a d E C G  
•   D o p pl er  E C H O ( m ust  b e  p erf or m e d  a n y ti m e  b et w e e n  D a y  9 0  a n d  Visit  1 3 ; if s u bj e ct 
t er mi n at es  e arl y fr o m t h e st u d y, t h e E C H O s h o ul d  b e s c h e d ul e d  as s o o n  as  pr a cti c al . If 
t h e  D a y  4 3  E C H O  w as  c o m pl et e d ≤ 3 0  d a ys  pri or t o  e arl y t er mi n ati o n, t h e  Visit  1 2 
E C H O  will  n ot  b e  p erf or m e d  pr o vi d e d t h e  p ar e nt/ g u ar di a n  a gr e es t o  bri n g t h e  s u bj e ct t o 
t h e  cli ni c f or t h e  c ar di a c f oll o w-u p  visit ( s e e T a bl e  1 0 ). 
•   Uri n e  pr e g n a n c y t est f or f e m al es  of  c hil d -b e ari n g  p ot e nti al  
•   L a b or at or y  e v al u ati o n ( s er u m  c h e mistr y  a n d  h e m at ol o g y,  a n d  uri n al ysis)  
•   Uri n e  T H C  p a n el  
•   W h ol e  bl o o d  C B D  
•   C oll e ct  pl as m a s a m pl e f or  b a c k gr o u n d  A E D  P K  e v al u ati o n  pri or t o t h e  m or ni n g  d os e  of 
st u d y  m e di c ati o n(s)  
•   T a n n er  St a gi n g  f or s u bj e cts  > 7  y e ars  of  a g e  (A p p e n di x  5 ) 
•   C oll e ct  a n d r e vi e w  di ar y  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e  di ar y  
•   C -S S R S  C hil dr e n’s  Si n c e  L ast  Visit  Ass ess m e nt ( A p p e n di x  2 ) 
•   C GI -I ( ass ess e d  b y  p ar e nt/ c ar e gi v er) 
•   C GI -I ( ass ess e d  b y i n v esti g at or)  
•   H e alt h c ar e  utili z ati o n  q u es ti o ns 
•   S l e e p q u alit y  a n d  m e alti m e  b e h a vi or  q u esti o ns   
•   K ar oli ns k a  Sl e e p i n ess S c al e ( A p p e n di x  8 ) 
•   P e ds Q L  G e n eri c  C or e  S c al e ( A p p e n di x  6 ) 
•   B RI E F  (A p p e n di x  3 ) 
•   Q O L C E  (A p p e n di x  4 ) 
•   P ar e nt/ C ar e gi v er  Q o L  usi n g t h e  E Q -5 D -5 L s c al e ( A p p e n di x  7 ) 
•   P e ds Q L  F a mil y I m p a ct  M o d ul e ( A p p e n di x  6 ) 
•   R e c or d  A Es  
•   R e c or d  A E SI  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 3  of  1 9 4  
•   C oll e ct  us e d,  p arti all y  us e d  a n d  u n us e d st u d y  m e di c ati o n;  p erf or m  dr u g  a c c o u nt a bilit y 
a n d r e vi e w  wit h  p ar e nt/ c ar e gi v er  
•   Dis p e ns e st u d y  m e di c ati o n f or t a p er f or s u bj e cts  n ot  e nr olli n g i n t h e  o p e n -l a b el 
e xt e nsi o n tri al  
•   Dis p e ns e st u d y  m e di c ati o n f or tr a nsiti o n  f or s u bj e cts  e nr olli n g i n t h e  o p e n-l a b el 
e xt e nsi o n tri al  
I nf or m e d  c o ns e nt f or t h e  o p e n-l a b el e xt e nsi o n tri al  m ust  b e si g n e d  at  Visit  1 2 (if  n ot si g n e d 
e arli er) i n  or d er t o  e nt er t h e  o p e n -l a b el e xt e nsi o n tri al . 
6. 2. 5. 1 1   
F oll o w -u p  Visit ( Cli ni c  Visit  1 3;  D a y  1 2 0 ) 
S u bj e cts  will r e p ort t o t h e  cli ni c i n t h e  m or ni n g  of  Visit  1 3.   S u bj e cts s h o ul d  n ot t a k e t h eir l ast 
d os e  of st u d y  m e di c ati o n  or  m or ni n g  d os e  of  a nti e pil e pti c  m e di c ati o n  pri or t o r e p orti n g t o t h e 
cli ni c s o t h at  4  bl o o d s a m pl es  c a n  b e  o bt ai n e d f or  st e a d y-st at e P K.  
F o r s u bj e cts  e nt e ri n g t h e  o p e n -l a b el e xt e nsi o n t ri al , t h e s u bj e ct  will  visit t h e  cli ni c  o n 
Visit  1 3 ( D a y  1 2 0 ).   T h e f oll o wi n g  will  b e r e c or d e d/ p erf or m e d  a n d t h e s u bj e ct  will 
i m m e di at el y  b e  e nr oll e d i n t h at s e p ar at e st u d y: 
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n) fr o m  di ar y si n c e  pr e vi o us  visit   
•   A Es  
•   A E SI  
•   C o n c o mit a nt  m e di c ati o ns  
•   C oll e ct  us e d,  p arti all y  us e d  a n d  u n us e d st u d y  m e di c ati o n;  p erf or m  dr u g  a c c o u nt a bilit y 
a n d r e vi e w  wit h  p ar e nt/ c ar e gi v er  
•   C oll e ct  pl as m a s a m pl e f or  Z X 0 0 8  P K  e v al u ati o n  pri or t o t h e  m or ni n g  d os e  of st u d y (l ast 
d os e  of  Pr ot o c ol  1 5 0 4 st u d y  m e di c ati o n)  a n d t h eir  us u al  A E D  m e di c ati o n(s)  
•   C oll e ct  a d diti o n al  pl as m a s a m pl es f or  Z X 0 0 8  P K  e v al u ati o n  at  1,  2,  a n d  4 -6  h o urs  p ost -
d os e  
If t h e s u bj e ct  d o es  n ot  e nt e r t h e  o p e n -l a b el e xt e nsi o n t ri al  ( or  dis c o nti n u es fr o m t h e st u d y 
e arl y) , t h e s u bj e ct  will  visit t h e  cli ni c  o n Visit  1 3 ( D a y  1 2 0 ) ( or  1 4  d a ys  aft er t h e  d a y  of 
dis c o nti n u ati o n) .  T h e f oll o wi n g  will  b e r e c or d e d/ p erf or m e d: 
•   R e vi e w  c urr e nt s ei z ur e  a cti vit y ( n u m b er/t y p e/ d ur ati o n ) fr o m  di ar y si n c e  pr e vi o us  visit 
•   A Es  
•   A E SI  
•   C o n c o mit a nt  m e di c ati o ns  
•   C oll e ct  us e d,  p arti all y  us e d  a n d  u n us e d st u d y  m e di c ati o n;  p erf or m  dr u g  a c c o u nt a bilit y 
a n d r e vi e w  wit h  p ar e nt/ c ar e gi v er  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 4  of  1 9 4  
6. 2. 6   
C A R DI A C  F O L L O W -U P  VI SI T ( C O H O R T  1:  C LI NI C  VI SI T S  1 8 , 
1 9 / C O H O R T  2: C LI NI C  VI SI T  1 4 ; 3 -6  M O N T H S  A F T E R  L A S T  D O S E  O F 
S T U D Y  M E DI C A TI O N ) 
If t h e s u bj e ct c o m pl et es t h e st u d y  b ut  d o es  n ot  e nt er t h e  o p e n -l a b el e xt e nsi o n tri al  or 
di s c o nti n u es fr o m t h e st u d y  e arl y, t h e s u bj e ct  will r et ur n t o t h e  cli ni c f or f oll o w-u p  c ar di a c 
t esti n g ( E C H O,  E C G,  a n d i n s o m e  c as es  p h ysi c al  e x a mi n ati o n).   T h e ti mi n g  a n d fr e q u e n c y  of 
e x a ms  ar e  pr es e nt e d  i n T a bl e  1 0 .  S u bj e cts  o n  bli n d e d  m e di c ati o n  w h o  ar e f o u n d t o  h a v e  b e e n 
o n  pl a c e b o  ar e  n ot r e q uir e d t o  p arti ci p at e i n f oll o w -u p t esti n g  o n c e t h e  bli n d is  br o k e n  at t h e 
e n d  of t h e st u d y . As t h e  E C H O  a n d  E C G  will  b e  a d mi nist er e d i n  a s e p ar at e  cli ni c  fr o m t h e 
p e di atri c  n e ur ol o g y  cli ni c,  a n  as y m pt o m ati c s u bj e ct r e c ei vi n g  a s e c o n d f oll o w -u p  E C H O  a n d 
E C G  d o es  n ot r e q uir e  a  p h ysi c al  e x a m i n ati o n.  
S u bj e cts  wit h  p ositi v e fi n di n gs  o n  E C H O,  E C G  a n d/ or  p h ysi c al  e x a m in ati o n  s h o ul d  c o nti n u e t o 
b e f oll o w e d  u ntil t h e fi n di n g is r es ol v e d  or st a bl e  a n d  u nli k el y t o  c h a n g e ,  wit h r e p orts 
s u b mitt e d  as  A E SI t o t h e  Z X 0 0 8 s af et y  d at a b as e.   
T a bl e  1 0 . S c h e d ul e  of  P ost -T r e at m e nt  C a r di a c  F oll o w -u p  
 
D u r ati o n  of  Bli n d e d a o r  F e nfl u r a mi n e  T r e at m e nt  
 
 
 
P a r a m et e r  
 
L ess t h a n   
2  w e e ks 
C u m ul ati v e  
 
 
 
2 t o  4  w e e ks  
 
 
>  4  a n d   
<  1 3  w e e ks  
 
 
 
>  1 3  w e e ks  
H a v e  h a d  a n y  c a r di a c 
si g n  o r s y m pt o m 
r e g a r dl ess  of t h e ti m e 
o n  st u d y d r u g b  
E C H O  
N o  
Y es,   
3  m o nt hs 
p ost - 
tr e at m e nt 
Y es,   
3  m o nt hs  p ost - 
tr e at m e nt 
Y es,   
3 -6  m o nt hs  p ost -tr e at m e nt 
Y es,   
3  a n d  6  m o nt hs  p ost -
tr e at m e nt,  a n d  u ntil 
r es ol v e d,  or st a bl e  a n d 
u nli k el y t o  c h a n g e  
E C G  
N o  
Y es,   
3  m o nt hs 
p ost - 
tr e at m e nt 
Y es,   
3  m o nt hs  p ost - 
tr e at m e nt 
Y es,   
3 -6  m o nt hs  p ost -tr e at m e nt 
Y es,  
3  a n d  6  m o nt hs  p ost -
tr e at m e nt  a n d  u ntil 
r es ol v e d,  or st a bl e  a n d 
u nli k el y t o  c h a n g e  
P h ysi c al 
e x a mi n ati o n  
N o  
Y es,   
3  m o nt hs 
p ost - 
tr e at m e nt 
Y es,   
3  m o nt hs  p ost - 
tr e at m e nt 
Y es,   
3  m o nt hs  p ost tr e at m e nt 
o nl y  
Y es,  
3  a n d  6  m o nt hs  p ost -
tr e at m e nt,  a n d  u ntil 
r es ol v e d,  or st a bl e  a n d 
u nli k el y t o  c h a n g e  
E C G  =  el e ctr o c ar di o gr a m;  E C H O  =  e c h o c ar di o gr a m; I P C A B  = I nt er n ati o n al  P e di atri c  C ar di ol o g y  A d vis or y  B o ar d  
a  If  bli n d is  br o k e n at t h e  e n d  of t h e st u d y  a n d  a s u bj e ct r e v e al e d t o  h a v e t a k e n  o nl y  pl a c e b o,  n o f urt h er  t esti n g is r e q uir e d. 
b  P ositi v e si g n  or s y m pt o m i n cl u d es  a n y  d e v el o p m e nt  of  v al v e t hi c k e ni n g  or r e g ur git ati o n  “tr a c e ”  or  gr e at er i n  mitr al,  a orti c ; 
mil d  or  gr e at er i n  p ul m o n ar y, tri c us pi d),  or si g n  or s y m pt o m i n di c ati v e  of  p ot e nti al  p ul m o n ar y  h y p ert e nsi o n  as  a dj u di c at e d 
b y t h e I P C A B.  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 5  of  1 9 4  
6. 3   
E S TI M A T E D  B L O O D  V O L U M E  C O L L E C TI O N  
T h e  m a xi m u m t ot al  bl o o d  v ol u m e  c oll e ct e d  d uri n g t h e  first  1 5  d a ys  of t h e st u d y f or  C o h ort  1 
will  b e  a p pr o xi m at el y  6 3 . 4 m L  f or t h e  P K  p orti o n  of t h e st u d y,  as  o utli n e d i n T a bl e  1 1 .  T h e 
m a xi m u m t ot al  bl o o d  v ol u m e  c oll e ct e d  d uri n g t h e tr a nsiti o n  p eri o d  of t h e st u d y f or  C o h ort  1 
will  b e  a p pr o xi m at el y  1 2 2. 1  m L  o v er  2 4  w e e ks.  
T a bl e  1 1 . Esti m at e d  Bl o o d  V ol u m e  C oll e cti o n  f o r  C o h o rt  1 
Ass ess m e nt  
S c r e e ni n g  
( D a y -1 4  t o -1 ) 
D a y  1 -2   
D a y  1 5  
T ot al   
S c r e e ni n g - 
D a y  1 5  
T r a nsiti o n  P e ri o d   
D a ys  4 3,  7 1,  9 9,  1 2 7, 
1 5 5,  1 8 3  
Cli ni c al  c h e mistr y  &  pr ol a cti n   
2  x  5  m L   
--  
--  
1 0  m L   
6  x  1 0  m L  
L H,  F S H,  estr a di ol, t est ost er o n e  
1  x  4  m L   
  
  
4  m L  
3  x  4  m L  ( e v er y  8 
w e e ks)  
H e m at ol o g y   
2  x  2 m L   
  
  
4  m L   
6  x  2 m L  
E pil e ps y  G e n ot y pi n g  
5  m L   
  
  
5  m L  
-- 
I G F-1 ,  G H 
1  x  2  m L   
  
  
2  m L  
3  x  2  m L  ( e v er y  8 
w e e ks)  
C o a g ul ati o n  
2  x  2. 7 m L   
  
  
5. 4  m L  
3  x  2. 7  m L  ( e v er y  8 
w e e ks)  
C a n n a bi di ol  
2  x  2  m L   
 
  
4  m L   
6  x  2  m L  
P K s a m pl e  ( Z X 0 0 8  a n d  b a c k gr o u n d 
A E D)  
--  
6  x  4 m L   
  
2 4  m L  
 
A E D  pl as m a s a m pl e  
-- 
  
2 m L   
2  m L   
6  x  2  m L  
V ol u m e f or fl us hi n g i n d w elli n g 
c at h et er  
-- 
6  x 
0. 5 m L  
  
3  m L  
 
A p pr o xi m at e t ot al  bl o o d  v ol u m e  p er 
s u bj e ct  
3 4 . 4  m L  
2 7 m L   
2  m L   
6 3 . 4 m L  
1 2 2. 1  m L  
A E D = a nti e pil e pti c  dr u g;  F S H =f olli cl e sti m ul ati n g  h or m o n e;  G H = gr o wt h  h or m o n e; I G F -1 =i ns uli n -li k e  gr o wt h f a ct or  1; 
L H -l ut ei ni zi n g  h or m o n e;  P K = p h ar m a c o ki n eti c 
T h e  m a xi m u m t ot al  bl o o d  v ol u m e  c oll e ct e d  d uri n g t h e st u d y  f or  C o h ort  2 (cli ni c al l a b or at or y 
t esti n g,  g e n ot y pi n g,  a n d  P K) will  b e  a p pr o xi m at el y  1 1 7. 2  m L ,  as  o utli n e d i n T a bl e  1 2 . 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 6  of  1 9 4  
T a bl e  1 2 . Esti m at e d  Bl o o d  V ol u m e  C oll e cti o n  f o r  C o h o rt  2 
 
B as eli n e  P e ri o d  
Tit r ati o n  +  M ai nt e n a n c e  P e ri o d  
  
 
Ass ess m e nt  
S c r e e ni n g  
( D a y -4 2 
t o -4 1)  
R a n d o m - 
i z ati o n 
D a y  -1  
D a y  2 2   
D a y  5 0   
D a y  7 8   
D a y  1 0 6  
Visit  1 3  
D a y  1 2 0   
T ot al  
Cli ni c al  c h e mistr y , 
pr ol a cti n  
5  m L   
5  m L   
5  m L   
5  m L   
5  m L   
5  m L  
 
4 2  m L  
L H,  F S H,  estr a di ol, 
t est ost er o n e 
2  m L   
2  m L   
2  m L   
2  m L   
2  m L   
2  m L  
 
-- 
H e m at ol o g y   
2  m L   
2  m L   
2  m L   
2  m L   
2  m L   
2  m L   
--  
1 2  m L  
E pil e ps y  G e n ot y pi n g   
5  m L   
--  
--  
--  
--  
--  
--  
5  m L  
I G F-1  a n d  G H   
2  m L   
2  m L   
2  m L   
2  m L   
2  m L   
2  m L   
--  
1 2  m L  
C o a g ul ati o n  
2. 7  m L   
2. 7  m L   
2. 7  m L   
2. 7  m L   
2. 7  m L   
2. 7  m L   
--  
1 6, 2  m L  
C a n n a bi di ol  
2  m L   
2  m L   
2  m L   
2  m L   
2  m L   
2  m L   
--  
1 2  m L  
Z X 0 0 8  P K s a m pl e   
--  
--  
  
  
--  
--  
4  ×  2  m L   
8  m L  
A E D  pl as m a s a m pl e   
  
1  x  2  m L   
1  x  2  m L   
1  x  2  m L   
--  
1  x  2  m L   
 
8  m L  
V ol u m e f or fl us hi n g 
i n d w elli n g  c at h et er 
--  
--  
--  
--  
--  
-- 
4  x  0. 5 
m L  
2  m L  
A p pr o xi m at e t ot al 
bl o o d  v ol u m e  p er 
s u bj e ct  
2 0. 7  m L   
1 7. 7  m L   
1 7. 7  m L   
1 7. 7  m L   
1 5. 7  m L  
 
1 7. 7  m L  
 
1 0  m L   
1 1 7. 2  m L  
A E D = a nti e pil e pti c  dr u g;  F S H =f olli cl e sti m ul ati n g  h or m o n e;  G H = gr o wt h  h or m o n e; I G F -1 =i ns uli n -li k e  gr o wt h f a ct or  1;  L H-
l ut ei ni zi n g  h or m o n e;  P K = p h ar m a c o ki n eti cs 
 
I n  c o n c or d a n c e  wit h  T h e  S e attl e  C hil dr e n’s  R es e ar c h  F o u n d ati o n  G ui d a n c e ( A p p e n di x  9), 
bl o o d  c oll e cti o n  v ol u m es f or  c hil dr e n  w ei g hi n g  u p t o  1 5  k g  will  b e:  
•   t h e  m a xi m u m  all o w a bl e  v ol u m e  of  bl o o d i n  o n e  dr a w is  2 2-3 0  m L ( 2. 5 %  of t ot al 
bl o o d  v ol u m e)  
•   t h e  m a xi m u m i n  a  3 0-d a y  p eri o d is  4 4 -6 0  m L  
O n  D a y  1 2 0 / Visit 1 3  t h e P K  bl o o d  dr a w  will  b e  c o m pl et e d  as t h e  pri orit y  a n d t h e  bl o o d  dr a w 
f or  c h e mistr y  a n d  h e m at ol o g y  will  b e s ki p p e d f or t h os e s u bj e cts  w h o  w ei g h l ess t h a n  1 3. 5  k g, 
u nl ess  m e di c al  c o n c er ns (f or  e x a m pl e, fr o m  pr e vi o us t ests  or r e p ort e d si d e  eff e cts)  pri oriti z e 
c h e mistr y  a n d/ or  h e m at ol o g y.  
If  bl o o d  c oll e cti o n is r estri ct e d  d u e t o  v ol u m e  or  d u e t o i n a bilit y t o  dr a w  a d e q u at e  v ol u m e, 
c oll e cti o n s h o ul d  b e  pri oriti z e d  as s h o w n i n  T a bl e  1 3 . 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 7  of  1 9 4  
T a bl e  1 3 : P ri o riti es f o r  Bl o o d  S a m pl e  C oll e cti o ns  
Ass ess m e nt  
P ri o rit y  
Z X 0 0 8  P K s a m pl e  
Pri orit y  1  
Cli ni c al  c h e mistr y  
Pri orit y  2  
C a n n a bi di ol  
Pri orit y  2  
A E D  pl as m a s a m pl e  
Pri orit y  2  
L H,  F S H,  estr a di ol,  t est ost er o n e,  G H,  pr ol a cti n 
Pri orit y  3  
H e m at ol o g y  
Pri orit y  3  
I G F-1  
Pri orit y  4  
G e n ot y pi n g  
O n e ti m e  c oll e cti o n  a n y ti m e  d uri n g  or 
aft er s cr e e ni n g  
C o a g ul ati o n  
O n e ti m e  c oll e cti o n  a n y ti m e  b ef or e  P K 
d a y  
A E D  =  a nti e pil e pti c  dr u g;  F S H =f olli cl e sti m ul ati n g  h or m o n e;  G H = gr o wt h  h or m o n e; I G F -1 =i ns uli n -li k e  gr o wt h f a ct or  1;  
L H  =  l ut ei ni zi n g  h or m o n e;  P K = p h ar m a c o ki n eti cs 
7.   
E F FI C A C Y,  S A F E T Y,  A N D  P H A R M A C O KI N E TI C  
A S S E S S M E N T S  
F or  a n  o v er vi e w  of t h e st u d y  v ari a bl es  a n d  m e as ur e m e nt ti m es, s e e  S c h e d ul e  of  Ass ess m e nts 
(T a bl e  1  f or  C o h ort  1 a n d  T a bl e  2  f or  C o h ort  2). 
V ari a bl es  us e d t o  m e as ur e tr e at m e nt  c o m pli a n c e  wit h r es p e ct t o  a d mi nistr ati o n  of t h e  I M P ar e 
d es cri b e d i n  S e cti o n  5. 8 . 
7. 1   
E F FI C A C Y  A S S E S S M E N T S :  C O H O R T  2 
B as eli n e is  d efi n e d  as t h e s ei z ur e fr e q u e n c y  d uri n g t h e  6 -w e e k  B as eli n e  P eri o d.     
R etr os p e cti v e  di ar y  d at a ( u p t o  6  m o nt hs)  will  b e  c oll e ct e d , if  a v ail a bl e, for  a n  e x pl or at or y 
e v al u ati o n  of t h e  d ur ati o n  of  b as eli n e  d at a  c a pt ur e  o n i nt er pr et ati o n  of  p ost -tr e at m e nt  eff e ct. 
F or  all  q u esti o n n air es  a n d r ati n g s c al es, t h e s a m e  e v al u at or  ( at t h e  cli ni c al sit e  a n d 
p ar e nt/ c ar e gi v er)  will  c o m pl et e t h e  ass ess m e nts f or t h e  d ur ati o n  of t h e st u d y .  S u bstit uti o ns  at 
t h e  cli ni c  wit h  a n ot h er r at er t h at  h as  est a blis h e d i nt er-r at er r eli a bilit y is  a c c e pt a bl e  o n  a n 
i nfr e q u e nt  b asis. F or t h e i n -cli ni c  q u esti o n n air es  a n d r ati n g s c al es  c o m pl et e d  b y t h e 
p ar e nt/ c ar e gi v er, if t h e s a m e  p ar e nt/ c ar e gi v er  c a n n ot  c o m pl et e t h e  q u esti o n n air e/r ati n g s c al e  at 
a  visit, t h e  q u esti o n n air e/r ati n g s c al e  will  n ot  b e  c o m pl et e d.   F or t h e  di ar y, t h e s a m e 
p ar e nt/ c ar e gi v er  will  c o m pl et e  all  e ntri es t hr o u g h o ut t h e st u d y.  
7. 1. 1   
S ei z u r e  Ass ess m e nt s 
S ei z ur e fr e q u e n c y  b y t y p e  a n d  d ur ati o n  (<  2  mi n ut es,  2 -1 0  mi n ut es,  >  1 0  mi n ut es)  will  b e 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 8  of  1 9 4  
r e c ord e d  d ail y  b y t h e  p ar e nt/ c ar e gi v er i n  a  di ar y .  S ei z ur e t y p es i n cl u d e:  
A:    
H e mi cl o ni c ( n ot e l at er ali z ati o n  –  ri g ht  b o d y, l eft  b o d y,  or i n d e p e n d e nt ri g ht  a n d 
l eft) 
B 1 :   F o c al  Wit h  o r  Wit h o ut Cl e ar,  O bs er v a bl e  M ot or  Si g ns  
B 2:   F o c al  Wit h o ut  Cl e ar,  O bs er v a bl e  M ot or  Si g ns  
C:    
S e c o n d aril y  G e n er ali z e d  T o ni c  Cl o ni c ( e v ol vi n g t o  bil at er al  c o n v ulsi v e s ei z ur e 
fr o m f o c al s ei z ur e) 
D:    
G e n er ali z e d  T o ni c  Cl o ni c  C o n v ulsi o n  
E:   
A bs e n c e  o r  At y pi c al  A bs e n c e 
F:    
M y o cl o ni c  
G:    
T o ni c  
H:    
At o ni c  
I:   
Cl o ni c  
J:   
T o ni c/ At o ni c ( c a n n ot  diff er e nti at e ;  als o  k n o w n  as ‘ dr o p  att a c k’) 
K:    
I nf a ntil e  S p as ms (if  u n d er  3  y e ars  of  a g e) 
L:    
E pil e pti c  S p as ms (if  3  y e ars  of  a g e  a n d  ol d er)  
 
O:    
Ot h er  
Effi c a c y  e n d p oi nts t h at  will  b e  d eri v e d fr o m t h e  di ar y  d at a i n cl u d e  fr e q u e n c y  of  c o n v ulsi v e 
s ei z ur es  a n d of  all s ei z ur es,  a n d  t h e n u m b er/ d ur ati o n  of s ei z ur e fr e e i nt er v als.  
S ei z ur es t h at  e v ol v e i nt o  S E  will  b e  c a pt ur e d  b y t y p e  a n d  d ur ati o n   
( > 1 0  mi n ut es ) as  ar e  all s ei z ur es .  Th e  di a g n osis  of  S E  m a d e  b y  a  m e di c al  pr of essi o n al  s h o ul d 
b e  e nt er e d  as  a n  A E  or  S A E  if  a  pr ol o n g e d s ei z ur e  or s eri es  of s ei z ur es  p ersists f or  3 0  mi n ut es 
or l o n g er,  r e g ar dl ess of  a d mi nistr ati o n  of r es c u e  m e di c ati o n.   S E l asti n g f or l es s t h a n  3 0 
mi n ut es s h o ul d  b e  e nt er e d  as  a n  A E,  u nl ess  o n e  of t h e  ot h er  S A E  crit eri a ( e g,  h os pit ali z ati o n) 
ar e  m et.  If t his i n ci d e nt i n v ol v es m ulti pl e s ei z ur es  cl os e i n ti m e , t h e  S E  d efi niti o n  a p pli es if t h e 
s ei z ur es  ar e  cl os e t o g et h er s u c h t h at  c o ns ci o us n es s is  n ot r e g ai n e d  b et w e e n i ct al  e v e nts. 
7. 1. 2   
Cli ni c al  Gl o b al I m p r essi o n  - I m p r o v e m e nt ( E x pl o r at o r y E n d p oi nt)  
B ot h t h e  p ar e nt/ c ar e gi v er  a n d t h e i n v esti g at or  will r at e t h eir  gl o b al i m pr essi o n  of t h e s u bj e ct ’s 
c o n diti o n t hr o u g h o ut t h e st u d y  a c c or di n g t o t h e  s c h e d ul e i n T a bl e  1  a n d  T a bl e  2 .  
T h e  Cli ni c al  Gl o b al I m pr essi o n ( C GI ) s c al e  m e as ur es t h e  c h a n g e i n t h e  s u bj e ct’s cli ni c al st at us 
fr o m  a s p e cifi c  p oi nt i n ti m e, i e, t h e  B as eli n e  P eri o d.  T h e  C GI r ati n g s c al e  p er mits  a  gl o b al 
e v al u ati o n  of t h e  s u bj e ct’s i m pr o v e m e nt  o v er ti m e.  T h e s e v erit y  of  a  p ati e nt’s  c o n diti o n is r at e d 
o n  a  7 -p oi nt s c al e r a n gi n g fr o m  1 ( v er y  m u c h i m pr o v e d ) t o  7 (v er y  m u c h  w ors e )  as f oll o ws:  
1 = v er y  m u c h i m pr o v e d  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  9 9  of  1 9 4  
2 = m u c h i m pr o v e d  
3 = mi ni m all y i m pr o v e d  
4 =  n o  c h a n g e  
5 = mi ni m all y  w ors e  
6 = m u c h  w ors e  
7 = v er y  m u c h  w ors e  
T h e  p ar e nt/ c ar e gi v er  will  b e  as k e d t o  i n di c at e t h e  a p pr o pri at e r es p o ns e t h at  a d e q u at el y 
d es cri b es  h o w  t h eir c hil d’s s y m pt o ms  h a v e i m pr o v e d  or  w ors e n e d r el ati v e t o  b as eli n e  b ef or e 
t h e  b e gi n ni n g  of t h e st u d y ( b ef or e  a n y st u d y  dr u g  w as t a k e n).   
T h e i n v esti g at or  will  b e  as k e d t o  i n di c at e t h e  a p pr o pri at e r es p o ns e t h at  a d e q u at el y  d es cri b es 
h o w t h e s u bj e ct’s s y m pt o ms  h a v e i m pr o v e d  or  w ors e n e d r el ati v e t o  b as eli n e  b ef or e t h e 
b e gi n ni n g  of t h e st u d y ( b ef or e  a n y  st u d y  dr u g  w as t a k e n).  A  p ar a gr a p h  d es cri bi n g s y m pt o ms 
a n d f u n cti o n  at  b as eli n e  will  b e  d o c u m e nt e d  i n t h e s o ur c e fil e pri or t o r ati n g.  
7. 1. 3   
Sl e e p  Q u alit y  a n d  M e al ti m e  B e h a vi or  Q u esti o ns  ( E x pl o rat o r y  E n d p oi nt)  
T h e  p ar e nt/ c ar e gi v er  will  b e  as k e d t o i n di c at e t h e  a p pr o pri at e r es p o ns e t h at  a d e q u at el y 
d es cri b es  t h eir  c hil d’s sl e e p  q u alit y  a n d  e ati n g  b e h a vi or si n c e st arti n g I M P b as e d  o n t h e 
f oll o wi n g  q u esti o ns: 
 
1.   Si n c e  y o ur  c hil d  h as st art e d t a ki n g t h e st u d y  m e di c a ti o n i n t his st u d y,  h a v e  y o u n oti c e d 
t h at s/ h e h as  b e e n  w a ki n g i n t h e  mi d dl e  of t h e  ni g ht  or  v er y  e arl y i n t h e  m or ni n g  m or e t h a n 
us u al ?  
o   M y  c hil d’s sl e e p is  m or e  dist ur b e d t h a n it  w as  b ef or e s/ h e st art e d t h e st u d y  m e di c ati o n  
o   M y  c hil d’s sl e e p  p att er ns  ar e t h e s a m e  as t h e y  w er e  b ef or e st arti n g t h e st u d y  m e di c ati o n  
o   M y  c hil d sl e e ps  b ett er t h a n  s/ h e  di d  b ef or e st arti n g t h e st u d y  m e di c ati o n  
 
2.   Si n c e  y o ur  c hil d  h as st art e d t a ki n g t h e st u d y  m e di c ati o n i n t his st u d y,  h a v e  y o u  n oti c e d 
t h at s/ h e  h as h a d  a  c h a n g e i n  t h eir  m e alti m e  b e h a vi or?  
o   M y  c hil d  h as  w ors e  m e alti m e  b e h a vi or  si n c e st arti n g t h e st u d y  m e di c ati o n  
o   M y  c hil d’s  m e alti m e  b e h a vi or  h as  n ot  c h a n g e d si n c e st arti n g t h e st u d y  m e di c ati o n  
o   M y  c hil d  h as  i m pr o v e d  his/ h er  m e alti m e b e h a vi or  si n c e st arti n g t h e st u d y  m e di c ati o n  
7. 1. 4   
K a r oli ns k a  Sl e e pi n ess  S c al e  ( E x pl o r at o r y  En d p oi nt)  
T h e  K ar oli ns k a  Sl e e pi n ess  S c al e ( A p p e n di x  8 )  will  b e  a d mi nist er e d a c c or di n g t o t h e s c h e d ul e 
i n T a bl e  1  a n d  T a bl e  2 .  T h e  K ar oli ns k a  Sl e e pi n ess s c al e is  a s elf -r e p ort s c al e t h at  m e as ur es t h e 
s u bj e ct’s  dr o wsi n ess.  It is  a  9 -p oi nt  v er b all y  a n c h or e d s c al e , w hi c h r a n g es fr o m ‘ e xtr e m el y 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 0  of  1 9 4  
al ert’  at  o n e  e n d  of t h e s c al e t o ‘ e xtr e m el y sl e e p y  –  fi g hti n g sl e e p’  at t h e  ot h er  e n d  of t h e s c al e. 
Wit hi n t his st u d y , t h e s c al e  will  b e  c o m pl et e d  b y t h e  o bs er v er i n  a n  e x pl or at or y  m a n n er. 
7. 1. 5   
Q u alit y  of  Lif e i n  C hil d h o o d  E pil e ps y  S c al e  
T h e  Q O L C E  (A p p e n di x  4 ),  a l o w-b ur d e n  p ar e nt/ c ar e gi v er  c o m pl et e d  ass ess m e nt t h at l o o ks  at 
h o w  e pil e ps y  aff e cts  d a y -t o-d a y f u n cti o ni n g  of t h eir  c hil d i n  v ari o us lif e  ar e as, i n cl u di n g 
p h ysi c al  a cti viti es,  w ell -b ei n g,  c o g niti o n, s o ci al  a cti viti es,  b e h a vi or  a n d  g e n er al  h e alt h,  will  b e 
c o n d u ct e d  a c c or di n g t o t h e s c h e d ul e i n  T a bl e  1  a n d  T a bl e  2 . T h e  Q O L C E  h as  b e e n  v ali d at e d i n 
c hil dr e n  a g e d  4  a n d  ol d er,  a n d t h er e  ar e  p u blis h e d  d at a  o n t h e  us e  of t h e  Q O L C E i n  c hil dr e n 
wit h  e pil e ps y  as  y o u n g  as  2  y e ars  of  a g e ( S a b a z  2 0 0 0 ; T al ars k a  2 0 0 7 ).  
7. 1. 6   
P e ds Q L  S c al e   
T h e  P e ds Q L  (A p p e n di x  6 ) is  a  m o d ul ar  a p pr o a c h t o  m e as uri n g  H R Q O L i n  h e alt h y  c hil dr e n  a n d 
a d ol es c e nts  a n d t h os e  wit h  a c ut e  a n d  c hr o ni c  h e alt h  c o n diti o ns.  T h e  P e ds Q L  M e as ur e m e nt 
M o d el  i n cl u d es b ot h  g e n e ri c  c or e s c al es  an d  dis e as e -s p e cifi c  m o d ul es i n  o n e  m e as ur e m e nt 
s yst e m. T h e  2 3 -it e m  P e ds Q L  G e n eri c  C or e  S c al es,  w hi c h  will  b e  us e d i n t his st u d y, w er e 
d esi g n e d t o  m e as ur e t h e  c or e  di m e nsi o ns  of  h e alt h  as  d eli n e at e d  b y t h e  W orl d  H e alt h 
Or g a ni z ati o n,  as  w ell  as r ol e (s c h o ol) f u n cti o ni n g.  T h e  4  M ulti di m e nsi o n al  S c al es  a n d  3 
S u m m ar y  S c or es  ar e:   
S c al es  
P h ysi c al  F u n cti o ni n g  ( 8 it e ms) 
E m oti o n al  F u n cti o ni n g  ( 5 it e ms) 
S o ci al  F u n cti o ni n g ( 5 it e ms) 
S c h o ol  F u n cti o ni n g  ( 5 it e ms) 
S u m m a r y  S c o r es  
T ot al  S c al e  S c o r e  ( 2 3 it e ms) 
P h ysi c al  H e alt h  S u m m a r y  S c o r e  ( 8 it e ms) 
Ps y c h os o ci al  H e alt h  S u m m a r y  S c o r e  ( 1 5 it e ms) 
T his s c al e  is  c o m pl et e d  b y t h e  p ar e nt/ c ar e gi v er  o n  b e h alf  of t h e s u bj e ct.  It will  b e  us e d  
a c c or di n g t o t h e s c h e d ul e i n  T a bl e  1  a n d  T a bl e  2 . 
7. 1. 7   
P a r e nt/ C a r e gi v e r  Q u alit y  of  Lif e  
T h e i m p a ct  o n t h e  q u alit y  of lif e  of t h e  p ar e nt/ c ar e gi v er r es p o nsi bl e f or  a  p ati e nt  wit h  D r a v et 
s y n dr o m e will  b e  ass ess e d  a c c or di n g t o t h e s c h e d ul e i n  T a bl e  1  a n d  T a bl e  2  usi n g  2  s c al es: t h e 
E Q -5 D -5 L  a n d t h e  P e ds Q L  F a mil y I m p a ct  M o d ul e .  P ar e nts/ c ar e gi v ers  w h o  d o  n ot  gi v e  c o ns e nt 
t o  c oll e ct t h es e r ati n gs s c al es  will  n ot  c o m pl et e t h e m.   T h e s a m e  p ar e nt/ c ar e gi v er s h o ul d 
c o m pl et e t h es e r ati n gs t hr o u g h o ut t h e st u d y. If t h at  p ers o n is  n ot  a v ail a bl e  at t h e  visit, t h e s c al es 
s h o ul d  n ot  b e  c o m pl et e d.    


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 1  of  1 9 4  
T h e  E Q -5 D -5 L ( A p p e n di x  7 ) is  a st a n d ar di z e d  m e as ur e  of  h e alt h st at us  us e d t o  pr o vi d e  a 
si m pl e, g e n eri c  ass ess m e nt f or  cli ni c al  a n d  e c o n o mi c  a p pr ais al.  It  c o nsists  of  6  q u esti o ns  a n d 
c a n  b e  c o m pl et e d i n l ess t h a n  1 0  mi n ut es.  
T h e  P e ds Q L  F a mil y I m p a ct  m o d ul e ( A p p e n di x  6 ) is  d esi g n e d t o  m e as ur e t h e i m p a ct  of 
p e di atri c  c hr o ni c  h e alt h  c o n diti o ns  o n  p ar e nts  a n d t h e f a mil y  b y  m e as uri n g  p ar e nt s elf -r e p ort e d 
p h ysi c al,  e m oti o n al, s o ci al,  a n d  c o g niti v e f u n cti o ni n g,  c o m m u ni c ati o n,  w orr y,  a n d f a mil y  d ai l y 
a cti viti es r el ati o ns hi ps.  T h e  p ar e nt/ c ar e gi v er  will  b e  as k e d t o i n di c at e t h e  a p pr o p ri at e r es p o ns e 
t h at  a d e q u at el y  d es cri b es  h o w t h e  c ar e  of t h eir  c hil d  wit h  Dr a v et s y n dr o m e h as i m p a ct e d t h eir 
q u alit y  of lif e  usi n g t h e s c al es  d es cri b e d  a b o v e.   T h e  P e ds Q L  F a mil y I m p a ct  m o d ul e  will  n ot  b e 
ass ess e d i n  t h e  N et h erl a n ds. 
7. 1. 8   
H e alt h c a r e  Utili z ati o n  Q u esti o ns  ( E x pl o r at o r y  En d p oi nt)  
I n  or d er t o  b ett er  u n d erst a n d t h e  h e alt h c ar e r es o ur c e  b ur d e n  ass o ci at e d  wit h t h e  m a n a g e m e nt  of 
D r a v et s y n dr o m e,  c ar e gi v ers  will  b e  as k e d  w hi c h  of t h e f oll o wi n g  h os pit al  a n d  c o m m u nit y-
b as e d  h e alt h c ar e s er vi c es t h e y  h a d i nt er a cti o ns  wit h  o v er t h e  pr e c e di n g  m o nt h:   e m er g e n c y 
r o o m s er vi c es,  a m b ul a n c e,  pl a n n e d  a n d  u n pl a n n e d  h os pit ali z ati o n, f a mil y  p h ysi ci a n s er vi c es, 
s p e e c h  a n d l a n g u a g e t h er a p y,  o c c u p ati o n al t h er a p y,  a n d  p h ysi c al t h er a p y.   T his i nf or m ati o n 
will  b e  c a pt ur e d i n t h e  C R F  as  o utli n e d i n  T a bl e  1  a n d  T a bl e  2 . 
7. 1. 9   
D r a v et  S y n d r o m e  O ut c o m e  M e as u r es ( E x pl o r at o r y  E n d p oi nt)  
T h e  E ur o p e a n  M e di ci n es  A g e n c y r e c o m m e n ds t h at t h e  ass ess m e nt  of  effi c a c y i n  cli ni c al 
i n v esti g ati o ns  of  m e di ci n al  pr o d u cts i n t h e tr e atm e nt  of  e pil e pti c  dis or d ers s h o ul d  b e  b as e d 
pri m aril y  u p o n s ei z ur e fr e q u e n c y/ o c c urr e n c e ( E M A  2 0 1 0 ). W hilst  of  u p m ost  i m p ort a n c e, it is 
als o r e c o g ni z e d t h at t h e i m p a ct  of  D r a v et s y n dr o m e as  e x p eri e n c e d  b y  p ati e nts  a n d  c ar ers 
e xt e n ds  b e y o n d t h e  dir e ct i m p a ct  of s ei z ur es ( N o l a n 2 0 0 8 ; D es n o us  2 0 1 1 ).   
D ra v et s y n dr o m e is  ass o ci at e d  wit h  cli ni c al  m a nif est ati o ns  ot h er t h a n t o ni c -cl o ni c s ei z ur es, 
m a n y  of  w hi c h  h a v e  a str o n g  i m p a ct  o n i n di vi d u al  a n d f a mil y  w ell-b ei n g,  a n d  p ersist i nt o 
a d ult h o o d:  m ulti pl e s ei z ur e t y p es,  d efi cits i n  c o g niti o n  a n d  e x e c uti v e f u n cti o n, sl e e p 
dist ur b a n c es,  a n d  b e h a vi or al  dist ur b a n c es .  A  Dr a v et  sy n dr o m e  c o m p osit e  e n d p oi nt  will  b e 
cr e at e d  usi n g  a s er i es  of  o ut c o m e  m e as ur es fr o m t h e  pr ot o c ol t o  cr e at e  a  c o m p osit e  e n d p oi nt t o 
ass ess tr e at m e nt  of  Dr a v et s y n dr o m e  wit h o ut  e m p h asis  o n  a si n gl e  e n d p oi nt.  T h e  o ut c o m es 
u n d er  e v al u ati o n i n t his st u d y  will i n cl u d e  m e as ur es f or  e x a m pl e s u c h  as s ei z ur e fr e q u e n c y, 
b e h a vi o ur,  q u alit y  of sl e e p , a n d  ot h ers.  T h e  m e as ur es t o s el e ct t h e  c o m p osit e  ar e i d e ntifi e d  as 
p art  of  a  pr oj e ct  wit h  p h ysi ci a n i nt er vi e ws  a n d i nt er vi e ws  wit h  p ati e nt’s f a mili es  a n d  ar e  p art  of 
a  pr oj e ct  o n  m ulti -di m e nsi o n al  o ut c o m e  m e as ur es.   


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 2  of  1 9 4  
7. 2   
S A F E T Y  A S S E S S M E N T S  
7. 2. 1   
D e m o g r a p hi cs,  M e di c al/ N e u r ol o gi c al/ E pil e ps y  Hist o r y,  a n d  P r e -St u d y 
M e di c ati o n  
S u bj e ct  d e m o gr a p hi cs (s e x,  a g e,  h ei g ht,  w ei g ht,  a n d  B MI) ,  all  o n g oi n g  c o n diti o ns  a n d r el e v a nt 
m e di c al  hist or y fr o m t h e  p ast  5  y e ars (i n cl u di n g  all  m aj or  h os pit ali z ati o ns  a n d s ur g eri es)  as 
w ell  as t h e s u bj e ct’s  c urr e nt  m e di c al st at us  will  b e r e c or d e d  at t h e  S cr e e ni n g  visit.   Si g nifi c a nt 
m e di c ati o ns t a k e n  d uri n g t h e  3 0  d a ys  pri or t o t h e  S cr e e ni n g  visit  will  b e  d o c u m e nt e d. 
M e di c ati o n  hist or y  will  b e  u p d at e d  as  o utli n e d i n  T a bl e  1  a n d  T a bl e  2 .  
7. 2. 2   
P h ysi c al  E x a mi n ati o ns  
C o m pl et e  a n d  a b br e vi at e d  p h ysi c al  e x a mi n ati o n s, i n cl u di n g  h ei g ht  a n d  w ei g ht,  will  b e 
c o n d u ct e d  b y t h e i n v esti g at or  or  d esi g n e e  d uri n g t h e  st u d y  as  o utli n ed  i n T a bl e  1  a n d  T a bl e  2 .  
A  c o m pl et e  st a n d ar d  of  c ar e  p h ysi c al  e x a mi n ati o n f or  e a c h s u bj e ct  will  b e  p erf or m e d  a n d  will 
c o v er t h e f oll o wi n g  b o d y s yst e ms:  g e n er al  a p p e ar a n c e, s ki n,  e y es,  e ars,  n os e, t hr o at,  h e art, 
l u ngs,  a b d o m e n,  n e ur ol o gi c al s yst e m, l y m p h  n o d es, s pi n e,  a n d  e xtr e miti es.   A n  a b br e vi at e d 
p h ysi c al  e x a mi n ati o n  f or  e a c h s u bj e ct  will  c o v er t h e f oll o wi n g  b o d y s yst e ms:  h e art, l u n gs,  a n d 
f oll o w  u p  of  ot h er s yst e ms  as  a p pr o pri at e  b as e d  o n l ast  e x a m  a n d r e p ort e d A Es .  
A n y  u nf a v or a bl e fi n di n gs  n ot  pr es e nt  at s cr e e ni n g  c o nsi d er e d  b y t h e i n v esti g at or  as  cli ni c all y 
si g nifi c a nt,  o c c urri n g  at  a n y  p oi nt i n t h e st u d y  will  b e  d o c u m e nt e d i n t h e  e C R F  as  a n  A E.   
7. 2. 3   
N e u r ol o gi c al  E x a mi n ati o ns  
C o m pl et e  a n d  a b br e vi at e d  n e ur ol o gi c al  e x a mi n ati o n  will  b e  c o n d u ct e d  b y t h e i n v esti g at or  or 
d esi g n e e  d uri n g t h e st u d y  as  o utli n e d i n  T a bl e  1  a n d  T a bl e  2 .   A  c o m pl et e st a n d ar d  of  c ar e 
n e ur ol o gi c al  e x a mi n ati o n f or  e a c h s u bj e ct  will  b e  p erf or m e d  a n d  will  c o v er t h e f oll o wi n g: 
cr a ni al  n er v es,  m us cl e str e n gt h  a n d t o n e,  r efl e x es,  c o or di n ati o n, s e ns or y f u n cti o n, a n d  g ait .   A n 
a b br e vi at e d  n e ur ol o gi c al  f oll o w-u p  e x a mi n ati o n  f or  e a c h s u bj e ct  will e v al u at e  a n y s y m pt o ms 
or s yst e ms f o u n d t o  b e  a b n or m al  a n d  u nst a bl e  or  p ot e nti all y  u nst a bl e  t h at  mi g ht  e v ol v e  d uri n g 
st u d y tr e at m e nt,  or t o i n v esti g at e  a n y r e p ort e d  or  o bs er v e d  A Es.    
A n y  u nf a v or a bl e fi n di n gs  n ot  pr es e nt  at s cr e e ni n g  c o nsi d er e d  b y t h e i n v esti g at or  as  cli ni c all y 
si g nifi c a nt,  o c c urri n g  at  a n y  p oi nt i n t h e st u d y  will  b e  d o c u m e nt e d  i n t h e  e C R F  as  a n  A E.  
7. 2. 4   
Vit al  Si g ns  
Vit al si g ns i n cl u di n g  bl o o d  pr ess ur e,  h e art r at e, t e m p er at ur e,  a n d r es pir at or y r at e  will  b e 
d o c u m e nt e d f or s u bj e cts  d uri n g  st u d y  as  o utli n ed  i n T a bl e  1  a n d  T a bl e  2 .  S u bj e cts  will  b e 
sitti n g f or  5  mi n ut es  pri or t o t h e  vit al si g ns  b ei n g  o bt ai n e d.   Bl o o d  pr ess ur e s h o ul d  b e  ass ess e d 
o n t h e s a m e  ar m f or  e a c h ti m e  of  d et er mi n ati o n.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 3  of  1 9 4  
7. 2. 5   
L a b o r at o r y  M e as u r e m e nts  
L a b or at or y s af et y  p ar a m et ers  will  b e  a n al y z e d  usi n g st a n d ar d  v ali d at e d  m et h o ds.   
T h e f oll o wi n g  p ar a m et ers  will  b e  ass ess e d  b y t h e l a b or at or y  as  d es cri b e d i n  T a bl e  1  a n d  
T a bl e  2 : 
•   H e m at ol o g y : h e m o gl o bi n,  h e m at o crit,  er yt hr o c yt es,  er yt hr o c yt e  m e a n 
c or p us c ul ar  v ol u m e, l e u k o c yt es,  m e a n  c or p us c ul ar  h e m o gl o bi n,  m e a n 
c or p us c ul ar  h e m o gl o bi n  c o n c e ntr ati o n,  n e utr o p hils,  l y m p h o c yt es, m o n o c yt es, 
e osi n o p hils,  b as o p hils  a n d  pl at el ets  
•   Bl o o d  Bi o c h e mistr y:  al b u mi n ( A L B),  al k ali n e  p h os p h at as e ( A P),  al a ni n e 
a mi n otr a nsf er as e ( A L T;  S G P T),  as p art at e  a mi n otr a nsf er as e ( A S T;  S G O T), 
bi c ar b o n at e,  bl o o d  ur e a  nitr o g e n ( B U N),  c al ci u m ( C a),  c hl ori d e ( Cl),  cr e ati ni n e, 
cr e ati n e  ki n as e,  g a m m a -gl ut a m yl tr a nsf er as e ( G G T),  gl o b uli n,  gl u c os e, l a ct at e 
d e h y dr o g e n as e ( L D H),  p h os p h or us,  p ot assi u m ( K), s o di u m ( N a),  t h yr oi d 
f u n cti o n ( T 3,  T 4,  a n d t h yr oi d sti m ul ati n g  h or m o n e ), t ot al  bilir u bi n,  dir e ct 
bilir u bi n, t ot al  c h ol est er ol, t ot al  pr ot ei n, tri gl y c eri d es,  uri c  a c i d.  
•   T ests  of  gr o wt h  a n d  pr e c o ci o us  p u b ert y:  Gr o wt h  h or m o n e ( G H), i ns uli n -li k e 
gr o wt h f a ct or -1 (I G F -1, l o w s e nsiti vit y),  pr ol a cti n,  L ut ei ni zi n g  H or m o n e  ( L H), 
F olli cl e  Sti m ul ati n g  H or m o n e  ( F S H), t est ost er o n e,  estr a di ol 
•   E pil e ps y  g e n ot y p e  p a n el  
•   B u c c al  s w a b f or C Y P 2 D 6  g e n ot y pi n g  
•   C o a g ul ati o n:  p r ot hr o m bi n ti m e ( P T)/int er n ati o n al  n or m ali z e d r ati o (I N R), 
a cti v at e d  p arti al t hr o m b o pl asti n ti m e ( P T T)  
•   W h ol e  bl o o d  c a n n a bi di ol  ( C B D) 
•   Uri n al ysis:  a n al ysis f or  p H,  gl u c os e,  k et o n es,  nitrit e,  pr ot ei n,  bilir u bi n, 
ur o bili n o g e n,  l e u k o c yt e  est er as e,  a n d  o c c ult  bl o o d.  Mi cr os c o pi c  a n al ysis  will  b e 
p erf or m e d f or  bl o o d,  all  c ell t y p es,  a n d  c asts.  
•   Uri n e  pr e g n a n c y t est:  Uri n e  pr e g n a n c y t esti n g  will  b e  p erf or m e d i n f e m al e 
s u bj e cts of  c hil d b e ari n g  p ot e nti al.  
•   Uri n e  T H C  p a n el  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 4  of  1 9 4  
T h e  i n v esti g at or  will r e c ei v e t h e l a b or at or y r e p ort fr o m t h e  c e ntr al l a b or at ory .   Aft er r e vi e wi n g 
t h e r e p ort  a n d  e v al u ati n g  a n y r es ults t h at  ar e  o utsi d e t h e  n or m al r a n g e, t h e i n v esti g at or  m ust 
si g n  a n d  d at e t h e l a b or at or y r e p ort.    
T ests r es ulti n g i n  a b n or m al  l a b or at or y  v al u es t h at  h a v e  b e e n  cl assifi e d  b y t h e i n v esti g at or  as 
a b n or m al,  cli ni c all y si g nifi c a nt s h o ul d  b e r e p e at e d  as s o o n  as  p ossi bl e  aft er r e c ei vi n g t h e 
l a b or at or y r e p ort t o r ul e  o ut l a b or at or y  err ors. 
At  S cr e e ni n g  a n y l a b or at or y  v al u es t h at  d e vi at e  fr o m t h e r ef er e n c e r a n g es  a n d  ar e  c o nsi d er e d 
b y t h e i n v esti g at or  as  cli ni c all y r el e v a nt  m ust  b e  d o c u m e nt e d  o n t h e  m e di c al  hist or y f or m  of 
t h e  e C R F.   A n y  d e vi ati o n  o utsi d e  of t h e r ef er e n c e r a n g e  c o nsi d er e d  b y t h e i n v esti g at or  as 
cli ni c all y si g nifi c a nt (i e,  cl assifi e d  as  a n  a b n or m al,  cli ni c all y si g nifi c a nt  v al u e)  at  a n y  visit  aft er 
s cr e e ni n g will  b e  d o c u m e nt e d i n t h e  e C R F  as  a n  A E (s e e  S e cti o n  8 ). 
7. 2. 6   
Pl as m a  S a m pl e f o r  C o n c o mit a nt  A nti e pil e pti c  D r u g(s)  
Pl as m a s a m pl es t o  e ns ur e t h at  c o n c o mit a nt  a nti e pil e pti c  dr u g(s) ( A E Ds)  d osi n g is  wit hi n  a n 
a c c e pt a bl e r a n g e  will  b e  c o n d u ct e d  d uri n g t h e  st u d y  as  o utli n e d i n  T a bl e  1  a n d  T a bl e  2 . 
S a m pl es  c oll e ct e d  at  Visit  6  will  b e  a n al y z e d  aft er  c oll e cti o n  as  a s af et y  m e as ur e.   S a m pl es 
c oll e ct e d  at  ot h er ti m e  p oi nts  will  b e  a n al y z e d  at st u d y  e n d  a n d  d o  n ot  c o nstit ut e s af et y 
ass ess m e nts.  
7. 3   
A D V E R S E  E V E N T S  
A d v ers e  e v e nts  will  b e  c oll e ct e d fr o m t h e ti m e  of si g ni n g t h e i nf or m e d  c o ns e nt f or m/ ass e nt 
f or m  u ntil t h e  e n d  of t h e st u d y, i n cl u di n g t h e f oll o w-u p  cli ni c  visit.   D et ails  of t h e  d efi niti o ns 
a n d  c at e g ori z ati o n  of  A Es,  a n d  pr o c e d ur es f or  t h e r e p orti n g  of  A Es,  ar e  a v ail a bl e i n S e cti o n  8 . 
S e v erit y  a n d  c a us alit y  of  A Es  will  b e  e v al u at e d  a c c or di n g t o t h e  crit eri a s p e cifi e d i n  S e cti o n  8. 2  
a n d  S e cti o n  8. 3 , r es p e cti v el y. T h e  o bs er v ati o n  p eri o d f or  A E r e p ort i n g is s p e cifi e d i n 
S e cti o n  8. 4 . At t h e  b e gi n ni n g  of  e a c h  visit  at t h e st u d y sit e, t h e st u d y  p ers o n n el  will s p e cifi c all y 
i n q uir e  a b o ut  a n y  A Es t h at  mi g ht  h a v e  o c c urr e d si n c e t h e l ast st u d y sit e  visit.  All  A Es  will  b e 
r e c or d e d  o n t h e  a p pr o pri at e  e C R F  p a g e.  
7. 3. 1   
El e ct r o c a r di o g r a ms  
T w el v e -l e a d  E C Gs  will  b e c o n d u ct e d  d uri n g st u d y  as  o utli n e d i n  T a bl e  1  a n d  T a bl e  2  aft er t h e 
s u bj e ct  h as  b e e n i n t h e s u pi n e  p ositi o n r esti n g  f or ≥ 5  mi n ut es . H e art r at e,  P R  d ur ati o n,  Q R S 
d ur ati o n,  Q T  d ur ati o n,  Q T c F ( Fri d eri ci a's  c orr e cti o n f or m ul a ),  a n d  will  b e r e a d  c e ntr all y. 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 5  of  1 9 4  
7. 3. 2   
D o p pl e r  E c h o c a r di o g r a p h y  
D o p pl er  e c h o c ar di o gr a p h y  will  b e  c o n d u ct e d  at  a f a cilit y  wit h  e x p eri e n c e f or t h e s u bj e ct’s  a g e 
d uri n g st u d y  as  o utli n e d  i n T a bl e  1  a n d  T a bl e  2 . D o p pl er  e c h o c ar di o gr a p h y  us es  ultr as o u n d  
t e c h n ol o g y t o  e x a mi n e t h e h e art  or  bl o o d  v ess els .  A n  E C H O  us es  hi g h fr e q u e n c y s o u n d  w a v es 
t o  cr e at e  a n i m a g e  of t h e  h e art  w hil e t h e  us e  of  D o p pl er t e c h n ol o g y  all o ws  d et er mi n ati o n  of t h e 
s p e e d  a n d  dir e cti o n  of  bl o o d fl o w  b y  utili zi n g t h e  D o p pl er  eff e ct . Pr e d et er mi n e d st a n d ar d 
g ui d eli n es  o n t h e  pr o p er  e v al u ati o n  of  c ert ai n  m e as ur e m e nts,  as  w ell  as  a b n or m alit y t hr es h ol ds,  
w er e  c o nstr u ct e d  b y  t h e S p o ns or ’s I P C A B pri or t o st u d y i niti ati o n .  T h es e t hr es h ol ds  ar e 
pr o vi d e d i n  T a bl e  1 6 .  A  m a n u al  of  pr o p er  E C H O t e c h ni q u e f or sit es is pr o vi d e d i n  a s e p ar at e 
d o c u m e nt . 
7. 3. 3   
T a n n e r  St a gi n g  
T a n n er  St a gi n g  (A p p e n di x  5 ) will  b e  ass ess e d  f or s u bj e cts  > 7  y e a rs  ol d d uri n g  t h e st u d y  as 
o utli n e d i n  T a bl e  1  a n d  T a bl e  2 . C o n c e pt u all y,  p u b ert al  m at ur ati o n  c a n  b e  d es cri b e d i n t er ms  of 
s e q u e n c e, ti mi n g,  a n d t e m p o.   P u b ert y  c o nsists  of  a s eri es  of  pr e di ct a bl e  e v e nts,  a n d t h e 
s e q u e n c e  of  c h a n g es i n s e c o n d ar y s e x u al  c h ar a ct eristi cs  h as  b e e n  c at e g ori z e d  b y s e v er al 
gr o u ps.  T h e st a gi n g s yst e m  us e d  m ost fr e q u e ntl y  w as  p u blis h e d  b y  M ars h all  a n d  T a n n er ( 1 9 6 9 , 
1 9 7 0 ) a n d t h e s e q u e n c e  of  c h a n g es  ar e  c o m m o nl y r ef err e d t o  as ‘ T a n n er st a g es’ .  
7. 3. 4   
C ol u m bi a -S ui ci d e  S e v e rit y  R ati n g  S c al e  
C -S S R S  (A p p e n di x  2 ) will  b e  ass ess e d  d uri n g  st u d y  as  o utli n e d i n T a bl e  1  a n d  T a bl e  2 . T h e 
C -S S R S is  a  v ali d at e d  r ati n g s c al e t h at ass ess es  s ui ci d al b e h a vi or  a n d i d e ati o n.  T h e s c al e is 
us e d t o  ass ess  a n d tr a c k s ui ci d e  e v e nts  a n d  pr o vi d es  a s u m m ar y  m e as ur e  of s ui ci d al t e n d e n c y.   
T h e  C -S S R S  v ersi o n  6/ 2 3/ 1 0 ( C hil dr e n's  B as eli n e/ S cr e e ni n g  a n d  C hil dr e n’s  Si n c e  L ast  Visit) 
will  b e  us e d i n t his st u d y  as  a p pr o pri at e f or t h e  a g e  a n d l e v e l  of i nt ell e ct u al  d e v el o p m e nt. 
S u bj e cts  w h o  ar e  y o u n g er t h a n  7  y e ars  c hr o n ol o gi c all y,  or  w h o  ar e  j u d g e d  b y t h e i n v esti g at or 
n ot t o  h a v e t h e  m e nt al  c a p a cit y t o  u n d erst a n d t h e  q u esti o ns  as s p e cifi e d  o n t h e  C -S S R S,  will 
n ot  c o m pl et e t h e r ati n g.   T h e i n v es ti g at or s h o ul d  us e  his/ h er j u d gm e nt t o s u bstit ut e 
i nt ell e ct u all y-a p pr o pri at e  q u esti o ns t o  pr o b e  t h e t e n d e n c y f or s elf-h ar m.  
If  a s u bj e ct  wit h t h e i nt ell e ct u al  c a p a cit y t o  c o m pl et e t h e  C-S S R S  h as t h eir  7t h  birt h d a y  d uri n g 
t h e st u d y,  us e  of t h e  C-S S R S s h o ul d  b e i niti at e d  at s u bs e q u e nt  visits.  
7. 3. 5   
B e h a vi o r  R ati n g I n v e nt o r y  of  E x e c uti v e  F u n cti o n ( B RI E F)  
T h e  B RI E F  is  a st a n d ar di z e d,  v ali d at e d r ati n g s c al e t o  m e as ur e  e x e c uti v e f u n cti o n i n  c hil dr e n 
a g es  2 -1 8  y e ars  wit hi n t h e  h o m e  a n d s c h o ol  e n vir o n m e nts ; it will  b e  ass ess e d  a c c or di n g t o t h e 
s c h e d ul e i n T a bl e  1  a n d  T a bl e  2 .   T h e  B RI E F  m e as ur es  m ulti pl e  as p e cts  of  e x e c uti v e 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 6  of  1 9 4  
f u n cti o ni n g; s c al es i n cl u d e I n hi bit ( c o ntr ol i m p uls es; st o p  b e h a vi or),  S hift ( m o v e fr e el y fr o m 
o n e  a cti vit y/sit u ati o n t o  a n ot h er; tr a nsiti o n ;  pr o bl e m-s ol vi n g fl e xi bilit y),  E m oti o n al  C o ntr ol 
( m o d ul at e  e m oti o n al r es p o ns es  a p pr o pri at el y), I niti at e ( b e gi n  a cti vit y;  g e n er at e i d e as),  W or ki n g 
M e m or y  ( h ol d i nf or m ati o n i n  mi n d f or  p ur p os e  of  c o m pl eti n g t as k), 
Pl a n/ Or g a ni z e / Or g a ni z ati o n  of  M at eri als ( a nti ci p at e f ut ur e  e v e nts; s et  g o als;  d e v el o p st e ps; 
gr as p  m ai n i d e as),  a n d  M o nit or ( c h e c k  w or k;  ass ess  o w n  p erf or m a n c e).   T h e  B RI E F  will  b e 
us e d t o  ass ess  c o g niti v e f u n cti o n i n s u bj e cts  w h o  ar e  ≥  5  y e ars  of  a g e  at  b as eli n e .   T h e  pr e-
s c h o ol  v ersi o n  of t h e  B RIE F ( B RI E F -P)  will  b e  us e d t o  ass ess  c o g niti v e f u n cti o n i n  c hil dr e n   
<  5  y e ars  of  a g e  at  b as eli n e .   
7. 4   
P H A R M A C O KI N E TI C  A S S E S S M E N T S   
C o h o rt  1:   Bl o o d s a m pl es f or  P K  ass ess m e nts  of  f e nfl ur a mi n e a n d its  m et a b olit e 
( n orf e nfl ur a mi n e), C L B  a n d its  m et a b olit e  N -C L B,  S T P ,  a n d V P A  will  b e  o bt ai n e d fr o m  all 
s u bj e cts  vi a  a n i n d w elli n g  c at h et er.  Pri or t o  o bt ai ni n g t h e  P K s a m pl e,  a b o ut  0. 5  m L s h o ul d  b e 
dr a w n  off  a n d  dis c ar d e d .   S a m pl es  will  b e  c oll e ct e d  wit hi n  o n e  h o ur  pri or t o  d osi n g  ( pr e-d os e), 
a n d  at  2,  4,  8,  1 2 ,  a n d  24 -3 6  h o urs  p ost -d os e.   Si x  s a m pl es ( o n e  pr e-d os e  a n d  fi v e p ost -d os e)  
will  b e  c oll e ct e d fr o m  e a c h s u bj e ct f or  a t ot al  of  a p pr o xi m at el y  2 7  m L.    
C o h o rt  2:   Bl o o d s a m pl es f or  P K  ass ess m e nt ( 2  m L)  of f e nfl ur a mi n e  a n d its  m et a b olit e 
( n orf e nfl ur a mi n e) will  b e  o b t ai n e d  at t h e f oll o wi n g ti m e  p oi nts: 
•   Visit  1 3 : wit hi n  1  h o ur  pri or t o t h e  m or ni n g  d os e,  a n d  1,  2,  a n d  4 -6  h o urs  aft er t h e 
m or ni n g  d os e.    
A  t ot al  of 4  P K s a m pl es  will  b e  dr a w n f or  e a c h s u bj e ct f or  a t ot al  of  a p pr o xi m at el y  8  m L  of 
bl o o d . 
W h e n  bl o o d  dr a ws f o r  P K  c oi n ci d e  wit h  ot h er  ass ess m e nts, t h e  P K  dr a ws t a k e  pr e c e d e n c e. 
T h e  pr o c e d ur e f or t h e  c oll e cti o n  a n d  h a n dli n g  of  P K s a m pl es is  o utli n e d i n  a s e p ar at e st u d y 
m a n u al . 
7. 5   
A P P R O P RI A T E N E S S  O F  M E A S U R E M E N T S  
All  of t h e  v ari a bl es  ass ess e d  ar e st a n d ar d t ests  or  pr o c e d ur es t h at  ar e  c o m m o nl y  us e d i n st u di es 
of t his t y p e.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 7  of  1 9 4  
8.   
A D V E R S E  E V E N T S  
8. 1   
D E FI NI TI O N S  
8. 1. 1   
A d v e rs e  E v e nt s 
A c c or di n g t o  I C H  g ui d eli n es,  a n  A E is  a n y  u nt o w ar d  m e di c al  o c c urr e n c e i n  a  p ati e nt  or  cli ni c al 
i n v esti g ati o n s u bj e ct  a d mi nist er e d  a  p h ar m a c e uti c al  pr o d u ct  a n d  w hi c h  d o es  n ot  n e c ess aril y 
h a v e  a  c a us al r el ati o ns hi p  wit h t his tr e at m e nt.   A n  A E  c a n, t h er ef or e,  b e  a n y  u nf a v or a bl e  a n d 
u ni nt e n d e d si g n (i n cl u di n g  a n  a b n or m al,  cli ni c all y si g nifi c a nt l a b or at or y fi n di n g), s y m pt o m,  or 
dis e as e t e m p or all y  ass o ci at e d  wit h t h e  us e  of  a  m e di ci n al (i n v esti g ati o n al)  pr o d u ct,  w h et h er  or 
n ot  c o nsi d er e d r el at e d t o t h e  m e di ci n al (i n v esti g ati o n al)  pr o d u ct.  T h e  p eri o d  of  o bs er v ati o n f or 
a d v ers e  e v e nts  e xt e n ds fr o m t h e ti m e t h e s u bj e ct  gi v es i nf or m e d  c o ns e nt  u ntil t h e  e n d  of st u d y .  
A d v ers e  e v e nts  m a y i n cl u d e:  
•   
E x a c er b ati o n (i e,  a n i n cr e as e i n t h e fr e q u e n c y  or s e v erit y)  of  a  pr e -e xisti n g  c o n diti o n.  
Ill n ess  pr es e nt  b ef or e st u d y  e ntr y s h o ul d  b e r e c or d e d i n t h e  m e di c al  hist or y s e cti o n  of 
t h e  e C R F  a n d  o nl y  b e r e p ort e d  as  a n  A E if t h er e is  a n i n cr e as e i n t h e fr e q u e n c y  or 
s e v erit y  of t h e  c o n diti o n  d uri n g t h e st u d y.  E x a c er b ati o n  of s ei z ur es  is c o nsi d er e d  a n 
A E if t h er e  w as  a n i n cr e as e i n fr e q u e n c y  b e y o n d t h e s u bj e ct's t y pi c al  pr e -st u d y 
fl u ct u ati o ns,  or i n t h e  e v e nt t h at s ei z ur es l e n gt h e n i n  d ur ati o n i n  a  cli ni c all y 
m e a ni n gf ul  w a y  c o m p ar e d  wit h  b as eli n e,  or if  a  n e w s ei z ur e t y p e  e m er g es.  
•   
A  cli ni c al  e v e nt  o c c urri n g  aft er  c o ns e nt  b ut  b ef or e  I M P a d mi nistr ati o n.  
•   
I nter c urr e nt  ill n ess es  wit h  a n  o ns et  aft er  a d mi nistr ati o n  of I M P. 
A d v ers e  e v e nts  d o  n ot i n cl u d e:  
•   
M e di c al  or s ur gi c al  pr o c e d ur es (t h e  c o n diti o n t h at l e a ds t o t h e  pr o c e d ur e is t h e  A E , 
e g , t o nsillitis is t h e  A E if  a t o nsill e ct o m y is  p erf or m e d) 
•   
Sit u ati o ns  w h er e  a n  u nt o w ar d  m e di c al  o c c urr e n c e  h as  n ot t a k e n  pl a c e.   F or  e x a m pl e:  
o   Pl a n n e d  h os pit ali z ati o ns  d u e t o  pr e -e xisti n g  c o n diti o ns,  w hi c h  h a v e  n ot 
w ors e n e d.  
o   H os pit ali z ati o ns t h at  o c c ur f or  pr o c e d ur es  n ot  d u e t o  a n  A E ( e g,  c os m eti c 
s ur g er y).  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 8  of  1 9 4  
o   H os pit ali z ati o ns f or  a  di a g n osti c  pr o c e d ur e  w h er e t h e  h os pit al st a y is l ess t h a n 
2 4  h o urs i n  d ur ati o n  or f or  n or m al  m a n a g e m e nt  pr o c e d ur es ( e g,  c h e m ot h er a p y).  
F or l a b or at or y s af et y  p ar a m et ers,  a n y i nst a n c es  of  a bs ol ut e  v al u es  b ei n g  o utsi d e t h e r ef er e n c e 
r a n g e  or  c h a n g es  at  a n y  visit  aft er st u d y st art t h at  ar e  c o nsi d er e d  b y t h e i n v esti g at or  as 
cli ni c all y si g nifi c a nt  m ust  b e  r e c or d e d i n t h e  e C R F  as  A Es.  I n  a d diti o n,  at t h e i n v esti g at or’s 
dis cr eti o n,  a n y  c h a n g es  or tr e n ds  o v er ti m e i n l a b or at or y  p ar a m et ers  c a n  b e r e c or d e d i n t h e 
e C R F  as  A Es if s u c h  c h a n g es  or tr e n ds  ar e  c o nsi d er e d t o  b e  cli ni c all y r el e v a nt,  e v e n if t h e 
a bs ol ut e  v al u es  ar e  wit hi n t h e r ef er e n c e r a n g e.  
L a b or at or y fi n di n gs  d o  n ot  n e e d t o  b e r e p ort e d  as  A Es i n t h e f oll o wi n g  c as es:  
1.   L a b or at or y  p ar a m et ers  ar e  alr e a d y  b e y o n d t h e r ef er e n c e r a n g e ,  u nl ess  a f urt h er 
i n cr e as e/ d e cr e as e  c a n  b e  c o nsi d er e d  a n  e x a c er b ati o n  of  a  pr e-e xisti n g  c o n diti o n.  
2.   A b n or m al l a b or at or y  p ar a m et ers  c a us e d  b y  m e c h a ni c al  or  p h ysi c al i nfl u e n c es  o n  t h e 
bl o o d s a m pl e ( e g,  h e m ol ysis)  a n d fl a g g e d  as s u c h  b y t h e l a b or at or y i n t h e 
l a b or at or y r e p ort. 
3.   A b n or m al  p ar a m et ers t h at  ar e  o b vi o usl y  bi ol o gi c all y i m pl a usi bl e ( e g,  v al u es t h at 
ar e i n c o m p ati bl e  wit h lif e).  
4.   A n  a b n or m al l a b or at or y  v al u e t h at  c a n n ot  b e  c o nf ir m e d  aft er a  r e p e ate d  a n al ysis, 
pr ef er a bl y i n t h e s a m e l a b or at or y ( e g , t h e  pr e vi o us r es ult  c o ul d  b e  m ar k e d  as  n ot 
v ali d  a n d s h o ul d  n ot  n e c ess aril y  b e r e p ort e d  as  a n  A E).   
8. 1. 2   
S e ri o us  A d v e rs e  E v e nt s 
A n  S A E is  d efi n e d  as  a n y  u nt o w ar d  m e di c al  o c c urr e n c e t h at  at  a n y  d os e:  
1.   
R es ults i n  d e at h  –  T h e  e v e nt  m ust  b e t h e  c a us e  of  d e at h f or t h e  S A E t o  m e et t his s eri o us 
crit eri o n.  
2.   
Is lif e-t h r e at e ni n g –  T h e t er m  “lif e -t hr e at e ni n g ” r ef ers t o  a n  e v e nt i n  w hi c h t h e s u bj e ct 
w as  at ris k  of  d e at h  at t h e ti m e  of t h e  e v e nt; it  d o es  n ot r ef er t o  a n  e v e nt t h at 
h y p ot h eti c all y  mi g ht  h a v e  c a us e d  d e at h if it  h a d  b e e n  m or e s e v er e.  
3.   
R e q ui r es i n -p ati e nt  h os pit ali z ati o n  o r  p r ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n  –  T h e 
S p o ns or  c o nsi d ers  “ h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n ” f or  at 
l e ast  2 4 h o urs  as t h e  d efi ni n g  crit eri o n f or  a n  S A E.   H os pit al  a d missi o ns f or  pl a n n e d 
s ur g er y  or f or  n or m al  dis e as e  m a n a g e m e nt  pr o c e d ur es ( e g,  c h e m ot h er a p y)  ar e  n ot 
c o nsi d er e d  as  d efi ni n g  crit eri a f or  S A Es.   


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 0 9  of  1 9 4  
4.   
R es ults i n  p e rsist e nt  o r si g nifi c a nt  dis a bilit y  o r i n c a p a cit y.  
5.   
Is  a  c o n g e nit al  a n o m al y  o r  bi rt h  d ef e ct.  
6.   
Is  m e di c all y si g nifi c a nt  –  A  m e di c all y si g nifi c a nt  e v e nt is  d efi n e d  as  a n  e v e nt t h at  d o es 
n ot  m e et  a n y  of t h e  ot h er  5  S A E  crit eri a,  b ut  w hi c h is j u d g e d  b y  a  p h ysi ci a n t o 
p ot e nti all y  j e o p ar di z e t h e s u bj e ct  or r e q uir e  m e di c al  or s ur gi c al i nt er v e nti o n t o  pr e v e nt 
o n e  of t h e  a b o v e  o ut c o m es list e d  as  a n  S A E  crit eri o n.  A n a p h yl a xis t h at is s u c c essf ull y 
tr e at e d  b y  a d mi nistr ati o n  of  e pi n e p hri n e  pri or t o  ot h er s e q u el a e is  a n  e x a m pl e  of  a 
p ot e nti all y  m e di c all y i m p ort a nt  e v e nt.  
F or t h e  p ur p os e  of  d at a  c oll e cti o n i n t his st u d y,  a  pr ol o n g e d s ei z ur e  or s eri es  of s ei z ur es fr o m 
w hi c h t h e s u bj e ct  d o es  n ot r e g ai n  c o ns ci o us n ess  b et w e e n i ct al  e v e nts, t h at is  at l e ast 
3 0  mi n ut es  i n  d ur ati o n, is t er m e d S E .  A si n gl e  e pis o d e  of  S E i n  a  2 4 -h o u r  p eri o d, r e g ar dl ess 
of  w h et h er r es c u e  m e di c ati o n  w as  a d mi nist er e d, s h o ul d  b e  e nt er e d i n t h e  A E  l o g  as  w ell  as i n 
t h e s ei z ur e  di ar y.  If t w o  or  m or e  e pis o d es  o c c ur  wit hi n  2 4  h o urs,  e a c h l asti n g  3 0  mi nut es  or 
m or e,  a n  S A E  of  S E  s h o ul d  b e r e c or d e d.   H os pit ali z ati o n t o  m a n a g e  S E, r e g ar dl ess  of t h e 
n u m b er  of  e pis o d es, s h o ul d  b e r e p ort e d  as  a n  S A E.  
A d v ers e  e v e nts t h at  d o  n ot f all i nt o t h e  a b o v e  c at e g ori es  ar e  d efi n e d  as  n o ns eri o us  A Es.  
8. 1. 3   
A d v e rs e  E v e nts  of  S p e ci al  I nt e r est  
As  p er I C H  g ui d a n c e ( E 2 F  D e v el o p m e nt  S af et y  U p d at e  R e p ort  2 0 1 1 ), t h e S p o ns or  h as 
i d e ntifi e d t h e f oll o wi n g A E SI  f or t h e  Z X 0 0 8  pr o gr a m (T a bl e  1 4 ). 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 0  of  1 9 4  
T a bl e  1 4 . A d v e rs e  E v e nts  of  S p e ci al I nt e r est   
M et a b oli c/ E n d o c ri n e  
1.   El e v at e d  pr ol a cti n l e v el  ≥ 2 x  a b o v e t h e  u p p er li mit  of  n or m al ( U L N)  
2.   H y p o gl y c e mi a  –  s er u m  bl o o d  gl u c o s e  m or e t h a n  2 0 %  b el o w t h e  gl u c os e l e v el  o n  D a y  -1  v al u e  or  m or e 
t h a n  1 0 %  b el o w  L L N (r ef er e n c e r a n g e  6 0 –  1 4 0  m g/ d L)  
N e u r o ps y c hi at ri c  
1 3.   S ui ci d al t h o u g hts, i d e ati o n  or  g est ur es  
L L N  = l o w er li mit  of  n or m al;  U L N  =  u p p er li mit  of  n or m al   
 
8. 1. 4   
A d v e rs e  E v e nts  R e q ui ri n g  H os pit ali z ati o n  
If  a s u bj e ct is tr e at e d i n  a  m e di c al f a cilit y ( h os pit al,  e m er g e n c y r o o m, fr e e-st a n di n g  cli ni c) 
r el at e d t o t h e  o c c urr e n c e  of  a n y  A E, t h e f oll o wi n g  d at a  will  b e  c oll e ct e d t o  m o d el  h e alt h  c ar e 
utili z ati o n i n  p ati e nts  wit h  D r a v et s y n dr o m e:  A E/r e as o n f or  h os pitali z ati o n/ cli ni c  visit;  d ur ati o n 
of t h e  visit i n  h o urs/ d a ys;  a d missi o n t o i nt e nsi v e  c ar e  u nit;  a n d  n a m e/ n u m b er  of  pr o c e d ur es 
p erf or m e d, i n cl u di n g  b ut  n ot li mit e d t o,  el e ctr o e n c e p h al o gr a m,  E C G,  E C H O,  p ositi v e  e missi o n 
t o m o gr a p h y ( P E T) s c a n,  M RI,  x-r a y,  c o m put e d t o m o gr a p h y  (C T) s c a n, s ur g er y,  a n d l u m b ar 
p u n ct ur e/s pi n al t a p.  
8. 2   
S E V E RI T Y  O F  A D V E R S E  E V E N T S  
T h e s e v erit y  of  A Es  (w h et h er  n o ns eri o us  or  s eri o us  A Es) is t o  b e  ass ess e d  b y t h e i n v esti g at or 
as f oll o ws ( T a bl e  1 5 ). 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 1  of  1 9 4  
T a bl e  1 5 . S e v e rit y  D efi niti o n  of  A d v e rs e  E v e nts   
S e v e rit y   
D efi niti o n  
Mil d   
A t y p e  of  A E  t h at is  us u all y tr a nsi e nt  a n d  m a y r e q uir e  o nl y  mi ni m al tr e at m e nt  or t h er a p e uti c 
i nt er v e nti o n.  T h e  e v e nt  d o es  n ot  g e n er all y i nt erf er e  wit h  us u al  a cti viti e s  of  d ail y li vi n g. 
M o d er at e   
A t y p e  of  A E  t h at is  us u all y  all e vi at e d  wit h  a d diti o n al s p e cifi c t h er a p e uti c i nt er v e nti o n.  T h e 
e v e nt i nt erf er es  wit h  us u al  a cti viti e s  of  d ail y li vi n g,  c a u si n g  dis c o mf ort  b ut  p os es  n o 
si g nifi c a nt  or  p er m a n e nt ris k  of  h ar m t o t h e r es e ar c h  p arti ci p a nt.  
S e v er e   
A t y p e  of  A E  t h at i nt err u pts  us u al  a cti viti es  of  d ail y li vi n g,  or si g nifi c a ntl y  aff e cts  cli ni c al 
st at us,  or  m a y r e q uir e i nt e nsi v e t h er a p e uti c i nt er v e nti o n.  
Cli ni c al  D at a I nt er c h a n g e  St a n d ar ds  C o ns orti u m  St u d y  D at a  T a b ul ati o n  M o d el  S e v erit y I nt e nsit y  S c al e f or 
A d v ers e  E v e nt  T er mi n ol o g y  
8. 3   
C A U S A LI T Y  O F  A D V E R S E  E V E N T S  
T h e  c a us al r el ati o ns hi p  of  a n  A E t o  I M P m ust  al w a ys  b e  ass ess e d  b y t h e i n v esti g at or.   All  A Es 
will  b e  cl assifi e d  as  eit h er  r el at e d  or  n ot  r el at e d  t o I M P. If a  c a us alit y  ass ess m e nt is  n ot 
pr o vi d e d  f or  a n A E (i n cl u di n g  a n  S A E),  t h e n t h at  A E  will  b e  c o nsi d er e d as  r el at e d t o I M P.  
T h e  d e gr e e  of  c ert ai nt y  wit h  w hi c h  a n  A E is  attri b ut e d t o  I M P or  a n  alt er n ati v e  c a us e ( e g, 
n at ur al  hist or y  of t h e  u n d erl yi n g  dis e as e,  c o n c o mit a nt  m e di c ati o n s)  will  b e  d et er mi n e d  b y  h o w 
w ell t h e  e v e nt  c a n  b e  u n d erst o o d i n t er ms  of:  
•   K n o w n  p h ar m a c ol o g y  of  Z X 0 0 8  
•   Cli ni c all y  a n d/ or  p at h o p h ysi ol o gi c all y  pl a usi bl e  c o nt e xt  
•   R e a cti o n  of  a si mil ar  n at ur e  pr e vi o usl y  o bs er v e d  wit h si mil ar  pr o d u cts,  or r e p ort e d 
i n t h e lit er at ur e f or si mil ar  pr o d u cts  as  b ei n g  pr o d u ct r el at e d ( e g,  h e ad a c h e, f a ci al 
fl us hi n g,  p all or) 
•   Pl a usi bilit y s u p p ort e d  b y  t h e t e m p or al r el ati o ns hi p ( e g, t h e  e v e nt  b ei n g r el at e d  b y 
ti m e t o  a d mi nistr ati o n  or t er mi n ati o n  of tr e at m e nt  wit h I M P dr u g  wit h dr a w a l  or 
r e pr o d u c e d  o n r e c h all e n g e) 
T h e f oll o wi n g  cl assifi c ati o ns s h o ul d  b e  us e d  i n  c at e g ori z ati o n  of r el at e d n ess: 
 
1.  N ot  R el at e d:   
C o n c o mit a nt ill n ess,  a c ci d e nt  or  e v e nt  wit h  n o r e as o n a bl e  ass o ci ati o n 
wit h st u d y  dr u g.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 2  of  1 9 4  
2.  R el at e d:  
T h e  e v e nt f oll o ws  a r e as o n a bl e t e m p or al s e q u e n c e fr o m  a d mi nistr ati o n 
of st u d y  dr u g  a n d is  d efi niti v e  p h ar m a c ol o gi c all y;  c a n n ot t o  b e 
attri b ut e d  t o c o n c urr e nt  dis e as e  or  ot h er f a ct ors  or  m e di c ati o ns.  A 
cli ni c all y r e as o n a bl e r es p o ns e s h o ul d  b e  o bs er v e d if t h e st u d y  dr u g is 
wit h dr a w n  or  d os e r e d u c e d.  
8. 4   
O B S E R V A TI O N  P E RI O D  F O R  A D V E R S E  E V E N T  R E P O R TI N G  
T h e  o bs er v ati o n  p eri o d f or  A E  a n d  S A E  r e p orti n g i n  a n i n di vi d u al s u bj e ct  will st art  at t h e ti m e 
of  gi vi n g  writt e n i nf or m e d  c o ns e nt f or  p arti ci p ati o n i n t h e  c urr e nt st u d y  a n d fi nis h  1 5  d a ys  aft er 
t h e l ast  d os e  of st u d y  dr u g  or t h e l ast  visit,  w hi c h e v er is l at er.  F or s u bj e cts  w h o  e nr oll i n t h e 
o p e n -l a b el e xt e n si o n tri al,  o n g oi n g  A Es  will  b e f oll o w e d i n t h at st u d y. 
If t h e in v esti g at or  b e c o m es  a w ar e  of  a n  S A E t h at  h as st art e d  aft er t h e  o bs er v ati o n  p eri o d  h as 
fi nis h e d,  a n d t h e  e v e nt  c o ul d in s o m e  w a y  b e  ass o ci at e d  wit h  I M P (irr es p e cti v e  of  w h et h er  or 
n ot it is  c o n si d er e d  b y t h e in v esti g at or t o  b e  c a us all y r el at e d t o  I M P), t h e n t his  m ust  als o  b e 
r e p ort e d t o t h e S p o ns or  (s e e S e cti o n  8. 6 ). 
8. 5   
A D V E R S E  E V E N T  R E P O R T I N G 
8. 5. 1   
A d v e rs e  E v e nts  
At  e a c h  cli ni c al  e v al u ati o n, t h e i n v esti g at or ( or  d el e g at e)  will  d et er mi n e  w h et h er  a n y  A Es  h a v e 
o c c urr e d.   A d v ers e  e v e nts  will  b e r e c or d e d i n t h e  A E  p a g e  of t h e  e C R F.   If  k n o w n, t h e  m e di c al 
di a g n osis  of  a n  A E s h o ul d  b e r e c or d e d i n  pr ef er e n c e t o t h e  listi n g  of i n di vi d u al si g ns  a n d 
s y m pt o ms.   T h e i n v esti g at or  m ust f oll o w  u p  o n t h e  c o urs e  of  a n  A E  u ntil r es ol uti o n  or 
st a bili z ati o n.  If  a n  A E is  o n g oi n g  aft er t h e  e n d  of st u d y  visit, t h e  A E  will  c o nti n u e t o  b e 
f oll o w e d  u p u ntil r es ol uti o n  or  st a bili z ati o n. 
If,  d uri n g t h e st u d y  p eri o d, a s u bj e ct  pr es e nts  wit h  a  pr e -e xisti n g  c o n diti o n t h at  w as  n ot  n ot e d  at 
t h e ti m e  of st u d y  e ntr y, t h e  c o n diti o n s h o ul d  b e r etr os p e cti v el y r e c or d e d i n t h e  M e di c al  Hist or y 
s e cti o n  of t h e  e C R F.  
8. 6   
S E RI O U S  A D V E R S E  E V E N T S  R E P O R TI N G  
T hi s st u d y  will  c o m pl y  wit h  all  a p pli c a bl e r e g ul at or y r e q uir e m e nts  a n d  a d h er e t o t h e f ull 
r e q uir e m e nts  of I C H  T o pi c  E 2 A (Cli ni c al  S af et y  D at a  M a n a g e m e nt:  D efi niti o ns  a n d  St a n d ar ds 
f or  E x p e dit e d  R e p orti n g 1 9 9 4 ). 
I n t h e  e v e nt  of a n  S A E t h e i n v esti g at or  or  d el e g at e  m ust:   
1.   E nt er  all r el e v a nt i nf or m ati o n i n t h e  A E  p a g e  of t h e  e C R F.  
2.   I nf or m t h e  M e di c al  M o nit or  or t h e  S p o ns or  of t h e  S A E  vi a  e m ail  or t el e p h o n e  wit hi n 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 3  of  1 9 4  
2 4  h o urs  of  b e c o mi n g  a w ar e  of t h e  S A E.  
3.   F oll o w t h e i niti al  n otifi c ati o n  wi t h  a  c o m pl et e d  S A E r e p ort f or m.  T h e  S A E f or m 
m ust  b e  e m ail e d  or f a x e d t o  I n v e nti v e  H e alt h  C ar e wit hi n  2 4  h o urs  of  b e c o mi n g 
a w ar e  of t h e  S A E.   
All  S A Es t h at  o c c u r  d u ri n g t h e  c o u rs e  of t h e st u d y,  b e gi n ni n g t h e  d a y I nf o r m e d  C o ns e nt 
is si g n e d, w h et h e r  o r  n ot  c a us all y  r el at e d t o  I M P m ust  b e  r e p o rt e d i m m e di at el y  vi a 
t el e p h o n e o r  e m ail  ( wit hi n  2 4 h o u rs  of t h e i n v esti g at o r  b e c o mi n g  a w a r e  of t h e  e v e nt) t o 
th e  S p o ns o r  o r  t h e  M e di c al  M o nit o r. 
C o nt a ct  d et ails  a n d  g ui d a n c e f or r e p orti n g  S A Es  will  b e  pr o vi d e d t o st u d y  sit e  b ef or e t h e st u d y 
st arts. 
8. 6. 1   
R e q ui r e m e nts f o r I m m e di at e  R e p o rti n g  of  S e ri o us  A d v e rs e  E v e nts  
T h e  mi ni m u m r e p orti n g r e q uir e m e nts f or i m m e di at e r e p orti n g  of  S A Es i n cl u d e:  
1.   I d e ntifi a bl e s u bj e ct 
2.   S us p e ct e d  dr u g  pr o d u ct  
3.   E v e nt  d es cri pti o n  
4.   I d e ntifi a bl e r e p orti n g s o ur c e 
I n  a d diti o n, t h e i n v esti g at or  m ust: 
1.   R e p o rt  all  S A Es t o t h e r el e v a nt I R B/I E C  wit hi n t h e ti m efr a m e s p e cifi e d  b y t h e 
I R B/I E C. 
2.   S u b mit f oll o w -u p r e p orts t o  th e  S p o ns or  Gl o b al  Cli ni c al  S af et y  a n d 
P h ar m a c o vi gil a n c e  a n d  t h e  M e di c al  M o nit or u ntil t h e  S A E  h as  r es ol v e d,  or, i n t h e 
c as e  of  p er m a n e nt i m p air m e nt,  u ntil st a bili z e d.  
3.   E ns ur e t h at t h e  A E t er m(s)  a n d  c a us alit y  ass ess m e nt f or  all  S A Es is  e nt er e d i n t h e 
e C R F.  
If t h e  mi ni m u m r e q uir e m e nts f or r e p orti n g  ar e f ulfill e d, t h e i n v esti g at or s h o ul d  n ot  w ait t o 
r e c ei v e  a d diti o n al i nf or m ati o n t o f ull y  d o c u m e nt t h e  e v e nt  b ef or e  n otif yi n g th e  S p o ns or .  
W h e n s u b mitti n g  S A E r e p orts t o t h e  S p o ns or , s u bj e cts s h o ul d  b e i d e ntifi e d  o nl y  b y t h eir 
s u bj e ct n u m b er  a n d  st u d y  n u m b er.  T h e i n v esti g at or s h o ul d  n ot i n cl u d e t h e s u bj e ct’s  n a m e  a n d 
a d dr ess.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 4  of  1 9 4  
S A E  U p d at e r e p orts  c a n  b e s u b mitt e d t o t h e  S p o ns or  a n y ti m e t h at  a d diti o n al r el e v a nt 
i nf or m ati o n  b e c o m es  a v ail a bl e.  I n  c as es  of  d e at h, t h e in v esti g at or s h o ul d s u p pl y t h e  S p o ns or  
a n d t h e I E C/I R B ( as  a p pli c a bl e, s e e  S e cti o n  8. 7 )  wit h  a n y  a d diti o n al r e q u est e d i nf or m ati o n  as it 
b e c o m es  a v ail a bl e ( e g,  a ut o ps y r e p orts  a n d  d et ail e d  m e di c al r e p orts).  O n c e  a n  S A E is r e p ort e d 
t o t h e S p o ns or ’s S af et y  Gr o u p,  a  S af et y  S p e ci alist  m a y  c o nt a ct  t h e i n v esti g at or  wit h f oll o w-u p 
q u esti o ns.  
T h e  pr o c e d ur e t o  b e f oll o w e d if  a n  o n g oi n g  A E  b e c o m es  a n  S A E  aft er t h e  e n d  of t h e 
o bs er v ati o n  p eri o d f or  A Es is  d es cri b e d i n  S e cti o n  8. 9 . 
8. 7   
R E P O R TI N G  O F  S E RI O U S  A D V E R S E  E V E N T S  B Y I N V E S TI G A T O R  T O 
I E C/I R B 
T h e ti m efr a m e  wit hi n  a n I E C/I R B  m ust  b e  n otifi e d  of  a  d e at h  or  a n  u n e x p e ct e d  S A E 
c o nsi d er e d  at l e ast  p ossi bl y r el at e d t o  t h e I M P is sti p ul at e d  by  e a c h i n di vi d u al I E C/I R B.  T h e 
in v esti g at or is r es p o nsi bl e f or  c o m pl yi n g  wit h t h e r e q uir e m e nts  f or I E C/I R B  n otifi c ati o n.  T h e 
in v esti g at or  will  n otif y t h e r el e v a nt I E C/I R B  wit hi n t h e  a p pli c a bl e ti m efr a m e  b y f or w ar di n g t h e 
s af et y r e p ort ( e g, M e d W at c h/ CI O M S f or m)  c o m pl et e d  b y t h e  S p o ns or  f or t h e  n otifi a bl e  e v e nt.  
8. 8   
R E P O R TI N G  O F  E V E N T S  O T H E R  T H A N  S E RI O U S  A D V E R S E  E V E N T S 
B Y I N V E S TI G A T O R  T O  S P O N S O R  
E v e n if  n o n e  of t h e  crit eri a f or  a n  S A E  ar e f ulfill e d,  a n y  of t h e f oll o wi n g  e v e nts  m ust  b e 
r e p ort e d  b y t h e in v esti g at or t o t h e  M e di c al  M o nit or  wit hi n  7 2  h o urs  fr o m t h e ti m e t h e 
i n v esti g at or is  n otifi e d. 
1.   H y p ers e nsiti vit y r e a cti o ns  
2.   P ul m o n ar y  h y p ert e nsi o n  
3.   C ar di a c  s y m pt o ms r e q uiri n g i nt er v e nti o n,  or  v al v ul o p at h y , if i d e ntifi e d 
o utsi d e  of st u d y -r el at e d m o nit ori n g  
8. 9   
F O L L O W -U P  O F  A D V E R S E  E V E N T S   
E v er y  eff ort s h o ul d  b e  m a d e t o f oll o w -u p s u bj e cts  w h o  c o nti n u e t o  e x p eri e n c e  a n  A E  or  a n 
S A E  o n  c o m pl eti o n  of t h e st u d y  or  u ntil t h e  A E r es ol v es . All f oll o w -u p i nf or m ati o n ( a n d 
att e m pt e d f oll o w -u p  c o nt a cts) s h o ul d  b e  d o c u m e nt e d i n t h e s u bj e ct’s  m e di c al r e c or ds.   D et ails 
of t h e s u bj e ct’s  pr o gr ess s h o ul d  als o  b e s u b mitt e d t o  t h e S p o ns or ’s Gl o b al  Cli ni c al  S af et y  a n d 
P h ar m a c o vi gil a n c e  a n d  t h e  M e di c al  M o nit or. 
S u bj e cts  w h o  ar e  dis c o nti n u e d fr o m t h e st u d y  or  c o m pl et e t h e st u d y  a n d  h a v e  b e e n f o u n d t o 
h a v e  a n y si g ns  of  v al v ul o p at h y  or  p ul m o n ar y  h y p ert e nsi o n  o n  E C H O  will  b e f oll o w e d  u ntil t h e 
c o n diti o n  h as r es ol v e d  or st a bili z e d  w h er e  n o f urt h er  c h a n g es  ar e li k el y , f or  a  mi ni m u m  of 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 5  of  1 9 4  
6  m o nt hs fr o m t h e l ast  d os e  of st u d y  m e di c ati o n,  u nl ess it is  d et er mi n e d  aft er  u n bli n di n g t h at 
t h e s u bj e ct  di d  n ot r e c ei v e Z X 0 0 8 . I n t h e  e v e nt  of  an  S A E  a  bl o o d s a m pl e f or  Z X 0 0 8  a n d  A E D 
P K s h o ul d  b e  c oll e ct e d  as s o o n  as f e asi bl e  (t his is  n ot r e q uir e d f or  S A Es t h at  o c c ur  b ef or e 
d osi n g  wit h st u d y  m e di c ati o n) . 
8. 9. 1   
F oll o w -u p  of  E c h o c a r di o g r a m  Fi n di n gs   
All  E C H Os  will  b e  e v al u at e d  b y  a  c e ntr al r e a d er fr o m  Bi o M e di c al  S yst e ms, I n c. ( B M S), i n 
c o ns ult ati o n  wit h  t h e I P C A B, if  w arr a nt e d.   Fi n din gs r el at e d t o  p ul m o n ar y  h y p ert e nsi o n  or 
v al v ul o p at h y  o n  a n y  of t h e f o ur  v al v es ( a orti c,  mitr al,  p ul m o n ar y,  tri c us pi d)  will  b e r e p ort e d t o 
t h e i n v esti g at or wit h  gr a d es  of  n or m al, tr a c e,  mil d,  m o d er at e  or s e v er e. If t h e  E C H O r es ult  h as 
pr o gr ess e d i n s e v erit y si n c e t h e l ast r e a di n g t h e n  n e w  o v ersi g ht  m e as ur es  will  b e  e n a ct e d  as 
d es cri b e d  b el o w i n  L e v els  1 -3.   T a bl e  1 6  d es cri b es  t h e s e v erit y  of  E C H O fi n di ngs  wit h t h e 
l e v el  of i n cr e asi n g  o v ersi g ht if t h e s u bj e ct is t o r e m ai n i n t h e st u d y. 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 6  of  1 9 4  
T a bl e  1 6 . Cli ni c al  M e as u r es  E n a ct e d  U p o n I n c r e asi n g  S e v e rit y  of  E C H O  Fi n di n gs   
 
V al v e  
S e v erit y  
A orti c  
Mitr al  
P ul m o n ar y  
Tri c us pi d  
N or m al  
L e v el  1  
L e v el  1  
L e v el  1  
L e v el  1  
Tr a c e  
L e v el  2  
L e v el  2  
L e v el  1  
L e v el  1  
Mil d  
L e v el  2  
L e v el  2  
L e v el  1  
L e v el  1  
M o d er at e   
L e v el  3  
L e v el  3  
L e v el  3  
L e v el  3  
S e v er e  
L e v el  3  
L e v el  3  
L e v el  3  
L e v el  3  
L e v el  1:   C o nti n u e  p er  pr ot o c ol  
L e v el  2:  
1.  If t h er e is a  d esir e t o  c o nti n u e st u d y  m e di c ati o n:  
a.   T h e i n v esti g at or  will  e v al u at e t h e  effi c a c y t o  d at e  b as e d  o n st u d y  di ari es  a n d 
c o ns ult  wit h t h e  p ar e nt/ g u ar di a n,  a n d  d et er mi n e  w h et h er st u d y tr e at m e nt  w as 
ass o ci at e d  wit h si g nifi c a nt,  m e a ni n gf ul  b e n efit i n  n u m b er, s e v erit y  a n d / or 
d ur ati o n  of s ei z ur es  a n d/ or  o n t h e i m p a ct  o n  d ail y f u n cti o ni n g.  
b.   T h e i n v esti g at or  will  c o nsi d er  w h et h er t h e s u bj e ct  h as  h a d r e as o n a bl e tri als ( d os e 
a n d  d ur ati o n)  of  ot h er  a v ail a bl e  a nti c o n v uls a nts ( e g,  V P A , C L B ,  or t o pir a m at e), 
al o n e  or i n  c o m bi n ati o n,  a n d  n ot  m ai nt ai n e d t h e l e v el  of s ei z ur e  c o ntr ol  a c hi e v e d 
wit h st u d y  m e di c ati o n.  
2.   If t h e i n v esti g at or f e els  c o nsi d er ati o n  of  c o nti n u e d tr e at m e nt is  w arr a nt e d c o nsi d eri n g 
b e n efit  a n d  p ot e nti al ris ks,  a n d t h e  p ar e nt/ g u ar di a n f e els str o n gl y t h at  t h e  c hil d  b e 
m ai nt ai n e d  o n t h e st u d y  m e di c ati o n  w h e n  u n d erst a n di n g t h e ris k s, t h e  p ar e nt/ g u ar di a n 
m ust si g n  a  n e w  c o ns e nt  w hi c h  d es cri b es  t h e  a d diti o n al ris ks a n d t h e  c hil d s h o ul d  pr o vi d e 
ass e nt if  a p pr o pri at e.  
a.   If  b ot h  of t h es e  c o n diti o ns  ar e  n ot  m et, t h e s u bj e ct is  dis c o nti n u e d fr o m 
tr e at m e nt. 
3.   T h e i n v esti g at or  pr e p ar es  a  c as e  hist or y  a n d r ati o n al e f or  c o nti n u ati o n t o  b e s u b mitt e d t o 
t h e I D S M C f or r e vi e w, i n cl u di n g  c o nsi d er ati o n  of  eff e cts  o n s ei z ur es  a n d  c o m or bi diti es. 
4.   T h e  C o -C h airs  of t h e I P C A B  ar e  al ert e d t o t h e r e q u est  a n d  pr e p ar e,  aft er  c o ns ult ati o n 
wit h  B M S,  a n  e v al u ati o n  of t h e  c ar di o p ul m o n ar y  ris ks a n d  pr o p os e d  m o nit ori n g  pl a n if 
a p pli c a bl e , f or s u b missi o n t o t h e I D S MC.  
5.   I DS M C  will r e vi e w t h e  s u b missi o ns fr o m t h e I n v esti g at or  a n d t h e I P C AB  a n d  u n bli n d t h e 
s u bj e ct tr e at m e nt if  w arr a nt e d.  
6.   I D S M C  m a k es  a  d et er mi n ati o n  of  a p pr o pri at e  p at h, i n cl u di n g t h e  p ossi bl e  o ut c o m es: 
a.   Dis c o nti n u e st u d y  m e di c ati o n  
b.   I n cr e as e fr e q u e n c y  of  E C H O  a n d  E C G  m o nit ori n g 
c.   A d d  a d diti o n al  E C G  a n d/ or  E C H O  m e as ur es t o  b e  m o nit or e d  
d.   R e d u c e t h e  d os e  of st u d y  m e di c ati o n  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 7  of  1 9 4  
L e v el  3:  
1.  T h e i n v esti g at or  will  e v al u at e  effi c a c y t o  d at e  b as e d  o n st u d y  di ari es  a n d  c o ns ult  wit h 
t h e  p ar e nt/ g u ar di a n,  a n d  d et er mi n e  w h et h er t h e  a c hi e v e d  b e n efit j ustifi es t h e 
c o nsi d er ati o n  of  c o nti n ui n g st u d y tr e at m e nt  b y t h e I D S M C.  MI NI M A L  effi c a c y 
crit eri a f or I D S M C  c o nsi d er ati o n:  
a.   S ei z ur es  m ust  b e  m or e t h a n  7 5 % i m pr o v e d ( n u m b er  of  c o n v ulsi v e s ei z ur es  p er 
2 8  d a ys)  o n tr e at m e nt  o v er  b as eli n e,  a n d i m pr o v e m e nt  m ust  b e  c o nsist e nt.   
b.   T h e  n u m b er,  t y p e,  d ur ati o n,  a n d  distri b uti o n  of s ei z ur es  at  b as eli n e s h o ul d  b e  of  a 
s e v erit y,  w hi c h j ustifi es t h e ris k s of  c ar di o p ul m o n ar y  c o m pli c ati o ns,  c o nsi d eri n g 
t h e s u bj e ct’s  a g e  a n d  o v er all  h e alt h. 
c.   S u bj e ct  h as  h a d r e as o n a bl e tri als ( d os e  a n d  d ur ati o n)  of  ot h er  a v ail a bl e 
a nti c o n v uls a nts ( e g,  V P A,  C L B , t o pir a m at e),  al o n e  or i n  c o m bi n ati o n,  a n d  n ot 
m ai nt ai n e d t h e l e v el  of s ei z ur e  c o ntr ol  a c hi e v e d  wit h st u d y  m e di c ati o n.  
2.   If t h e i n v esti g at or f e els  c o nsi d er ati o n  of  c o nti n u e d tr e at m e nt is  w arr a nt e d c o nsi d eri n g 
b e n efit  a n d  p ot e nti al ris ks,  a n d t h e  p ar e nt/ g u ar di a n f e els str o n gl y t h at t h e  c hil d  b e 
m ai nt ai n e d  o n t h e st u d y  m e di c ati o n  w h e n  u n d erst a n di n g t h e ris ks, t h e  p ar e nt/ g u ar di a n 
m ust si g n  a  n e w  c o ns e nt  w hi c h  d es cri b es  t h e  a d diti o n al ris ks a n d t h e  c hil d s h o ul d 
pr o vi d e  ass e nt if  p ossi bl e.  
a.   If  b ot h  of t h es e  c o n diti o ns  ar e  n ot  m et, t h e s u bj e ct is  dis c o nti n u e d fr o m 
tr e at m e nt. 
3.   T h e i n v esti g at or  pr e p ar es  a  c as e  hist or y  a n d r ati o n al e f or  c o nti n u ati o n t o  b e s u b mitt e d 
t o t h e I D S M C f or r e vi e w,  w hi c h i n cl u d es  eff e cts  of st u dy  m e di c ati o n  o n s ei z ur es  a n d 
c o m or bi diti es r el at e d t o  D r a v et s y n dr o m e. 
4.   T h e  C o -C h airs  of t h e I P C A B  ar e  al ert e d t o t h e r e q u est,  a n d i n  c o ns ult ati o n  wit h  B M S 
pr e p ar e  a n  e v al u ati o n  of t h e ris k s a n d  pr o p os e d  m o nit ori n g  pl a n if  a p pl i c a bl e f or 
s u b missi o n t o t h e I DS M C.  
5.   I D S M C  will r e vi e w t h e s u b missi o n fr o m t h e I n v esti g at or  a n d t h e I P C A B  a n d  u n bli n d 
t h e s u bj e ct tr e at m e nt if  w arr a nt e d. 
6.   I D S M C  m a k es  a  d et er mi n ati o n  of  a p pr o pri at e  p at h, i n cl u di n g t h es e  p ossi bl e  o ut c o m es: 
a.   Dis c o nti n u e st u d y  m e di c ati o n  
b.   I n cr e as e fr e q u e n c y  of  E C H O  a n d  E C G  m o nit ori n g 
c.   A d d  a d diti o n al  E C G  a n d/ or  E C H O  m e as ur es t o  b e  m o nit or e d  
d.   R e d u c e t h e  d os e  of st u d y  m e di c ati o n  
 
8. 1 0   
P R E G N A N C Y  
T his st u d y is  o p e n t o f e m al e  a n d  m al e  s u bj e cts. W h e n e v er  p ossi bl e,  a  pr e g n a n c y i n  a f e m al e 
s u bj e ct  or t he f e m al e  p art n er  of  a  m al e s u bj e ct  e x p os e d t o  I M P s h o ul d  b e f oll o w e d t o t er m s o  as 
t o  ass ess  a n y  p ot e nti al  o c c urr e n c e  of  c o n g e nit al  a n o m ali es  or  birt h  d ef e cts.   A n y f oll o w-u p 
i nf or m ati o n, i n cl u di n g  pr e m at ur e t er mi n ati o n  a n d t h e st at us  of t h e  m ot h er  a n d  c hil d  aft er 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 8  of  1 9 4  
d eli v er y, s h o ul d  b e r e p ort e d  b y t h e i n v esti g at or t o  t h e S p o ns or  usi n g  a  p r e g n a n c y 
re p orti n g/ o ut c o m e  for m.   
9.   
D A T A  H A N D LI N G  P R O C E D U R E S  
9. 1   
R E C O R DI N G  O F  D A T A  
T h e i n v esti g at or ( or  d el e g at e)  will  m ai nt ai n i n di vi d u al r e c or ds f or  e a c h s u bj e ct.  T h es e r e c or ds 
s h o ul d i n cl u d e  d at es  w h e n  a s u bj e ct  visit e d t h e st u d y sit e,  st u d y-r e q uir e d i nf or m ati o n  a n d  d at a, 
a n d  ot h er  n ot es  as  a p pr o pri at e.  T h es e r e c or ds  c o nstit ut e s o ur c e  d at a .  
A n  e C R F  a n d  a  s u bj e ct di ar y  will  b e  pr o vi d e d  b y t h e  S p o ns or  ( or  d el e g at e) f or  e a c h s u bj e ct 
e nr oll e d i nt o t h e st u d y.  St u d y sit e st aff  will  e nt er  d at a  dir e ctl y i nt o t h e  v ali d at e d  el e ctr o ni c  d at a 
c a pt ur e ( E D C) s yst e m  b y  c o m pl eti n g t h e  e C R F  vi a  a s e c ur e i nt er n et  c o n n e cti o n.   T h e 
in v esti g at or is r es p o nsi bl e f or  e ns uri n g  a c c ur at e  a n d  pr o p er  c o m pl eti o n  of t h e  e C R F  a n d s u bj e ct 
di ar y  f or r e c or di n g  d at a  a c c or di n g t o t h e i nstr u cti o ns  gi v e n i n t h e  e C R F a n d  s u bj e ct di ar y .  
All  e ntri es i n t h e  e C R F  m ust  b e  b a c k e d  u p  b y t h e r el e v a nt s o ur c e  d at a  at t h e st u d y sit e.  All 
s o ur c e  d at a  will  b e  k e pt  a c c or di n g t o  all  a p pli c a bl e r e g ul at or y r e q uir e m e nts (s e e  S e cti o n  1 2. 8 ). 
S o ur c e  d at a  m ust  b e  c o m pl et e d l e gi bl y f or  e a c h s u bj e ct  e nr oll e d i nt o  t h e st u d y  a n d si g n e d  b y 
t h e in v esti g at or ( or  d el e g at e).   
D at a  e ntr y i n t h e  e C R F  a n d s u bj e ct  di ar y  m ust  b e  c o m pl et e d i n  a ti m el y  m a n n er s o t h at  t h e y 
al w a ys r efl e ct t h e l at est  o bs er v ati o ns  o n t h e s u bj e cts  e nr oll e d i n t h e st u d y.   
T h e  s u bj e ct’s di ar y  will  b e  c o m pl et e d  b y t h e  p ar e nt/ c ar e gi v er  at  h o m e.  D at a  e ntri es  will  b e 
r e vi e w e d b y t h e i n v esti g at or  f or  c o m pl eti o n  a n d  c o nsist e n c y.  
9. 2   
D A T A  Q U A LI T Y  A S S U R A N C E  
A n i niti ati o n  m e eti n g  will  b e  h el d  b ef or e st arti n g t h e st u d y,  d uri n g  w hi c h t h e st u d y  d esi g n, 
pr o c e d ur es t o  b e f oll o w e d,  a n d  m e as ur es f or  e ns uri n g st a n d ar di z e d  p erf or m a n c e  will  b e 
e x pl ai n e d  b y  a  d el e g at e fr o m t h e  S p o ns or ,  a n d  a  c o m m o n  u n d erst a n di n g  of t h e re q uir e m e nts  of 
t h e st u d y  will  b e r e a c h e d  wit h t h e i n v esti g at or  a n d  ot h er r el e v a nt  p ers o n n el  at t h e st u d y sit e.  
D at a  g e n er at e d t hr o u g h o ut t h e st u d y  will  b e  m o nit or e d  a n d t h e  d at a  e nt er e d i n t h e  e C R Fs  will 
b e  c h e c k e d  a g ai nst t h e s u bj e ct r e c or ds f or  c o m pl et e n ess  a n d  a c c ur a c y.  T h e  S p o ns or ’s st u d y 
m o nit or  will  p erf or m t his f u n cti o n.  
T h e  c o m p ut er s yst e m  us e d f or st u d y  d at a  h a n dli n g  will  b e f ull y  2 1  C o d e  of  F e d er al  R e g ul ati o ns 
(C F R ) P art  1 1  c o m pli a nt.   All  cr e ati o n,  m o difi c ati o n  or  d el eti o n  of  el e ctr o ni c st u d y r e c or ds  will 
b e  d o c u m e nt e d t hr o u g h  a n  a ut o m at e d  A u dit  Tr ail.  F oll o wi n g  c o m pl eti o n  of  e C R F  p a g es  a n d 
e ntr y  of t h e  d at a i nt o  a  d at a b as e, t h e  d at a  will  b e  c h e c k e d  el e ctr o ni c all y f or  c o nsist e n c y  a n d 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 1 9  of  1 9 4  
pl a usi bilit y.  D at a  q u eri es  will  b e  g e n er at e d f or  q u esti o n a bl e  d a t a  a n d r es p o ns e cl arifi c ati o n  will 
b e  s o u g ht fr o m t h e i n v esti g at or.  T h es e  d at a  q u eri es  m ust  b e r es ol v e d i n  a ti m el y  m a n n er  b y t h e 
in v esti g at or ( or  d el e g at e).  
9. 3   
R E C O R D  R E T E N TI O N  
A st u d y  d o c u m e nt  bi n d er  will  b e  p r o vi d e d  b y t h e S p o ns or  f or t h e in v esti g at or  at  e a c h sit e f or 
all r e q uisit e st u d y  d o c u m e nts ( c o nstit uti n g t h e  “I n v esti g at or  St u d y  Fil e ”).   
F oll o wi n g  c o m pl eti o n  of t h e st u d y, t h e i n v esti g at or  will r et ai n  c o pi es  of  t h e  a p pr o v e d st u d y 
pr ot o c ol,  I C F, r el e v a nt s o ur c e  d o c u m e nts,  a n d  all  ot h er s u p p orti n g  d o c u m ent ati o n r el at e d t o t h e 
st u d y  a c c or di n g t o  a p pli c a bl e r e g ul at or y r e q uir e m e nts.   
T h e i n v esti g at or is r es p o nsi bl e f or  ar c hi vi n g t h e I n v esti g at or  St u d y  Fil e, t h e s u bj e ct’s r e c or ds, 
a n d t h e s o ur c e  d at a  a c c or di n g t o  a p pli c a bl e r e g ul at or y r e q uir e m e nts.  T h es e  d o c u m e nts  h a v e t o 
b e  ar c hi v e d f or  at l e ast  1 5  y e ars  or  at l e ast  2  y e ars  aft er t h e l ast  a p pr o v al  of  a  m ar k eti n g 
a p pli c ati o n i n  a n I C H r e gi o n ,  b ut s h o ul d  b e r et ai n e d f or l o n g er if r e q uir e d  b y r e g ul at or y 
r e q uir e m e nts  or  b y  a gr e e m e nt  wit h t h e S p o ns or .  
If t h e in v esti g at or  c a n  n o l o n g er  m ai nt ai n t h e  ar c hi v e  of st u d y r e c or ds ( e g,  d u e t o r etir e m e nt  or 
r el o c ati o n), t h e S p o ns or  m ust  b e i nf or m e d i n  writi n g  a b o ut  a n y  c h a n g e i n r es p o nsi bilit y f or 
r e c or d r et e nti o n, i n cl u di n g t h e  n a m e  of t h e  n e w r es p o nsi bl e  p art y,  c o nt a ct i nf or m ati o n,  a n d 
l o c ati o n  of t h e st u d y r e c or ds.  R e c or ds  m a y  n ot  b e  d estr o y e d  wit h o ut  pri or  writt e n  c o ns e nt fr o m 
t h e S p o ns or . 
1 0.   
S T A TI S TI C S   
1 0. 1   
D E T E R MI N A TI O N  O F  S A M P L E  SI Z E  
N o f or m al  h y p ot h esis t ests  ar e  pl a n n e d f or t h e  P K  e n d p oi nts st u di e d i n  C o h ort  1.   T h us, t h e 
s a m pl e si z e f or  C o h ort  1 is  b as e d  o n  pr a cti c al  c o nsi d er ati o ns i n cl u di n g t h e  e x p e ct e d  a v ail a bilit y 
of  a p pr o pri at e s u bj e cts.   T h e  P K  d at a fr o m  C o h ort  1  will  b e  us e d i n  c o m bi n ati o n  wit h  P B P K  
m o d els t h at  ar e  b ei n g  d e v el o p e d  usi n g r o b ust  d at a fr o m  a d ults  a n d  fr o m  e xisti n g  P B P K  m o d els 
f or t h e  c o n c o mit a nt  m e di c ati o ns. I n t his  w a y, t h e  d at a fr o m  Z X 0 0 8-1 5 0 4  will  b e l e v er a g e d  wit h 
e xisti n g  P K i nf or m ati o n  o n f e nfl ur a mi n e, stiri p e nt ol,  cl o b a z a m  a n d  v al pr o at e  a ci d t o  c o nfir m 
t h e  e x p e ct ati o ns  d eri v e d fr o m t h e  m e c h a nism -b as e d  P B P K  m o d els.   A n al ysis  of t h e  d at a i n t his 
w a y  all o ws f or t h e  c o nfir m ati o n  of t h e  a p pr o pri at e n ess  of t h e  e xt e nsi o n  of t h e  P B P K  m o d el 
fr o m  a d ults t o  c hil dr e n  a n d  a r o b ust  ass ess m e nt  of t h e  p ot e nti al f or  a  dr u g-dr u g i nt er a cti o n 
b et w e e n  Z X 0 0 8  a n d stir i p e nt ol w hil e li miti n g  e x p os ur e t o  a s m all er  n u m b er  of  p ati e nts.  T h e 
1 8 -2 0 s u bj e cts t ar g et e d f or t h e  P K  p h as e  of t h e st u d y is  e x p e ct e d t o  b e s uffi ci e nt t o  all o w f or 
t h e  e xt e nsi o n  of t h e  P K i nf or m ati o n  g ai n e d i n t h e  o n g oi n g  P K st u d y i n  a d ults  a n d  e xisti n g 
P B P K  m o d els t o  p e di atri c  p ati e nts  wit h  Dr a v et s y n dr o m e . 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 0  of  1 9 4  
T h e s a m pl e si z e f or  C o h ort  2 is  b as e d  o n r es ults fr o m  St u d y  1,  t h e r a n d o mi z e d,  pl a c e b o-
c o ntr oll e d  st u d y i n s u bj e cts  wit h Dr a v et s y n dr o m e  s p o ns or e d  b y  Z o g e ni x ( L a g a e  2 0 1 7) .  T h e 
st a n d ard  d e vi ati o n ( S D ) of t h e  p er c e nt a g e  c h a n g e i n s ei z ur e fr e q u e n c y fr o m  b as eli n e  t o t h e  e n d 
of st u d y ( D a y  9 9)  w as  5 0 %  f or t h e  0. 8  m g/ k g/ d a y  gr o u p  a n d  6 9 % f or t h e  0. 2  m g/ k g/ d a y. F or 
t h e s a m pl e si z e  c al c ul ati o n f or  C o h ort  2, t h e  S D is  ass u m e d t o  b e i nt er m e di at e  b et w e e n t h e  S Ds 
o bs er v e d i n t h e  hi g h  a n d l o w  d os e  gr o u ps i n  St u d y  1 .  Ass u mi n g  a n  S D  of  5 8,  a n d  usi n g  a t w o-
si d e d t est  at t h e  α = 0. 0 5 si g nifi c a n c e l e v el,  a s a m pl e si z e  of  4 5  s u bj e cts  p er tr e at m e nt  gr o u p 
aff or ds  9 0 %  p o w er t o  d et e ct  a  diff er e n c e i n  m e a n  c h a n g e  i n s ei z ur e fr e q u e n c y fr o m  b as eli n e  of 
4 0  p er c e nt a g e  p oi nts.   T h us, t h e t ot al s a m pl e si z e  f or  C o h ort  2 is  pl a n n e d t o  b e a p pr o xi m at el y 
9 0  s u bj e cts (4 5  p er  ar m).  
1 0. 2   
A N A L Y SI S  P O P U L A TI O N S  ( C O H O R T  2) 
1 0. 2. 1   
S af et y ( S A F)  P o p ul ati o n   
All s af et y  a n al ys es  will  b e  p erf or m e d  o n t h e  S af et y ( S A F ) P o p ul ati o n  d efi n e d  as  all r a n d o mi z e d 
s u bj e cts  w h o r e c ei v e  at l e ast  o n e  d os e  of  Z X 0 0 8  or  pl a c e b o .  S u bj e cts  will  b e  a n al y z e d 
a c c or di n g t o t h e tr e at m e nt  a ct u all y r e c ei v e d.  
1 0. 2. 2   
M o difi e d  I nt e nt-t o-T r e at ( m I TT)  P o p ul ati o n   
T h e  m o difi e d I nt e nt -t o-Tr e at ( m I T T) P o p ul ati o n is  d efi n e d  as  all r a n d o mi z e d s u bj e cts  w h o 
r e c ei v e  at l e ast  o n e  d os e  of  Z X 0 0 8  or  pl a c e b o  a n d f or  w h o m  at l e ast  o n e  w e e k  of  di ar y  d at a  ar e 
a v ail a bl e.  S u bj e cts  will  b e  a n al y z e d  a c c or di n g t o t h e tr e at m e nt  gr o u p t o  w hi c h t h e y  w er e 
r a n d o mi z e d.  T h e  pri m ar y  c o m p aris o n of  Z X 0 0 8  0. 5  m g/ k g/ d a y  t o  pl a c e b o,  as  w ell  as  k e y 
s e c o n d ar y  a n al ys es,  will  b e  p erf or m e d  o n t h e  m I T T  P o p ul ati o n. 
1 0. 2. 3   
P e r  P r ot o c ol ( P P)  P o p ul ati o n   
T h e  P er  Pr ot o c ol ( P P ) P o p ul ati o n is  d efi n e d  as  all r a n d o mi z e d s u bj e cts  w h o r e c ei v e  at l e ast  o n e 
d os e  of  Z X 0 0 8  or  pl a c e b o,  c o m pl et e t h e  e ntir e  1 2  w e e k  M ai nt e n a n c e  P eri o d,  a n d  h a v e  n o 
m aj or  pr ot o c ol  d e vi ati o ns t h at  w o ul d  h a v e  a si g nifi c a nt i m p a ct  o n  cli ni c al  o ut c o m e.  S u bj e cts 
wi ll  b e  a n al y z e d  a c c or di n g t o t h e tr e at m e nt t h e y r e c ei v e d.  T h e  pri m ar y  a n d  k e y s e c o n d ar y 
effi c a c y  a n al ys es  will  b e r e p e at e d  o n t h e  P P  P o p ul ati o n if t h er e  ar e s u bst a nti al  diff er e n c es i n 
t h e  m a k e u p  of t h e m I T T  a n d  P P  P o p ul ati o ns. 
1 0. 3   
T R E A T M E N T  G R O U P S  
S u bj e cts  i n  Co h ort  2  will  b e r a n d o ml y  assi g n e d t o tr e at m e nt  wit h  eit h er  Z X 0 0 8  (0. 5  m g/ k g/ d a y , 
m a xi m u m  d os e  2 0  m g/ d a y)  or  pl a c e b o.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 1  of  1 9 4  
1 0. 4   
T R E A T M E N T  P E RI O D S  
1 0. 4. 1   
C o h o rt  1  T r e at m e nt  P e ri o ds  
P K  E v al u ati o n  P eri o d  
T h e  P K  E v al u ati o n  b e gi ns  w h e n  a s u bj e ct r e c ei v es  his  or  h er si n gl e  d os e  of  Z X 0 0 8  a n d 
c o nti n u es f or  1 5  d a ys  aft er w ar d.  
Tr a nsiti o n  P eri o d  
F or  p arti ci p ati n g s u bj e cts, t h e tr a nsiti o n  p eri o d  b e gi ns i m m e di at el y  aft er t h e  P K  E v al u ati o n 
p eri o d  a n d  c o nti n u es f or  a  m a xi m u m  of  2 4  w e e ks.  
1 0. 4. 2   
C o h o rt  2  T r e at m e nt  P e ri o ds  
B as eli n e  P eri o d  
T h e  B as e li n e  P eri o d  c o v ers t h e  a p pr o xi m at el y 4 2 -d a y s p a n j ust  pri or t o r a n d o mi z ati o n  a n d t h e 
st art  of tr e at m e nt.   T h e  b as eli n e fr e q u e n c y  of  c o n v ulsi v e s ei z ur es  will  b e  c al c ul at e d fr o m  d at a 
c oll e ct e d  d uri n g t his  p eri o d.  
Titr ati o n  P eri o d  
T h e  Titr ati o n  P eri o d  c o v ers t h e  ti m e  p eri o d  d uri n g  w hi c h s u bj e cts ar e titr at e d t o  t h e  assi g n e d 
ra n d o mi z e d  d os e . It  b e gi ns  o n t h e first  d a y  of tr e at m e nt (St u d y  D a y  1)  a n d  c o n cl u d es  o n  St u d y 
D a y  2 1 . T h e  Titr ati o n  P eri o d  a p pli es t o  all s u bj e cts i n cl u di n g  pl a c e b o r e ci pi e nts.    
M ai nt e n a n c e  P eri o d  
T h e  M ai nt e n a n c e  P eri o d  c o v ers t h e  1 2  w e e ks  f oll o wi n g t h e  e n d  of t h e titr ati o n  p eri o d. 
Titr ati o n  +  M ai nt e n a n c e ( T  +  M)  P eri o d  
T h e  T  +  M  p eri o d  c o m bi n es t h e  Titr ati o n  a n d  M ai nt e n a n c e  p eri o ds.  T h e  T  +  M  p eri o d is 
c o nsi d er e d t h e tr e at m e nt  p eri o d.  
F oll o w -u p  P eri o d  
T h e  F oll o w -u p  P eri o d  b e gi ns i m m e di at el y  at t h e  e n d  of  T  +  M  p eri o d  a n d  e xt e n ds  t hr o u g h Visit 
1 3  ( D a y 1 2 0 ).  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 2  of  1 9 4  
1 0. 5   
S T A TI S TI C A L  A N A L Y S E S  A N D  M E T H O D S  
All  effi c a c y , s af et y,  a n d  P K d at a  will  b e s u m m ari z e d.   C o nti n u o us  d at a  will  b e s u m m ari z e d 
usi n g  d es cri pti v e st atisti cs i n cl u di n g  m e a ns,  S Ds ,  m e di a ns, l o w er  a n d  u p p er  q u artil es, a n d 
r a n g es.  C at e g ori c al  v ari a bl es  will  b e s u m m ari z e d  wit h fr e q u e n ci es  a n d  p er c e nt a g es.  
C o nfi d e n c e i nt er v als  will  b e  c al c ul at e d f or  k e y  p ar a m et e rs  or  esti m at es  as  w arr a nt e d. 
A  c o m pl et e  d es cri pti o n  of t h e st atisti c al  a n al ys es  a n d  m et h o ds  will  b e  a v ail a bl e i n  a  st atisti c al 
a n al ysis  pl a n ( S A P ),  w hi c h  will  b e fi n ali z e d  b ef or e t h e  d at a b as e is l o c k e d. 
1 0. 5. 1   
Effi c a c y  A n al ys es  
T h e  pri m ar y  a n d  k e y s e c o n d ar y  effi c a c y  a n al ys es  t h at c o m p ar e  Z X 0 0 8 t o  pl a c e b o  will  b e 
p erf or m e d  usi n g s u bj e cts fr o m  C o h ort  2  o nl y.  Effi c a c y  e n d p oi nts, s u c h  as  c o n v ulsi v e s ei z ur e 
fr e q u e n c y,  ass ess e d i n  C o h ort  1  d uri n g t h e  Tr a nsiti o n  P eri o d  will  b e s u m m ari z ed  wit h 
d es cri pti v e st atisti cs  o nl y.   
1 0. 5. 1. 1   
Pri m ar y  Effi c a c y  A n al ysis  –  C o h ort  2  
T h e  pri m ar y  effi c a c y  e n d p oi nt is t h e  c h a n g e i n t h e  m e a n  c o n v ulsi v e s ei z ur e fr e q u e n c y ( M C S F) 
p er  2 8  d a ys  b et w e e n t h e  B as eli n e  a n d  T  +  M  p eri o ds.  T h e  M C S F  will  b e  c al c ul at e d fr o m  all 
a v ail a bl e  d at a  c oll e ct e d  d uri n g t h e  B as eli n e  or  T  +  M  P eri o ds.   
T h e  pri m ar y  e n d p oi nt  will  b e  a n al y z e d  usi n g  a n  a n al ysis  of  c o v ari a n c e ( A N C O V A)  m o d el  wit h 
tr e at m e nt  gr o u p (Z X 0 0 8  or  pl a c e b o )  a n d  a g e  gr o u p ( <  6  y e ars,  ≥ 6  y e ars)  as f a ct ors,  a n d  wit h 
b as eli n e f r e q u e n c y  as  a  c o v ari at e.   T h e  pri m ar y  a n al ysis  will  c o m p ar e t h e  Z X 0 0 8  gr o u p t o t h e 
pl a c e b o  gr o u p  usi n g  a t w o -si d e d t est  at t h e  α = 0. 0 5 l e v el  of si g nifi c a n c e.  
Si n c e t h e  A N C O V A  us e d i n t h e  pri m ar y  a n al ysis r eli es  o n  ass u m pti o ns  of  n or m alit y, t h e 
pri m ar y  e n d p o i nt  will  als o  b e  a n al y z e d  usi n g  a  n o n p ar a m etri c  m et h o d t h at  d o es  n ot r e q uir e  as 
stri n g e nt  ass u m pti o ns.   A  n o n p ar a m etri c t est  will  b e  us e d t o  c o m p ar e t h e  Z X 0 0 8  gr o u p t o t h e 
pl a c e b o  gr o u p  w hil e str atif yi n g f or  a g e  gr o u p. If  n or m alit y  ass u m pti o ns  ar e  n ot  m et, t h e r es ults 
of t h e  n o n p ar a m etri c  t est  will  b e  us e d t o  ass ess t h e  pri m ar y  o bj e cti v e. 
A d diti o n al  a n al ys es  will  c o m p ar e t h e  p er c e nt a g e  c h a n g es  b et w e e n t h e  b as eli n e  M C S F  a n d t h e 
M C S F  m e as ur e d i n d e p e n d e ntl y  d uri n g t h e  Titr ati o n  P eri o d  al o n e  a n d t h e  M ai nt e n a n c e  P eri o d 
al o n e.  
1 0. 5. 1. 2   
K e y  S e c o n d a r y  A n al ys es  –  C o h ort  2  
T h e first  k e y s e c o n d ar y  e n d p oi nt  –  t h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥ 5 0 % r e d u cti o n 
fr o m  b as eli n e i n  c o n v ulsi v e s ei z ur e fr e q u e n c y –  is  d eri v e d  dir e ctl y fr o m t h e  pri m ar y  e n d p oi nt. 
T h at is, t h e  pr o p orti o n  of s u bj e cts i n t h e  Z X 0 0 8  gr o u p  w h o  h a v e  a  c h a n g e i n  c o n v ulsi v e 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 3  of  1 9 4  
fr e q u e n c y  of  at l e ast 5 0  p er c e nt a g e  p oi nts  will  b e  c o m p ar e d t o t h e  a n al o g o us  pr o p orti o n i n t h e 
pl a c e b o  gr o u p.  T h e  c o m p aris o n  will  b e  m a d e  usi n g  a l o gisti c r e gr essi o n  m o d el t h at 
i n c or p or at es t h e s a m e f a ct ors  a nd  c o v ari at es  as t h e  A N C O V A  us e d i n t h e  pri m ar y  a n al ysis.  T h e 
a n al ys es  will  b e  p erf or m e d  usi n g  d at a  c oll e ct e d  o v er t h e  T  +  M  p eri o d . 
T h e l o n g est i nt er v al  b et w e e n  c o n v ulsi v e s ei z ur es  will  b e  c al c ul at e d f or  e a c h s u bj e ct  o v er t h e 
e ntir e  T  +  M  p eri o d.   T h e  Z X 0 0 8  a n d  pl a c e b o  gr o u ps  will  b e  c o m p ar e d  usi n g  a  Wil c o x o n  t est. 
W h e n e v er f e asi bl e, s e c o n d ar y  a n al ys es  will  b e r e p e at e d  usi n g  p ost -tr e at m e nt  d at a  c oll e ct e d 
d uri n g t h e  Titr ati o n  P eri o d  al o n e  a n d  d uri n g t h e  M ai nt e n a n c e  P eri o d  al o n e.  
1 0. 5. 1. 3   
M ulti pli cit y  Str at e g y  a n d  T esti n g  Hi er ar c h y  –  C o h ort  2  
T h e  effi c a c y  a n al ys es  will  e m pl o y  a s eri al  g at e k e e p er str at e g y t o  m ai nt ai n t h e  T y p e  1  err or r at e 
at  α = 0. 0 5  a cr oss t h e f a mil y  of  a n al ys es t h at s u p p ort t h e  pri m ar y  a n d  k e y s e c o n d ar y  o bj e cti v es. 
T h e str at e g y s p e cifi es  a  hi er ar c h y  of si g nifi c a n c e t ests  w h er e  e a c h t est  a cts  as  a  g at e k e e p er t o 
t h e t ests  b el o w it.  
T h e  pri m ar y  a n d  k e y s e c o n d ar y  e n d p oi nts  will  b e  ass ess e d i n t h e f oll o wi n g  or d er  e nt aili n g 
c o m p aris o ns  b et w e e n t h e  Z X 0 0 8  a n d  pl a c e b o  gr o u ps  o n  
•   T h e  c h a n g e i n  M C S F fr o m  b as eli n e.  
•   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥  5 0 % r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e 
s ei z ur e fr e q u e n c y.  
•   T h e l o n g est  c o n v ulsi v e s ei z ur e -fr e e i nt er v al. 
1 0. 5. 2   
S af et y  A n al ys es  
S u m m ari es  of  s af et y  d at a f or s u bj e cts i n  C o h ort  2 will  b e  pr es e nt e d  b y tr e at m e nt  –  Z X 0 0 8  at 
assi g n e d  d os e  or  pl a c e b o  –  s e p ar at el y f or t h e  Titr ati o n,  M ai nt e n a n c e  a n d  T  +  M  p eri o ds.  T h e 
n u m b er  a n d  p er c e nt a g e  of s u bj e cts i n  e a c h tr e at m e nt  gr o u p  wit h  A Es  will  b e  dis pl a y e d  b y  b o d y 
s yst e m  a n d  pr ef err e d t er m  usi n g t h e  M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es ( M e d D R A). 
S u m m ari es  of  A Es  b y s e v erit y  a n d r el ati o ns hi p t o st u d y  dr u g  will  als o  b e  pr es e nt e d.  A s e p ar at e 
s u m m ar y  will  b e  pr o vi d e d f or  all  S A Es.  S el e ct e d s u m m ari es  wil l  b e r e p e at e d  br o k e n  o ut  b y  a g e 
gr o u p, i e, f or  a g es  <  6  y e ars  a n d  ≥  6  y e ars.  
H e m at ol o g y  a n d  c h e mistr y l a b or at or y r es ults  f or s u bj e cts i n  C o h ort  2 will  b e s u m m ari z e d  b y 
d es cri pti v e st atisti cs  at  e a c h ti m e  p oi nt  a v ail a bl e.  M e a n  c h a n g e fr o m  b as eli n e  will  als o  b e 
c al c ul at e d f or  c o nti n u o us  h e m at ol o g y  a n d  c h e mistr y r es ults  at  all ti m e  p oi nts  a v ail a bl e.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 4  of  1 9 4  
L a b or at or y t ests,  vit al si g ns,  p h ysi c al  e x a mi n ati o ns,  n e ur ol o gi c al  e x a mi n ati o ns,  E C G,  D o p pl er 
E C H O ,  C-S S R S,  T a n n er  St a gi n g r es u lts,  et c,  will  b e s u m m ari z e d  a p pr o pri at el y,  b y tr e at m e nt. 
All s af et y s u m m ari es  f or s u bj e cts i n  C o h ort  2 will  b e  b as e d  o n t h e  S A F  P o p ul ati o n.  
F or s u bj e cts i n  C o h ort  1, s af et y  will  b e s u m m ari z e d  b y tr e at m e nt r e gi m e n  a n d  b y tr e at m e nt 
p eri o d,  eit h er t h e  P K  E v a l u ati o n  or  Tr a nsiti o n  P eri o d.  S u m m ari es  will  als o  b e  pr o d u c e d f or  all 
s u bj e cts i n  C o h ort  1  c o m bi n e d r e g ar dl ess  of r e gi m e n.  A Es, l a b or at or y r es ults,  vit al  si g ns  a n d 
ot h er  e n d p oi nts  will  b e  d es cri b e d  usi n g si mil ar st atisti cs  as t h os e  us e d f or  C o h ort  2.  
1 0. 5. 3   
P h a r m a c o ki n eti c  A n al ys es  
All  d at a fr o m  C o h ort  1  will  b e  e v al u at e d  usi n g  P K  a n al ysis  m et h o ds  a n d t h e  m et h o ds  will  b e 
d es cri b e d i n  d et ail i n  a s e p ar at e  P K  a n al ysis  pl a n.  W hil e t h e  a p pr o a c h es  will  b e si mil ar f or  all 
a n al yt es  of i nt er est (f e nfl ur a mi n e/ n orf e nfl ur a m i n e, C L B / n-d es m et h yl cl o b a z a m,  V P A ,  a n d 
S T P ), t h e y  will  b e t ail or e d t o t h e  a v ail a bilit y  of  pr e vi o us  P K i nf or m ati o n  a n d/ or  e xisti n g  P K 
m o d els.  T h e f ull  m et h o ds  a n d r es ults  of t h e  p o p ul ati o n  P K  a n al ysis  of  d at a fr o m t his st u d y  will 
b e  pr o vi d e d i n  a s e p ar at e r e p ort.   
T h e  cli ni c al st u d y r e p ort  will  c o nt ai n  a  bri ef s u m m ar y  of t h e  a n al ysis i n cl u di n g:  o v er vi e ws  of 
t h e  m o d els  a p pli e d t o t h e  c o n c e ntr ati o n-ti m e  d at a f or  e a c h  a n al yt e, t h e  p o p ul ati o n  m e a n  a n d 
i nt eri n di vi d u al  v ari a bilit y  esti m at es ( as  a p pr o pri at e) fr o m th e fits  of t h e  p o p ul ati o n  P K  m o d els; 
s u m m ar y st atisti cs  of t h e  pl as m a  c o n c e ntr ati o ns  b y  P K s a m pli n g ti m e  b y  r e gi m e n.  
E a c h  of t h e t hr e e  r e gi m e ns fr o m  C o h ort  1  will  b e  c o m p ar e d t o t h e  ot h ers  b as e d  o n t h e  P K 
m e as ur e m e nts  o bt ai n e d f or  e a c h  a n al yt e.  F or  e x a m pl e,  a li n e ar  m o d el i n c or p or ati n g l o g -
tr a nsf or m e d  d at a  will  b e  us e d t o  esti m at e t h e  g e o m etri c  m e a n r ati o  a n d t h e  9 0 %  c o nfi d e n c e 
i nt er v al ( CI)  of f e nfl ur a mi n e A U C fr o m ti m e  z er o t o ti m e =t ( A U C 0 -t) m e as ur e d fr o m t h e 
Z X 0 0 8  0. 2  m g/ k g/ d a y  +  C L B  +  V P A  +  S T P  gr o u p  ( R e gi m e n  3) t o t h e  a n al o g o us  q u a ntit y 
m e as ur e d fr o m t h e  Z X 0 0 8  0. 2  m g/ k g/ d a y  +  C L B  +  V P A  gr o u p ( R e gi m e n  1).  A n al o g o us 
t e c h ni q u es  will  b e  a p pli e d t o  c o m p aris o ns  b as e d  o n t h e  ot h er  a n al yt es:  n orf e nfl ur a mi n e,  S T P, 
C L B ,  N-C L B,  a n d  V P A.  T h e s et  of  a n al ys es  will  b e r e p e at e d f or  e a c h  p air  of  r e gi m e ns. 
T h e  pl as m a  c o n c e ntr ati o n  d at a fr o m  C o h ort  2  will  als o  b e  a n al y z e d  usi n g  p o p ul ati o n  P K 
m et h o ds.  F e nfl ur a mi n e/ n orf e nfl ur a mi n e  c o n c e ntr ati o n -ti m e  d at a fr o m s u bj e cts e nr oll e d i n 
C o h ort  2  will  b e  p o ol e d  wit h t h at fr o m  s u bje cts  i n  C o h ort  1 i n  or d er t o  ass ess t h e a p pli c a bilit y  
of t h e  p o p ul ati o n  P K  m o d el  t o  pr e di ct  pl as m a  c o n c e ntr ati o ns fr o m  m ulti pl e  d osi n g. 
M o difi c ati o ns t o t h e  m o d el  will  b e  m a d e  as  n e c ess ar y t o  a c hi e v e  a n  a d e q u at e fit t o t h e st e a d y -
st at e  P K  d at a. P l as m a  P K  ex p os ur e ( A U C 0 -t)  will  b e  d eri v e d f or  e a c h  p ati e nt fr o m  C o h ort  2 
w h o  u n d er g o es  P K s a m pli n g.  T h e r es ults  of t h e  a n al ysis  of  P K  d at a  c oll e ct e d i n  s u bj e cts fr o m 
C o h ort  2  will  b e r e p ort e d s e p ar at el y.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 5  of  1 9 4  
1 0. 5. 4   
A n al ysis  of  E x pl o r at o r y  E n d p oi nts  
As st at e d  a b o v e , o n e  of t h e  ai ms  of t his r es e ar c h  pr o gr a m  is t o  d et er mi n e  a  c or e s et  of  p ati e nt 
r el e v a nt  o ut c o m es t o  u n d erst a n d t h e i m p a ct of  Dr a v et s y n dr o m e  b e y o n d s ei z ur e fr e q u e n c y.   T o 
m e et t his  o bj e cti v e  a s et  of  c or e  o ut c o m e  m e as ur es  h a v e  b e e n i d e ntifi e d t o i n cl u d e i n t his tri a l.  
T h e s el e cti o n  of i nstr u m e nts  w as  dri v e n  b y  d at a fr o m i n  d e pt h i nt er vi e ws  wit h f or m al  a n d 
i nf or m al  c ar ers  of  y o u n g  p e o pl e  wit h  Dr a v et s y n dr o m e.   S o m e  of t h es e  m e as ur es  h a v e  n ot  b e e n 
us e d  pr e vi o usl y i n  Dr a v et  s y n dr o m e.   T h er ef or e, i n  a d diti o n t o t esti n g t h e  m ai n st u d y 
h y p ot h es es  a n  a d diti o n al  S A P  will  b e  d e v el o p e d t o  d es cri b e  t h e  e x pl or at or y a n al ys es t h at t est 
t h e  ps y c h o m etri c  p erf or m a n c e ( or  m e as ur e m e nt  a c c ur a c y)  of t h e  c or e  o ut c o m e  m e as ur es.   T h e 
p erf or m a n c e  of t h e s c al es  will  b e  b e n c h m ar k e d  a g ai nst s ei z ur e  b ur d e n  as  a n  o bj e cti v e  e n d p oi nt.  
T his is  b as e d  o n  a  w or ki n g  h y p ot h esis t h at  Dr a v et  s y n dr o m e p ati e nts’ s u bj e cti v e  o ut c o m es 
(s u c h  as  H R Q L)  ar e  h e a vil y i nfl u e n c e d  b y t h eir s ei z ur e  b ur d e n (i n cl u di n g  n at ur e  of s ei z ur es 
a n d fr e q u e n c y).   T h er ef or e , c h a n g es i n s ei z ur e  b ur d e n s h o ul d  pr e di ct  c h a n g es i n t h e  c or e 
o ut c o m e  m e as ur es.   T his  h y p ot h esis  will  b e t est e d  usi n g  ps y c h o m etri c  m et h o ds.    
1 0. 6   
A N A L Y S E S  P R O VI D E D  T O  A N I N D E P E N D E N T  D A T A  A N D  S A F E T Y 
M O NI T O RI N G  C O M MI T T E E  
A s af et y  o v ersi g ht  m o nit ori n g  pl a n  will  b e i n  pl a c e  wit h  a n I D S M C  e v al u ati n g  d at a fr o m t h e 
s u bj e cts.  D et ails  will  b e  pr o vi d e d i n t h e I D S M C  c h art er.  T h e I D S M C’s  pri m ar y r es p o nsi bilit y 
is t o  e ns ur e t h at st u d y s u bj e cts ar e  n ot  e x p os e d t o  u n a nti ci p at e d  h ar m t h at  c o ul d  h a v e  b e e n 
pr e v e nt e d  b y ti m el y  r evi e w  a n d  i nt er v e nti o n.   T h e I DS M C is  est a b lis h e d t o r e vi e w s af et y  d at a 
at  pr e d efi n e d ti m e  p oi nts,  a n d t o r e c o m m e n d t o  th e  S p o ns or  w h et h er t o  c o nti n u e,  m o dif y , or 
t er mi n at e t h e st u d y  as  n e c ess ar y.   T h e I DS M C is  c o m p os e d  of  e x p ert  p er m a n e nt  m e m b ers  w h o 
c o v er  r el e v a nt s p e ci alti es (n e ur ol o g y,  c ar di ol o g y,  p e di atri cs ,  a n d st atisti cs).   T h e I DS M C 
m e m b ers  m a y r e q u est  assist a n c e fr o m  a  n u m b er  of  a d diti o n al  a n d  h o c  m e m b ers if  n e e d e d.   
1 1.   
E T HI C A L  &  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   
E T HI C A L  C O N SI D E R A TI O N S  
T h e  pr o c e d ur es s et  o ut i n t his st u d y  pr ot o c ol  ar e  d esi g n e d t o  e ns ur e t h at t h e  S p o ns or  a n d t h e 
in v esti g at or  a bi d e  b y t h e  p ri n ci pl es  of t h e  c urr e nt I C H  G C P g ui d eli n e  o n t h e  c o n d u ct, 
e v al u ati o n  a n d  d o c u m e nt ati o n  of t his st u d y,  as  d es cri b e d i n I C H  T o pi c  E 6  G ui d eli n e . I C H  G C P 
is  a n i nt er n ati o n al  et hi c al  a n d s ci e ntifi c  q u alit y st a n d ar d f or  d esi g ni n g,  c o n d u cti n g, r e c or di n g, 
a n d r e p orti n g st u di es t h at i n v ol v e t h e  p arti ci p ati o n  of  h u m a n s u bj e cts.  C o m pli a n c e  wit h t his 
st a n d ar d  pr o vi d es  p u bli c  ass ur a n c e t h at t h e ri g hts, s af et y,  a n d  w ell -b e i n g  of st u d y s u bj e cts  ar e 
pr ot e ct e d,  a n d t h at t h e  cli ni c al st u d y  d at a  ar e  cr e di bl e.  
T h e st u d y  will  als o  b e  c arri e d  o ut  a c c or di n g t o  all  a p pli c a bl e i nt er n ati o n al  a n d  n ati o n al 
r e g ul at or y r e q uir e m e nts. 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 6  of  1 9 4  
T h e  S p o ns or  a n d t h e i n v esti g at or  m ust i nf or m  e a c h  ot h er ( e g,  d uri n g  a st u d y i niti ati o n  visit,  vi a 
e -m ail,  et c) t h at  all  et hi c al  a n d l e g al r e q uir e m e nts  h a v e  b e e n  m et  b ef or e t h e first s u bj e ct is 
e nr oll e d i nt o t h e st u d y.  
1 1. 2   
I N F O R M E D  C O N S E N T  
T h e i n v esti g at or is r es p o nsi bl e f or  o bt ai ni n g  a s u bj e ct’s  writt e n i nf or m e d  c o n s e nt t o  p arti ci p at e 
i n t h e st u d y. 
A  S u bj e ct I nf or m ati o n  S h e et  a n d  a  m ast er I C F  will  b e  pr e p ar e d  b y  t h e S p o ns or  a c c or di n g t o t h e 
pr o visi o ns  of I C H  G C P  a n d l o c al l e g al r e q uir e m e nts.  
All s u bj e cts  will  b e i nf or m e d t h at t h e st u d y  will  b e r e gist er e d i n t h e  p u bli c  d at a b as e  at 
Cli ni c al Tri als. g o v i n  a c c or d a n c e  wit h t h e  F D A  A m e n d m e nts  A ct  of  2 0 0 7 ( S e cti o n  1 2. 3 ). 
B ef or e  u n d er g oi n g s cr e e ni n g  pr o c e d ur es f or  p ossi bl e  e nr oll m e nt i nt o t h e st u d y, s u bj e cts  m ust 
b e i nf or m e d, i n  a n  u n d erst a n d a bl e f or m,  a b o ut t h e  n at ur e, s c o p e,  a n d  p ossi bl e  c o ns e q u e n c es  of 
t h e st u d y.  T his i nf or m ati o n  m ust  b e  gi v e n  or all y t o s u bj e cts  b y  a  p h ysi ci a n  or  m e di c all y 
q u alifi e d  p ers o n ( a c c or di n g t o  a p pli c a b l e r e g ul at or y r e q uir e m e nts)  w h o is  w ell i nf or m e d  a b o ut 
t h e  n at ur e, s c o p e,  a n d  p ossi bl e  c o ns e q u e n c es  of t h e st u d y.  Writt e n i nf or m ati o n  a b o ut t h e st u d y 
will  als o  b e  pr o vi d e d i n  a  S u bj e ct I nf or m ati o n  S h e et.  T h e  d at e  o n  w hi c h t his  or al  a n d  writt e n 
i nf or m ati o n o n t h e st u d y  w as  pr o vi d e d t o t h e s u bj e ct,  a n d  b y  w h o m it  w as  pr o vi d e d,  m ust  b e 
d o c u m e nt e d i n t h e I C F.  
As s p e cifi e d i n I C H  G C P  S e cti o n  4. 8  a n d t h e  U S  2 1 C F R  S e cti o n  5 0. 2 5, t h e i nf or m e d  c o ns e nt 
dis c ussi o n  m ust  e m p h asi z e t h at  p arti ci p ati o n i n t h e st u d y is  v ol u nt ar y  a n d t h at s u bj e cts  h a v e t h e 
ri g ht t o  wit h dr a w t h eir  c o ns e nt  at  a n y ti m e  wit h o ut  gi vi n g  a r e as o n  a n d  wit h o ut  a n y 
dis a d v a nt a g e f or t h eir s u bs e q u e nt  c ar e.  
S u bj e cts  m ust  b e  gi v e n  a m pl e ti m e  a n d  o p p ort u nit y t o i n q uir e  a b o ut  d et ails  of t h e st u d y  a n d t o 
c o ns i d er t h eir  p arti ci p ati o n i n t h e st u d y. If,  aft er r e a di n g t h e  S u bj e ct I nf or m ati o n  S h e et  a n d t h e 
I C F,  c o ns e nt is  gi v e n t o  p arti ci p at e i n t h e st u d y, t h e n t h e I C F  m ust  b e si g n e d  a n d  p ers o n all y 
d at e d  b y t h e s u bj e ct  a n d t h e  p ers o n  c o n d u cti n g t h e i nf or m e d  c o ns e nt  dis c ussi o n ( a n d  a n 
i m p arti al  wit n ess, if r e q uir e d).  T h e s u bj e ct  will  b e  pr o vi d e d  wit h  a  c o p y  of t h e si g n e d I C F.  
V erifi c ati o n  of t h e si g n e d I C F  will  b e r e c or d e d i n t h e s u bj e ct’s  e C R F.  T h e  ori gi n al si g n e d I C F 
will  b e fil e d  wit h t h e s u bj e ct’s r e c or ds  a n d  a  c o p y  will  b e  pl a c e d  i n t h e I n v esti g at or  St u d y  Fil e. 
T h e  S u bj e ct I nf or m ati o n  S h e et  a n d I C F  h a v e t o  b e  a p pr o v e d  b y t h e I E C/I R B  b ef or e t h e y  c a n  b e 
us e d i n t h e st u d y.  
T h e  S u bj e ct I nf or m ati o n  S h e et  a n d I C F  m ust  b e r e vis e d  w h e n e v er i m p ort a nt  n e w i nf or m ati o n 
b e c o m es  a v ail a bl e t h at  m a y  b e r el e v a nt t o t h e s u bj e ct’s  c o ns e nt.  A n y r e visi o n  of t h es e 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 7  of  1 9 4  
d o c u m e nts  m ust  b e  a p pr o v e d  b y t h e I E C/I R B  b ef or e t h e y  c a n  b e  us e d i n t h e st u d y.  S u bj e cts 
m ust  b e i nf or m e d i n  a ti m el y  m a n n er if  n e w i nf or m ati o n  b e c o m es  a v ail a bl e t h at  m a y  b e  
r el e v a nt t o t h eir  willi n g n ess t o  c o nti n u e  p arti ci p ati o n i n t h e st u d y.  T h e  c o m m u ni c ati o n  of t his 
i nf or m ati o n s h o ul d  b e  d o c u m e nt e d  b y  h a vi n g  all  p arti es  c o n c er n e d si g n  a n d  p ers o n all y  d at e t h e 
r e vis e d I C F. 
S u bj e ct  o r  S u bj e ct’s  L e g all y  A c c e pt a bl e  R e p r es e nt ati v e  U n a bl e t o  R e a d  
If  a s u bj e ct is  u n a bl e t o r e a d,  or if  a l e g all y  a c c e pt a bl e r e pr es e nt ati v e is  u n a bl e t o r e a d,  a n 
i m p arti al  wit n ess s h o ul d  b e  pr es e nt  d uri n g t h e  e ntir e i nf or m e d  c o ns e nt  dis c ussi o n.  Aft er t h e 
I C F  a n d  a n y  ot h er  writt e n i nf or m ati o n pr o vi d e d t o t h e s u bj e ct,  p ar e nt  or  g u ar di a n  h as  b e e n r e a d 
a n d  e x pl ai n e d t o t h e s u bj e ct  or t h e s u bj e ct’s l e g all y  a c c e pt a bl e r e pr es e nt ati v e,  a n d  aft er t h e 
s u bj e ct  or t h e s u bj e ct’s l e g all y  a c c e pt a bl e r e pr es e nt ati v e  h as  or all y  c o ns e nt e d t o t h e s u bj e ct’s 
p arti ci p ati o n i n t h e st u d y  a n d, if  c a p a bl e  of  d oi n g s o,  h as si g n e d  a n d  p ers o n all y  d at e d t h e I C F, 
t h e  wit n ess s h o ul d  als o si g n  a n d  p ers o n all y  d at e t h e I C F.  B y si g ni n g t h e I C F, t h e  wit n ess  att ests 
t h at t h e i nf or m ati o n i n t h e I C F  a n d  a n y  ot h er  writt e n i nf or m ati o n w as  a c c ur at el y  e x pl ai n e d t o, 
a n d  a p p ar e ntl y  u n d erst o o d  b y, t h e s u bj e ct  or t h e s u bj e ct’s l e g all y  a c c e pt a bl e r e pr es e nt ati v e,  a n d 
t h at i nf or m e d  c o ns e nt  w as fr e el y  gi v e n  b y t h e s u bj e ct  or t h e s u bj e ct’s l e g all y  a c c e pt a bl e 
r e pr es e nt ati v e. 
Ass e nt f o r  S u bj e cts  U n d e r t h e  A g e  of  C o ns e nt ( P e di at ri c  S u bj e cts)  
All  s u bj e cts  ar e u n d er t h e  a g e  of  c o ns e nt (i e , p e di atri c s u bj e cts  u n d er  1 8  y e ars  of  a g e) ; t h e 
writt e n i nf or m e d  c o ns e nt  of  a l e g all y  a c c e pt a bl e r e pr es e nt ati v e is r e q uir e d.  P e di atri c s u bj e cts 
w h o  c a n  u n d erst a n d t h e  n at ur e, s c o p e,  a n d  p ossi bl e  c o ns e q u e n c es  of t h e st u d y  m ust  als o  gi v e 
t h eir ass e nt ,  or all y  a n d/ or i n  writi n g  vi a t h e  ass e nt  d o c u m e nt,  as  a p pr o pri at e.  Aft er t h e I C F  a n d 
a n y  ot h er  writt e n i nf or m ati o n t o  b e  pr o vi d e d t o s u bj e cts  h as  b e e n r e a d  a n d  e x pl ai n e d t o t h e 
s u bj e ct  a n d t h e s u bj e ct’s l e g all y  a c c e pt a bl e r e pr es e nt ati v e,  a n d  aft er t h e s u bj e ct  a n d t h e l e g all y 
a c c e pt a bl e r e pr es e nt ati v e  h a v e  or all y  c o ns e nt e d t o t h e s u bj e ct’s  p arti ci p ati o n i n t h e st u d y  a n d, if 
c a p a bl e  of  d oi n g s o, t h e s u bj e ct  h as si g n e d  a n d  p ers o n all y  d at e d t h e  ass e nt  d o c u m e nt , t h e 
l e g all y  a c c e pt a bl e r e pr es e nt ati v e s h o ul d si g n  a n d  p ers o n all y  d at e t h e I C F.  B y si g ni n g t h e I C F, 
t h e l e g all y  a c c e pt a bl e r e pr es e nt ati v e  att ests t h at t h e i nf or m ati o n i n t h e I C F  a n d  a n y  ot h er 
writt e n i nf or m ati o n  w as  a c c ur at el y  e x pl ai n e d t o,  a n d  a p p ar e ntl y  u n d erst o o d  b y, t h e s u bj e ct,  a n d 
t h at ass e nt  w as fr e el y  gi v e n  b y t h e s u bj e ct.  
1 1. 3   
R E G U L A T O R Y  C O N S I D E R A TI O N S  A N D  I N D E P E N D E N T  E T HI C S 
C O M MI T T E E/ I N S TI T U TI O N A L  R E VI E W  B O A R D  
T h e  S p o ns or  ( or  d el e g at e)  will s u b mit t h e  a p pr o pri at e  d o c u m e nts t o  all  a p pli c a bl e  c o m p et e nt 
r e g ul at or y  a ut h oriti es  a n d I E C/I R Bs,  a n d  will  a w ait  all r el e v a nt  a p pr o v al  b ef or e  e nr olli n g  a n y 
s u bj e cts i nt o t h e st u d y.  Writt e n  a p pr o v al s h o ul d  m e nti o n t h e st u d y  pr ot o c ol  b y st u d y titl e, st u d y 
n u m b er,  a n d  v ersi o n  d at e.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 8  of  1 9 4  
T h e  S p o ns or  ( d el e g at e) will  e ns ur e t h at t h e i n v esti g at ors  c o n d u ct t h e st u d y  as sti p ul at e d i n t his 
st u d y  pr ot o c ol  a n d i n  a c c or d a n c e  wit h  all  a p pli c a bl e r e g ul at or y r e q uir e m e nts.  T h e  S p o ns or  
( d el e g at e) is  o bli g e d t o  o bt ai n  evi d e n c e  of t h e i n v esti g at or’s  q u alifi c ati o n t o  p erf or m t h e 
cl i ni c al st u d y.  T h er ef or e, t h e in v esti g at or  h as t o  pr o vi d e  a si g n e d  a n d  d at e d  c o p y  of  his  or  h er 
pr of essi o n al  c urri c ul u m  vit a e ( pr e p ar e d  n o  m or e t h a n  2  y e ars  b ef or e h a n d  a n d  pr ef er a bl y  writt e n 
i n  E n glis h)  b ef or e t h e st art  of t h e st u d y, i n cl u di n g i nf or m ati o n  o n  his  or  h er  e x p eri e n c e i n 
c o n d u cti n g  cli ni c al st u di es  a c c or di n g t o I C H  G C P  a n d  ot h er  a p pli c a bl e r e g ul at or y 
r e q uir e m e nts. 
Writt e n  n otifi c ati o n  of t h e i d e ntit y  a n d  o c c u p ati o n  of t h e  m e m b ers  of t h e I E C/I R B is  als o 
r e q uir e d  b y th e  S p o ns or  ( d el e g at e).  S h o ul d t h e I E C/I R B  b e  u n willi n g t o  pr o vi d e t his 
i nf or m ati o n,  a l ett er st ati n g t h at t h e  c o m mitt e e  w as  c o nstit ut e d i n  a c c or d a n c e  wit h  a p pli c a bl e 
r e g ul at or y r e q uir e m e nts s h o ul d  b e  pr o vi d e d. 
1 1. 4   
P R O T O C O L  C O M P LI A N C E   
T h e i n v esti g at or  m ust  c o n d u ct t h e st u d y i n  c o m pli a n c e  wit h t his st u d y  pr ot o c ol  as  a gr e e d t o  b y 
t h e S p o ns or  a n d, if r e q uir e d,  b y  a n y  c o m p et e nt r e g ul at or y  a ut h orit y,  a n d  w hi c h  h as  b e e n 
a p pr o v e d  b y,  or  gi v e n  a f a v or a bl e  o pi ni o n  b y, t h e I E C/I R B.  
T h e i n v esti g at or s h o ul d  n ot i m pl e m e nt  a n y  d e vi ati o n fr o m,  or  c h a n g es t o, t h e st u d y  pr ot o c ol 
wit h o ut  a gr e e m e nt  b y t h e  S p o ns or  ( d el e g at e) a n d  pri or r e vi e w  a n d  d o c u m e nt e d  a p pr o v al  or 
f a v or a bl e  o pi ni o n fr o m t h e I E C/I R B  of  a n  a m e n d m e nt t o t h e st u d y  pr ot o c ol.  E x c e pti o ns i n cl u d e 
o nl y  c as es  of  m e di c al  e m er g e n c y t o  a d dr ess i m m e di at e  h a z ar ds t o st u d y s u bj e cts,  or  w h e n t h e 
c h a n g es i n v ol v e  o nl y l o gisti c  or  a d mi nistr ati v e  as p e cts  of t h e st u d y.  
I n t h e  e v e nt  of  a  m e di c al  e m er g e n c y, t h e i n v esti g at or  at  e a c h sit e  m a y i nstit ut e  a n y  m e di c al 
pr o c e d ur es  d e e m e d  a p pr o pri at e t o  a d dr ess  a n i m m e di at e  h a z ar d t o  a s u bj e ct  wit h o ut  pri or 
I E C/I R B  a p pr o v al  or f a v or a bl e  o pi ni o n.  As s o o n  as  p ossi bl e, t h e i m pl e m e nt e d  d e vi ati o n  or 
c h a n g e, t h e r e as o n(s) f or it,  a n d, if  a p pr o pri at e, t h e  pr o p os e d st u d y  pr ot o c ol  a m e n d m e nt(s) 
s h o ul d  b e s u b mitt e d t o: 
•   T h e  S p o ns or  ( d el e g at e) f or  a gr e e m e nt. 
•   T h e I E C/I R B f or r e vi e w  a n d  a p pr o v al  or f a v or a bl e  o pi ni o n (if r e q uir e d).  
•   T h e  a p pli c a bl e  c o m p et e nt r e g ul at or y  a ut h orit y (if r e q uir e d).  
D et ails  of t h e  pr o c e d ur e f or i m pl e m e nti n g st u d y  pr ot o c ol  a m e n d m e nts  ar e  a v ail a bl e i n 
S e cti o n  1 2. 1 0 . 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 2 9  of  1 9 4  
At t h e  e arli est  o p p ort u nit y, t h e i n v esti g at or ( or  d el e g at e)  m ust i nf or m t h e  S p o ns or  ( d el e g at e) 
a b o ut  a n y  n ot a bl e  pr ot o c ol  d e vi ati o ns  a n d  e x pl ai n  a n y  d e vi ati o n fr o m t h e  a p pr o v e d st u d y 
pr ot o c ol i n t h e  e C R F  a n d/ or i n t h e  Pr ot o c ol  D e vi ati o n  L o g, if  a p pli c a bl e.  
1 2.   
A D MI NI S T R A TI V E  A S P E C T S  
1 2. 1   
C LI NI C A L  T RI A L  A G R E E M E N T  
T his st u d y  will  b e  c o n d u ct e d  u n d er  a  Cli ni c al  Tri al  A gr e e m e nt  b et w e e n t h e  S p o ns or  ( or 
d el e g at e)  a n d t h e r es p e cti v e i nstit uti o ns r e pr es e nti n g t h e st u d y sit es.  A n y fi n a n ci al s u p p ort 
gi v e n t o t h e st u d y sit es  will  b e  d et ail e d i n t h e  Cli ni c al  Tri al  A gr e e m e nt.  T h e  Cli ni c al  Tri al 
A gr e e m e nt,  w hi c h  m ust  b e si g n e d  b ef or e t h e st art  of  a n y st u d y r el at e d  pr o c e d ur es,  will  cl e arl y 
d eli n e at e t h e r es p o nsi biliti es  a n d  o bli g ati o ns  of t h e i n v esti g at or  a n d t h e  S p o ns or  ( d el e g at e),  a n d 
will f or m t h e  c o ntr a ct u al  b as is  u p o n  w hi c h t h e st u d y  will  b e  c o n d u ct e d.  
1 2. 2   
FI N A N CI A L  DI S C L O S U R E  B Y I N V E S TI G A T O R  
Pri or t o st u d y i niti ati o n, t h e i n v esti g at or  a n d  a n y s u bi n v esti g at or(s) t o  b e  dir e ctl y i n v ol v e d i n 
t h e tr e at m e nt  or  e v al u ati o n  of st u d y s u bj e cts  at  e a c h st u d y sit e  will  dis cl ose t o t h e  S p o ns or  
( d el e g at e) a n y r el e v a nt fi n a n ci al  or  pr o pri et ar y i nt er ests i n  eit h er t h e st u d y  pr o d u ct  or t h e 
S p o ns or  c o m p a n y.  T h e  a p pr o pri at e  dis cl os ur e f or m(s)  will  b e  pr o vi d e d  b y t h e  S p o ns or  
( d el e g at e) f or t his  p ur p os e.  A n y r el e v a nt  u p d at es t o t h e fi n an ci al  dis cl os ur e i nf or m ati o n t h at 
o c c ur  d uri n g t h e  c o n d u ct  of t h e st u d y,  or  d uri n g  o n e  y e ar  aft er  c o m pl eti o n  of t h e st u d y,  will  b e 
pr o vi d e d  b y t h e i n v esti g at or  a n d s u bi n v esti g at or(s) t o t h e  S p o ns or  ( d el e g at e).  All fi n a n ci al 
dis cl os u r e i nf or m ati o n  pr o vi d e d b y t h e i n v esti g at or  a n d s u bi n v esti g at or(s)  will  b e s u b mitt e d t o 
a p pr o pri at e  c o m p et e nt  a ut h oriti es  a c c or di n g t o t h e  a p pli c a bl e r e g ul at or y r e q uir e m e nts.  
1 2. 3   
C LI NI C A L  S T U D Y  R E GI S T R A TI O N  A N D  R E S U L T S  DI S C L O S U R E  
T h e  S p o ns or  will  pr o vi d e t h e r el e v a nt st u d y  pr ot o c ol i nf or m ati o n i n  a  p u bli c  d at a b as e  
( Cli ni c al Tri als. g o v)  b ef or e  or  at  c o m m e n c e m e nt  of t h e st u d y,  as r e q uir e d  b y t h e  2 0 0 7  F D A 
A m e n d m e nts  A ct.  T h e  S p o ns or  ( d el e g at e) m a y  als o  pr o vi d e st u d y i nf or m ati o n f or i n cl usi o n i n 
n ati o n al r e gistri es  a c c or di n g t o l o c al r e g ul at or y r e q uir e m e nts.  
If  a  p ot e nti al s u bj e ct  c o nt a cts t h e S p o ns or  r e g ar di n g  p arti ci p ati o n i n t h e st u d y, th e i n v esti g at or 
a gr e es t h at t h e  S p o ns or  ( d el e g at e) m a y f or w ar d t h e r el e v a nt st u d y sit e  a n d  c o nt a ct  d et ails t o t h e 
s u bj e ct.  B as e d  o n t h e i n cl usi o n  a n d  e x cl usi o n  crit eri a f or t h e st u d y , t h e in v esti g at or  will  ass ess 
t h e s uit a bilit y  of t h e s u bj e ct f or  e nr oll m e nt i nt o t h e st u d y. R es ults  of t his st u d y  will  b e 
d is cl os e d  a c c or di n g t o t h e r el e v a nt r e g ul at or y r e q uir e m e nts.  All  p u bli c ati o ns i n  p e er-r e vi e w e d 
m e di c al j o ur n als r es ulti n g fr o m t his st u d y  will  b e list e d i n t h e  ori gi n al st u d y  pr ot o c ol 
r e gistr ati o n r e c or d  o n  Cli ni c al Tri als. g o v.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 0  of  1 9 4  
1 2. 4   
S T U D Y  FI L E S  A N D  M A T E RI A L S  
B ef or e t h e st art  of  a n y st u d y r el at e d  pr o c e d ur es,  all  ess e nti al  d o c u m e nts s p e cifi e d  b y I C H  G C P 
a n d  ot h er  a p pli c a bl e r e g ul ati o ns  m ust  b e  a v ail a bl e i n t h e r el e v a nt fil es  m ai nt ai n e d  b y t h e  
S p o ns or  ( or  d el e g at e)  a n d t h e in v esti g at or.  A n I n v esti g at or  St u d y  Fil e  pr e p ar e d  b y t h e  S p o ns or  
( or  d el e g at e),  c o nt ai ni n g  all  a p pli c a bl e  d o c u m e nts f or  us e  at t h e st u d y sit e, will  b e  m a d e 
a v ail a bl e t o t h e i n v esti g at or  b ef or e t h e st art  of t h e st u d y.  A list  of  p ers o n n el  a n d  or g a ni z ati o ns 
r es p o nsi bl e f or  c o n d u ct  of t h e st u d y as  w ell  as t h e list  of i n v esti g at ors  will  b e i n cl u d e d i n t h e 
I n v esti g at or  St u d y  Fil e.  T h e r es p e cti v e fil es  will  b e  k e pt  a n d  u p d at e d  b y t h e S p o ns or  ( or 
d el e g at e)  a n d t h e i n v esti g at or,  as  a p pli c a bl e.  
All st u d y  d o c u m e nt ati o n  a n d  m at eri als  m ai nt ai n e d i n t h e I n v esti g a t or  St u d y  Fil e  at t h e st u d y 
sit e  m ust  b e  a v ail a bl e f or i ns p e cti o n  b y t h e  S p o ns or ’s st u d y  m o nit or ( or  d el e g at e) t o  d et er mi n e 
t h at  all r e q uir e d  d o c u m e nt ati o n is  pr es e nt  a n d  c orr e ct (s e e S e cti o n  1 2. 9 ).  
T h e st u d y  m a y  b e  a u dit e d  or i ns p e ct e d  b y  q u alifi e d  d el e g at es fr o m t h e  S p o ns or  or  a  c o m p et e nt 
r e g ul at or y  a ut h orit y (s e e S e cti o n  1 2. 1 1 ). 
1 2. 5   
I NI TI A TI O N  O F  T H E  S T U D Y  
B ef or e t h e st art  of t h e st u d y  at  e a c h st u d y sit e, t h e  S p o ns or ’s st u d y  m o nit or ( or  d el e g at e)  will 
visit t h e st u d y sit e t o  e ns ur e  a d e q u a c y  of t h e f a ciliti es  a n d t o  dis c uss r es p o nsi biliti es r e g ar di n g 
st u d y  pr ot o c ol  a d h er e n c e  wit h t h e i n v esti g at or  a n d  ot h er  p ers o n n el i n v ol v e d i n t h e st u d y.  
T h e i n v esti g at or  m a y  n ot  e nr oll  a n y s u bj e cts i nt o t h e st u d y  b ef or e t h e  S p o ns or  h as r e c ei v e d 
writt e n  a p pr o v al  or  a f a v or a bl e  o pi ni o n fr o m t h e I E C/I R B f or  c o n d u cti n g t h e st u d y  a n d  a 
f or m al  m e eti n g  h as  b e e n  c o n d u ct e d  b y t h e S p o ns or ’s st u d y  m o nit or ( or  d el e g at e) t o i niti at e t h e 
st u d y (st u d y i niti ati o n  visit).  T his  m e eti n g  will i n cl u d e  a n i n v e nt or y  of st u d y s u p pli es  a n d  a 
d et ail e d r e vi e w  of t h e st u d y  pr ot o c ol  a n d  pr o c e d ur es , t h e  e C R F, I M P  a c c o u nt a bilit y, a n d t h e 
s u bj e ct di ar y . 
1 2. 6   
S U B J E C T  R EI M B U R S E M E N T  
W h er e r el e v a nt, s u bj e cts  will  b e r ei m b urs e d f or r e as o n a bl e tr a v el  c osts  ass o ci at e d  wit h 
p arti ci p ati o n i n t his  st u d y,  aft er  pr es e nt ati o n  of r e c ei pts  f or t h e tr a v el i n  q u esti o n,  at  a r at e t o  b e 
a p pr o v e d  b y t h e I E C/I R B.  S u bj e cts  will  n ot  b e  p ai d f or  p arti ci p ati n g i n t h e st u d y .  
1 2. 7   
LI A BI LI T Y  A N D I N S U R A N C E  
T h e  ci vil li a bilit y  of t h e i n v ol v e d  p arti es  wit h r es p e ct t o fi n a n ci al l oss  d u e t o  p ers o n al i nj ur y 
a n d  ot h er  d a m a g e t h at  m a y  aris e  as  a r es ult  of t his st u d y  b ei n g  c o n d u ct e d  ar e  g o v er n e d  b y t h e 
a p pli c a bl e l e g al r e q uir e m e nt(s).  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 1  of  1 9 4  
T h e  S p o ns or  will  pr o vi d e i ns ur a n c e t o t h e i n v esti g at or if r e q uir e d  b y t h e  a p pli c a bl e r e g ul at or y 
a n d l e g al r e q uir e m e nt(s).  
If r e q uir e d b y l o c al l a w, s u bj e cts t a ki n g  p art i n t his st u d y  will  b e i ns ur e d  a g ai nst  a n y i nj ur y 
c a us e d  b y t h e st u d y i n  a c c or d a n c e  wit h t h e  a p pli c a bl e r e g ul at or y  a n d l e g al r e q uir e m e nt(s).   
1 2. 8   
S U B J E C T I D E N TI FI C A TI O N  A N D  C O N FI D E N TI A LI T Y  
All st u d y  d o c u m e nts, i n cl u di n g t h e s t u d y  pr ot o c ol  a n d  e C R Fs,  ar e t h e  c o nfi d e nti al  pr o p ert y  of 
t h e S p o ns or  a n d s h o ul d  b e tr e at e d  as s u c h.  
All s u bj e cts s cr e e n e d f or t h e st u d y  will  b e  d o c u m e nt e d i n  a s cr e e ni n g l o g i n  c o m pli a n c e  wit h 
t h e r e q uir e m e nts  of i n di vi d u al st u d y sit es.  S u bj e cts  n ot  e nr oll e d i nt o t h e st u d y  will  b e 
d o c u m e nt e d  as s u c h i n t h e s cr e e ni n g l o g t o g et h er  wit h t h e r e as o n f or  n ot  h a vi n g  b e e n  e nr oll e d.   
T h e i n v esti g at or  will  m ai nt ai n  a  p ers o n al list  of s u bj e ct  n a m es  a n d s u bj e ct  n u m b ers ( S u bj e ct 
I d e ntifi c ati o n  List) f or  p arti ci p a nts i n t h e st u d y t o  e n a bl e r e c or ds t o  b e i d e ntifi e d  at  a l at er  d at e. 
T h es e r e c or ds s h o ul d  b e r et ai n e d i n  a  c o nfi d e nti al  m a n n er f or t h e  d ur ati o n sti p ul at e d  b y 
a p pli c a bl e r e g ul at or y r e q uir e m e nts.  All s u bj e ct  n a m es  will  b e  k e pt i n  c o nfi d e n c e  a n d  will  n ot 
b e r e v e al e d t o t h e  S p o ns or .  S u bj e ct  n a m es  m ust  b e  m a d e  u nr e a d a bl e  o n  a n y  d o c u m e nts  m a d e 
a v ail a bl e t o t h e  S p o ns or . 
S u bj e cts  p arti ci p ati n g i n t h e st u d y  will  b e i d e ntifi e d i n t h e  e C R F  b y t h e s u bj e ct  n u m b er  all ott e d 
t o t h e m  d uri n g t h e st u d y.  
T h e I C F  will i n cl u d e  a st at e m e nt t h at  all st u d y fi n di n gs, irr es p e cti v e  of t h e  m e di u m  o n  w hi c h 
t h e y  ar e st or e d,  will  b e  h a n dl e d i n stri ct est  c o nfi d e n c e i n  a c c or d a n c e  wit h  a p pli c a bl e  d at a 
pr ot e cti o n l a ws ( e g, t h e  E ur o p e a n  D at a  Pr ot e cti o n  Dir e cti v e [ 9 5/ 4 6/ E C]  a n d t h e  U S A  H e alt h 
I ns ur a nc e  P ort a bilit y  a n d  A c c o u nt a bilit y  A ct,  a n d  will  b e  e v al u at e d  b y t h e  S p o ns or  a n d/ or  a 
c o m p et e nt r e g ul at or y  a ut h orit y i n  a n  a n o n y mi z e d f or m.  T h e s u bj e cts  ar e  als o t o  b e i nf or m e d 
t h at t h eir  m e di c al r e c or ds  m a y  b e  a u dit e d  or i ns p e ct e d  b y  q u alifi e d  d el e g at es fro m t h e  S p o ns or  
or  a  c o m p et e nt r e g ul at or y  a ut h orit y.  T h e s u bj e ct’s  writt e n  c o ns e nt  a ut h ori zi n g  dir e ct  a c c ess t o 
his  m e di c al r e c or ds,  a n d  c o m p ut er  pr o c essi n g  a n d  p u blis hi n g  of  his  a n o n y m o us  p ers o n al  d at a, 
m ust  b e  o bt ai n e d  pri or t o  p arti ci p ati o n i n t h e st u d y.  
A s u bj e ct’s i d e n tit y  will  b e  dis cl os e d  b y t h e in v esti g at or  o nl y i n  c as e  of  e m er g e n c y (i e, t o 
a d dr ess  a n y i m m e di at e  h e alt h  h a z ar d).  
1 2. 9   
M O NI T O RI N G  O F  T H E  S T U D Y  
T h e i n v esti g at or  at  e a c h sit e  will  all o w t h e  S p o ns or ’s st u d y  m o nit or ( or  d el e g at e) r e as o n a bl e 
a c c ess  t o t h e  e C R Fs  a n d  dir e ct  a c c ess t o r el at e d s o ur c e  d o c u m e nts f or  m o nit ori n g  p ur p os es  as 
fr e q u e ntl y  as t h e S p o ns or  d e e ms  n e c ess ar y.  T h es e  d o c u m e nts i n cl u d e r e c or ds  of t ests 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 2  of  1 9 4  
p erf or m e d  as  a r e q uir e m e nt f or  p arti ci p ati n g i n t h e st u d y  as  w ell  as  ot h er  m e di c al r e c or ds 
r e q uir e d t o  c o nfir m i nf or m ati o n  c o nt ai n e d i n t h e  e C R F, s u c h  as  p ast  hist or y  a n d s e c o n d ar y 
di a g n os es.  
B ef or e  e a c h  m o nit ori n g  visit, t h e i n v esti g at or ( or  d el e g at e) s h o ul d r e c or d  all  d at a  g e n er at e d 
si n c e t h e l ast  m o nit ori n g  visit i n t h e  e C R F.  T h e i n v esti g at or  a n d  ot h er r el e v a nt  p ers o n n el  at 
e a c h st u d y sit e  will  b e  e x p e ct e d t o  c o o p er at e  wit h t h e  S p o ns or ’s st u d y  m onit or t o  assist i n 
pr o vi di n g  a n y  missi n g i nf or m ati o n.  
T h e st u d y  m o nit or  will r e q uir e  a c c ess t o t h e I n v esti g at or  St u d y  Fil e t o  e ns ur e  c o m pl et e n ess  of 
all  d o c u m e nt ati o n r e q uir e d f or t h e st u d y.  T h e st u d y  m o nit or  will  e ns ur e t h at t h e  in v esti g at or  at 
e a c h sit e  h as  b e e n  pr o vi d e d  wit h  a d e q u at e  m e a ns f or  or g a ni z ati o n  a n d fili n g  of st u d y 
d o c u m e nt ati o n (s e e  S e cti o n  1 2. 4 ). 
T h e  d at e  o n  w hi c h t h e st u d y  m o nit or ( or  d el e g at e)  visit s t h e st u d y sit e  will  b e r e c or d e d i n t h e 
Sit e  Visit  L o g.  D uri n g  m o nit ori n g  visits, t h e st u d y sit e’s  c o or d i n at or (if  a p pli c a bl e)  a n d t h e 
in v esti g at or s h o ul d  b e  a v ail a bl e, t h e s o ur c e  d o c u m e nt ati o n s h o ul d  b e  a c c essi bl e,  a n d  a s uit a bl e 
e n vir o n m e nt s h o ul d  b e  pr o vi d e d f or t h e st u d y  m o nit or t o r e vi e w st u d y r el at e d  d o c u m e nt ati o n.  
T h e  m ai n  o bj e cti v es  of  m o nit ori n g  visits  c o n d u ct e d  b y t h e st u d y  m o nit or i n cl u d e:  
•   R es ol uti o n  of  a n y  pr o bl e ms.  
•   E x a mi n ati o n  of  all st u d y  d o c u m e nt ati o n f or  c o m pl eti o n,  a d h er e n c e t o t h e st u d y 
p r ot o c ol,  a n d  p ossi bl e  A Es. 
•   Cl arifi c ati o n  of i n c o nsist e n ci es  or  missi n g  d at a.  
•   V erifi c ati o n  of st u d y  d at a  a g ai nst s o ur c e  d o c u m e nts.  
•   C h e c ks t h at  in v esti g at or  o bli g ati o ns  h a v e  b e e n f ulfill e d.  
•   R e vi e w  of I C Fs  a n d  d at es  of  c o ns e nt.  
•   I ns p e cti o n  of I M P wit h r es p e ct t o st or a g e, l a b eli n g,  a n d  d o c u m e nt ati o n.  
•   Dr u g  a c c o u nt a bilit y  
Aft er  e a c h s u bj e ct’ s  visit t o t h e st u d y sit e, t h e i n v esti g at or ( or  d el e g at e)  will  e ns ur e t h at  all  d at a 
h a v e  b e e n  e nt er e d i nt o t h e  e C R F  c orr e ctl y  a n d i n  a ti m el y  m a n n er,  aft er  w hi c h  t h e in v esti g at or 
will si g n t h e  e C R F.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 3  of  1 9 4  
1 2. 1 0   
P R O T O C O L  A M E N D M E N T S  
A  “s u bst a nti al ”  a m e n d m e nt  of  a st u d y  pr ot o c ol is  a n y  writt e n  d es cri pti o n  of  c h a n g e(s) t o,  or 
f or m al  cl arifi c ati o n  of,  a st u d y  pr ot o c ol t h at  m a y  h a v e  a si g nifi c a nt i m p a ct  o n t h e s af et y  or 
p h ysi c al  or  m e nt al i nt e grit y  of s u bj e cts, t h e s ci e ntifi c  v al u e  of t h e  st u d y, t h e  c o n d u ct  or 
m a n a g e m e nt  of t h e st u d y,  or  t h e  q u alit y  or s af et y  of  a n y I M P us e d i n t h e st u d y.  T h e I E C/I R B 
m ust  a p pr o v e  all s u bst a nti al  pr ot o c ol  a m e n d m e nts  pri or t o t h eir i m pl e m e nt ati o n. If r e q uir e d  b y 
a p pli c a bl e l o c al r e g ul at or y r e q uir e m e nts, t h e  l o c al r e g ul at or y  a ut h orit y  m ust  als o  a p pr o v e  all 
s u bst a nti al  pr ot o c ol  a m e n d m e nts  pri or t o t h eir i m pl e m e nt ati o n.  
A  “ n o n -s u bst a nti al ”  a m e n d m e nt  of  a st u d y  pr ot o c ol i n cl u d es  mi n or  c orr e cti o ns  or  cl arifi c ati o ns 
t h at  h a v e  n o si g nifi c a nt i m p a ct  o n t h e  w a y t h e stu d y is t o  b e  c o n d u ct e d  a n d  h as  n o  eff e ct  o n t h e 
s af et y  of  p arti ci p ati n g s u bj e cts ( e g,  c h a n g e i n st u d y  m o nit or,  c o nt a ct  d et ails,  et c). If r e q uir e d  b y 
a p pli c a bl e l o c al r e g ul at or y r e q uir e m e nts, t h e I E C/I R B,  a n d/ or t h e l o c al r e g ul at or y  a ut h orit y 
s h o ul d  b e  n otifi e d  of  all  n o n-s u bst a nti al  pr ot o c ol  a m e n d m e nts.  T h e s u bst a nti al  a n d  n o n -
s u bst a nti al  pr ot o c ol  a m e n d m e nts  will  b e i nt e gr at e d i nt o  a n  u p d at e d st u d y  pr ot o c ol  at t h e 
dis cr eti o n  of t h e  S p o ns or  if t h e  c h a n g es t o t h e  ori gi n al st u d y  pr ot o c ol  ar e  n u m er o us,  or if 
r eq uir e d  b y  a p pli c a bl e r e g ul at or y r e q uir e m e nts.  
1 2. 1 1   
A U DI T S  A N D I N S P E C TI O N S  
T h e st u d y  m a y  b e  a u dit e d  or i ns p e ct e d  b y  q u alifi e d  d el e g at es fr o m t h e  S p o ns or  or  a  c o m p et e nt 
r e g ul at or y  a ut h orit y.  
I n t h e  e v e nt  of  a n  a u dit  b y t h e S p o ns or , t h e in v esti g at or  m ust  m a k e  all  st u d y r el at e d 
d o c u m e nt ati o n  a v ail a bl e t o t h e  a u dit or(s).  R e g ul at or y  a ut h oriti es  m a y r e q u est  a c c ess t o  all 
st u d y r el at e d  d o c u m e nt ati o n, i n cl u di n g s o ur c e  d o c u m e nts, f or i ns p e cti o n  a n d  c o p yi n g i n 
k e e pi n g  wit h  a p pli c a bl e r e g ul ati o ns.  T h e  S p o ns or  will i m m e di at el y  n otif y t h e i n v esti g at or ( or 
vi c e  v ers a)  of  a n  u p c o mi n g  a u dit  or i ns p e cti o n.  
If  a n  au dit  or i ns p e cti o n  o c c urs, t h e i n v esti g at or  a n d r el e v a nt  p ers o n n el  at t h e st u d y sit e  m ust 
all o c at e s uffi ci e nt ti m e t o  dis c uss t h e fi n di n gs  a n d  a n y r el e v a nt iss u es.  
1 2. 1 2   
C LI NI C A L  S T U D Y  R E P O R T  
Aft er  c o m pl eti o n  of t h e st u d y,  a  cli ni c al st u d y r e p ort  c o v eri n g  cli ni c al  a n d st atisti c al  as p e cts  of 
t h e st u d y  will  b e  pr e p ar e d  b y t h e S p o ns or  ( or  d el e g at e) i n  c o nsult ati o n  wit h t h e  c o or di n ati n g 
in v esti g at or.  As r e q uir e d  b y t h e  a p pli c a bl e r e g ul at or y r e q uir e m e nts, t h e  cli ni c al st u d y r e p ort 
will  b e si g n e d  b y t h e  S p o ns or ’s r es p o nsi bl e  m e di c al  offi c er  as  w ell  as t he  c o or di n ati n g 
in v esti g at or (if  a p pli c a bl e).  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 4  of  1 9 4  
Pr o gr ess r e p orts  a n d/ or  a s u m m ar y  of t h e  cli ni c al st u d y r e p ort  will  b e  pr o vi d e d t o t h e I E C/I R B 
a n d  c o m p et e nt r e g ul at or y  a ut h oriti es i n  a c c or d a n c e  wit h  a p pli c a bl e r e q uir e m e nts.  
1 2. 1 3   
U S E  O F  D A T A  A N D  P U B L I C A TI O N S 
T h e ri g hts  a n d  o bli g ati o ns  of i n v esti g at ors  a n d t h e  S p o ns or  c o n c er ni n g  a n y f or m al  pr es e nt ati o n 
or  p u bli c ati o n  of  d at a  c oll e ct e d  as  a  dir e ct  or i n dir e ct r es ult  of t his st u d y  will  b e  a d dr ess e d 
s p e cifi c all y i n t h e  Cli ni c al  Tri al  A gr e e m e nt f or t h e st u d y (s e e  S e cti o n  1 2. 1 ). 
F or  m ulti c e nt er st u di es, t h e first  p u bli c ati o n  m ust  b e  b as e d  u p o n  all  d at a  o bt ai n e d fr o m  all 
a n al ys es,  as sti p ul at e d i n t h e st u d y  pr ot o c ol  b y t h e  bi ost atisti ci a n  a n d  n ot  b y t h e i n v esti g at or s. 
In v esti g at ors  p arti ci p ati n g i n  m ulti c e nt er st u di es  m ust  a gr e e  n ot t o  pr es e nt  d at a  g at h er e d 
i n di vi d u all y  or  b y  a s u b gr o u p  of st u d y sit es  b ef or e t h e f ull, i niti al  p u bli c ati o n is  a v ail a bl e or  5  
y e ars  aft er t h e l ast  cli ni c al st u d y  visit,  w hi c h e v er is l at er , u nl ess t his  h as  b e e n  a gr e e d t o  b y  all 
ot h er i n v esti g at ors  a n d  b y t h e  S p o ns or . 
T h e  S p o ns or  m ust r e c ei v e  a  c o p y  of  a n y i nt e n d e d  c o m m u ni c ati o ns i n  a d v a n c e  of t h e  pr o p os e d 
s u b missi o n  d at e.  T his is t o  all o w t h e  S p o ns or  ti m e t o r e vi e w t h e  c o m m u ni c ati o n f or  a c c ur a c y 
(t h us  a v oi di n g  p ot e nti al  dis cr e p a n ci es  wit h s u b missi o ns t o r e g ul at or y  a ut h oriti es), t o  v erif y t h at 
c o nfi d e nti al  a n d/ or  pr o pri et ar y i nf or m ati o n is  n ot i n a d v ert e ntl y  di v ul g e d, t o  pr o vi d e  a n y 
r el e v a nt s u p pl e m e nt ar y i nf or m ati o n,  a n d t o  all o w  est a blis h m e nt of  c o -a ut h ors hi p ( as 
a p pr o pri at e).  T h e  a ut h ors hi p  of  c o m m u ni c ati o ns  arisi n g fr o m  p o ol e d  d at a  will i n cl u d e 
in v esti g at ors fr o m st u d y sit es t h at  c o ntri b ut e d  d at a  as  w ell  as r el e v a nt  p ers o n n el fr o m t h e 
S p o ns or .  O w n ers hi p  of  all  d at a  will r e m ai n  wit h t h e S p o ns or . 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 5  of  1 9 4  
1 3.   
R E F E R E N C E  LI S T  
Ar as  L M, Isl a, J,  Mi n g or a n c e -L e M e ur,  A.   T h e  E ur o p e a n  p ati e nt  wit h  Dr a v et s y n dr o m e:   R es ults 
fr o m  a  p ar e nt-r e p ort e d s ur v e y  o n  a nti e pil e pti c  dr u g  us e i n t h e  E ur o p e a n  p o p ul ati o n  wit h  Dr a v et 
s y n dr o m e.   E pil e ps y  &  B e h a vi or  2 0 1 5;  4 4: 1 0 4 -1 0 9.  
C e nt er f or  Dis e as e  C o ntr ol.  C ar di a c  v al v ul o p at h y  ass o ci at e d  wit h  e x p os ur e t o f e nfl ur a mi n e  or 
d e xf e nfl ur a mi n e:  U. S.  D e p art m e nt  of  H e alt h  a n d  H u m a n  S er vi c es I nt eri m  P u bli c  H e alt h 
R e c o m m e n d ati o ns,  N o v e m b er  1 9 9 7.  M or bi dit y  a n d  M ort ali t y  W e e kl y  R e p ort.  1 9 9 7; 
4 6( 4 5): 1 0 6 1 -1 0 8 4.  
C e ul e m a ns,  B,  B o el,  M,  L e yss e ns,  K,  et  al.   S u c c essf ul  us e  of f e nfl ur a mi n e  as  a n  a d d -o n 
tr e at m e nt f or  Dr a v et s y n dr o m e.   E pil e psi a  2 0 1 2;  5 3( 7):  1 1 3 1-1 1 3 9.  
C e ul e m a ns  B,  S c h o o nj a ns  A ,  G u n ni n g B ,  G a m m ait o ni A ,  L a g a e L.  L o w -d os e f e nfl ur a mi n e  
si g nifi c a ntl y r e d u c es s ei z ur e fr e q u e n c y i n  Dr a v et s y n dr o m e:  a  pr os p e cti v e st u d y  of  a  n e w  c o h ort 
of  B el gi a n  p ati e nts.   A m eri c a n  E pil e ps y  S o ci et y  A n n u al  M e eti n g,  D e c e m b er  4 -8,  2 0 1 5, 
P hil a d el p hi a,  P A  ( A bst. 2. 2 6 2),  2 0 1 5 . 
C e ul e m a ns  B,  S c h o o nj a ns  A,  M ar c h a u  F ,  P a eli n c k  B,  a n d  L a g a e  L. Fi v e -y e ar  e xt e n d e d f oll o w -
u p st at us  of  1 0  p ati e nts  wit h  Dr a v et s y n dr o m e tr e at e d  wit h f e nfl ur a mi n e.  E pil e psi a,  5 7( 7): e 1 2 9 –
e 1 3 4,  2 0 1 6  d oi:  1 0. 1 1 1 1/ e pi. 1 3 4 0 7  
C hir o n  C  a n d  D ul a c  O.   T h e  p h ar m a c ol o gi c tr e at m e nt  of  Dr a v et s y n dr o m e.   E pil e psi a  2 0 1 1; 
5 2( S u p pl.  2): 7 2 – 7 5.  
C o n n oll y  H M,  Cr ar y J L,  M c G o o n  M D,  H e nsr u d  D D  et  al.   V al v ul ar  h e art  dis e as e  ass o ci at e d 
wit h f e nfl ur a mi n e -p h e nt er mi n e.   N e w  E n gl J  M e d  1 9 9 7; 3 3 7( 9): 5 8 1 -8.  Err at u m i n:  N  E n gl J  M e d 
1 9 9 7  D e c  1 1; 3 3 7( 2 4): 1 7 8 3.  
D es n o us  B,  G o uj o n  E,  B ell a v oi n e  V,  et  al.  P er c e pti o ns  of f e v er  a n d f e v er  m a n a g e m e nt  pr a cti c es 
i n  p ar e nts  of  c hil dr e n  wit h  Dr a v et s y n dr o m e.  E pil e ps y  a n d  B e h a vi or.  2 0 1 1;  2 1: 4 4 6-8.  
Dr a v et  C,  B ur e a u  M,  O g u ni  H,  F u k u y a m a  Y,  C o k ar  O.   S e v er e  m y o cl o ni c  e pil e ps y i n i nf a n c y: 
Dr a v et s y n dr o m e.   A d v  N e ur ol  2 0 0 5;  9 5:  7 1 -1 0 2.  
Dr a v et  C.  L es  e pil e psi es  gr a v es  d e l’ e nf a nt.   Vi e  M e d.  1 9 7 8; 8: 5 4 3 – 5 4 8.  
Dr a v et  C.   S e v er e  m y o cl o ni c  e pil e ps y i n i nf a nts  a n d its r el at e d  s y n dr o m es.   E pil e psi a  2 0 0 0;  4 1: 7 . 
Dr a v et,  C.  T h e  c or e  Dr a v et s y n dr o m e  p h e n ot y p e.  E pil e psi a,  5 2:  3 – 9.  d oi: 1 0. 1 1 1 1/j. 1 5 2 8 -
1 1 6 7. 2 0 1 1. 0 2 9 9 4. x  
E M A  2 0 0 7.   S T P  S m P C  a n d  E P A R  S ci e ntifi c  Dis c ussi o n.   A v ail a bl e  at 
htt p:// w w w. e m a. e ur o p a. e u/ e m a/i n d e x.js p ? c url = p a g es/ m e di ci n es/ h u m a n/ m e di ci n es/ 0 0 0 6 6 4/ h u m a
n _ m e d _ 0 0 0 7 4 2.js p & mi d = W C 0 b 0 1 a c 0 5 8 0 0 1 d 1 2 4.   A c c ess e d  3 1 J ul y  2 0 1 5.  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 6  of  1 9 4  
E M A  2 0 1 0.  G ui d eli n e  o n  cli ni c al i n v esti g ati o n  of  m e di ci n al  pr o d u cts i n t h e tr e at m e nt  of 
e pil e pti c  dis or d ers.  E M A J ul y  2 0 1 0.   A v ail a bl e  at: 
htt p:// w w w. e m a. e ur o p a. e u/ d o cs/ e n _ G B/ d o c u m e nt _li br ar y/ S ci e ntifi c _ g ui d eli n e/ 2 0 1 0/ 0 1/ W C 5 0 0
0 7 0 0 4 3. p df .   A c c ess e d  1 7 J a n u ar y  2 0 1 6. 
H urst,  D L.   E pi d e mi ol o g y  of s e v er e  m y o cl o ni c  e pil e ps y  of i nf a n c y.   E pil e psi a  1 9 9 0; 3 1: 3 9 7 -4 0 0.  
I C H T o pi c  E 2 F : D e v el o p m e nt  S af et y  U p d at e  R e p ort,  2 0 1 1 . 
I C H  T o pi c  E 2 A: Cli ni c al  S af et y  D at a  M a n a g e m e nt:  D efi niti o ns  a n d  St a n d ar ds f or  E x p e dit e d 
R e p orti n g , 1 9 9 4 . 
M ars h all  W A,  T a n n er J M.   V ari ati o ns i n  t h e  p att er n  of  p u b et al  c h a n g es i n  b o ys.  Ar c h  Dis  C hil d 
1 9 7 0;  4 5: 1 3.  
M ars h all  W A,  T a n n er J M.  V ari ati o ns i n  p att er n  of  p u b ert al  c h a n g es i n  girls.  Ar c hi v es  of  Dis e as e 
i n  C hil d h o o d.  1 9 6 9; 4 4( 2 3 5): 2 9 1-3 0 3.  
N as h ef  L,  S o  E L,  R y vli n  P,  T o ms o n  T.  U nif yi n g t h e  d efi niti o ns  of s u d d e n  u n e x p e ct e d  d e at h i n 
e pil e ps y.  E pil e psi a  2 0 1 2; 5 3,  2 2 7 – 2 3 3.  
N ol a n  K,  C a mfi el d  C S  a n d  C a mfi el d  P R.  C o pi n g  wit h  a  c hil d  wit h  D r a v et s y n dr o m e: I nsi g hts 
fr o m f a mili es. J o ur n al  of  C hil d  N e ur ol o g y.  2 0 0 8;  2 3: 6 9 0-4.  
S a b a z  M,  C ari ns  D,  L a ws o n  J,  N h e u  N  et  al.  V ali d ati o n  of  a  N e w  Q u alit y  of  Lif e  M e as ur e f or 
C hil dr e n  wit h  E pil e ps y.  E pil e psi a  2 0 0 0;  4 1( 6): 7 6 5 -7 7 4.  
S h or v o n  S,  T o ms o n  T.   S u d d e n  u n e x p e ct e d  d e at h i n  e pil e ps y.  L a n c et  2 0 1 1; 3 7 8:  2 0 2 8 – 3 8.  
S kl u z a c e k J,  W atts  K,  P ars y  O,  Wi c al  B,  C a mfi el d  P,  Dr a v et s y n dr o m e  a n d  p ar e nt  ass o ci ati o ns: 
T h e I D E A  L e a g u e  e x p eri e n c e  wit h  c o m or bi d  c o n diti o ns,  m ort alit y,  m a n a g e m e nt,  a d a pt ati o n,  a n d 
gri ef.  E pil e psi a,  5 2( S u p pl.  2): 9 5 – 1 0 1,  2 0 1 1  d oi:  1 0. 1 1 1 1/j. 1 5 2 8 -1 1 6 7. 2 0 1 1. 0 3 0 1 2. x  
T al ars k a  D.  T h e  us ef ul n ess  of  Q u alit y  of  Lif e  C hil d h o o d  E pil e ps y ( Q O L C E)  q u esti o n n air e i n 
e v al u ati n g t h e  q u alit y  of lif e  of  c hil dr e n  wit h  e pil e ps y.  A d v a n c es  M e d.  S ci  2 0 0 7;  5 2 s u p pl  1: 1 9 1 -
1 9 3.  
W o n g J,  R e d d y  S S,  Kl ei n  A L.   A n or e cti c  dr u gs  a n d  v al v ul ar  h e art  dis e as e:  a  bi ol o gi c al  a n d 
cli ni c al  p ers p e cti v e.   Cl e v el a n d  Cli ni c al J o ur n al  of  M e di ci n e  1 9 9 8;  6 5: 3 5 -4 1.  
Z X 0 0 8 I n v esti g at or’s  Br o c h ur e  V ersi o n  3 , J a n u ar y  5,  2 0 1 6. 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 7  of  1 9 4  
1 4.   
A P P E N DI C E S  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 8  of  1 9 4  
A P P E N DI X  1  –  LI S T  O F  P R O HI BI T E D  C O N C O MI T A N T 
M E DI C A TI O N S  A N D  F O O D S  
 
G e n e ri c  N a m e  
G e n e ri c  N a m e  
alf e nt a nil  
n ar atri pt a n  
al m otri pt a n  
n ef a z o d o n e  
al pr e n ol ol  
n ortri pt yli n e  
a mitri pt yli n e  
o n d a ns etr o n  
a m p h et a mi n e  
o x c ar b a z e pi n e  
ast e mi z ol e  
o x y c o d o n e  
at o m o x eti n e  
p ar o x eti n e  
b uf ur al ol  
p er p h e n a zi n e  
b u pr o pi o n  
p h e n a c eti n  
b us pir o n e  
p h e n o b ar bit al  
c af er g ot  
p h e n yt oi n  
c a n n a bi di ol  
pr o m et h a zi n e  
c ar b a m a z e pi n e  
pr o p af e n o n e  
c eri v ast ati n  
r eti g a bi n e/ e z o g a bi n e 
cit al o pr a m  
ris p eri d o n e 
cl o mi pr a mi n e  
rit o n a vir 
c o d ei n e  
ri z atri pt a n 
c y pr o h e pt a di n e  
s el e gili n e 
d esi pr a mi n e  
s ertr ali n e  
d e xtr o m et h or p h a n  
S tiri p e nt ol ( C o h ort  1,  R e gi m e ns  1  a n d  2) 
d ul o x eti n e  
s u m atri pt a n 
el etri pt a n  
t el a pr e vir 
e n c ai ni d e  
T H C  a n d  d eri v ati v es  
er g ot a mi n e t artr at e  
tr a m a d ol 
esli c ar b a z e pi n e  
tr a z o d o n e 
f el b a m at e 
v orti o x eti n e  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 3 9  of  1 9 4  
 
  
 
 
f e nt a n yl 
z ol mitri pt a n  
fl u o x eti n e 
z u cl o p e nt hi x ol  
fl u v o x a mi n e 
 
fr o v atri pt a n 
 
i mi pr a mi n e 
 
l e v a c et yl m et h a d ol ( L A A M) 
 
li n e z oli d 
 
m e p eri di n e  
 
m et h a d o n e  
 
m et o cl o pr a mi d e  
 
m e xil eti n e  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 0  of  1 9 4  
A P P E N DI X  2  –  C O L U M BI A  –  S UI CI D E  S E V E R T Y  R A TI N G  S C A L E  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 1  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 2  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 3  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 4  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 5  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 6  of  1 9 4  
A P P E N DI X  3  –  B E H A VI O R  R A TI N G I N V E N T O R Y  O F  E X E C U TI V E 
F U N C TI O N   
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 7  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 8  of  1 9 4  
 
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 4 9  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 0  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 1  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 2  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 3  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 4  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 5  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 6  of  1 9 4  
A P P E N DI X  4  –  Q U A LI T Y  O F  LI F E I N  C HI L D H O O D  E PI L E P S Y  S C A L E  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 7  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 8  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 5 9  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 0  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 1  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 2  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 3  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 4  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 5  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 6  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 7  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 8  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 6 9  of  1 9 4  
A P P E N DI X  5  –  T A N N E R  S T A GI N G  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 0  of  1 9 4  
 
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 1  of  1 9 4  
A P P E N DI X  6  –  P E D S Q L  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 2  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 3  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 4  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 5  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 6  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 7  of  1 9 4  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 8  of  1 9 4  
 
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 7 9  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 0  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 1  of  1 9 4  
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 2  of  1 9 4  
A P P E N DI X  7  –  E Q -5 D -5 L  Q U E S TI O N N AI R E  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 3  of  1 9 4  
 
 
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 4  of  1 9 4  
A P P E N DI X  8  –  K A R O LI N S K A  S L E E PI N E S S  S C A L E  
H er e  ar e s o m e  d es cri pt ors  a b o ut  h o w  al ert  or sl e e p y  y o u  mi g ht  b e f e eli n g ri g ht  n o w.  Pl e as e 
r e a d t h e  c ar ef ull y  a n d  CI R C L E t h e  n u m b er t h at  b est  c orr es p o n ds t o t h e st at e m e nt  d e cri bi n g 
h o w  y o u f e el  at t h e  m o m e nt.  
1.    E xtr e m el y  al ert  
2.   V er y  Al ert  
3.   Al ert  
4.   R at h er  Al ert  
5.   N eit h er  al ert  n or sl e e p y  
6.   S o m e si g ns  of sl e e pi n ess  
7.   Sl e e p y,  b ut  n o  diffi c ult y r e m ai ni n g  a w a k e  
8.   Sl e e p y, wit h s o m e  eff ort t o  k e e p  al ert  
9.   E xtr e m el y sl e e p y, fi g hti n g sl e e p  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 5  of  1 9 4  
A P P E N DI X  9  –  M A XI M U M  A L L O W A B L E  B L O O D  D R A W  V O L U M E S  
 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 6  of  1 9 4  
A P P E N DI X  1 0  –  S U M M A R Y  O F  P R O T O C O L  A M E N D M E N T  2. 3. 8 3 .3  
S u m m a r y  of  C h a n g es  f r o m  A m e n d m e nt  2.3 . 8 t o  A m e n d m e nt  3. 3  of t h e  p r ot o c ol. 
T h e  pr ot o c ol  a m e n d m e nt  n u m b er  w as  u p d at e d t o  A m e n d m e nt  3. 3,  2  F e br u ar y  2 0 1 8.  
R ati o n al e: I n c r e as e  n  of  C o h o rt  2  b as e d  o n  r es ults f r o m  St u d y  1  w hi c h s h o w t h at t h e  S D  c a n  r a n g e 
b et w e e n  5 0 %  a n d  6 9 % . 
O ri gi n al  T e xt  
A m e n d m e nt  T e xt  
S y n o psi s  a n d  S e cti o n  3. 2,  4. 7  
A p pr o xi m at el y  8 5 s u bj e cts  will  b e s cr e e n e d t o 
o bt ai n  8 0 s u bj e cts  w h o  e nt er t h e  B as eli n e  P eri o d.  Of 
t h es e  8 0 s u bj e cts, it is  esti m at e d t h at  at l e ast  7 0 
s u bj e cts  will  b e r a n d o mi z e d i nt o t h e  Titr ati o n 
P eri o d.   
S y n o psi s  a n d  S e cti o n  3. 2,  4. 7  
A p pr o xi m at el y  1 1 5  s u bj e cts  will  b e s cr e e n e d t o 
o bt ai n  8 0 s u bj e cts  w h o  e nt er t h e  B as eli n e  P eri o d.  Of 
t h es e  8 0 s u bj e cts, it is  esti m at e d t h at  at l e ast  7 0 
r a n d o mi z e  a p p r o xi m at el y  9 0  s u bj e cts will  b e 
r a n d o mi z e d i nt o t h e  Titr ati o n  P eri o d. 
S y n o psi s  a n d  S e cti o n  3. 2  
A p pr o xi m at el y  2 5 s u bj e cts  will  b e s cr e e n e d t o 
e ns ur e  2 0 s u bj e cts  e nt er t h e st u d y  a n d  c o m pl et e  all 
P K  ass ess m e nts.  S u bj e cts  w h o  dis c o nti n u e  pri or t o 
c o m pl eti o n  of  all st u d y -r el at e d  pr o c e d ur es  m a y  b e 
r e pl a c e d. 
S y n o psi s  a n d  S e cti o n  3. 2  
A p pr o xi m at el y  2 5 s u bj e cts  will  b e s cr e e n e d t o 
e ns ur e  1 8 -2 0  s u bj e cts  e nt er t h e st u d y  a n d  c o m pl et e 
all  P K  ass ess m e nts.  S u bj e cts  w h o  dis c o nti n u e  pri or 
t o  c o m pl eti o n  of  all st u d y-r el at e d  pr o c e d ur es  m a y 
b e r e pl a c e d.  
R ati o n al e: I n c r e as e  n  of  C o h o rt  2  b as e d  o n  r es ults f r o m  St u d y  1  w hi c h s h o w t h at t h e  S D  c a n  r a n g e 
b et w e e n  5 0 %  a n d  6 9 % . 
O ri gi n al  T e xt  
A m e n d m e nt  T e xt  
S y n o psi s  a n d  S e cti o n  1 0. 1:  
T h e s a m pl e si z e f or  C o h ort  2 is  b as e d  o n r es ults fr o m 
t h e  o nl y r a n d o mi z e d,  pl a c e b o-c o ntr oll e d st u di es i n 
s u bj e cts  wit h  Dr a v et s y n dr o m e  c a n  b e f o u n d i n t h e 
E ur o p e a n  P u bli c  Ass ess m e nt R e p ort ( E P A R) f or  S T P 
(E M A  2 0 0 7 ).   T h e  E P A R s u m m ari z es t h e r es ults 
fr o m t w o st u di es:  S TI C L O  Fr a n c e  a n d  S TI C L O It al y.  
I n t h e  S T P  gr o u ps, t h e st a n d ar d  d e vi ati o n ( S D)  of t h e 
p er c e nt a g e  c h a n g e i n  s ei z ur e fr e q u e n c y fr o m  b as eli n e 
t o  Mo nt h  2  w a s  4 2 % i n t h e  Fr e n c h tri al  a n d  2 6 % i n 
t h e It ali a n tri al.  T h e  a n al o g o us  S Ds f or  pl a c e b o 
gr o u ps  w er e  3 8 %  a n d  6 2 %.  A n  S D  of  5 0 %  w as 
ass u m e d f or t h e  pri m ar y  a n al ysis i n t his tri al 
c o m p ari n g  Z X 0 0 8 t o  pl a c e b o  o n t h e  c h a n g e fr o m 
b as eli n e i n s ei z ur e fr e q u e n c y.  Usi n g  a t w o -si d e d t est 
at t h e  α = 0. 0 5 si g nifi c a n c e l e v el,  a s a m pl e si z e  of  3 5 
s u bj e cts  p er tr e at m e nt  gr o u p  aff or ds  9 0 %  p o w er t o 
d et e ct  a  diff er e n c e i n  m e a n  c h a n g e fr o m  b as eli n e  of 
4 0  p er c e nt a g e  p oi nts.   T h us, t h e t ot al s a m pl e si z e f or 
C o h ort  2 is  pl a n n e d t o  b e  7 0 s u bj e cts ( 3 5  p er  ar m).  
S y n o psi s  a n d  S e cti o n  1 0, 1:  
T h e s a m pl e si z e f or  C o h ort  2 is  b as e d  o n r es ults fr o m 
St u d y  1,  t h e o nl y  r a n d o mi z e d,  pl a c e b o-c o ntr oll e d 
st u di e sst u d y i n s u bj e cts  wit h  Dr a v et s y n dr o m e 
s p o ns o r e d  b y  Z o g e ni x ( L a g a e  2 0 1 7).  c a n  b e  f o u n d 
i n t h e  E ur o p e a n  P u bli c  Ass e ss m e nt  R e p ort ( E P A R) 
f or  S T P (E M A  2 0 0 7 ).   T h e  E P A R s u m m ari z e s t h e 
r es ults fr o m t w o st u di e s:  S TI C L O  Fr a n c e  a n d 
S TI C L O It al y.  I n t h e  S T P  gr o u ps, t T h e st a n d ar d 
d e vi ati o n ( S D)  of t h e  p er c e nt a g e  c h a n g e i n s ei z ur e 
fr e q u e n c y fr o m  b as eli n e t o M o nt h  2  w as  4 2 % i n t h e 
Fr e n c h tri al  a n d  2 6 % i n t h e It ali a n tri al.  T h e 
a n al o g o us  S D s f or  pl a c e b o  gr o u ps  w er e  3 8 %  a n d 
6 2 %.  A n  S D  of  5 0 %  w as  ass u m e d f or t h e  pri m ar y 
a n al ysis i n t his tri al  c o m p ari n g  Z X 0 0 8 t o  pl a c e b o  o n 
th e  c h a n g e fr o m  b as eli n e i n s ei z ur e fr e q u e n c y.  U  t h e 
e n d  of st u d y ( D a y  9 9)  w as  5 0 % f o r t h e  0. 8 
m g/ k g/ d a y  g r o u p  a n d  6 9 % f o r t h e  0. 2  m g/ k g/ d a y 
g r o u p.  F o r  t h e s a m pl e si z e  c al c ul ati o n f o r  C o h o rt 
2, t h e  S D is  ass u m e d t o  b e i nt e r m e di at e  b et w e e n 
t h e  S Ds  o bs e r v e d in t h e  hi g h  a n d l o w  d os e  g r o u ps 
i n  St u d y  1.  Ass u mi n g  a n  S D  of  5 8  a n d  usi n g  a t w o -
si d e d t est  at t h e  α = 0. 0 5 si g nifi c a n c e l e v el,  a s a m pl e 
si z e  of 3 5 4 5  s u bj e cts  p er tr e at m e nt  gr o u p  aff or ds 
9 0 %  p o w er t o  d et e ct  a  diff er e n c e i n  m e a n  c h a n g e  i n 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 7  of  1 9 4  
s ei z u r e f r e q u e n c y fr om  b as eli n e  of  4 0  p er c e nt a g e 
p oi nts.   T h us, t h e t ot al s a m pl e si z e f or  C o h ort  2 is 
pl a n n e d t o  b e  7 0 a p p r o xi m at el y  9 0  s u bj e cts (3 5 4 5  
p er  ar m).  
S y n o psi s  a n d  S e cti o n  1 0. 1:  
T h e  2 0 s u bj e ct s t ar g et e d f or t h e  P K  p h as e  of t h e 
st u d y i s  e x p e ct e d t o  b e s uffi ci e nt t o  all o w f or t h e 
e xt e nsi o n  of t h e  P K i nf or m ati o n  g ai n e d i n t h e 
o n g oi n g  P K st u d y i n  a d ult s  a n d  e xi sti n g  P B P K 
m o d el s t o  p e di atri c  p ati e nt s  wit h  Dr a v et  s y n dr o m e.  
S y n o psi s  a n d  S e cti o n  1 0. 1:  
T h e 1 8 -2 0  s u bj e ct s t ar g et e d f or t h e  P K  p h as e  of 
t h e  st u d y i s  e x p e ct e d t o b e s uffi ci e nt t o  all o w f or 
t h e  e xt e nsi o n  of t h e  P K i nf or m ati o n  g ai n e d i n t h e 
o n g oi n g  P K st u d y i n  a d ult s  a n d  e xi sti n g  P B P K 
m o d el s t o  p e di atri c  p ati e nt s  wit h  Dr a v et 
s y n dr o m e.  
R ati o n al e:  U p d ati n g  St atisti c al  A n al ysis  a n d  effi c a c y  o bj e cti v es t o  ali g n  wit h  St a ti sti c al  A n al ysis  Pl a n: 
M o vi n g  C GI f r o m  e x pl o r at o r y t o  s e c o n d a r y  o bj e cti v es,  r e m o vi n g  4 0 %  d e c r e as e i n  s ei z u r e f r e q u e n c y  a n d 
a d di n g  5 0 %  d e c r e as e i n  s ei z u r e f r e q u e n c y t o  s e c o n d a r y  o bj e cti v es  
O ri gi n al  T e xt  
A m e n d m e nt  T e xt  
S y n o psi s  a n d  S e cti o n  2. 2  
T h e  k e y  s e c o n d ar y  effi c a c y  o bj e cti v es  of t h e  st u d y  ar e 
r el at e d t o  C o h ort  2  a n d i n cl u d e: 
o   T o  d e m o nstr at e t h at  Z X 0 0 8 is  s u p eri or t o  pl a c e b o 
o n t h e f oll o wi n g  e n d p oi nts:  
–   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥ 
4 0 % r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e 
s ei z ur e fr e q u e n c y.  
–   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥ 
5 0 % r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e 
s ei z ur e fr e q u e n c y.  
–  
T h e l o n g est  c o n v ulsi v e s ei z ur e -fr e e i nt er v al. 
S y n o psi s  a n d  S e cti o n  2. 2  
T h e  k e y s e c o n d ar y  effi c a c y  o bj e cti v es  of t h e  st u d y  ar e 
r el at e d t o  C o h ort  2 a n d i n cl u d e:  
o   T o  d e m o nstr at e t h at  Z X 0 0 8 is  s u p eri or t o  pl a c e b o 
o n t h e f oll o wi n g  e n d p oi nts:  
–   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥ 
4 0 % r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e 
s ei z ur e fr e q u e n c y.  
–   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥ 
5 0 % r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e 
s ei z ur e fr e q u e n c y.  
–  
T h e l o n g est  c o n v ulsi v e s ei z ur e -fr e e i nt er v al. 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 8  of  1 9 4  
S y n o psis  a n d  S e cti o n  2. 3  
 
A d diti o n al  s e c o n d ar y  effi c a c y  o bj e cti v es  of t h e st u d y 
( C o h ort  2)  ar e: 
o   T o  d e m o nstr at e t h at  Z X 0 0 8 is  s u p eri or t o  pl a c e b o 
o n t h e f oll o wi n g  e n d p oi nts:  
–   T h e  n u m b er  of  c o n v ulsi v e s ei z ur e -fr e e  d a ys. 
–   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  ≥ 
7 5 % r e d u cti o ns fr o m  b a s eli n e i n  c o n v ulsi v e 
s ei z ur e fr e q u e n c y.  
–   T h e  c h a n g e fr o m  b as eli n e i n  n o n -c o n v ulsi v e 
s ei z ur e fr e q u e n c y.  
–   T h e  c h a n g e fr o m  b as eli n e i n  c o n v ulsi v e  + 
n o n -c o n v ulsi v e s ei z ur e fr e q u e n c y.  
–   T h e i n ci d e n c e  of r es c u e  m e di c ati o n  us a g e.  
–   T h e i n ci d e n c e  of  h o s pit ali z ati o n t o tr e at 
s ei z ur es.  
–   T h e i n ci d e n c e  of st at us  e pil e pti c us ( S E).  
–   T h e  c h a n g e fr o m  b as eli n e i n  h e alt h -r el at e d 
q u alit y  of lif e ( H R Q O L)  m e as ur e d  usi n g  t h e 
P e di atri c  Q u alit y  of  Lif e I n v e nt or y ™  
( P e ds Q L)  G e n eri c  C or e  S c al e. 
–   T h e  c h a n g e fr o m  b as eli n e i n  P e ds Q L  F a mil y 
I m p a ct  m o d ul e s c or e. 
–   C h a n g e fr o m  b as eli n e i n s u bj e cts’  q u alit y  of 
lif e  m e as ur e d  usi n g t h e Q u alit y  of  Lif e i n 
C hil d h o o d  E pil e ps y  ( Q O L C E) 
–   T h e  c h a n g e fr o m  b as eli n e i n t h e  H R Q O L  of 
t h e  p ar e nt/ c ar e gi v er  usi n g t h e  st a n d ar di z e d 
m e as ur e  of  h e alt h  st at us ( E Q -5 D -5 L) s c al e.  
–   T h e  c h a n g e fr o m  b as eli n e  o n t h e i m p a cts  of 
t h e  c o n diti o n  o n  p ar e nts  a n d t h e f a mil y  usi n g 
t h e  P e ds Q L f a mil y i m p a ct  m o d ul e.  
 
 
 
S y n o psis  a n d  S e cti o n  2. 3  
 
A d diti o n al  s e c o n d ar y  effi c a c y  o bj e cti v es  of t h e st u d y 
( C o h ort  2)  ar e: 
o   T o  d e m o nstr at e t h at  Z X 0 0 8 is  s u p eri or t o  pl a c e b o 
o n t h e f oll o wi n g  e n d p oi nts:  
–   T h e  n u m b er  of  c o n v ulsi v e s ei z ur e -fr e e  d a ys. 
–   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  ≥ 
2 5 %  o r  ≥  7 5 % r e d u cti o ns fr o m  b as eli n e i n 
c o n v ulsi v e s ei z ur e fr e q u e n c y.  
–   T h e  c h a n g e fr o m  b as eli n e i n  n o n -c o n v ulsi v e 
s ei z ur e fr e q u e n c y.  
–   T h e  c h a n g e fr o m  b as eli n e i n  c o n v ulsi v e  + 
n o n -c o n v ulsi v e s ei z ur e fr e q u e n c y.  
–   T h e i n ci d e n c e  of r es c u e  m e di c ati o n  us a g e.  
–   T h e  i n ci d e n c e  of  h o s pit ali z ati o n t o tr e at 
s ei z ur es.  
–   T h e i n ci d e n c e  of st at us  e pil e pti c us ( S E).  
–   T h e  c h a n g e fr o m  b as eli n e i n  h e alt h -r el at e d 
q u alit y  of lif e ( H R Q O L)  m e as ur e d  usi n g t h e 
P e di atri c  Q u alit y  of  Lif e I n v e nt or y ™  
( P e ds Q L)  G e n eri c  C or e  S c al e. 
–   T h e  c h a n g e fr o m  b as eli n e i n  P e ds Q L  F a mil y 
I m p a ct  m o d ul e s c or e. 
–   C h a n g e fr o m  b as eli n e i n s u bj e cts’  q u alit y  of 
lif e  m e as ur e d  usi n g t h e Q u alit y  of  Lif e i n 
C hil d h o o d  E pil e ps y  ( Q O L C E) 
–   T h e  c h a n g e fr o m  b as eli n e i n t h e  H R Q O L  of 
t h e  p ar e nt/ c ar e gi v er  usi n g t h e  st a n d ar di z e d 
m e as ur e  of  h e alt h st at us ( E Q -5 D -5 L) s c al e.  
–   T h e  c h a n g e fr o m  b as eli n e  o n t h e i m p a cts  of 
t h e  c o n diti o n  o n  p ar e nts  a n d t h e f a mil y  usi n g 
t h e  P e ds Q L f a mil y i m p a ct  m o d ul e.  
–   Cli ni c al  Gl o b al I m p r essi o n  –  
I m p r o v e m e nt ( C GI-I)  r ati n g,  as  ass ess e d 
b y t h e  p ri n ci p al i n v esti g at o r . 
–   C GI -I  r ati n g,  as  ass ess e d  b y t h e 
p a r e nt/ c a r e gi v e r.  
S y n o psis  a n d  S e cti o n  2. 4  
 
E x pl or at or y  o bj e cti v es  of t his  st u d y ( C o h ort  2) i n cl u d e:  
–   T o  ass ess t h e  c h a n g e fr o m  b as eli n e i n  h e alt h  a n d 
s o ci al  c ar e r es o ur c e  us e.   T h es e  m e as ur es i n cl u d e 
pl a n n e d  a n d  u n pl a n n e d  h o s pit al  visits,  us e  of 
a m b ul a n c es,  g e n er al  pr a ctiti o n er ( G P)  visits, 
s p e e c h  a n d l a n g u a g e t h er a p y  utili z ati o n, 
o c c u p ati o n al  a n d  p h ysi c al t h er a p y  utili z ati o n.  
–   Cli ni c al  Gl o b al I m pr essi o n  –  I m pr o v e m e nt ( C GI-
I) r ati n g,  as  ass ess e d  b y t h e  pri n ci p al i nv e sti g at or . 
S y n o psis  a n d  S e cti o n  2. 4  
 
E x pl or at or y  o bj e cti v es  of t his  st u d y ( C o h ort  2) i n cl u d e:  
–   T o  ass ess t h e  c h a n g e fr o m  b as eli n e i n  h e alt h  a n d 
s o ci al  c ar e r es o ur c e  us e.   T h es e  m e as ur es i n cl u d e 
pl a n n e d  a n d  u n pl a n n e d  h o s pit al  visits,  us e  of 
a m b ul a n c es,  g e n er al  pr a ctiti o n er ( G P)  visits, 
s p e e c h  a n d l a n g u a g e t h er a p y  utili z ati o n, 
o c c u p ati o n al  a n d  p h ysi c al t h er a p y  utili z ati o n.  
–   Cli n i c al  Gl o b al I m pr essi o n –  I m pr o v e m e nt ( C GI-
I) r ati n g,  as  ass ess e d  b y t h e  pri n ci p al i n v e sti g at or. 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 8 9  of  1 9 4  
–   C GI -I r ati n g,  as  a ss ess e d  b y t h e  p ar e nt/ c ar e gi v er. 
–   C h a n g e fr o m  b as eli n e i n sl e e p  q u alit y.   
–   C h a n g e fr o m  b as eli n e i n  m e alti m e  b e h a vi or.  
–   C GI -I r ati n g,  as  a ss ess e d  b y t h e  p ar e nt/ c ar e gi v er. 
–   C h a n g e fr o m  b as eli n e i n sl e e p  q u alit y.   
–   C h a n g e fr o m  b as eli n e i n  m e alti m e  b e h a vi or.  
S e cti o n  1 0. 5 . 1. 1  P ri m a r y  Effi c a c y  A n al ysis –  C o h o rt 
2  
T h e first  k e y s e c o n d ar y  e n d p oi nt  –  t h e  pr o p orti o n  of 
s u bj e cts  w h o  a c hi e v e  a  ≥  4 0 % r e d u cti o n fr o m  b as eli n e i n 
c o n v ulsi v e s ei z ur e fr e q u e n c y  –  is  d eri v e d  dir e ctl y fr o m 
t h e  pri m ar y  e n d p oi nt.  T h at is, t h e  pr o p orti o n  of s u bj e cts i n 
t h e  Z X 0 0 8  gr o u p  w h o  h a v e  a  c h a n g e i n  c o n v ulsi v e 
fr e q u e n c y  of  at l e a st  4 0  p er c e nt a g e  p oi nts  will  b e 
c o m p ar e d t o t h e  a n al o g o us  pr o p orti o n i n t h e  pl a c e b o 
gr o u p.  T h e  c o m p aris o n  will  b e  m a d e  usi n g  a l o gisti c 
r e gr essi o n  m o d el t h at i n c or p or at es t h e s am e f a ct ors  a n d 
c o v ari at es  as t h e  A N C O V A  us e d i n t h e  pri m ar y  a n al ysis. 
T h e s e c o n d s e c o n d ar y  e n d p oi nt, t h e  pr o p orti o n  a c hi e vi n g 
a  >  5 0 % r e d u cti o n i n  c o n v ulsi v e s ei z ur es,  will  b e 
a n al y z e d si mil arl y.  T h e  a n al ys es  will  b e  p erf or m e d  usi n g 
d at a  c oll e ct e d  o v er t h e  T  +  M  p eri o d.  
T h e l o n g est i nt er v al  b et w e e n  c o n v ulsi v e s ei z ur es  will  b e 
c al c ul at e d f or  e a c h  s u bj e ct  o v er t h e  e ntir e  T  +  M  p eri o d.  
T h e  Z X 0 0 8  a n d  pl a c e b o  gr o u ps  will  b e  c o m p ar e d  usi n g  a 
l o g r a n k t e st. 
S e cti o n  1 0. 5 . 1. 1  P ri m a r y  Effi c a c y  A n al ysis –  C o h o rt 
2  
T h e first  k e y s e c o n d ar y  e n d p oi nt  –  t h e  pr o p orti o n  of 
s u bj e cts  w h o  a c hi e v e  a  ≥  5 0 %  r e d u cti o n fr o m  b as eli n e i n 
c o n v ulsi v e s ei z ur e fr e q u e n c y  –  is  d eri v e d  dir e ctl y fr o m 
t h e  pri m ar y  e n d p oi nt.  T h at is, t h e  pr o p orti o n  of s u bj e cts i n 
t h e  Z X 0 0 8  gr o u p  w h o  h a v e  a  c h an g e i n  c o n v ulsi v e 
fr e q u e n c y  of  at l e a st 5 0  p er c e nt a g e  p oi nts  will  b e 
c o m p ar e d t o t h e  a n al o g o us  pr o p orti o n i n t h e  pl a c e b o 
gr o u p.  T h e  c o m p aris o n  will  b e  m a d e  usi n g  a l o gisti c 
r e gr essi o n  m o d el t h at i n c or p or at es t h e s a m e f a ct ors  a n d 
c o v ari at es  as t h e  A N C O V A  us e d i n t h e  pri m ar y  a n al ysis. 
T h e s e c o n d s e c o n d ar y  e n d p oi nt, t h e  pr o p orti o n  a c hi e vi n g 
a  >  5 0 % r e d u cti o n i n  c o n v ulsi v e s ei z ur es,  will  b e 
a n al y z e d si mil arl y.  T h e  a n al ys es  will  b e  p erf or m e d  usi n g 
d at a  c oll e ct e d  o v er t h e  T  +  M  p eri o d.  
T h e l o n g est i nt er v al  b et w e e n  c o n v ulsi v e s ei z ur es  will  b e 
c al c ul at e d f or  e a c h  s u bj e ct  o v er t h e  e ntir e  T  +  M  p eri o d.  
T h e  Z X 0 0 8  a n d  pl a c e b o  gr o u ps  will  b e  c o m p ar e d  usi n g  a 
Wil c o x o n t est.  
S e cti o n  1 0. 4. 1. 3  M ulti pli cit y  St r at e g y  a n d  T esti n g 
Hi e r a r c h y  –  C o h o rt  2  
T h e  effi c a c y  a n al ys e s  wil l  e m pl o y  a s eri al  g at e k e e p er 
str at e g y t o  m ai nt ai n t h e  T y p e  1  err or r at e  at  α = 0. 0 5  a cr oss 
t h e f a mil y  of  a n al ys e s t h at s u p p ort t h e  pri m ar y  a n d  k e y 
s e c o n d ar y  o bj e cti v es.  T h e str at e g y  s p e cifi e s  a  hi er ar c h y  of 
si g nifi c a n c e t ests  w h er e  e a c h t est  a cts  as  a  g at e k e e p er t o 
t h e t ests  b el o w it.  
T h e  pri m ar y  a n d  k e y  s e c o n d ar y  e n d p oi nts  will  b e  ass e ss e d 
i n t h e f oll o wi n g  or d er  e nt aili n g  c o m p aris o ns  b et w e e n t h e 
Z X 0 0 8  a n d  pl a c e b o  gr o u ps  o n  
•   T h e  c h a n g e i n  M C S F fr o m  b a s eli n e.  
•   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥  4 0 % 
r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e s ei z ur e 
fr e q u e n c y. 
S e cti o n  1 0. 4. 1. 3  M ulti pli cit y  St r at e g y  a n d  T esti n g 
Hi e r a r c h y  –  C o h o rt  2  
T h e  effi c a c y  a n al ys e s  will  e m pl o y  a s eri al  g at e k e e p er 
str at e g y t o  m ai nt ai n t h e  T y p e  1  err or r at e  at  α = 0. 0 5  a cr oss 
t h e f a mil y  of  a n al ys e s t h at s u p p ort t h e  pri m ar y  a n d  k e y 
s e c o n d ar y  o bj e cti v es.  T h e str at e g y  s p e cifi e s  a  hi er ar c h y  of 
sig nifi c a n c e t ests  w h er e  e a c h t est  a cts  as  a  g at e k e e p er t o 
t h e t ests  b el o w it.  
T h e  pri m ar y  a n d  k e y  s e c o n d ar y  e n d p oi nts  will  b e  ass e ss e d 
i n t h e f oll o wi n g  or d er  e nt aili n g  c o m p aris o ns  b et w e e n t h e 
Z X 0 0 8  a n d  pl a c e b o  gr o u ps  o n  
•   T h e  c h a n g e i n  M C S F fr o m  b a s eli n e.  
•   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥  4 0 % 
r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e s ei z ur e 
fr e q u e n c y. 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 9 0  of  1 9 4  
•   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥  5 0 % 
r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e s ei z ur e 
fr e q u e n c y. 
•   T h e l o n g est  c o n v ulsi v e s ei z ur e -fr e e i nt er v al. 
 
•   T h e  pr o p orti o n  of s u bj e cts  w h o  a c hi e v e  a  ≥  5 0 % 
r e d u cti o n fr o m  b as eli n e i n  c o n v ulsi v e s ei z ur e 
fr e q u e n c y. 
•   T h e l o n g est  c o n v ulsi v e s ei z ur e -fr e e i nt er v al. 
 
S e cti o n  1 0. 5 . 2  S af et y  A n al y s es 
H e m at ol o g y  a n d  c h e mistr y l a b or at or y r es ults f or s u bj e cts 
i n  C o h ort  2  will  b e s u m m ari z e d  usi n g s hift t a bl es t h at 
t a b ul at e t h e  pr o p orti o n  of s u bj e cts  w h o  h a v e l a b r es ults 
t h at  c h a n g e fr o m  b a s eli n e.  S hift t a bl es  will  b e  pr es e nt ed 
f or  e a c h ti m e  p oi nt  w h er e l a b r es ults  ar e  c oll e ct e d b y 
d es cri pti v e st atisti c s  at  e a c h ti m e  p oi nt  a v ail a bl e.  M e a n 
c h a n g e fr o m  b as eli n e  will  als o  b e  c al c ul at e d f or 
c o nti n u o us  h e m at ol o g y  a n d  c h e mistr y r es ults  at  all ti m e 
p oi nts  a v ail a bl e.  
S e cti o n  1 0. 5 . 2  S afet y  A n al y s es  
H e m at ol o g y  a n d  c h e mistr y l a b or at or y r es ults f or s u bj e cts 
i n  C o h ort  2  will  b e s u m m ari z e d usi n g s hift t a bl es t h at 
t a b ul at e t h e  pr o p orti o n  of s u bj e cts  w h o  h a v e l a b r es ults 
t h at  c h a n g e fr o m  b a s eli n e.  S hift t a bl es  will  b e  pr es e nt e d 
f or  e a c h ti m e p oi nt  w h er e l a b r es ults  ar e  c oll e ct e d  b y 
d es c ri pti v e st atisti cs  at  e a c h ti m e  p oi nt  a v ail a bl e .  M e a n 
c h a n g e fr o m  b as eli n e  will  als o  b e  c al c ul at e d f or 
c o nti n u o us  h e m at ol o g y  a n d  c h e mistr y r es ults  at  all ti m e 
p oi nts  a v ail a bl e.  
R ati o n al e:  U p d at es t o  T a bl e  1 5,  A d v e rs e  E v e nts  of  S p e ci al I nt e r est   
O ri gi n al  T e xt  
A m e n d m e nt  T e xt  
T a bl e  1 4  A d v e rs e  E v e nts  of  S p e ci al I nt e r est  
C V/ R es pi r at o r y  
1.  
C h est  p ai n  –  a n y  p ai n i n st er n al  ar e a t h at is 
d es cri b e d f or  e x a m pl e  as  cr u s hi n g,  b ur ni n g,  s h ar p,  
st a b bi n g or  d ull.  
2.  
D ys p n e a/s h ort n ess  of  br e at h  –  a n y si g n s  of 
diffi c ult  or l a b or e d  br e at hi n g  u nr el at e d t o  a  pr e vi o u s  
m e di c al  c o n diti o n t h at  h a s  n ot  w ors e n e d.  
3.  
P ersi st e nt  c o u g h  –  l o n g er t h a n  4  w e e ks 
wit h o ut  a  c o nfir m e d i d e ntifi e d  p at h o g e n ( or  a n y  
ot h er  p ersi st e nt  c o u g h t h at t h e i n v esti g at or f e els is  
s us pi ci o us). 
T a bl e  1 4  A d v e rs e  E v e nts  of  S p e ci al I nt e r est  
C V/ R es pi r at o r y  
1.  
C h est  p ai n  –  a n y  p ai n i n st er n al  ar e a t h at is 
d es cri b e d f or  e x a m pl e  as  cr u s hi n g,  b ur ni n g, s h ar p,  
st a b bi n g or  d ull.  
2.  
D ys p n e a/s h ort n ess  of  br e at h  –  a n y si g n s  of 
diffi c ult  or l a b or e d  br e at hi n g  u nr el at e d t o  a  pr e vi o u s  
m e di c al  c o n diti o n t h at  h a s  n ot  w ors e n e d.  
3.  
P ersi st e nt  c o u g h  –  l o n g er t h a n  4  w e e ks 
wit h o ut  a  c o nfir m e d i d e ntifi e d  p at h o g e n ( or  a n y  
ot h er  p ersi st e nt  c o u g h t h at t h e  i n v esti g at or f e els is 
s us pi ci o us). 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 9 1  of  1 9 4  
4.  
I n cr e as e i n  bl o o d  pr e ss ur e  > 3 0 % fr o m 
S cr e e ni n g  bl o o d  pr e ss ur e  or s yst oli c  pr ess ur e  ≥ 1 4 0  
m m H g  or  di a st oli c  pr e ss ur e  ≥ 9 0 m m H g  aft er  
r e p e at e d  m e as ur es  d uri n g  o n e  visit ( O nl y if t h e 
r e p e at  m e a s ur es i n tri pli c at e  c o nfir m t h e fi n di n g,  a n d 
i n t h e I n v esti g at or’s  o pi ni o n t h e fi n di n g i s  n ot  d u e t o 
t h e s u bj e ct’s  a git ati o n  of  n o n-c o o p er ati o n, s h o ul d 
t his  b e r e p ort e d  as  a n  A E SI).  Bl o o d  pr es s ur e s h o ul d 
b e r e p e at e d  at  a p pr o pri at e ti m es  wit hi n t h e  vi sit.  
5.  
N e w  o ns et  h e art  m ur m ur  
6.  
T a c h y c ar di a  –  a  p ersist e nt  H R  > 3 0 % 
a b o v e t h e s cr e e ni n g  v al u e  a n d  u nr el at e d t o 
e x er cis e,  e x erti o n  or  a n xi et y.  ( O nl y if t h e r e p e at 
m e as ur es i n tri pli c at e  c o nfir m t h e fi n di n g,  a n d i n 
t h e I n v esti g at or’s  o pi ni o n t h e fi n di n g is  n ot  d u e t o 
t h e s u bj e ct’s  a git ati o n  of  n o n-c o o p er ati o n, s h o ul d 
t his  b e r e p ort e d  as  a n  A E SI).  H e art r at e s h o ul d  b e 
r e p e at e d  at  a p pr o pri at e ti m es  wit hi n t h e visit.  
7.  
Br a d y c ar di a  –  a  p ersi st e nt  H R  < 5 0 
b p m.  ( O nl y if t h e r e p e at  m e as ur es i n  tri pli c at e 
c o nfir m t h e fi n di n g,  a n d i n t h e I n v esti g at or’s 
o pi ni o n t h e fi n di n g is  n ot  d u e t o t h e s u bj e ct’s 
a git ati o n  of  n o n -c o o p er ati o n, s h o ul d t his  b e 
r e p ort e d  as  a n  A E SI) H e art r at e s h o ul d  b e 
r e p e at e d  at  a p pr o pri at e ti m es  wit hi n t h e visit.  
8.  
Si g n s t h at  c o ul d i n di c at e ri g ht  v e ntri c ul ar  f ail ur e: 
  
P eri p h er al  e d e m a  
  
As cit e s  
  
S y n c o p e  
  
D e c o m p e ns at e d ri g ht 
v e ntri c ul ar f ail ur e  –  
s y m pt o m s i n cl u d e s h ort n ess 
of  br e at h, fr e q u e nt  c o u g hi n g 
es p e ci all y  w h e n l yi n g fl at, 
a b d o mi n al s w elli n g  a n d 
p ai n,  di z zi n ess, f ai nti n g,  a n d 
f ati g u e 
4.  
I n cr e as e i n  bl o o d  pr e ss ur e  > 3 0 % fr o m 
S cr e e ni n g  bl o o d  pr e ss ur e  or s yst oli c  pr ess ur e  ≥ 1 4 0  
m m H g  or  di a st oli c  pr e ss ur e  ≥ 9 0 m m H g  aft er  r e p e at e d 
m e as ur es  d uri n g  o n e  vi sit ( O nl y if t h e r e p e at 
m e as ur es i n tri pli c at e  c o nfir m t h e fi n di n g,  a n d i n t h e 
I n v esti g at or’s  o pi ni o n t h e fi n di n g is  n ot  d u e t o t h e 
s u bj e ct’s  a git ati o n  of  n o n -c o o p er ati o n, s h o ul d t his  b e 
r e p ort e d  as  a n  A E SI).  Bl o o d  pr ess ur e s h o ul d  b e 
r e p e at e d  at  a p pr o pri at e ti m es  wit hi n t h e  visit. 
5.  
N e w  o ns et  h e art  m ur m ur  
6.  
T a c h y c ar di a  –  a  p ersist e nt  H R  > 3 0 % 
a b o v e t h e s cr e e ni n g  v al u e  a n d  u nr el at e d t o 
e x er cis e,  e x erti o n  or  a n xi et y.  ( O nl y if t h e r e p e at 
m e as ur es i n tri pli c at e  c o nfir m t h e fi n di n g,  a n d i n 
t h e I n v esti g at or’s  o pi ni o n t h e fi n di n g is  n ot  d u e t o 
t h e s u bj e ct’s  a git ati on  of  n o n -c o o p er ati o n, s h o ul d 
t his  b e r e p ort e d  as  a n  A E SI).  H e art r at e s h o ul d  b e 
r e p e at e d  at  a p pr o pri at e ti m es  wit hi n t h e visit.  
7.  
Br a d y c ar di a  –  a  p ersi st e nt  H R  < 5 0 
b p m.  ( O nl y if t h e r e p e at  m e as ur es i n tri pli c at e 
c o nfir m t h e fi n di n g,  a n d i n t h e I n v esti g a t or’s 
o pi ni o n t h e fi n di n g is  n ot  d u e t o t h e s u bj e ct’s 
a git ati o n  of  n o n -c o o p er ati o n, s h o ul d t his  b e 
r e p ort e d  as  a n  A E SI) H e art r at e s h o ul d  b e r e p e at e d 
at  a p pr o pri at e ti m es  wit hi n t h e  visit.  
8.  
Si g n s t h at  c o ul d i n di c at e ri g ht  v e ntri c ul ar  f ail ur e: 
  
P eri p h er al  e d e m a  
  
As cit e s  
  
S y n c o p e  
  
D e c o m p e ns at e d ri g ht 
v e ntri c ul ar f ail ur e  –  
s y m pt o m s i n cl u d e s h ort n ess 
of  br e at h, fr e q u e nt  c o u g hi n g 
es p e ci all y  w h e n l yi n g fl at, 
a b d o mi n al s w elli n g  a n d 
p ai n,  di z zi n ess, f ai nti n g,  a n d 
f ati g u e 


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 9 2  of  1 9 4  
9.   Si g n s  o n  E C H O i n di c ati v e  of  p ot e nti al  v al v ul o p at h y 
(≤1 8  y e ars  of  a g e)  
  
V al v e r e g ur git ati o n ( a orti c  or  mitr al)  
  
M o d er at e  or s e v er e v al v e r e g ur git ati o n 
(tri c us pi d  or p ul m o n ar y)  
  
M e a n  Mitr al  v al v e  gr a di e nt  ≥  4  m m H g  
  
M e a n  A orti c  v al v e  gr a di e nt  ≥  1 5  m m H g  
  
M e a n  Tri c us pi d  v al v e  gr a di e nt  ≥  4  m m H g  
  P e a k  P ul m o n ar y  v al v e  gr a di e nt  ≥  2 1  m m H g  
1 0.   Si g ns  o n  E C H O i n di c ati v e  of  p ot e nti al  
v al v ul o p at h y ( > 1 8  y e ars  of  a g e)  
  
Mil d  or  gr e at er s e v erit y  v al v e r e g ur git ati o n 
( a orti c  or mitr al ) 
  
M o d er at e  or s e v er e v al v e  r e g ur git ati o n 
(tri c us pi d  or p ul m o n ar y)  
  
M e a n  Di at oli c  Mitr al  v al v e  gr a di e nt  ≥  4  
m m H g  
  
M e a n  S yst oli c  A orti c  v al v e  gr a di e nt  ≥  1 5  
m m H g  
  
M e a n  Di ast oli c  Tri c us pi d  v al v e  gr a di e nt  ≥  4  
m m H g  
  
P e a k  S y st oli c  P ul m o n ar y  v al v e  gr a di e nt  ≥  2 1 
m m H g  
1 1.   Si g ns  o n  E C H O  i n di c ati v e  of  p ul m o n ar y 
h y p ert e nsi o n ( ≤1 8  y e ars  of  a g e)  
a.  Tri c us pi d  R e g ur git ati o n J et  v el o cit y  >  2. 8  m/ s 
wit h  or  wit h o ut t h e f oll o wi n g fi n di n gs,  O R  
b.  O n e  of t h e f oll o wi n g fi n di n gs i n t h e 
a bs e n c e  of  b ei n g  a bl e t o  m e as ur e 
Tri c us pi d  R e g ur git ati o n J et  v el o cit y:  
i.C h a n g e i n ri g ht  v e ntri cl e/l eft  v e ntri cl e  b as al 
di a m et er r ati o  >  1. 0  
ii. Ri g ht  v e ntri c ul ar  a c c el er ati o n ti m e  <  1 0 0  
ms e c  
9.   Si g n s  o n  E C H O i n di c ati v e  of  p ot e nti al  v al v ul o p at h y 
(≤1 8  y e ars  of  a g e)  
  
V al v e r e g ur git ati o n ( a orti c  or  mitr al)  
  
M o d er at e  or s e v er e v al v e r e g ur git ati o n 
(tri c us pi d  or p ul m o n ar y)  
  
M e a n  Mitr al  v al v e  gr a di e nt  ≥  4  m m H g  
  
M e a n  A orti c  v al v e  gr a di e nt  ≥  1 5  m m H g  
  
M e a n  Tri c us pi d  v al v e  gr a di e nt  ≥  4  m m H g  
  P e a k  P ul m o n ar y  v al v e  gr a di e nt  ≥  2 1  m m H g  
1 0 .   Si g ns  o n  E C H O i n di c ati v e  of  p ot e nti al v al v ul o p at h y 
( > 1 8  y e ars  of  a g e) 
  
Mil d  or  gr e at er s e v erit y  v al v e r e g ur git ati o n 
( a orti c  or mitr al ) 
  
M o d er at e  or s e v er e v al v e r e g ur git ati o n 
(tri c us pi d  or p ul m o n ar y)  
  
M e a n  Di at oli c  Mitr al  v al v e  gr a di e nt  ≥  4  
m m H g  
  
M e a n  S yst oli c  A orti c  v al v e  gr a di e nt  ≥  1 5  
m m H g  
  
M e a n  Di ast oli c  Tri c us pi d  v al v e  gr a di e nt  ≥  4  
m m H g  
  
P e a k  S y st oli c  P ul m o n ar y  v al v e  gr a di e nt  ≥  2 1 
m m H g  
1 1 .   Si g ns  o n  E C H O i n di c ati v e  of  p ul m o n ar y 
h y p ert e nsi o n ( ≤1 8  y e ars  of  a g e)  
a.  Tri c us pi d  R e g ur git ati o n J et  v el o cit y  >  2. 8  m/ s 
wit h  or  wit h o ut t h e f oll o wi n g fi n di n gs,  O R  
b.  O n e  of t h e f oll o wi n g fi n di n gs i n t h e 
a bs e n c e  of  b ei n g  a bl e t o  m e as ur e 
Tri c us pi d  R e g ur git ati o n J et  v el o cit y:  
i. C h a n g e i n ri g ht  v e ntri cl e/l eft  v e ntri cl e 
b as al  di a m et er r a ti o  > 1. 0  
ii. Ri g ht  v e ntri c ul ar  a c c el er ati o n ti m e  <  1 0 0  
ms e c  


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 9 3  of  1 9 4  
iii. Dil at ati o n  of t h e i nf eri or  v e n a  c a v a 
( di a m et er > 2 1  m m  a n d  < 5 0 % i ns pir at or y 
d e cr e as e)  a n d/ or ri g ht  atri u m  
i v. 
C h a n g e i n t h e  g e o m etr y  of t h e 
i nt er v e ntri c ul ar s e pt u m i n s y st ol e 
(fl att e ni n g)  wit h l eft  v e ntri c ul ar 
e c c e ntri cit y i n d e x  > 1. 1 i n s yst ol e  a n d/ or 
i n di ast ol e  
v.  E arl y  di a st oli c  p ul m o n ar y r e g ur git ati o n 
v el o cit y  >  2. 2  m/s  
vi.  Tri c us pi d  A n n ul ar  Pl a n e  S yst oli c 
E x c ursi o n  b el o w  1 8  m m  or  b el o w  Z -s c or e 
–  2  
1 2.   Si g ns  o n  E C H O i n di c ati v e  of  p ul m o n ar y  
h y p ert e nsi o n ( > 1 8  y e ars  of  a g e)  
a.  Tri c us pi d  R e g ur git ati o n J et  v el o cit y  >  2. 8 
m/s  wit h  or  wit h o ut t h e f oll o wi n g 
fi n di n gs, O R  
b.  O n e  of t h e f oll o wi n g fi n di n gs i n t h e 
a bs e n c e  of  b ei n g  a bl e t o  m e as ur e 
Tri c us pi d  R e g ur git ati o n J et  v el o cit y:  
vii.  C h a n g e i n ri g ht  v e ntri cl e/l eft  v e ntri cl e 
b as al  di a m et er r ati o  >  1. 0  
viii.  Ri g ht  v e ntri c ul ar  o utfl o w tr a ct fl o w  
a c c el er ati o n ti m e  <  1 0 0  m s e c  
i x. Dil at ati o n  of t h e i nf eri or  v e n a  c a v a 
( di a m et er > 2 1  m m  a n d  < 5 0 % 
i ns pir at or y  c oll a ps e)  a n d/ or ri g ht  atri al 
dil at ati o n  
x.  C h a n g e i n t h e  g e o m etr y  of t h e 
i nt er v e ntri c ul ar s e pt u m i n s y st ol e 
(fl att e ni n g)  wit h l eft  v e ntri c ul ar 
e c c e ntri cit y i n d e x  > 1. 1 i n s yst ol e 
a n d/ or i n  di ast ol e  
xi.  E arl y  di a st oli c  p ul m o n ar y r e g ur git ati o n 
fl o w  v el o cit y  >  2. 2 m/s  
xii.  Tri c us pi d  A n n u l ar  Pl a n e  S yst oli c 
E x c ursi o n  b el o w  1 8  m m  
 
iii. Dil at ati o n  of t h e i nf eri or  v e n a  c a v a 
( di a m et er > 2 1  m m  a n d  < 5 0 % 
i ns pir at or y  d e cr e as e)  a n d/ or ri g ht 
atri u m  
i v. C h a n g e i n t h e  g e o m etr y  of t h e 
i nt er v e ntri c ul ar s e pt u m i n s y st ol e 
(fl att e ni n g)  wit h l eft v e ntri c ul ar 
e c c e ntri cit y i n d e x  > 1. 1 i n s yst ol e 
a n d/ or i n  di ast ol e  
v.  E arl y  di a st oli c  p ul m o n ar y r e g ur git ati o n 
v el o cit y  >  2. 2  m/s  
vi.  Tri c us pi d  A n n ul ar  Pl a n e  S yst oli c 
E x c ursi o n  b el o w  1 8  m m  or  b el o w  Z -s c or e 
–  2  
1 2 .   Si g ns  o n  E C H O i n di c ati v e  of  p ul m o n ar y 
h y p ert e nsi o n ( > 1 8  y e ars  of  a g e)  
c.  Tri c us pi d  R e g ur git ati o n J et  v el o cit y  >  2. 8 
m/s  wit h  or  wit h o ut t h e f oll o wi n g fi n di n gs,  
O R  
d.  O n e  of t h e f oll o wi n g fi n di n gs i n t h e 
a bs e n c e  of  b ei n g  a bl e t o  m e as ur e 
Tri c us pi d  R e g ur git ati o n J et  v el o cit y:  
vii.  C h a n g e i n ri g ht  v e ntri cl e/ l eft  v e ntri cl e 
b as al  di a m et er r ati o  >  1. 0  
viii.  Ri g ht  v e ntri c ul ar  o utfl o w tr a ct fl o w  
a c c el er ati o n ti m e  <  1 0 0  m s e c  
i x. Dil at ati o n  of t h e i nf eri or  v e n a  c a v a 
( di a m et er > 2 1  m m  a n d  < 5 0 % 
i ns pir at or y  c oll a ps e)  a n d/ or ri g ht  atri al 
dil at ati o n  
x.  C h a n g e i n t h e  g e o m etr y  of t h e 
i nt er v e ntri c ul ar s e pt u m i n s y st ol e 
(fl att e ni n g)  wit h l eft  v e ntri c ul ar 
e c c e ntri cit y i n d e x  > 1. 1 i n s yst ol e 
a n d/ or i n  di ast ol e  
xi.  E arl y  di a st oli c  p ul m o n ar y r e g ur git ati o n 
fl o w  v el o cit y  >  2. 2 m/s  
xii.  Tri c us pi d  A n n ul ar  Pl a n e  S yst oli c 
E x c ursi o n  b el o w  1 8  m m   


Z o g e ni x  I nt er n ati o n al  Li mit e d  
Z X 0 0 8,  F e nfl ur a mi n e  H y dr o c hl ori d e  
Z X 0 0 8 -1 5 0 4  Cli ni c al  St u d y  Pr ot o c ol  A m e n d m e nt  3. 3 ( U S/ C A N)  2  F e br u a r y  2 0 1 8  
C o nfi d e nti al  
P a g e  1 9 4  of  1 9 4  
M et a b oli c/ E n d o c ri n e  
1.  
El e v at e d  pr ol a cti n l e v el  ≥ 2 x  a b o v e t h e  u p p er 
li mit  of  n or m al ( U L N) 
2.  
G al a ct orr h e a  
3.  
G y n e c o m asti a  
4.  
I n cr e as e i n f asti n g s er u m  bl o o d  gl u c os e  ≥ 2 x 
U L N  
5.  
H y p o gl y c e mi a  –  < 3. 0  m m ol/l  or  5 4  m g/ dl, 
w h et h er t h at l e v el is  ass o ci at e d  wit h s y m pt o ms  or  n ot   
N e u r o ps y c hi at ri c  
1.  S er ot o ni n  s y n dr o m e ( At l e ast  3  of f oll o wi n g 
s y m pt o m s  m ust  b e  pr es e nt:  A git ati o n,  
r estl es s n es s, c o nf u si o n,  b ot h i n cr e as e d  H R 
a n d  bl o o d  pr es s ur e,  dil at e d  p u pils,  m us cl e 
t wit c hi n g,  m us cl e ri gi dit y,  h y p er hi dr osi s, 
di arr h e a,  h e a d a c h e, s hi v eri n g, tr e m ors,  b ot h 
n a us e a  a n d  v o miti n g)  
2.  H all u ci n ati o n s  
3.  Ps y c h o sis  
4.  E u p h ori a  
5.  M o o d  dis or d ers:  d e pr essi o n  a n d  a n xi et y if 
t h e y ris e t o  a l e v el  of  a  di s or d er 
6.  
S ui ci d al t h o u g hts, i d e ati o n  or  g est ur es  
G e nit o u ri n a r y  
1.  Pri a pis m  
 
 
M et a b oli c/ E n d o c ri n e  
1.  
El e v at e d  pr ol a cti n l e v el  ≥ 2 x  a b o v e t h e  u p p er 
li mit  of  n or m al ( U L N) 
2.  
G al a ct orr h e a  
3.  
G y n e c o m asti a  
4.  
I n cr e as e i n f asti n g s er u m  bl o o d  gl u c os e  ≥ 2 x 
U L N  
5  2 . 
H y p o gl y c e mi a  –  < 3. 0  m m ol/l  or  5 4  m g/ dl, 
w h et h er t h at l e v el is  ass o ci at e d  wit h s y m pt o ms  or  n ot   
N e u r o ps y c hi at ri c  
1.  S er ot o ni n  s y n dr o m e ( At l e ast  3  of f oll o wi n g 
s y m pt o m s  m ust  b e  pr es e nt:  A git ati o n,  
r estl es s n es s, c o nf u si o n,  b ot h i n cr e as e d  H R  a n d 
bl o o d  pr e ss ur e,  dil at e d  p u pil s,  m u s cl e t wit c hi n g, 
m u s cl e ri gi dit y,  h y p er hi dr o sis,  di arr h e a, 
h e a d a c h e, s hi v eri n g, tr e m ors,  b ot h  n a us e a  a n d  
v o miti n g)  
2.  H all u ci n ati o n s  
3.  Ps y c h o sis  
4.  E u p h ori a  
5.  
M o o d  dis or d ers:  d e pr essi o n  a n d  a n xi et y if 
t h e y ris e t o  a l e v el  of  a  di s or d er 
6.  
S ui ci d al t h o u g hts, i d e ati o n  or  g est ur es  
G e nit o u ri n a r y  
1.  Pri a pis m  
 
 

SAP_001.pdf: 
Zogenix International Limited 
ZX008-1504 Cohort 2 
ZX008 
Final Clinical Study Report 
Confidential 
21 December 2018 
Page 1 of 61 
16.1.9 
Documentation of Statistical Methods 
The documents listed below are provided on the following pages: 
Statistical Analysis Plan – Cohort 2 (Protocol No: ZX008-1504) dated 25 June 2018 


CONFIDENTIAL
Final: 25 June 2018
STATISTICAL ANALYSIS PLAN – COHORT 2
Zogenix International Limited
ZX008-1504
Page 1
STATISTICAL ANALYSIS PLAN
Zogenix International Limited 
A subsidiary of Zogenix, Inc. 
5858 Horton Street, Suite 455
Emeryville, CA 94608 USA
A Multicenter, 2-Cohort Trial to First Assess the Pharmacokinetic and 
Safety Profile of a Single Dose of ZX008 (Fenfluramine Hydrochloride) 
Oral Solution When Added to Standard of Care (Cohort 1), Followed 
by a Randomized, Double-blind, Placebo-controlled Parallel Group 
Evaluation of the Efficacy, Safety, and Tolerability of ZX008 as 
Adjunctive Antiepileptic Therapy to Stiripentol Treatment in Children
and Young Adults with Dravet Syndrome (Cohort 2)
Protocol No: ZX008-1504
Prepared by:
Francis Ruvuna
and Revised by:
Gosford A. Sawyerr 
and Revised by:
Darren Hughes
inVentiv Health Clinical
This document contains confidential information of Zogenix International Limited.  Any viewing or disclosure 
of such information that is not authorized in writing by Zogenix International Limited is strictly prohibited.  
Such information may be used solely for the purpose of reviewing or performing this study.
prohibited. 
dy.
3DJHRI


3DJHRI


3DJHRI


CONFIDENTIAL
Final: 25 June 2018
STATISTICAL ANALYSIS PLAN – COHORT 2
Zogenix International Limited
ZX008-1504
Page 3
REVISION HISTORY
Statistical Analysis Plan DRAFT 1.0 Sanjay Mitter based on 8 February 2016 version (Protocol Amendment 
2.0)  
Statistical Analysis Plan DRAFT 2.0 Francis Ruvuna based on 29 December 2016 version (Protocol 
Amendment 2.3, Version 3.0)  
Statistical Analysis Plan DRAFT 2.1 Gosford Sawyerr, based on 20 February 2017 version (Protocol 
Amendment 2.5)
Statistical Analysis Plan DRAFT 2.2 Darren Hughes, based on 10 July 2017 version (Protocol Amendment 
2.5)  
3DJHRI


CONFIDENTIAL
Final: 25 June 2018
STATISTICAL ANALYSIS PLAN – COHORT 2
Zogenix International Limited
ZX008-1504
Page 4
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.................................................................... 6
1. 
INTRODUCTION............................................................................................................................. 8
2. 
STUDY OBJECTIVES..................................................................................................................... 8
2.1 
Primary Objective............................................................................................................................ 8
2.2 
Key Secondary Objectives............................................................................................................... 8
2.3 
Additional Secondary Objectives .................................................................................................... 9
2.4
Safety Objective .............................................................................................................................. 9
2.5 
Pharmacokinetic Objective............................................................................................................10
2.6 
Exploratory Objectives..................................................................................................................10
3. 
STUDY DESIGN............................................................................................................................11
3.1 
Overall Study Design and Plan......................................................................................................11
3.2 
Cohort 2 Study Treatment .............................................................................................................11
3.2.1
Treatment Arms (Cohort 2) ...............................................................................................11
3.2.2 
Treatment Periods (Cohort 2) ............................................................................................12
4. 
SCHEDULE OF ASSESSMENTS ................................................................................................. 15
5. 
ANALYSIS POPULATIONS.........................................................................................................18
5.1 
Cohort 2.........................................................................................................................................18
5.1.1 
Enrolled Population ...........................................................................................................18
5.1.2
Intention-to-Treat (Randomized) Population.....................................................................18
5.1.3 
Modified Intention-to-Treat (mITT) Population................................................................18
5.1.4 
Per Protocol (PP) Population.............................................................................................18
5.1.5 
Safety Population...............................................................................................................18
6. 
STATISTICAL METHODOLOGY................................................................................................19
6.1 
Statistical and Analytical Issues .................................................................................................... 19
6.1.1
Statistical Methods.............................................................................................................19
6.1.2 
Multiplicity Strategy and Testing Hierarchy .....................................................................19
6.1.3 
Subgroups..........................................................................................................................20
6.1.4 
Baseline Definition ............................................................................................................20
6.1.5 
Other Definitions ...............................................................................................................20
6.1.6 
Visit Windows ...................................................................................................................20
6.1.7
Handling of Dropouts and Missing Data ...........................................................................21
6.1.8 
Conversion of time interval ...............................................................................................23
6.1.9 
Pooling of Investigative Sites and Interaction of treatment by Site...................................23
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6.1.10 
Determination of Sample Size .......................................................................................23
6.2 
Subject Characteristics ..................................................................................................................24
6.2.1 
Disposition.........................................................................................................................24
6.2.2 
Protocol Deviations ...........................................................................................................24
6.2.3 
Demographics and Baseline Characteristics......................................................................25
6.2.4 
Treatment Exposure and Compliance................................................................................25
6.2.5 
Prior and Concomitant Medications and Therapies...........................................................26
6.2.6 
Prior and Concomitant Antiepileptic Treatment................................................................27
6.2.7 
Medical History .................................................................................................................27
6.3 
Efficacy Analyses..........................................................................................................................27
6.3.1 
Primary Efficacy Analysis................................................................................................. 28
6.3.2 
Key Secondary Analyses ...................................................................................................30
6.3.3 
Additional Secondary Endpoint Analyses .........................................................................32
6.3.4 
Exploratory Analyses.........................................................................................................40
6.4 
Safety Analyses .............................................................................................................................42
6.4.1 
Adverse Events..................................................................................................................42
6.4.2 
Adverse Events of Special Interest (AESI)........................................................................44
6.4.3 
Physical Examination ........................................................................................................44
6.4.4 
Neurological Examination................................................................................................. 45
6.4.5 
Vital Signs, Weight, and BMI ...........................................................................................45
6.4.6 
Electrocardiogram..............................................................................................................45
6.4.7 
Doppler Echocardiography................................................................................................45
6.4.8 
Tanner Staging...................................................................................................................46
6.4.9 
Laboratory Parameters.......................................................................................................47
6.4.10 
Columbia-Suicide Severity Rating Scale.......................................................................48
6.4.11 
Brief Rating Inventory of Executive Function (BRIEF)................................................49
6.5 
Pharmacokinetics  (PK/PD) Analysis............................................................................................49
6.6 
Analysis of Other Assessments .....................................................................................................50
6.7 
Interim Analysis ............................................................................................................................50
6.8 
Independent Data and Safety Monitoring Committee ...................................................................50
6.9 
Changes to Methods Planned in the Protocol ................................................................................50
7. 
REFERENCES................................................................................................................................51
8. 
APPENDICES ................................................................................................................................52
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ABBREVATION
DEFINITION
AE
Adverse Event
AED
Antiepileptic Drug
AESI
Adverse Event of Special Interest
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Chemical
BID
bis in die; two times per day
BMI
Body Mass Index
BRIEF
Behavior Rating Inventory for Executive Function
C-SSRS
Columbia-Suicide Severity Rating Scale
CBD
Cannabidiol
CDISC
Clinical Data Interchange Standards Consortium
CGI
Clinical Global Impression
CRU
Clinical Research Unit
DS
Dravet syndrome
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
electronic Case Report Form
EOS
End of study
EPAR
European Public Assessment Report
EQ-5D-5L
Standardized measure of health status
ET
Early Termination
FAS
Full Analysis Set
HR
Heart Rate
IDSMC
Independent Data and Safety Monitoring Committee
IMP
Investigational Medicinal Product
IPCAB
International Pediatric Cardiology Advisory Board
IR
Incidence rate
IVR
Interactive Voice Randomization
IWR
Interactive Web Response (System)
Kg
Kilogram
Kg/ m2
Kilogram per meter square
MCSF
Mean Convulsive Seizure Frequency
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mg/kg/day
milligram per kilogram per day
min
Minutes
mITT
modified Intent-to-Treat
mL
Milliliter
MMRM
Mixed Effects Model for Repeated Measures
msec
Millisecond
PedsQL
Pediatric Quality of Life Inventory
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STATISTICAL ANALYSIS PLAN – COHORT 2
Zogenix International Limited
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ABBREVATION
DEFINITION
PD
Pharmacodynamics
PK
Pharmacokinetics
PP
Per Protocol
QoL
Quality of Life
QOLCE
Quality of Life in Childhood Epilepsy
QTcF
corrected QT interval using Fredericia method
SAE
Serious Adverse Event
SAF
Safety Population
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SMEI
Severe Myoclonic Epilepsy Of Infancy
SOC
System Organ Class
T+M
Titration plus Maintenance Periods
TEAE
Treatment Emergent Adverse Event
THC
Tetrahydrocannabinol
TSH
Thyroid Stimulating Hormone
WHO-DD
World Health Organization Drug Dictionary
ZX008
Fenfluramine Hydrochloride Oral Solution
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STATISTICAL ANALYSIS PLAN – COHORT 2
Zogenix International Limited
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1. INTRODUCTION
ZX008 (fenfluramine hydrochloride) is under clinical development for the adjunctive treatment of 
patients with Dravet syndrome (DS).  DS, also known as severe myoclonic epilepsy of infancy (SMEI), is 
a rare and severe form of epilepsy first described by Charlotte Dravet in 1978 (Dravet 1978). The 
condition most commonly appears during the first year of life as frequent febrile seizures. As the 
condition progresses, other types of seizures typically occur, including myoclonic seizures and status 
epilepticus (Dravet 1978). Following the appearance of these seizures, affected children develop several 
co-morbid conditions including psychomotor regression, ataxia, sleep disturbance, and cognitive 
impairment. Intellectual impairment begins to become apparent around age 2 years due to lack of 
intellectual/behavioral progression. Dravet children often have a lack of coordination, poor development 
of language, hyperactivity, and difficulty relating to others (Dravet 1978; Hurst 1990).  DS is a highly 
treatment-resistant and refractory epilepsy syndrome.  The vast majority of patients who survive to 
adulthood are wholly dependent on around-the-clock caregivers and eventually live in institutional care 
homes. To date, only one treatment, Diacomit® (stiripentol) is approved, and only in Europe and Canada, 
as adjunctive therapy in patients with SMEI (Dravet syndrome), and must be co-administered with 
clobazam and valproate.
Zogenix has developed a new formulation of fenfluramine hydrochloride, ZX008, for the adjunctive 
treatment of DS.  This study is two cohort study designed to assess the Pharmacokinetic and Safety 
Profile of Single Dose of ZX008 (Cohort 1), followed by a randomized, double-blind placebo-controlled 
Cohort 2 to assess the efficacy and safety of ZX008 compared to placebo in a cohort of patients taking 
stiripentol as one of their background AEDs. This statistical analysis plan presents a detailed plan of 
analyses of the Cohort 2 part of the study. Cohort 2 is designed to formally evaluate and provide evidence 
of the efficacy and safety of ZX008 versus Placebo.   
2. STUDY OBJECTIVES 
2.1 PRIMARY OBJECTIVE
The primary efficacy objective of this multicenter two-cohort study is related to the double-blind, 
placebo-controlled part of the study (Cohort 2): 
x
To demonstrate that ZX008 is superior to placebo as adjunctive therapy in the treatment of 
symptoms of Dravet syndrome in children and young adults based on change in the frequency of 
convulsive seizures between baseline and the combined Titration and Maintenance Periods (T + 
M) in Cohort 2. 
2.2 KEY SECONDARY OBJECTIVES
The key secondary efficacy objectives of the study are related to the double-blind, placebo-controlled part 
of the study (Cohort 2), to demonstrate that ZX008 is superior to placebo on the following endpoints:
x
7KHSURSRUWLRQRIVXEMHFWVZKRDFKLHYHD% reduction from baseline in convulsive seizure 
frequency.
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STATISTICAL ANALYSIS PLAN – COHORT 2
Zogenix International Limited
ZX008-1504
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x
The longest convulsive seizure-free interval. 
2.3 ADDITIONAL SECONDARY OBJECTIVES
Additional secondary efficacy objectives of the study (Cohort 2) are to demonstrate that ZX008 is 
superior to placebo on the following endpoints: 
x
The number of convulsive seizure-free days.
x
The proportion of subjects who achieve a RUUHGXFWLRQIURPEDVHOLQHLQFRQYXOVLYH
seizure frequency. 
x
The change from baseline in non-convulsive seizure frequency.
x
The change from baseline in convulsive + non-convulsive seizure frequency.
x
The incidence of rescue medication usage.
x
The incidence of hospitalization to treat seizures.
x
The incidence of status epilepticus (SE).
x
Clinical Global Impression – Improvement (CGI-I) rating, as assessed by the principal 
investigator 
x
Clinical Global Impression – Improvement (CGI-I) rating, as assessed by the parent/caregiver 
x
The change from baseline in health related quality of life (HRQOL) measured using the Pediatric 
Quality of Life Inventory™ (PedsQL) Generic Core Scale.
x
Change from baseline in subjects’ Quality of Life measured using the Quality of Life in 
Childhood Epilepsy (QOLCE). 
x
The change from baseline in the HRQOL of the parent/caregiver using the standardized measure 
of health status (EQ-5D-5L) scale. 
x
The change from baseline on the impact of condition of parents and the family using the PedsQL 
family impact module.
2.4 SAFETY OBJECTIVE
The safety objectives of the study are:
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CONFIDENTIAL
Final: 25 June 2018
STATISTICAL ANALYSIS PLAN – COHORT 2
Zogenix International Limited
ZX008-1504
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x
To evaluate the safety and tolerability of ZX008 administered as a single oral dose when added to 
standard of care treatment for Dravet syndrome (CLB + VPA; CLB + VPA + STP)  (Cohort 1).
x
To compare the safety and tolerability of ZX008 to placebo with regard to adverse events (AEs), 
laboratory parameters, physical examination, neurological examination, vital signs (blood 
pressure, heart rate, temperature, and respiratory rate), electrocardiograms (ECGs), 
echocardiograms (ECHOs), and body weight, and assessment of cognitive function (Cohort 2). 
Cognitive Function will be assessed using the age-appropriate versions of the BRIEF. 
2.5 PHARMACOKINETIC OBJECTIVE
The pharmacokinetic (PK) objectives of the study:
x
To assess the PK profile of ZX008 administered as a single oral dose with clobazam (CLB) + 
valproate (VPA) or with CLB + VPA + stiripentol (STP) in subjects ages 2-18 years of age with 
Dravet syndrome (Cohort 1).  
x
Model PK of ZX008 in single and multiple dose regimens using fenfluramine/nor-fenfluramine 
concentration-time data from subjects in Cohorts 1 and 2. 
o
A separate analysis plan will be developed to address Cohort 1 results. 
2.6 EXPLORATORY OBJECTIVES
Exploratory objectives of this study (Cohort 2) include:
x
The change from baseline in health and social care resource use including planned and unplanned 
hospital visits, use of ambulances, general practitioner (GP) visits, speech and language therapy 
utilization, occupational and physical therapy utilization.  
x
Change from baseline in sleep quality. 
x
Change from baseline in meal time behavior. 
x
Effect of study medication on sleepiness (Karolinska Sleepiness Scale). 
x
Assessment of a Dravet syndrome composite endpoint including seizure frequency and severity 
and subjective patient-relevant outcome measures (e.g., behavior, sleepiness, etc) using data from 
the collected rating scales will be performed.
o
A separate analysis plan will be developed to explore this endpoint.
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STATISTICAL ANALYSIS PLAN – COHORT 2
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3. STUDY DESIGN
3.1 OVERALL STUDY DESIGN AND PLAN
This is a multicenter, two-cohort trial to assess the pharmacokinetic and safety profile of a single dose of 
ZX008 (fenfluramine hydrochloride) oral solution when added to Dravet syndrome treatment regimen 
containing VPA and CLB, with or without STP (Cohort 1), followed by a randomized, double-blind, 
placebo-controlled parallel group evaluation of the efficacy, safety, and tolerability of ZX008 as 
adjunctive therapy for seizures in children and young adults with Dravet syndrome (Cohort 2). PK and 
safety data from Cohort 1 from 13 subjects together with data from Study ZX008-1505 (healthy volunteer 
drug-drug interaction study) informed the dose of ZX008 0.5 mg/kg/day, maximum 20 mg/day, to be 
used in Cohort 2. Approximately 2-3 sites in France and the Netherlands were involved in the 
pharmacokinetic portion of the trial (Cohort 1). Up to 30 study sites in Canada, France, Germany, 
Netherlands, United Kingdom, Spain and United States will enroll participants for Cohort 2. Details of 
Cohort 1 Study Design will be presented in a separate analysis plan.
3.2 COHORT 2 STUDY TREATMENT
The study period of cohort 2 subjects comprises a Baseline period (6 weeks), a T+M period (15 weeks:
(21 days for dose titration + 12 weeks maintenance), a Taper period or transition period, and a Post 
Dosing visit after study completion or early termination. 
Upon completion of the Baseline Period, subjects who qualify for the study will be randomized (1:1) in a 
double-blind manner to receive ZX008 (0.5 mg/kg/day, 20 mg/day maximum) or placebo. Randomization 
ZLOOEHVWUDWLILHGE\DJHJURXS\HDUV\HDUVWRHQVXUHEDODQFHDFURVVWUHDWPHQWDUPVDQGLQLWLDOO\LW
was hoped that at least 40% of subjects will be in each age group. The actual % of subjects in each 
stratum may be different from this goal. Subjects will be assigned a randomization number by the 
IVR/IWR system upon confirmation that the subject qualifies for enrollment in the Titration Period. All 
subjects will be titrated to their randomized dose during the Titration Period. Titration will occur in 3
steps starting with a 0.2 mg/kg/day dose of ZX008 (or placebo equivalent) on Study Days 1-7, increased 
to a dose of 0.4 mg/kg/day on Study Day 8-14, and then increased to a dose of 0.5 mg/kg/day on Study 
Days 15-21; the maximum daily dose at any point is 20 mg/day. The duration of the titration period will 
be 21 days.  
There will be cardiac safety follow-up of 3 to 24 months after study drug discontinuation for early 
termination or for subjects who complete the study but do not enroll in the open-label extension study. 
These results will be presented elsewhere.
3.2.1 Treatment Arms (Cohort 2)
The ZX008 dose of 0.5 mg/kg/day was chosen as the active dose (maximum 20 mg/day) to be used as the 
test arm in Cohort 2, based on the results of the cohort 1 PK study.  
Treatment ARM:  ZX008 – 0.5 mg/kg/day 
ZX008 drug product is an oral aqueous solution of fenfluramine hydrochloride buffered to pH 5 and 
provided in concentrations of 1.25 mg/mL, 2.5 mg/mL, and 5 mg/mL.  ZX008 0.5 mg/kg/day will be 
divided into twice daily doses up to a maximum of 20 mg/day. 
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STATISTICAL ANALYSIS PLAN – COHORT 2
Zogenix International Limited
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Treatment ARM: Placebo
Placebo is identical to ZX008 and is composed of identical ingredients used in the ZX008 formulation, 
except that it does not contain the active ingredient, fenfluramine hydrochloride.  Placebo will be given 
twice daily.
3.2.2 Treatment Periods (Cohort 2)
Titration Period:
Study medication (ZX008 0.5 mg/kg/day or placebo) will be administered as equal doses BID in the 
morning and in the evening approximately 12 hours apart, with food. Each dose should be separated by a 
minimum of 8 hours and a maximum of 12 hours. A missed dose of study medication may be taken later, 
up to 8 hours before the next scheduled dose; otherwise, the missed dose should not be given. 
Administration of the IMP will be based on the subject’s weight at Visit 3 (Study Day -1). At Visit 8 (Day 
50), if the subject’s weight has changed ±25% of the weight at Day-1, the IMP dose will be recalculated 
to reflect the change in weight. Subjects will be dosed using the oral dosing syringe provided. 
In order to maximize tolerability, the dose for each subject will be titrated to 0.5 mg/kg/day. All subjects 
will start with a dose of ZX008 of 0.2 mg/kg/day (or placebo equivalent), administered in divided doses 
BID (maximum: 20 mg/day) on Study Days 1-7.  
The dose will be increased to ZX008 0.4 mg/kg/day (or placebo equivalent) administered in divided doses 
BID (maximum 20 mg/day) on Study Days 8-14. The dose of ZX008 will be increased to 0.5 mg/kg/day 
(or placebo equivalent) administered in divided doses BID (maximum: 20 mg/day) on Study Days 15-21. 
The titration algorithm is shown below.    
Table 2:
Titration Algorithm
Final Dose of 
ZX008 
Titration Step 1 Study 
Day 1-7
Titration Step 2 
Study Days 8-14
Titration Step 3 
Study Days 15-21 
ZX008 0.5 
mg/kg/day 
ZX008 0.2 mg/kg/day 
ZX008 0.4 
mg/kg/day 
ZX008 0.5 mg/kg/day 
Placebo 
Placebo 
Placebo 
Placebo 
Note: maximum daily dose of ZX008 is 20 mg; the dosing regimen for all doses is BID
Maintenance Period:
After completion of the Titration Period, subjects will enter the Maintenance Period and continue to 
receive ZX008 0.5 mg/kg/day or placebo and be treated for an additional 12 weeks on stable dosage. 
Study medication will continue to be administered BID in the morning and in the evening, approximately 
12 hours apart, with food. Each dose should be separated by a minimum of 8 hours and a maximum of 12 
hours. A missed dose of study medication may be taken later up to 8 hours before the next scheduled 
dose; otherwise, the missed dose should not be given.
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STATISTICAL ANALYSIS PLAN – COHORT 2
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Taper Period:
Subjects who complete all of the Maintenance Period and will not be continuing into the open-label 
extension study, and subjects who discontinue from the study early, will be tapered off of study 
medication. Study medication will continue to be administered as equal doses BID in the morning and in 
the evening approximately 12 hours apart, with food. Each dose should be separated by a minimum of 8 
hours and a maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. IMP will be administered 
using the oral dosing syringe provided. 
The taper algorithm is indicated below.
Table 3.  Taper Algorithm
Randomized Dose 
Taper Step 1 Day 1-4
after study completion 
or early termination 
Taper Step 2 Days 5-8
after study completion 
or early termination 
Taper Step 3 Days 9-14
after study completion 
or early termination 
ZX008 0.5 mg/kg/day 
ZX008 0.4 mg/kg/day 
ZX008 0.2 mg/kg/day 
No study drug 
administration  
Placebo 
Placebo 
Placebo 
No study drug 
administration
Note: maximum daily dose of ZX008 is 20 mg.
Transition Period:
Subjects who complete the Maintenance Period and will be continuing into the open-label extension study 
will be transitioned from double-blind study medication to open-label ZX008 (hypothetical transition is 
depicted in Table 4). Study medication will be administered as equal doses BID in the morning and in the 
evening approximately 12 hours apart, with food. Each dose should be separated by a minimum of 8 
hours and a maximum of 12 hours. A missed dose of study medication may be taken later up to 8 hours 
before the next scheduled dose; otherwise, the missed dose should not be given. Study medication will be 
administered using the oral dosing syringe provided. 
All subjects entering the open-label extension study will be transitioned from their blinded daily dose 
(placebo, or assigned dose of ZX008) to the 0.2 mg/kg dose during the interval between Visits 12 and 13, 
without breaking the blind. The IVR/IWR system will assign two bottles of IMP to the subject, one for 
each step in the transition. A new bottle of IMP will be started by the subject at each level of the transition 
step.
Table 4.  
Transition Algorithm 
Randomized Dose Selected for 
Cohort 2
Step 1 Days 1-7 after study 
completion
Step 2 Days 8-14 after study 
completion
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STATISTICAL ANALYSIS PLAN – COHORT 2
Zogenix International Limited
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Page 14
ZX008 0.5 mg/kg/day
ZX008 0.4 mg/kg/day
ZX008 0.2 mg/kg/day
Placebo
ZX008 0.2 mg/kg/day
ZX008 0.2 mg/kg/day
Note: maximum daily dose of ZX008 is 20 mg
Subjects who had been randomized to placebo increase their dose to 0.2 mg/kg/day beginning on Day 1 of 
the transition (the day following Visit 12). The transition algorithm for subjects assigned to ZX008 will 
depend on the final dose selected for Cohort 2. Dosage will be decreased in 0.2 mg/kg/day steps every 7 
days until subjects are at a dose of 0.2 mg/kg/day. 
 
 
 
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STATISTICAL ANALYSIS PLAN – COHORT 2
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CONFIDENTIAL
Final: 25 June 2018
4. SCHEDULE OF ASSESSMENTS
Table 5. 
Cohort 2: Schedule of Assessments
Study
Assessments
Baseline Periodc
Titration + Maintenance Period
Screening
Ran
domi
zatio
n
Titration Period
Maintenance Period
Follow
-up
Cardiac 
Follow-
upc
Visit Number
1
2 
(Phon
e)
3
4 
(phone 
or 
clinic)
5
6
7 
(Phone
) 
8
9 
(phone
) 
10
11 
(Phone)
12
(EOS/
ETb) 
13
14
Study Day
-43 to -42 
or -42 to -
41
-21 
-1
1
8
15
22
36
50
64
78
92
106
120
3-6  mos. 
Post last 
study 
drug 
dose
Informed Consent (subject and parent)
X
Informed Consent (EQ-5D-5L QoL of 
parent.caregiver)
X
Inclusion/Exclusion Criteria
X
X
Demographics
X
Medical/Neurological History
X
Epilepsy history and status
X
Collect retrospective seizure diary data
X
Prior Medication
X
X
Physical Examination, complete
X
X
X
Xc
Physical Examination, abbreviated
X
X
X
X
Xc
Neurological Examination, complete
X
X
Neurological Examination, abbreviated
X
X
X
Vital signs
X
X
X
X
X
X
X
Weight, Height, BMI
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Xc
Doppler ECHO
X
Xd
Xd
Xc
Urine pregnancy teste
Xe
X
X
X
X
X
Clinical laboratory evaluation (hematology/clinical 
chemistry/urinalysis, etc)
X
X
X
X
X
X
Plasma sample for ZX008 PK
Xf
Plasma sample for background AEDs
Xg
Xg
Xg
Xg
Buccal swab for CYP2D6 genotyping
X
Urine THC Panel/Whole blood CBD
X
X
X
X
X
X
Tanner Staging (for subjects >7 years old)
X
X
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STATISTICAL ANALYSIS PLAN – COHORT 2
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CONFIDENTIAL
Final: 25 June 2018
Study
Assessments
Baseline Periodc
Titration + Maintenance Period
Screening
Ran
domi
zatio
n
Titration Period
Maintenance Period
Follow
-up
Cardiac 
Follow-
upc
Visit Number
1
2 
(Phon
e)
3
4 
(phone 
or 
clinic)
5
6
7 
(Phone
) 
8
9 
(phone
) 
10
11 
(Phone)
12
(EOS/
ETb) 
13
14
Study Day
-43 to -42 
or -42 to -
41
-21 
-1
1
8
15
22
36
50
64
78
92
106
120
3-6  mos. 
Post last 
study 
drug 
dose
Subject Diary
D
R
C/R/
D
R
C/R/D
C/R/D
R
C/R/D
R
C/R/D
R
C/R/Dh
C/R
Epilepsy genotype panel
Xl
Study Medication
D
Ri
C/R/D
C/R/D
R
C/R/D
R
C/R/D
R
C/R/Dh
C/R
C-SSRS
X
X
X
X
X
X
CGI-I (assessed by parent/caregiver)
X
X
X
X
X
CGI-I (assessed by principal investigator)
X
X
X
X
X
Sleep quality and mealtime behavior 
questions
X
X
Karolinska Sleepiness Scale
X
X
X
BRIEF
X
X
QOLCE
X
X
Healthcare utilization questions
X
X
X
X
X
PedsQL Generic Core Scale
X
X
PedsQL Family Impact Module
X
X
EQ-5D-5L (QoL of parent/caregiver)
X
X
Randomize subject
X
First Day of Study Drug Administration
Xj
Open-label consent form
Daily Diary Completion
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events of special interest
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
AED=antiepileptic drug; BMI=body mass index; BRIEF=Behavior Rating Inventory of Executive Function; C=Collect; CBD=cannabidiol; CYP2D6=cytochrome P 450 2D6; D=Dispense; ECG=electrocardiogram; ECHO=echocardiogram; 
EOS=end of study; ET=early termination; EQ-5D-5L=standardized measure of health status; mos=months; PK=pharmacokinetics; QoL=quality of life; QOLCE=Quality of Life in Childhood Epilepsy; R=Review; THC=tetrahydrocannabinol
a: The Baseline Period is comprised of the initial screening for the study and the assessment of baseline seizure activity recorded daily in the diary. The procedures to be completed at the Screening visit may be completed in a single day or split so that they 
are completed over the 2-day period (i.e., Days -43 to - 42 or Days -42 to -41).
b: Subjects who are discontinued early and those who complete the study and choose not to enroll in the separate open-label extension will be tapered off study medication over a 2-week period. Subjects who choose to continue in the separate open-label 
extension trial will undergo a 2-week transition period prior to enrollment.
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c: Follow-up ECG, ECHO, and physical examination will be performed 3-6 months after early termination, or for those subjects who complete the study but do not enter the open-label extension trial (see Section 6.2.6).
d: The Visit 8 ECHO must be performed any time between Study Day 40 and Study Day 54. The Visit 12 ECHO must be performed any time between Study Day 90 and Study Day 113; if a subject discontinues early from the study, the ECHO should be 
VFKHGXOHGDVVRRQDVSUDFWLFDO,IWKH6WXG\'D\(&+2ZDVFRPSOHWHGGD\VSULRUWRHDUO\WHUPLQDWLRQWKH9LVLW(&+2 will not be performed provided the parent/guardian agrees to bring the subject to the clinic for the cardiac follow-up visit.
e: Females of child-bearing potential
f: Plasma sample for PK assessment will be conducted prior to the dose at the Follow-up visit and 1, 2, and 4-6 hours after dose administration for Subjects continuing into the open-label extension trial.
g: Plasma sample for assessment of background AED(s) will be conducted prior to the dose of AED(s) at Visits 3, 6, 8 and 12.
h: Study drug/diary dispensed for the transition for subjects entering the open-label extension trial and for tapering for subjects exiting the study.
i: Site personnel will review study medication dosing procedure (titration) with parent/caregiver.
j: Study drug administration begins in the morning of Study Day 1.
k: Only adverse events related to cardiac safety will be collected at this visit.
l: Mandatory one time collection any time during or after screening and before Visit 10.
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5. ANALYSIS POPULATIONS 
5.1 COHORT 2
5.1.1 Enrolled Population
The Enrolled population includes all subjects who gave informed consent/assent.   
5.1.2 Intention-to-Treat (Randomized) Population
The ITT (or Randomized) population includes all subjects randomized to receive study treatment.  
5.1.3 Modified Intention-to-Treat (mITT) Population
The mITT Population is defined as all randomized subjects who receive at least one dose of 
ZX008 or placebo and for whom at least one week of diary data are available. Subjects will be 
analyzed according to the treatment group to which they were randomized. The primary 
comparison of ZX008 0.5 mg/kg/day to placebo, as well as key secondary analyses, will be 
performed on the mITT Population. 
5.1.4 Per Protocol (PP) Population
The per protocol population includes all randomized subjects who receive at least one dose of 
ZX008 or placebo, complete at least 4 weeks of the Maintenance Period, and have no important 
protocol deviations that would have a significant impact on clinical outcome. Subjects will be 
analyzed according to the treatment group to which they were randomized.  Protocol deviations 
will be reviewed and the list of deviations warranting exclusion from the PP Population will be 
finalized prior to study unblinding. 
For cohort 2, the primary and key secondary efficacy analyses will be repeated on the PP 
Population. 
5.1.5 Safety Population
All safety analyses will be performed on the SAF Population defined as all randomized subjects
who receive at least one dose of ZX008 or placebo. Subjects will be analyzed according to the
treatment group to which they were randomized. 
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6. STATISTICAL METHODOLOGY
6.1 STATISTICAL AND ANALYTICAL ISSUES
6.1.1 Statistical Methods
Tabulations will be produced for demographics, baseline, efficacy, and safety parameter.
Continuous data will be summarized using descriptive statistics including the number of 
observations, means, standard deviations, medians, lower and upper quartiles, and ranges.  
Categorical variables will be summarized showing number of observations, frequencies, and 
percentages. 
This SAP provides summary of statistical methods for comparing the regimens in the double-
blind study (cohort 2).   
Confidence intervals will be calculated at the 95% confidence level for key parameters or 
estimates as described in the sections below. Two-sided statistical significance testing (alpha 
level = 0.05) comparing treatment to placebo will be performed for the primary and secondary 
endpoints as described in the respective sections below. 
All statistical analyses and summaries will be performed using SAS statistical software 
(Version 9.3 or later version that will be in use at the time of analysis, unless otherwise noted).  
Adverse events will be coded using the most recent MedDRA version available at the time of 
analysis and the actual version used will be footnoted in the respective adverse events summary 
tables.  Concomitant medications will be coded using the available recent version of World 
Health Organization (WHO) Drug dictionary and the version used will be footnoted in the 
respective medications summary tables.
6.1.2 Multiplicity Strategy and Testing Hierarchy 
The multiplicity issues in the statistical inference in this study arise from multiple endpoints.   
The efficacy analyses will employ a serial gatekeeper strategy to maintain the Type 1 error rate at 
Į DFURVVWKHIDPLO\RIDQDO\VHVWKDWVXSSRUWWKHSULPDU\DQGNH\VHFRQGDU\REMHFWLYHV
All statistical analyses will be performed and results tabulated with test statistics, p-values, and/or 
95% confidence intervals.
Formal statistical testing will be performed for one primary endpoint and two key secondary 
endpoints for the comparison of ZX008 0.5 mg/kg with Placebo. In order to preserve the overall 
7\SHHUURUUDWHDWĮ WKHVHWHVWVZLOOSURFHHGDVIROlows:
Step 1: The primary efficacy endpoint (mean convulsive seizure frequency per 28 days) will be 
formally tested first between the ZX008 0.5 mg/kg and Placebo group. If the comparison is 
VWDWLVWLFDOO\VLJQLILFDQWDWĮ -sided) level, the hypothesis testing will proceed to Step 2. 
Otherwise formal testing of the other hypotheses stops. 
6WHS7KHVHFRQGDU\HIILFDF\HQGSRLQWSURSRUWLRQRIVXEMHFWVZKRDFKLHYHDUHGXFWLRQ
from baseline in convulsive seizure frequency) will be compared between the ZX008 and Placebo 
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JURXS,IWKHFRPSDULVRQLVVWDWLVWLFDOO\VLJQLILFDQWDWĮ -sided) level, hypothesis testing 
will proceed to Step 3. Otherwise formal testing of the other hypotheses stops. 
Step 3: The endpoint longest convulsive seizure-free interval endpoint will be compared between 
=;DQG3ODFHERXVLQJDVLJQLILFDQFHOHYHORIĮ -sided).  
6.1.3 Subgroups
Select efficacy and safety outputs may be further broken down by the following subgroups: 
•
Age strata: \HDUV\HDUV
6.1.4 Baseline Definition
The baseline period for Cohort 2 consists of 42 days immediately preceding first administration 
of study treatment. Any assessment performed during these 42 days before first administration of 
study treatment will be considered a baseline assessment. Study day 1 will be the first day of 
study drug administration. 
For the analysis of frequency of convulsive seizures endpoints where a baseline convulsive 
seizure frequency is needed, baseline will include all data from the baseline period of 42 days 
immediately preceding Day 1 (Visit 3).  For all other endpoints, baseline is the last non-missing 
result prior to first dose from the Baseline period. 
 
6.1.5 Other Definitions
Treatment completers are those subjects that are compliant with IMP at least 85% of dosing days 
and fulfill at least one of the following criteria:
•
Subjects that did not discontinue from the trial prior to end of study visit (Visit 12).
•
Cohort 2 Subjects that complete the Treatment Period T+M starting from study Day 1 
(Visit 3) through the protocol defined end of study visit (Visit 12). 
•
Subjects that enroll in the open label extension study.
6.1.6 Visit Windows
The following rules will be used to window data into treatment periods tabulations.  For all by-
visit tabulations, the nominal visit as recorded on the CRF will be used. 
Double Blind 
Treatment Period
The Double-Blind Treatment Period start date is the date of first 
dose. The Double-Blind Treatment Period end date is the last date 
the patient was on study treatment.
The Double-Blind Treatment Period includes time from first 
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treatment start date, which includes 21 days of Titration period, 12 
weeks of Maintenance period and Taper/Transition period (14 days) - 
For subjects who discontinue early from the study, the double-blind 
treatment period end date will be the date at the early termination 
visit (Visit 12).
Titration Period
The Titration Period covers up to the first 21 days of treatment while 
subjects are titrated to their randomized dose. It begins on the first 
day of treatment (Study Day 1) and extends through Visit 6 (when 
the patient has reached their randomization dose). The Titration 
Period applies to all subjects including placebo recipients.  If a 
subject withdraws from the study prior to treatment in the 
maintenance period, all safety assessments and events up to and 
including the date of study withdrawal will be tabulated in the 
titration period.
Maintenance Period
The Maintenance Period covers the 12 weeks following the end of 
the titration period. It begins on the date of Visit 6 + 1 day and 
extends through the end of study/early termination visit (Visit 12).
Titration +Maintenance 
Period (T+M)
The T+M period combines the Titration and Maintenance periods, 
beginning on the date of first treatment (Study Day 1) and extending 
to the end of the 12 week Maintenance Period. The primary efficacy 
endpoint is calculated based on data from the T+M period.
Taper/Transition Period
The Taper/Transition period consists of approximate 14- days 
starting from end of study/early termination visit (Visit 12) + 1 day. 
For patients who are not entering into the open-label extension study, 
patients will gradually be tapered off of study medication. 
Patients entering the open-label extension study will first enter the 
transition phase where all patients will be on a dose of 0.2mg/kg/day 
at the end of this phase. The end date of this period is considered to 
be the date recorded at Visit 13.
6.1.7 Handling of Dropouts and Missing Data
There will be no imputation of missing data for efficacy endpoints.  
Seizure Diaries:
Seizures are recorded in the Daily Seizure Diary (DSD), while the End of Day Diary (EDD) 
provides Yes/No confirmation that that seizures were experienced for a specific date, or that the 
date was seizure free.
x
If no seizures are entered in the DSD and the EDD confirms seizure freedom, the number 
of seizures for that date is zero.
x
If seizures are entered in the DSD and the EDD states seizure freedom, the seizures 
recorded for that date supersede the EDD stating seizure freedom.
x
If no seizures are entered in the DSD and there is no response in the EDD, that day will 
be considered to have missing diary data. 
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x
If no seizures are entered in the DSD and there is a Yes response in the EDD, that day 
will be considered to have missing diary data.   
Unless specified otherwise in the relevant sections describing analyses for individual parameters, 
missing diary data will not be imputed for efficacy variables. Hence for subjects missing some of 
the daily measurements, the available data will be used. No explicit imputation will be performed 
for subjects who drop out prior to end of study (Visit 12). 
Handling of missing date information for AEs:
x
The term missing date refers to a completely missing date or to an incomplete date/partial 
date where parts are not available, e.g. missing month/day/year. 
x
Missing start and end dates will be imputed conservatively, i.e. missing values will be 
imputed in such a way that the duration of the AE is considered with the longest possible 
duration and such that, whenever the AE may potentially start after first IMP, the AE will 
be handled as a TEAE.
x
The missing start date and End date of AE will be imputed for the purpose of calculating 
treatment emergent status and assigning events to treatment periods using definitions 
given in the following table.
Handling of missing date information for AEs: 
x
The term missing date refers to a completely missing date or to an incomplete date/partial 
date where parts are not available, e.g., missing month/day/year.  
x
Missing start and end dates will be imputed conservatively, i.e., missing values will be 
imputed in such a way that the duration of the AE is considered with the longest possible 
duration and such that, whenever the AE may potentially start after the first dose of IMP, 
the AE will be handled as a TEAE. 
x
The missing start date and end date of an AE will be imputed for the purpose of 
calculating treatment-emergent status and assigning events to treatment periods using the 
definitions given in the following table.
Adverse events
Partial  
/Missing 
Start Date
Missing day – If the AE start day is missing but month and year are present, then 
impute the 1st of the month unless the month and year are the same as the first 
dose of study drug. If this is the case, then impute the day of the first dose.
Missing day and month – If the AE start day and month both are missing but year 
is present, then impute 1st January unless the year is the same as first dose date. If 
this is the case, then impute the day and month of the first dose.
Completely missing – Impute the first dose date unless the end date suggests it 
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could have started prior to this date, in which case impute the 1st January of the 
same year as the end date.  
When imputing a start date, ensure that the new imputed date is sensible, i.e., is 
prior to the end date of the AE.
Partial 
/Missing 
End Date
Missing day – If the AE end date is missing but month and year are present, then
impute the last day of the month, unless the year and month are the same as the 
first dose of study drug. If this is the case, then impute the date of the last dose. 
Missing day and month – If the AE has missing day and month but year is present, 
then impute 31st December.
Completely Missing – Need to look at whether the AE is still ongoing before 
imputing a date and also when it started in relation to starting study drug. If the 
ongoing flag is missing, then assume that the AE is still present (i.e., do not impute 
a stop date). If the AE has stopped and the start date is prior to first dose date, then 
impute the first dose date. If the AE started on or after the first dose date, then 
impute an end date that is after the last dose date.
6.1.8 Conversion of time interval
In case a time interval was calculated in days and needs to be converted into weeks, months or 
years the following conversion factors need to be used: 
1 week    = 7 days 
1 month  = 30.4 days
1 year     = 365.25 days 
6.1.9 Pooling of Investigative Sites and Interaction of treatment by Site 
The primary analysis will use data pooled across all investigative sites.  Region (UK, US, 
Canada, France, Germany, Netherlands, Spain) and site differences may be explored in 
preliminary analyses depending on the number of subjects randomized by each site/region.   
6.1.10 Determination of Sample Size
The sample size for Cohort 2 was estimated from the results of two randomized, placebo-
controlled trials for the treatment of Dravet syndrome with stiripentol. The results from the two 
trials, STICLO France and STICLO Italy, were reported in the European Public Assessment 
Report (EPAR) for stiripentol (EMA, 2007). In the stiripentol groups, the standard deviation (SD) 
of the percentage change in seizure frequency from baseline to month 2 was 42% in the STICLO 
France trial and 26% in the STICLO Italy trial. The analogous SDs for placebo groups were 38% 
and 62%. For the current trial, an SD of 50% was assumed for the primary analysis comparing 
ZX008 to placebo on the change from baseline in seizure frequency. Using a two-sided test at the 
Į VLJQLILFDQFHOHYHODVDPSOHVL]HRIVXEMHFWVSHUWUHDWPHQWJURXSDIIRUGVSRZHUWR
detect a difference in mean change from baseline of 40 percentage points.
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In December 2016 results from a double-blind, placebo-controlled Phase 3 study with Epidiolex 
to treat seizures in Dravet syndrome were presented at the American Epilepsy Society Meeting 
(http://ir.gwpharm.com/events.cfm). In the Epidiolex study, active drug reduced seizures by 39% 
compared to a reduction of 13% in the placebo.  Review of the data suggested that the standard 
deviation was relatively large, likely above 50% in both treatment groups.  In consideration of 
this new data, the expected SD was increased to 55. Other assumptions in the sample size 
calculation have remained unchanged. A sample size of approximately 80 subjects (40 per arm) 
affords 90% power to detect a difference in mean change from baseline of 40 percentage points 
with 55% SD.  Given the variability seen in the STICLO and Epidiolex trials, the sample size for 
the current trial was increased from 35 to 40 subjects per treatment arm for a total of 80 subjects. 
6.2 SUBJECT CHARACTERISTICS
6.2.1 Disposition
Subject disposition will be presented per treatment group and overall.  
For subjects enrolled but not randomized to treatment and for the reasons for not being 
randomized, the denominator used to calculate the percentage will be the number of enrolled 
subjects. For all other calculations the denominator will be the number of subjects randomized.  
Completion and discontinuation data for all randomized subjects will be listed and sorted by 
treatment and site.
6.2.2 Protocol Deviations
Major protocol deviations will be summarized showing number and percent by treatment and 
overall based on the SAF. Major protocol deviations are those that have the potential to impact 
patient safety or affect data integrity.  Major protocol deviations may be grouped into different 
important clinical categories such as
•
Violation of inclusion/exclusion criteria
•
Violation of randomization inclusion criteria
•
Time schedule deviations of IMP
•
Non-compliance regarding intake of IMP
•
Inappropriate intake of concomitant medication 
•
Missing essential data
•
Subject not discontinued as per protocol 
•
Other non-compliance 
Multiple deviations can occur in the same subject and thus a subject may be counted in more than 
1 deviation category.
Major protocol deviations will be presented in a subject data listing for all enrolled population, 
sorted by treatment and site. 
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6.2.3 Demographics and Baseline Characteristics
Subject demographics and baseline characteristics will be summarized descriptively per 
treatment group and overall, for the SAF and mITT populations.  
 6XEMHFW'HPRJUDSKLFV
The following demographic characteristics will be summarized: 
x
Age at screening [years]
x
&DWHJRULFDODJHDV\HDUVDQG\HDUV. 
x
Sex
x
Race
x
Ethnicity
x
Height [m]
x
Weight [kg]
x
BMI [kg/m2] 
All subject demographics data will be listed for the enrolled population. 
 2WKHU%DVHOLQH&KDUDFWHULVWLFV
Epilepsy genotype panel data will be descriptively summarized as per data type (categorical). 
Additional analyses of genetic data may be prepared in a separate report.  
The primary genotype mutation for each subject will be listed for the safety population. 
6.2.4 Treatment Exposure and Compliance
 7UHDWPHQW([SRVXUH
Exposure will be summarized for the safety population. 
Duration of exposure to treatment (i.e., time on treatment in days) will be calculated per subject 
as the number of days with IMP intake during the study and will be summarized using descriptive 
statistics (mean, standard deviation, median, and range) for the safety population. The per subject 
duration of exposure will be calculated as follows: 
Date of last IMP administration – Date of first IMP intake + 1
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The duration of exposure summary statistics will be presented by treatment group for the 
combined Titration, Maintenance and Taper/Transition periods. Also, the exposure subject data 
listing will be presented. 
 &RPSOLDQFH
Compliance will be summarized for the SAF and mITT.  
Study medication is to be administered twice daily, and compliance is recorded in the eDiary as 
full (both doses), partial (less than full daily dose) or missed (both doses) each day.  From this, 
compliance will be calculated by assuming that a missed dose=0% of dose consumed, 
partial=50% of dose consumed, and full=100% of dose consumed. For each subject, a daily 
compliance score will be thus obtained. 
Compliance will be summarized for the SAF population over the course of T+M and 
Maintenance only, reported by treatment group. 
6.2.5 Prior and Concomitant Medications and Therapies
Medications (collected on the prior/concomitant medication eCRF pages) will be coded using the 
World Health Organization Drug Dictionary (WHO-DD). The following algorithm will be used 
to define prior and concomitant: 
Concomitant medications will be defined as those medications that were initiated after study drug 
administration or those that were ongoing at the time of study drug administration. 
The medication will be assumed to be prior medication if it cannot be definitively shown that the 
medication did not start or continue during the double-blind treatment period. 
If the start date or stop date of a medication is partially missing, the date will be compared as far 
as possible with the date of the start of administration of study drug. The following approach will 
be taken:
x
If the start date of medication is complete and occurs on or after the day of the first dose, 
the medication will be assumed concomitant.  If the start date occurs prior to the first 
dose date but the end date is on or after the first dose date or the medication is recorded 
as ongoing, the medication will be considered concomitant. 
x
If the start day is missing but the start month and year are complete, a medication will 
only be excluded as being concomitant if the start month/year is before the month/year of 
study drug administration and if the stop date (either full date, month and year if missing 
day, or year if missing month and day) is before study drug administration. 
x
If the start day and month are missing but the start year is complete, a medication will 
only be excluded as concomitant if the start year is before the year of study drug 
administration and if the stop date (either full date, month and year if missing day, or year 
if missing month and day) is before study drug administration. 
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x
If the start date is completely missing and the stop date is prior to first dose or completely 
missing, the medication will be assumed to be a prior medication. 
Medications will be summarized by treatment and overall for prior and concomitant medications 
by Anatomical Therapeutic Chemical (ATC) classification and preferred therapeutic Term (Level 
2: pharmacological or therapeutic subgroup and Level 3: chemical or therapeutic or 
pharmacological subgroup). For each medication the number and percentage of subjects will be 
displayed.  
Summary tables will be presented for SAF population. 
All prior and concomitant medications/treatments will be listed for the SAF population. 
6.2.6 Prior and Concomitant Antiepileptic Treatment
Treatments (collected on the prior/concomitant antiepileptic treatment eCRF page) will be coded 
using the World Health Organization Drug Dictionary (WHO-DD). 
Prior and concomitant antiepileptic will be defined and analyzed for the SAF similar to 
concomitant medications as described in section 6.2.5. 
All prior and concomitant antiepileptic treatments will be listed for the SAF population. 
6.2.7 Medical History
Medical history will be summarized and sorted alphabetically, by primary System Organ Class 
and Preferred Term coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA). The number and percentage of subjects will be displayed for each System 
Organ Class and Preferred Term within treatment group.
Medical history will be presented for the SAF population. 
All prior and concomitant medical history data of subjects will be listed for the SAF population. 
6.3 EFFICACY ANALYSES
The analysis of the primary and secondary efficacy parameters will be performed on the mITT 
population, except where noted.  
The primary and key secondary efficacy analyses will be repeated on the PP Population, in order 
to assess the impact of major protocol deviations on the key inference. 
All primary and key secondary variables will be analyzed for data obtained for the T+M period, 
and will be repeated for data obtained during the M period only. 
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6.3.1 Primary Efficacy Analysis 
The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) 
per 28 days between the Baseline and T+M periods. For each subject, the convulsive seizure 
frequency (CSF) will be calculated from all available data collected during the Baseline and T+M 
Periods, and the treatment group MCSF per 28 days (MCSF) will be calculated for the baseline 
and T+M period.
The baseline period is the 42 days immediately preceding the Randomization visit and the T+M 
period is planned for 15 weeks (including 3 weeks titration). However, actual durations will be 
computed for each subject based on the individual subject’s start and stop dates for each period 
with the exception that if the baseline period is longer than 42 days, the average for the baseline 
period will be the 42 days’ data immediately preceding the Randomization date.
The convulsive seizure frequency will be counted from the daily diary records provided by the 
Subject or Parent/Caregiver.
For any individual subject, the convulsive seizure frequency per 28 days during the baseline 
period (CSFB) will be derived as follows:
CSFB = 28 ×  Total number of convulsive seizures during the Baseline Period
Total number of days in the Baseline Period with nonmissing diary data 
For each treatment group, the mean is obtained by averaging over the subjects in the treatment 
group.
Similarly, for each subject, the convulsive seizure frequency per 28 days for the T+M period 
(CSFT+M) is derived as below:
The percentage change from baseline for any individual subject will be estimated by
(CSFT+M - CSFB)*100/CSFB 
The difference from baseline will be estimated by CSF்ାெെCSF஻.
Corresponding treatment group means are designated with “M” preceding the quantity. For each 
treatment group, descriptive statistics for MCSF during baseline, T +M study period,  as well as 
the differences and % changes from baseline, will include the number of observations, mean, 
VWDQGDUGGHYLDWLRQPHGLDQPLQLPXPDQGPD[LPXPRYHUDOODQGE\DJHJURXS\HDUV
years). 
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T + M Period: 
The primary analysis will compare the ZX008 0.5 mg/kg/day group to the placebo group using a 
two-VLGHGWHVWDWĮ OHYHORIVLJQLILFDQFH
The primary endpoint (CSFT+M) will be analyzed using an analysis of covariance (ANCOVA) 
model with treatment group (ZX008 or Placebo) and age JURXS\HDUV\HDUVDV
data
diary 
 
nonmissing
 with 
period
 
M
+
T
 
in the
 
days
 
of
number 
 
Total
period
 
M
+
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in the
 
seizures
 
convulsive
 
of
number 
 
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classification factors, log baseline frequency (CSFB) as a covariate in the model, and log CSFT+M
as response.  Treatment group means and the difference from placebo will be estimated with least 
squares means from the analysis model along with 95% confidence intervals and associated 2-
sided p-values. Estimated treatment group means and CI endpoints will be exponentiated for 
presentation. 
The null hypothesis  
H଴: ߤ୞଴଴଼െߤ୔= 0,
will be tested against the alternative
H୅: ߤ୞଴଴଼െߤ୔്0,
where μZ008 and μP  represent the ZX008 0.5 mg/kg and Placebo group means (on the log scale), 
respectively.
Rejection of the null hypothesis in favor of the alternative, in the presence of a statistically 
significantly bigger reduction in mean convulsive seizure frequency from baseline for the 
treatment group compared to the placebo group, (two-sided p-value < 0.05) will be regarded as 
evidence of a treatment benefit in favor of ZX008 0.5 mg/kg group.
Sample SAS code for the ANCOVA described above is as follows:
   
proc glm data=temp; 
class agegrp trtp;
model csftm = bcsf agegrp trtp  / SS3;
lsmeans  trtp / pdiff stderr; 
where  trtp = randomized treatment group (with codes 1, 2 indicating placebo, and 0.5 mg 
groups). 
bcsf = log( CSF஻),  
csftm = log(CSFT+M) 
agegrp = age group.
Additional statements may be used to obtain estimates and 95% confidence interval. Endpoints of 
the CIs may be exponentiated to obtain CI on the original scale. Fitted values and residuals may 
be plotted to check model assumptions.  
Since the ANCOVA used in the primary analysis relies on assumptions of normality, the primary 
endpoint will also be analyzed using a nonparametric method that does not require as stringent 
assumptions.  A nonparametric ANCOVA will be used to analyze the data, with ranks of the 
baseline CSFB as a covariate and ranks of CSFT+M as response. If normality assumptions are not 
met, the results of the nonparametric test will be used to assess the primary objective.
Treatment by Baseline Seizure Category:
The primary analysis described above will be repeated with baseline seizure frequency as a 
categorical variable, rather than a covariate.
Baseline seizure frequency per 28 days will be categorized as either < 10; 10-50; or >50 
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M Period only:  
The primary analysis described above will be repeated using data from the Maintenance period 
only as response.  For subjects who did not reach the Maintenance period, their Transition period 
data will be used to represent their M period data.
A similar ANCOVA model will be used, and if distributional assumptions are not met, a 
nonparametric analysis will be performed.
 6XSSOHPHQWDU\DQG6HQVLWLYLW\$QDO\VHV
Per Protocol Analysis
Additionally, the primary efficacy analysis will be repeated on the per protocol population (which 
excludes subjects with important protocol deviations that may affect the inference on efficacy 
such as a change in dose or type of concomitant AED medication). 
Percentage Reduction from Baseline
The ANCOVA employed in the primary analysis uses log CSFT+M as the response and adjusts for 
baseline seizure frequency by incorporating CSFB as a factor in the model. The alternative 
approach described here calculates the percentage change in CSF from baseline directly and uses 
that quantity as the response variable in an ANCOVA model. Specifically, the ANCOVA will use 
the percentage change from the T+M period as the response variable, baseline CSF as a covariate, 
and treatment and age stratum as classification factors. A parametric ANCOVA will then be used 
to compare ZX008 treatment group to placebo treatment group.   
If the distributional assumptions for the parametric analysis are not met, a nonparametric 
ANCOVA based on the ranks as the dependent response variable, and using the ranks of the 
baseline as covariate will be used for the analysis.
Criteria for Establishing Efficacy
While several supportive and/or supplementary analyses are specified above, the main criterion 
for demonstrating efficacy will be the primary analysis for the mITT population. It is conceivable 
that some or all of the supplemental analyses may not reach statistical significance. However, it is 
expected that the direction of effect will be consistent in favor of ZX008 versus Placebo. 
6.3.2 Key Secondary Analyses
 3URSRUWLRQRIVXEMHFWVZLWK5HGXFWLRQIURP%DVHOLQHLQ&RQYXOVLYH
6HL]XUH)UHTXHQF\5HVSRQGHU5DWH
Subjects with a percent reduction in convulsive seizures of at least 50 percentage points from 
baseline will be identified and the overall proportion within each treatment tabulated.  That is, the 
proportion of subjects in the ZX008 0.5 mg/kg/day group who have a decrease in convulsive 
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frequency of at least 50 percentage points will be compared to the analogous proportion in the 
placebo group.   
The comparison between ZX800 treatment group and Placebo group will be made using a logistic 
regression model that incorporates the same factors as the ANCOVA used in the primary 
analysis.  This will model a categorical response variable (achieved at least a 50 percentage point 
reduction, yes or no) as a function of treatment (ZX008 and placebo), baseline seizure frequency 
DQGDJHJURXS\HDUV\HDUV
Descriptive statistics will be presented by treatment group, and will include the number and 
proportion of suEMHFWV\HDUV\HDUVDQGRYHUDOODFKLHYLQJWKHUHGXFWLRQDORQJZLWKWKH
model estimated odds ratio (including a 95% confidence interval) and p-value for comparison of 
ZX008 0.5 mg/kg/day to placebo. 
 3URSRUWLRQRIVXEMHFWVZLWKRU&RQYXOVLYH6HL]XUHV
The proportion of subjects with either 0 or 1 convulsive seizure will be identified, descriptive 
statistics will be presented by treatment group, and will include the number and proportion of 
subjects.
A Fisher’s exact test will compare the proportion of subjects with a 100% reduction, and also 
with at most 1 convulsive seizure, in the ZX008 0.5 mg/kg/day to the analogous proportion in the 
placebo group. 
 /RQJHVW&RQYXOVLYH6HL]XUH)UHH,QWHUYDO
The longest interval between convulsive seizures will be analyzed.
For each subject, the longest interval between convulsive seizures will be calculated over the 
entire T+M period. This will be derived as the maximum of the number of days between 
consecutive convulsive seizures. The intervals between consecutive convulsive seizures will be 
calculated as below, after which the longest interval between convulsive seizures will be derived. 
If a subject has two consecutive days of missing diary data, the end of the current seizure-free 
interval will be the first date of missing diary data, and a new one begun on the next date that 
diary data are available and no seizure occurs [In that case, for purpose of calculation of this 
variable, all intervening days, after the 2nd day, with missing diary data, will be assumed to have 
a convulsive seizure occurrence, until the first available date with non missing diary data.]
Let Date0 (=Day1) be the first day of treatment. If convulsive seizure occurs on five days having 
dates as Date1, Date2, Date3, Date4 and Date5, where
Date5>Date4>Date3>Date2>Date1Date0, and let LDT = Last date of treatment in the
maintenance period, ZKHUH/'7'DWHthen the time interval between convulsive seizures will
be calculated as follows:
I1=Date2 - Date1
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I2=Date3 - Date2
I3=Date4 – Date3,
I4=Date5 – Date4.
For completeness, we calculate the time to the first seizure as
I0=Date1 – Date0,
and the time from the last seizure to end of treatment as
I5 = LDT – Date5.
Here the duration of the longest interval =Maximum (I0, I1, I2, I3, I4, I5).
If the subject does not experience a seizure during treatment, then the last available diary date
will be used to compute the duration of the longest interval as follows:
The longest interval=last available diary date – Date0
The median time of the longest convulsive seizure-free interval will be presented. Additional 
summary statistics will be presented, including mean, minimum, maximum, the 25th and 75th 
percentiles, 95% confidence intervals on the difference in medians between groups (Hodges- 
Lehman estimator).
The Wilcoxon rank sum test will be used to test for differences between ZX800 and
placebo, and the p-value from this test will be presented. Boxplots of the longest interval data will 
accompany all descriptive statistics and all data will be provided in a data listing.
6.3.3 Additional Secondary Endpoint Analyses
 1XPEHURI&RQYXOVLYH6HL]XUH)UHH'D\V
Convulsive seizure free days will be taken from the parent/caregiver diary data.
A convulsive seizure free day will be defined as a day for which diary data are available and no 
convulsive seizures have been reported.  The total number of convulsive seizure free days will be 
summed for the entire T+M period and similarly for the baseline period.
Seizure free days per 28 days at baseline = (number of seizure free days during 
baseline)*28/(number of days during baseline with non-missing diary data)
Seizure free days per 28 days during T+M Period = (number of seizure free days during T+M 
Period)*28/(number of days during T+M Period with non-missing diary data)
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The ZX008 treatment group will be compared to the placebo on the number of seizure free days 
per 28 days during T + M using a similar approach as the primary analysis incorporating the 
baseline seizure-free frequency as a covariate.
 5HVSRQGHU$QDO\VHV3URSRUWLRQZLWKRU5HGXFWLRQIURP%DVHOLQHLQ
&RQYXOVLYH6HL]XUH)UHTXHQF\
A step-function response curve will be generated for the mITT population. This graph will plot 
the % of subjects (y-axis) against percentage reduction in seizure frequency per 28 days in the 
T+M period (x-axis). The horizontal axis will be the % reduction, and the vertical axis will be the 
RIVXEMHFWVDFKLHYLQJWKDWUHGXFWLRQ,QWKHJUDSKVXEMHFWVH[SHULHQFLQJDQLQFUHDVHRUQR
decrease in seizure frequenc\LHUHGXFWLRQZLOOEHUHJDUGHGDVKDYLQJDUHGXFWLRQLQ
seizure frequency. Hence the ordinate for the 0 time point may not necessarily be at 100%.  For 
example, if 15% of subjects have no reduction in seizure frequency during T+M period compared 
to the baseline period, the graph will start on the y-axis at 85%. The graph will be generated for 
all subjects, by treatment group. 
x
7KHSURSRUWLRQDFKLHYLQJDUHGXFWLRQIURPEDVHOLQHLQFRQYXOVLYHVHL]XUHVZLOOEH
analyzed using the same method ePSOR\HGIRUWKHUHGXFWLRQIURPEDVHOLQHHQGSRLQW
x
7KHSURSRUWLRQDFKLHYLQJDUHGXFWLRQIURPEDVHOLQHLQFRQYXOVLYHVHL]XUHVZLOOEH
DQDO\]HGXVLQJWKHVDPHPHWKRGHPSOR\HGIRUWKHUHGXFWLRQIURPEDVHOLQHHQGSRLQW
 &KDQJHIURP%DVHOLQHLQ1RQ&RQYXOVLYH6HL]XUH)UHTXHQF\
Algorithms for calculating mean non-convulsive seizure frequency and change from baseline will 
follow the same methods as described for the primary endpoint. 
Change from baseline in non-convulsive seizures will be presented by seizure types (e.g.,
absence, myoclonic).
The statistical comparison of treatment group and placebo will be done using a nonparametric 
ANCOVA similar to the method described in 6.3.1.1. Here the analysis will use the ranks of the 
non-convulsive seizure frequencies as the response variable, treatment as a factor, and the ranks 
of the baseline non-convulsive seizure frequencies as a covariate. Data will be displayed by 
treatment group as described for the primary endpoint. 
 &KDQJHIURP%DVHOLQHLQ&RQYXOVLYH6HL]XUH)UHTXHQF\E\6HL]XUH7\SH
Algorithms for calculating mean convulsive seizure frequency and change from baseline for each 
seizure type (GTC, tonic, clonic, hemiclonic, tonic-atonic, and focal seizures with an observable 
motor component) will follow the same methods as described for the primary endpoint. 
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Change from baseline in non-convulsive seizures will be presented for all non-convulsive 
seizures and by seizure types (e.g., focal, generalized). 
The statistical comparison of treatment group and placebo will be done using a nonparametric 
ANCOVA similar to the method described in 6.3.1.1. Here the analysis will use the ranks of the 
non-convulsive seizure frequencies as the response variable, treatment as a factor, and the ranks 
of the baseline non-convulsive seizure frequencies as a covariate. Data will be displayed by 
treatment group as described for the primary endpoint. 
 &KDQJHIURP%DVHOLQHLQ&RQYXOVLYH1RQ&RQYXOVLYH6HL]XUH)UHTXHQF\
The change from baseline in convulsive + non-convulsive seizure frequency will be calculated as 
described for the primary endpoint, but considering both convulsive and non-convulsive seizures.
The statistical comparison of treatment group and placebo will be performed using a 
nonparametric ANCOVA similar to that described above for the analysis of non-convulsive 
seizures.  Data will be displayed by treatment group as described for the primary endpoint. 
 ,QFLGHQFHRI5HVFXH0HGLFDWLRQ8VDJH
Use of rescue medication is recorded on the daily diary. In the event of prolonged seizures or 
status epilepticus, rescue medication is administered according to each subject’s personalized 
regimen consisting of one or more medications.  If the first rescue administration does not control 
the seizures, a second or even third round might be administered.  The second and third round 
might use medications or doses different from the first round of rescue meds. 
Rescue medication will be summarized by treatment group and by active treatment vs. Placebo 
for the following:
x
The number of days rescue medication was taken (normalized to 28 days) will be 
summarized for the T + M period by the mean, standard deviation (SD), median and 
range. The ZX008 treatment group will be compared to the placebo group using a rank 
ANCOVA analogous to that described in Section 6.3.1.1. Specifically, the ANCOVA 
will use ranks of rescue medication frequency during T+M as the response, and will 
incorporate treatment group as a classification factor and the ranks of rescue medication 
frequency during Baseline as a covariate.
 +RVSLWDOL]DWLRQDQG2WKHU5HVRXUFH8WLOL]DWLRQWR7UHDW6HL]XUHV
In order to better understand the healthcare resource burden associated with the management of 
Dravet syndrome, caregivers will be asked which of the following hospital and community-based 
healthcare services they had interactions with over the preceding month:  emergency room 
services, ambulance, planned and unplanned hospitalization, family physician services, speech 
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and language therapy, occupational therapy, and physical therapy.  This information will be 
captured in the CRF.
 ,QFLGHQFHRI6WDWXV(SLOHSWLFXV
The incidence of status epilepticus will be evaluated based on cases captured as such with 
emergency treatment at treatment centers and entered as adverse events into the safety database, 
and also as convulsive seizures lasting longer than 10 min from the seizure diary.  According to 
the International League Against Epilepsy definition, seizures over five minutes duration are to be 
considered SE.   
The number and percentage of subjects with status epilepticus recorded as an AE will be 
presented by treatment group for the baseline and the T+M period per 28 days. 
In addition, from the diary data, change from baseline in the number and percentage of 
convulsive seizures with duration >10 min for the baseline and T+M period will be reported. The 
number and percentage of subjects will be presented by treatment group for the baseline and the 
T+M period per 28 days. 
All seizures recorded in the AE database as status epilepticus should also be included in the 
seizure diary. An edit check will be performed to identify the overlap between seizures related to 
hospitalization for SE and seizures entered into the diary as seizures > 10 min.  (The definition of 
SE includes seizures lasting 5 min or longer, so not all SE will be recorded in the >10 min 
category.) 
To ensure that all instances of SE are accounted for, a composite endpoint will be constructed that 
combines episodes of SE recorded as AEs with any other convulsive seizure with a duration > 10 
min. The ZX008 and placebo groups will be compared on the composite endpoint using a 
Cochran-Mantel-Haenszel test with age group as stratification factor. 
 'XUDWLRQRI3URORQJHG6HL]XUHV
Duration of convulsive seizures at baseline and on treatment will be presented by treatment group 
using categories as <2 min, 2-10 min and >10 min. 
To obtain a baseline probability distribution for the 3 categories, we will proceed as follows: For 
each subject, we will calculate the percentage of their total number of baseline seizures that is in 
each category. (For example, if the subject had 5 seizures, with 2 in the first category and 3 in the 
last category, their percentage distribution would be 40%, 0%, and 60% in the <2, 2-10, and >10 
categories. We can calculate similar numbers for the next subject, and so on.) We will then
average these over all subjects to obtain the % of subjects’ seizures that were <2 min in duration, 
the % between 2-10 min in duration, and the % >10 min in duration. These 3 percentages should 
total 100%. Thus we will obtain a distribution of seizure duration for baseline.
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Using the seizure duration data obtained for the T+M period, we will proceed similarly, to obtain 
a distribution for the T+M period. 
It is expected that treatment with ZX008 will result in shorter duration of seizures (as well as 
fewer seizures) during T+M compared to placebo, i.e., the probability of longer seizures (>10 
min) will be higher for the placebo group than for the ZX008 arms. This may be assessed by 
comparing the probability of a >10 min seizure during T+M to the same during baseline, for a 
treatment group, to the same for the Placebo group. It is expected that the ZX008 group will have 
greater odds of a reduction in proportion of seizures >10 min than the Placebo group. However, 
treatment with ZX008 may result in fewer seizures overall yet the duration of residual seizures 
may not be shorter.  Should the primary or key secondary endpoints be positive for a given 
dose(s), but the duration of seizures not be shortened per above, exploratory evaluations may be 
undertaken to better understand the effect.
 4XDOLW\RI/LIHLQ&KLOGKRRG(SLOHSV\42/&(6FDOH
The parent/caregiver will complete this questionnaire for this assessment that looks at how 
epilepsy affects day-to-day functioning of their child in various life areas, including physical 
activities, well-being, cognition, social activities, behavior and general health, at baseline period 
(Visit 3), at Maintenance period (Visit 8) and at End of study (Visit 12).  There is also one 
question on overall quality of life administered as part of the QOLCE.
The QOLCE scores items with a possible 5 point response.  To calculate subscale scores, the 5 
point item scores will first be reverse coded as necessary so that scores of 5 represent the best 
possible response and 1 represents the worst possible response.  Item scores will then be 
transformed to a 0-100 scale as follows: 1-0, 2-25, 3-50, 4-75, 5-100.  After transformation, a
score for each subject for each subscale is calculated by averaging that subject’s responses to 
each item in the subscale.  The 16 subscale scores per subject are then averaged to obtain an 
overall quality of life score for each subject. The mean and SD across all subjects is then 
calculated for each subscale including the overall quality of life. The higher the subscale and 
overall quality of life scores, the better the response.
Table 2: Subscales of QOLCE:
Domain
Subscale
Item
Section 3: Physical
Physical Restrictions
3.1 a-j
Section 3: Physical
Energy/Fatigue
3.2 a,b
Section 4: Well-being
Depression
4.1 a,d,e,l
Section 4: Well-being
Anxiety
4.1 b,g,j,n,o,p
Section 4: Well-being
Control/helplessness
4.1 c,f,h,i
Section 4: Well-being
Self-esteem
4.1 k,m,q,r,s
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Section 5: Cognition
Attention/Concentration
5.1 a,d,e,f,g
Section 5: Cognition
Memory
5.1 j,k,l,m,n,o
Section 5: Cognition
Language
5.1 p,q,r,s,t,u,v,w
Section 5: Cognition
Other Cognitive
5.1 b,c,h
Section 6: Social Activities
Social Interactions
6.1 c,f,h
Section 6: Social Activities
Social Activities
6.1. a,e, and 6.2
Section 6: Social Activities
Stigma Item
6.1 i
Section 7: Behavior
Behavior
7.1 a,c,f,g,h,i,j,k,l,m,o,q,r,s,t
Section 8: General Health
General Health
8.1
Section 2 (USA Version or 
Section 9 (Australia Version) 
Quality of life item
2.1 or 9.1
Overall Quality of Life
Average of the above 16 
subscale scores
For each treatment group at Baseline and End of Study/ET, the mean (SD) score will be presented 
for each QOLCE subscale and for the overall quality of life score.
In addition, the change from baseline in each QOLCE subscale score will be calculated for each 
subject by subtracting the baseline score from the score measured at End of Study/ET. The 
change from baseline for each treatment group will be summarized by the mean (SD) and 
treatment groups will be compared using a Wilcoxon test. 
Individual subject data for the domains will be listed.
 3HGLDWULF4XDOLW\RI/LIH,QYHQWRU\3HGV4/*HQHULF&RUH6FDOH
The PedsQL 4.0 is a quality of life scale that measures four functional areas (physical, emotional, 
social, and school functioning). The scale is available in age-appropriate instruments with child 
self-report and parent proxy-report formats. In this study, the age appropriate categories for the 
administration of the instrument were ages 2-4, 5-7, 8-12 and 13-18 years, and the Parent Reports 
were used.
There are 8 items for Physical Functioning, and 5 questions each for Emotional, Social, and 
School Functioning. Each of the responses to the 23 items is initially scored on a 5 point Likert 
scale from 0 (Never) to 4 (Almost always). Scores will be linearly transformed to a scale of 0 to 
100, where 0=100, 1=75, 2=50, 3=25 and 4=0, and higher scores mean better health related 
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quality of life. If more than 50% of the items in the scale are missing, the scale scores should not 
be computed. A mean score is calculated as the sum of the items over the number of items 
answered. If some of the answers on a scale are missing but 50% or more of the items in the scale 
are completed, then impute the mean of the completed items in a scale. The scaled results will be 
combined across age categories to produce a single score for each functional area.
A Psychosocial Health Summary score is computed as the sum of the items over the number of 
items answered in the Emotional, Social, and School Functioning Scales. 
A Physical Health Summary score is made up of the Physical Functioning Scale Score.
The Total Score is computed as the sum of all the items over the number of items answered on all 
the Scales.
Descriptive statistics at both Baseline and EOS/ET will be provided for the Psychosocial Health 
Summary score, the Physical Health Summary score and Total Score. 
The change from baseline for the Total Score will be calculated for each subject by subtracting 
the Total Score measured at Baseline from the Total Score measured at End of Study/ET. The 
change from baseline will be summarized with descriptive statistics and treatment groups will be 
compared on the Total Score using a Wilcoxon test.
The next two ratings evaluate the change from baseline in the responsible parent/caregiver’s 
quality of life during the time the subject is in the trial: 
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(4'/6FDOH
The impact on the quality of life of the parent/caregiver responsible for a patient with DS will be 
assessed at Baseline (Visit 3) and at End of study (Visit 12) using the EQ-5D-5L.
The EQ-5D-5L health questionnaire is a health-related quality of life instrument with 5 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension has 5 possible levels: no problems, slight problems, moderate problems, severe 
problems and extreme problems.  
The summary of results will follow the EQ-5D-5L guideline results presentation. For the “Health 
Profiles” descriptive system summary results will show the number, and proportion (%) of 
subjects in each Item score (No Problems, Slight Problems, Moderate Problem, Severe Problem, 
Extreme Problems) by treatment at baseline and at the end of study. In addition, the item scores 
will be classified into two categories as “No Problems” and “Problems”, the latter comprised of 
moderate, severe and extreme problems. Summary results will show number of patients and 
proportion (%) with “No Problems” and with “Problems” by treatment at baseline and at end of 
study time point.   
For the VAS measure of overall self-rated health status, descriptive statistics summary results will 
be presented for the VAS score showing number of subjects, mean, standard deviation, median, 
and range by each treatment at baseline and end of study time points. 
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The change from baseline in VAS will be calculated by subtracting the VAS score at baseline 
from the VAS score obtained at End of Study/ET. The change in VAS will be summarized using 
descriptive statistics, and treatment groups will be compared using a Wilcoxon test.
The quality of life of parent/caregiver individual data will be listed using EQ-5D-5L scale.
 3HGLDWULF4XDOLW\RI/LIH,QYHQWRU\3HGV4/)DPLO\,PSDFW0RGXOH
6FDOH
The PedsQL™ Family Impact Module was designed to measure the impact of pediatric chronic 
health conditions on parents and the family. The PedsQL™ Family Impact Module measures 
parent self-reported physical, emotional, social, and cognitive functioning, communication, and 
worry. The Module also measures parent-reported family daily activities and family relationships.
There are 6 items for Physical Functioning, 5 items each for Emotional Functioning, Cognitive 
Functioning and Worry, 4 for Social Functioning, and 3 for Communication. There are 
additionally 3 questions for Daily Activities and 5 for Family Relationships. 
Each of the responses to the 36 items is initially scored on a 5 point Likert scale from 0(Never) to 
4 (Almost always). Scores will be linearly transformed to a scale of 0 to 100, where 0=100, 1=75, 
2=50, 3=25 and 4=0, and higher scores mean better health related quality of life. If more than 
50% of the items in the scale are missing, the scale scores should not be computed. A mean score 
is calculated as the sum of the items over the number of items answered. If some of the answers 
on a scale are missing but 50% or more of the items in the scale are completed, then impute the 
mean of the completed items in a scale.
The Parent HRQL Summary Score (20 items) is computed as the sum of the items divided by the 
number of items answered in the Physical, Emotional, Social, and Cognitive Functioning scales. 
The Family Functioning Summary Score (8 items) is computed as the sum of the items divided by 
the number of items answered in the Daily Activities and Family Relationships scales.
The Total Score is the sum of all 36 items divided by the number of items answered. 
Descriptive statistics for baseline and EOS/ET will be provided for the summary scores. The 
change from baseline will be calculated and ZX008 and placebo groups will be compared using 
the same methods as specified for the PedsQL 4.0 analysis.
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The parent/caregiver will rate their global impression of the subject’s condition during Titration 
period (Visit 5 and Visit 6), Maintenance period (Visit 8 and 10), and at End of study (Visit 12). 
The CGI-I scale measures the change in the subject’s clinical status from a specific point in time, 
i.e., the Baseline Period. The CGI-I rating scale permits a global evaluation of the subject’s 
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improvement over time. The severity of a patient’s condition is rated on a 7-point scale ranging 
from 1 (very much improved) to 7 (very much worse) as follows: 
1=very much improved 
2=much improved 
3=minimally improved
4= no change 
5=minimally worse
6=much worse 
7=very much worse 
The mean (SD) CGI-I score, and the number and percentage of subjects who showed 
improvement (i.e., had a score of 3 or lower), and the number and percentage who did not 
improve (i.e., had a score of 4 or higher) will be presented for each for each treatment group at 
each assessment time point. Each assessment time point will also include a comparison between 
each active treatment and the placebo group using the Cochran-Mantel-Haenszel test stratified by 
age group, and a frequency distribution of the number and percentage of subjects in each category 
in the scale. A histogram of the frequency distribution will be presented. 
The number and percentage of subjects who showed good or very good improvement (i.e., had a 
score of 2 or lower), and the number and percentage who did not improve (i.e., had a score of 3 or 
higher) will also be presented for each for each treatment group at each assessment timepoint as 
an exploratory analysis.  
Individual subject CGI-I data will be listed.
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CGI-I score data assessed by the investigator will be summarized and analyzed by the same 
method used for CGI-I score data recorded by parent/caregiver as above.
6.3.4 Exploratory Analyses 
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The parent/caregiver will be asked to indicate the appropriate response that adequately describes 
their child’s sleep quality since starting IMP at Titration period (Visit 6), Maintenance period 
(Visit 8 and 10), and at End of study (Visit 12). The following question will be asked: 
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6LQFH\RXUFKLOGKDVVWDUWHGWDNLQJWKHVWXG\PHGLFDWLRQLQWKLVVWXG\KDYH\RXQRWLFHGWKDW
VKHKDVEHHQZDNLQJLQWKHPLGGOHRIWKHQLJKWRUYHU\HDUO\LQWKHPRUQLQJPRUHWKDQXVXDO"
The response will be noted as below- 
x
My child’s sleep is more disturbed than it was before s/he started the study medication  
x
My child’s sleep patterns are the same as they were before starting the study medication 
x
My child sleeps better than s/he did before starting the study medication  
For each time point, the number and % of subjects in the response categories will be presented, 
by treatment group. 
All sleep quality assessment data will be presented in the subject data listing.
 &KDQJHIURPEDVHOLQHLQPHDOWLPHEHKDYLRU
The parent/caregiver will be asked to indicate the appropriate response that adequately describes 
their child’s eating behavior since starting IMP at Titration period (Visit 6), Maintenance period 
(Visit 8 and 10), and at End of study (Visit 12). The following question will be asked: 
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VKHKDVKDGDFKDQJHLQWKHLUPHDOWLPHEHKDYLRU"
x
My child has worse meal time behavior since starting the study medication 
x
My child’s meal time behavior has not changed since starting the study medication 
x
My child has improved his/her meal time behavior since starting the study medication 
For each time point, the number and % of subjects in the response categories will be presented, 
by treatment group. 
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The Karolinska Sleepiness Scale will be administered according to the schedule visit time points 
in Table 1.  The Karolinska Sleepiness scale is a self-report scale that measures the subject’s 
drowsiness. It is a 9-point verbally anchored scale, which ranges from ‘extremely alert’ at one 
end of the scale to ‘extremely sleepy – fighting sleep’ at the other end of the scale. Within this 
study, the scale will be completed by the observer in an exploratory manner. 
Score
Description
1
Extremely alert
2
Very alert
3
Alert
4
Rather alert
5
Neither alert nor sleepy
6
Some signs of sleepiness
7
Sleepy, but no effort to keep awake
8
Sleepy, some effort to keep awake
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9
Very sleepy, great effort to keep awake, fighting sleep
Descriptive statistics will be presented for each time point where measured and will include 
number and percent of subjects in each category, mean, standard deviation, median, minimum 
and maximum. The ZX008 0.5 mg/kg/day and placebo groups will be compared on change from 
baseline using a Wilcoxon rank sum test.  
Additionally, scores of 1-6 will be categorized as “Active” and scores of 7-9 categorized as 
“Sleepy”. These categorizations will be summarized using counts and percent (%) of subjects by 
treatment by each visit time point. A Fisher’s exact test will compare the proportion of subjects 
reporting sleepy scores (7, 8 or 9) in the ZX008 0.5 mg/kg/day to the analogous proportion in the 
placebo group. 
All Karolinska Sleepiness data will be presented in the subject data listing.
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As stated in the protocol, a Dravet syndrome composite endpoint will be created using outcome 
measures from the protocol to create a composite endpoint to assess treatment of Dravet 
syndrome without emphasis on a single endpoint. The outcomes under evaluation in this study 
will include measures for example such as seizure frequency, behaviour, quality of sleep, and 
others. The measures to select the composite are identified as part of a project with physician 
interviews and interviews with patient’s families and are part of a project on multi-dimensional 
outcome measures discussed in the protocol. A separate SAP will be developed to describe the 
exploratory analyses that test the psychometric development and performance (or measurement 
accuracy) of the core outcome measures for the composite endpoint and the results will be 
reported separately.
6.4 SAFETY ANALYSES
All safety analyses will be performed for the Safety population (SAF) and will be reported by 
treatment group, and overall. 
6.4.1 Adverse Events
An AE is defined as any unfavorable and unintended sign (including an abnormal, clinically 
significant laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. The period of observation for adverse events extends from the time the 
subject gives informed consent until the end of the titration/transition period (Visit 13). For 
patients who continue into the open-label extension study, AEs of special interest will continue to 
be monitored for up to 6 months after the last dose of study medication. 
A TEAE is defined as any AE that based on start date information occurs after the first intake of 
study treatment. All other AEs occurring after enrollment and prior to the first administration of 
study treatment are defined as non-treatment emergent AEs (non-TEAEs).
Any missing relationship will be considered as “related.”
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The severity of AEs (whether non-serious or serious AEs) will be assessed by the investigator as 
follows: 
Severity Definition of Adverse Events:
Mild - A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.
Moderate - A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant.
Severe - A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
Any missing severity will be imputed as “severe.”
The original terms used by the investigators in the eCRFs to identify AEs will be coded using the 
most recent version of the MedDRA implemented by the sponsor at the end of the study. 
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The number and percent of patients with at least one of the following events will be 
summarized in an overall summary table: 
x
TEAE. 
x
Serious TEAE
x
Related TEAE
x
Related serious TEAE. 
x
TEAE leading to treatment discontinuation 
x
Death
The percentage denominator for the calculation of percentage will be the number of subjects in 
the SAF. 
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The following summaries will display the number and percentage of subjects with adverse events 
by system organ class (SOC) and preferred term (sorted alphabetically) for each treatment group 
and overall: 
x
All TEAEs 
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x
Serious TEAEs  
x
TEAEs by Maximum Severity
x
Study Drug Related TEAEs 
x
All AEs that lead to premature discontinuation from the study 
An additional summary will tally the number and percent of subjects in each treatment group who 
experience an AE that occurs in at least 5% of subjects. The summary will be presented by 
preferred term in decreasing order of incidence.
The summaries will be provided for the double-blind treatment period. No inferential statistical 
methods (i.e., methods that yield p-values) will be used to compare treatment groups on the 
frequency or severity of AEs.
Additionally, the following listings will be produced for all enrolled subjects: 
x
All AEs, events considered to be TEAE will be identified in the listing
x
Serious AEs
x
AEs that lead to premature discontinuation from the study 
x
Deaths
6.4.2 Adverse Events of Special Interest (AESI)
As per ICH guidance (E2F Development Safety Update Report [2011]), the sponsor has identified 
the following AESIs for the ZX008 in below table (Table 14 of protocol)- 
Table 5 – Adverse Events of Special Interest:
Metabolic/Endocrine
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Neuropsychiatric
1.Suicidal thoughts, ideation or gestures
All adverse events of special interest will be listed separately. 
6.4.3 Physical Examination 
A complete physical examination will be performed at Screening Visit (Visit 1), day of 
randomization (visit 3) prior to first dose of study medication, end of study (EOS) visit, and at the 
Cardiac follow-up visit for patients who do not enter the open-label extension study. An 
abbreviated physical exam is performed at Day 15 (Visit 5), 22 (Visit 6), 50 (Visit 8), 78 (Visit 
10) and at the Cardiac follow-up visit for patients who do not enter the open-label extension 
study.   
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All physical examination results will be presented in a subject data listing, including the 
description of abnormalities. New, clinically meaningful abnormalities are reported as adverse 
events.
6.4.4 Neurological Examination
A complete neurological examination will be performed at Screening Visit (Visit 1) and EOS 
(Visit 12). 
All neurological examination results will be presented in a subject data listing including the 
description of abnormalities.
6.4.5 Vital Signs, Weight, and BMI 
Vital signs data including blood pressure, heart rate, temperature, respiratory rate, weight, and 
BMI will be documented for subjects during study at screening visit (visit 1), randomization (visit 
3) prior to first dose of study medication, titration period (visit 5 and visit 6), and maintenance 
period (visit 8 and visit 10) and at EOS visit (visit 12). 
The mean values and change from baseline to each on-study visit time point evaluation will be 
summarized for vital signs and weight by treatment group.  Vital signs, Weight and BMI data will 
be presented for each patient in a data listing. The most extreme abnormal values for each subject 
will also be listed.
6.4.6 Electrocardiogram
12-Lead ECGs data (PR, QRS, QT, QTcF, and HR) will be documented for subjects during study 
at baseline (Visit 1 and Visit 3), Day 50 (Visit 8), at End of Study (Visit 12) and at Cardiac 
Follow-up (Visit 14).
Analysis of Echocardiograms will be included in a separate report from Biomedical Systems.
6.4.7 Doppler Echocardiography
Doppler echocardiography will be conducted at a facility with experience for the subject’s age at 
Screening, Maintenance period (Visit 8), End of study (Visit 12), and Cardiac Follow-up (Visit 
14). ECHO uses ultrasound technology to examine the heart or blood vessels. An ECHO uses 
high frequency sound waves to create an image of the heart while the use of Doppler technology 
allows determination of the speed and direction of blood flow by utilizing the Doppler effect. 
Predetermined standard guidelines on the proper evaluation of certain measurements, as well as 
abnormality thresholds, were constructed by the sponsor’s IPCAB prior to study initiation. These 
thresholds are provided in the table below: 
Signs on ECHO indicative of potential
Valvulopathy 
x
valve regurgitation (aortic or mitral)
x
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Normal Values for Children 2-18 years
x
No regurgitation
x
Mean Mitral valve gradient < 4 mmHg
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or pulmonary)
x
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x
0HDQ$RUWLFYDOYHJUDGLHQW
mmHg
x
Mean Tricuspid valve gradient >
4mmHg
x
Mean Pulmonary valve gradient > 
21mmHg 
x
Mean Aortic valve gradient < 15 
mmHg
x
Mean Tricuspid valve gradient < 
4mmHg
x
Mean Pulmonary valve gradient < 
21mmHg 
Signs on ECHO indicative of pulmonary hypertension
a. Tricuspid Regurgitation Jet velocity > 2.8 msec with or without the following findings OR 
b. One of the following findings in the absence of being able to measure Tricuspid Regurgitation 
Jet velocity:
i. Change in right ventricle/left ventricle basal diameter ratio > 1.0
ii. Right ventricular acceleration time < 100 msec
iii. Dilatation of the inferior caval vein (diameter>21 mm and <50% inspiratory decrease) 
and/or right atrium
iv. Change in the geometry of the interventricular septum in systole (flattening) with left 
ventricular eccentricity index >1.1 in systole and/or in diastole
v. Early diastolic pulmonary regurgitation velocity > 2.2 m/sec 
vi. Tricuspid Anular Plane Systolic Excursion below 18 mm or below Z-score – 2
Results of ECHOs will be presented in a separate report from Biomedical Systems. 
6.4.8 Tanner Staging
Tanner Staging will be assessed for subjects >7 years old during the study at baseline period 
(Visit 3) and End of study (Visit 12). Conceptually, pubertal maturation can be described in terms 
of sequence, timing, and tempo.  Puberty consists of a series of predictable events, and the 
sequence of changes in secondary sexual characteristics has been categorized by several groups.  
The onset and progress of pubertal changes will be recorded on a 5 point scale for boys and girls 
separately. Boys are rated for genital development and pubic hair growth through stage I to stage 
V. Girls are rated for breast development and pubic hair growth through stage I to stage V.
The number and percentage of subjects in each Tanner Stage will be presented for all visits by 
treatment group separately for boys and girls overall and also broken out for the following age 
groups: 
>7 years to <=11,  
>11 years to <=15, 
>15 years to <=18. 
All Tanner staging data will be presented in the subject data listing.
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6.4.9 Laboratory Parameters
Laboratory safety parameters will be analyzed by a central laboratory using standard validated 
methods. 
All laboratory safety data will be collected as per the schedule of assessments given in Table 2.
The following laboratory parameters will be summarized: 
x
Hematology: hemoglobin, hematocrit, erythrocytes, erythrocyte mean corpuscular 
volume, leukocytes, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, neutrophils, lymphocytes, monocytes, eosinophils, basophils and platelets 
x
Blood Biochemistry: albumin (ALB), alkaline phosphatase (AP), alanine 
aminotransferase (ALT; SGPT), aspartate aminotransferase (AST; SGOT), bicarbonate, 
blood urea nitrogen (BUN), calcium (Ca), carbon dioxide (CO2), chloride (Cl), 
creatinine, creatine kinase, gamma-glutamyl transferase (GGT), globulin, glucose, lactate 
dehydrogenase (LDH), phosphorus, potassium (K), sodium (Na), thyroid function (T3, 
T4, and thyroid stimulating hormone [TSH]), total bilirubin, direct bilirubin, total 
cholesterol, total protein, triglycerides, uric acid.  
x
Tests of growth and precocious puberty: Growth hormone (GH), insulin-like growth 
factor-1 (IGF-1, low sensitivity), prolactin, Luteinizing Hormone (LH), Follicle 
Stimulating Hormone (FSH), testosterone, estradiol 
x
 Coagulation: Prothrombin time (PT)/International normalized ratio (INR), activated 
partial thromboplastin time (PTT) 
x
Whole blood cannabidiol (CBD) 
x
Urinalysis: analysis for pH, glucose, ketones, nitrite, protein, bilirubin, urobilinogen, 
leukocyte esterase, and occult blood. Microscopic analysis will be performed for blood, 
all cell types, and casts.
x
Urine pregnancy test: Urine pregnancy testing will be performed in female subjects of 
childbearing potential. 
x
Urine THC panel
Observed continuous laboratory data will be summarized by type of laboratory test/parameter by 
treatment group. Changes from baseline will also be presented for all continuous laboratory 
parameters by treatment group over time.
Categorical laboratory parameters will be summarized by presenting the number and % of 
subjects in each category by visit and by treatment arm. 
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All laboratory values (including invalid values, reference ranges, and possible flags (low, high,)) 
will be presented in the subject data listings.
A listing of subjects with Potentially Clinical Significant laboratory results will be provided. In 
this listing, those values outside the sponsor defined alert ranges will be marked and further 
available details about clinical relevance and diagnosis will be added.
A special listing will be presented which will provide for each subject and each lab parameter the 
maximum out-of-range value over both Baseline and during the T+M period. The visit on which 
this highest or lowest value occurred will be included. 
6.4.10 Columbia-Suicide Severity Rating Scale 
Columbia-Suicide Severity Rating Scale data will be collected as per at screening visit (Visit 1), 
at randomization (visit 3), Titration period (at visit 6), maintenance period (at Visit 8 and 10) and 
at End of study visit (Visit 12). 
Subjects who are younger than 7 years chronologically, or who are judged by the investigator not 
to have the mental capacity to understand the questions as specified on the C-SSRS, will not 
complete the rating. The investigator should use his/her judgment to substitute intellectually-
appropriate questions to probe the tendency for self-harm.
If a subject with the intellectual capacity to complete the C-SSRS has their 7th birthday during 
the study, use of the C-SSRS should be initiated at subsequent visits. 
All individual subject C-SSRS data will be listed.
Suicidal Ideation:
The following outcomes are C-SSRS categories for suicidal ideation and have binary responses 
(yes/no):
Category
Outcome Description
1
Wish to be dead
2
Non-specific active suicidal thoughts
3
Active suicidal ideation with any methods (not plan) without intent to act
4
Active suicidal ideation with some intent to act, without specific plan
5
Active suicidal ideation with specific plan and intent
Suicidal Behavior:
The following outcomes are C-SSRS categories for suicidal behavior and have binary responses 
(yes/no):
Category
Outcome Description
6
Preparatory acts or behavior
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7
Aborted attempt
8
Interrupted attempt
9
Actual attempt (non-fatal)
10
Completed suicide
Suicidal behavior is assessed as a “yes” answer at any time during the T + M period to any one of 
the five questions (6-10) above.  The number and percentage of subjects who had suicidal 
behavior, as well as the number and percentage having a “yes” response to each category (6-10) 
at least once during the T + M period. The denominator will be the number of subjects 
completing the C-SSRS at least once during the T + M period. 
Self-injurious behavior without suicidal intent:
The number and percentage of subjects having reported anytime during the T+M period 
experiencing a ‘Self-injurious behavior without suicidal intent’ event (Question 11) will be 
provided.
6.4.11 Brief Rating Inventory of Executive Function (BRIEF)
The Behavior Rating Inventory of Executive Function (BRIEF™) and its preschool version, 
BRIEF-P, are standardized, validated rating scales to measure executive function in children 
within the home and school environments that will be assessed by the parent according to the 
schedule in Table 1 (i.e. at Randomization (Visit 3), at Maintenance period (Visit 8) and at End of 
study visit (Visit 12).  
The BRIEF measures multiple aspects of executive functioning; scales include Inhibit, Shift, 
Emotional Control, Initiate, Working Memory, Plan/Organize, Organization of Materials and 
Monitor.  
The original BRIEF was the basis for the development of the BRIEF-P. The BRIEF-P Rating 
Form consists of 63 items that measure various aspects of executive functioning: Inhibit, Shift, 
Emotional Control, Working Memory, and Plan/Organize.  
For the BRIEF and the BRIEF-P, mean scores at Baseline, End of Study/ET and mean change 
from baseline to End of Study/ET, and descriptive statistics will be presented by treatment group 
for the Safety population (SAF). The change from baseline in the ZX008 and placebo groups will 
be compared using Wilcoxon tests. 
6.5 PHARMACOKINETICS  (PK/PD) ANALYSIS
The results of the analysis of PK data collected in subjects from Cohort 2 will be reported 
separately.
In the main report (CSR), individual subject plasma concentration data from cohort 2 will be 
listed. Summary statistics for the concentration data will be provided by analyte.
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6.6 ANALYSIS OF OTHER ASSESSMENTS
Not applicable.
6.7 INTERIM ANALYSIS
No formal interim analysis of this specific study is planned. 
6.8 INDEPENDENT DATA AND SAFETY MONITORING COMMITTEE  
The IDSMC is an independent advisory body that monitors participant safety, data quality and 
progress of the clinical trial. The IDSMC charter will outline the roles and responsibilities of the 
committee and guide its operations and frequency of meetings. The IDSMC will consist of 
individuals external to the sponsor who have relevant clinical trial expertise and experience in 
safety assessment.
At regularly defined intervals, the IDSMC will convene to review and monitor study progress, 
AEs and SAEs, other measures of safety such as ECGs or ECHOs, and efficacy data as dictated 
by the charter. 
The IDSMC will:
x
Be responsible for providing recommendations to the sponsor surrounding study conduct 
matters that affect safety.
x
Review safety data at ad hoc time points and identify if significant safety concerns arise 
during the study. 
x
Review pharmacokinetic data and any other data that may affect subject continuation.
x
Make recommendations regarding the continuation, suspension, or termination of the 
study. 
The list of tables, listings, and figures will be provided to the IDSMC as per IDSMC charter.

6.9 CHANGES TO METHODS PLANNED IN THE PROTOCOL 
x
Protocol states that safety data will be summarized separately for the titration and 
maintenance periods as well as for the combined T+M period. Instead safety will be 
summarized only for the combined T+M.. 
x
Protocol states that subjects in the safety population will be summarized by the treatment 
actually received. However, safety data will be presented by randomized treatment group 
except where noted otherwise.
x
Protocol states that a sensitivity analysis for the primary efficacy endpoint will be 
conducted by adding a factor indicating whether a subject had a change in prescribed 
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dose or type of concomitant AED medication during the T+M Period, however this is not 
planned to be conducted.  
x
The protocol stated that the longest interval between convulsive seizures will be analyzed 
using a log-rank test. Instead groups will be compared with a Wilcoxon test.  
x
Responder analyses – 7KHSURWRFROLQFOXGHGDUHVSRQVHDQDO\VLVDVRQHRIWKHNH\
secondary endpoints. It was decided to not include this in the hierarchical testing of 
secondary endpoints.  
x
An analysis of the percentage of subjects who achieve a 25% reduction in seizures was 
added., 
x
The Protocol states that the BRIEF rating scale will be used to evaluate cognition in 
children aged 2-18.  The BRIEF-P will be used for children aged 2-4, and the BRIEF will 
evaluate children aged 5-18.  The Protocol further states that the cognition subscale of the 
BRIEF will be used to evaluate cognition. The BRIEF and the BRIEF-P will be used to 
evaluate cognition.
x
The Protocol states the Clinical Global Impression ratings by Investigator and Caregiver 
are exploratory endpoints. They are secondary endpoints. 
x
The protocol states the sample size is approximately 70 randomized subjects.  As 
explained in Section 6.1.10, the sample size was adjusted to approximately 80 
randomized subjects based on data from the completed study of Epidiolex in Dravet 
syndrome. 

7. REFERENCES
Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O.  Severe myoclonic epilepsy in infancy: 
Dravet syndrome.  Adv Neurol 2005; 95: 71-102. 
Dravet C. Les epilepsies graves de l’enfant.  Vie Med. 1978;8:543–548.
Dravet C.  Severe myoclonic epilepsy in infants and its related syndromes.  Epilepsia 2000; 41:7.
EMA 2007.  Stiripentol SmPC and EPAR Scientific Discussion.  Available at 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000664/huma
n_med_000742.jsp&mid=WC0b01ac058001d124.  Accessed 31 July 2015. 
Hurst, DL.  Epidemiology of severe myoclonic epilepsy of infancy.  Epilepsia 1990;31:397-400.
Sabaz M, Carins D, Lawson J, Nheu N et al. Validation of a New Quality of Life Measure for 
Children with Epilepsy. Epilepsia 2000; 41(6):765-774. 
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Sabaz M, Carins D, Lawson J, Nheu N et al. The health related quality of life of children with 
refractory Epilepsy: A comparison of those with and without intellectual disability 2001; 
42(5):621-628. 
ICH Topic E2F: Development Safety Update Report, 2011. 
Shorvon S, Tomson T.  Sudden unexpected death in epilepsy. Lancet 2011;378: 2028–38. 
Talarska D. The usefulness of Quality of Life Childhood Epilepsy (QOLCE) questionnaire in 
evaluating the quality of life of children with epilepsy. Advances Med. Sci 2007; 52 suppl 1:191-
193.
8. APPENDICES
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APPENDIX 1: List of Tables, Figures, and Listings
Table/ Figure/ Listing
Number
Table Header
14.1
Demographic data and other baseline characteristics
14.1.1
Subject disposition
Table
14.1.1.1b
Overall Subject Disposition – All Enrolled Subjects
Table
14.1.1.2b
Major Protocol Deviations – Safety Population
Table 
14.1.1.3b
Study Populations
14.1.2
Demographic and other baseline characteristics
Table
14.1.2.1b
Demographic and Baseline Characteristics – Safety Population
Table
14.1.2.2b
Demographic and Baseline Characteristics – mITT Population
14.1.3
Medical history
Table
14.1.3.1b
Medical History– Safety Population
14.1.4
Prior and concomitant medication/treatment
Table
14.1.4.1b
Prior Medications and Therapies/Treatments – Safety Population
Table
14.1.4.2b
Concomitant Medications and Therapies/Treatments – Safety 
Population
Table
14.1.4.3b
Prior Antiepileptic Treatment  – Safety Population
Table
14.1.4.4.1b
Concomitant Antiepileptic Treatment – Safety Population
Table
14.1.4.4.2b
Number of Subjects by Number of Concomitant Antiepileptic 
Treatments – Safety Population
14.1.5
Treatment Exposure and compliance
Table
14.1.5.1b
Duration of Treatment Exposure – Safety Population
Table 
14.1.5.2b
Compliance to IMP Intake – Safety Population
14.2
Efficacy, pharmacokinetics, and pharmacodynamics
14.2.1
Efficacy – ZX008 vs Placebo
Table 
14.2.1.1.1b
Convulsive Seizure Frequency per 28 Days: Summary Statistics –
mITT Population
Table 
14.2.1.1.2b
Convulsive Seizure Frequency per 28 Days: Summary Statistics by 
Age Group – mITT Population
Table 
14.2.1.2b
Convulsive Seizure Frequency per 28 Days : Parametric Analysis –
mITT Population
Table 
14.2.1.3b
Convulsive Seizure Frequency per 28 Days : Nonparametric 
Analysis – mITT Population
Table 
14.2.1.4b
Percentage Change in Convulsive Seizure Frequency per 28 Days: 
Parametric Analysis – mITT Population
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Table 
14.2.1.5b
Percentage Change in Convulsive Seizure Frequency per 28 Days: 
Nonparametric Analysis – mITT Population
Table
14.2.1.6b
Mean Convulsive Seizure Frequency – Exploratory Efficacy 
Analysis of Subjects who are SCN1A Mutation Positive – mITT 
Population
Table 
14.2.1.7b
Convulsive Seizure Frequency per 28 Days: Parametric Analysis –
PP Population
Table 
14.2.1.8b
Convulsive Seizure Frequency per 28 Days: Nonparametric 
Analysis – PP Population
Table 
14.2.1.9b
Percentage Change in Convulsive Seizure Frequency per 28 Days:
Parametric Analysis - PP Population
Table 
14.2.1.10b
Percentage Change in Convulsive Seizure Frequency per 28 Days: 
Nonparametric Analysis – PP Population
Table 
14.2.1.11b
Percentage Change in Convulsive Seizure Frequency per 28 Days 
by Baseline Convulsive Seizure Frequency (BCSF) Category: 
Parametric Analysis – mITT Population
14.2.2
Efficacy – Proportion of subjects who achieve various %
reductions in convulsive seizure frequency
Table
14.2.2.1.1b
Percent Reduction in Convulsive Seizure Frequency – mITT 
Population
Table
14.2.2.1.2b
Percent of Subjects Achieving Complete or Nearly Complete 
Convulsive Seizure Freedom – mITT Population
Figure
14.2.2.2b
Cumulative Response Curve for % Reduction in Seizure Frequency 
per 28 Days per 28 Days  – mITT Population
Table
14.2.2.3b
Percent Reduction in Convulsive Seizure Frequency – PP
Population
Figure
14.2.2.4b
Cumulative Response Curve for % Reduction in Convulsive 
Seizure Frequency per 28 Days - PP Population
Figure
14.2.2.5b
Cumulative Response Curve for % Subjects Experiencing Various 
% Reductions in Convulsive Seizure Frequency – All Subjects 
Increased and Decreased - mITT Population
14.2.3
Efficacy – Longest interval between convulsive seizures
Table
14.2.3.1b
Duration of Longest Interval (Days) between Convulsive Seizures 
– mITT Population
Figure
14.2.3.2b
Boxplot of Duration of Longest Interval between Convulsive
Seizures – mITT Population
Table
14.2.3.3b
Duration of Longest Interval (Days) between Convulsive Seizures
– PP Population
14.2.4
Efficacy – Number of convulsive seizure free days
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Table
14.2.4.1b
Number of Convulsive Seizure Free Days per 28 Days: Parametric 
Analysis – mITT Population
Table
14.2.4.2b
Number of Convulsive Seizure Free Days per 28 Days: 
Nonparametric Analysis – mITT Population
14.2.6
Efficacy – Change from baseline in non-convulsive and 
convulsive + non-convulsive seizure frequency
Table
14.2.6.1b
Change from Baseline in Non-Convulsive Seizure Frequency:
Nonparametric Analysis – mITT Population
Table
14.2.6.2b
Change from Baseline in Non-Convulsive Seizure Frequency by 
Seizure Type: Nonparametric Analysis – mITT Population
Table
14.2.6.3b
Change from Baseline in Convulsive + Non-Convulsive Seizure
Frequency: Nonparametric Analysis – mITT Population
Table
14.2.6.4b
Change from Baseline in Convulsive Seizure Frequency by Seizure 
Type: Nonparametric Analysis – mITT Population
14.2.7
Efficacy – Incidence of rescue medication
Table
14.2.7.1b
Days with Rescue Medication Usage  – mITT Population
Table
14.2.7.2b
Days with Rescue Medication Usage – PP Population
14.2.8
Efficacy – Incidence of hospitalization to treat seizure
Table
14.2.8.1b
Hospitalization and Other Healthcare Resource Utilization to Treat 
Seizure – mITT Population
14.2.9
Efficacy – Incidence of status epilepticus and Duration of 
Prolonged Seizures
Table
14.2.9.1b
Number of Episodes of Status Epilepticus (SE) - mITT Population
Table
14.2.9.2b
Duration of Seizures – Distribution - mITT Population
14.2.10
Efficacy – Clinical Global Impression – Improvement rating by 
Parent/Caregiver and Investigator
Table
14.2.10.1b
Clinical Global Impression – Improvement (CGI-I) Rating by 
Parent/Caregiver – mITT Population
Figure
14.2.10.2b
CGI-I Rating by Parent/Caregiver – mITT Population
Table
14.2.10.3b
Clinical Global Impression – Improvement Rating by Investigator –
mITT Population
Figure
14.2.10.4b
CGI-I Rating by Investigator – mITT Population
14.2.11
Efficacy – Quality of Life in Childhood Epilepsy Scale
Table
14.2.11.1b
Quality of Life in Childhood Epilepsy (QOLCE) – mITT 
population
14.2.12
Efficacy – Peds QL
Table
14.2.12.1b
Pediatric Quality of Life Inventory (Peds QL) - (Version 4.0) -
Parent Report – mITT Population
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Table
14.2.12.2b
PedsQL Family Impact Module (Version 2.0) – Parent Report –
mITT Population
14.2.13
Efficacy –Quality of Life of the Parent /Caregiver using EQ-
5D-5L Sale
Table
14.2.13.1b
QOL of Parent/Caregiver based on EQ-5D-5L – Health Profile 
Summary Original Response Categories  – mITT Population
Table
14.2.13.2b
QOL of Parent/Caregiver based on EQ-5D-5L - Health Profile 
Summary Using Dichotomized Response Categories – mITT 
Population
Table
14.2.13.3b
QOL of Parent/Caregiver based on EQ-5D-5L - Overall Health 
Status Using VAS (0-100) Scale - mITT Population
14.2.14
Sleep Quality and Mealtime Behavior
Table
14.2.14.1b
Sleep Quality  and Mealtime Behavior  – mITT population
14.2.15
Karolinska Sleepiness Scale
Table
14.2.15.1b
Karolinska Sleepiness Scale – Frequency Distribution – mITT 
population
Table
14.2.15.2b
Karolinska Sleepiness Scale – Summary Statistics – mITT 
population
14.3
Safety
14.3.1
Display of adverse events
Table
14.3.1.1b
Overview of Number of Subjects with TEAE – Safety Population
Table
14.3.1.2b
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term – Safety Population 
Table
14.3.1.3b
TEAEs Leading to Study Discontinuation by Primary SOC and PT 
– Safety Population 
Table
14.3.1.4b
Serious TEAEs by Primary SOC and PT – Safety Population
Table
14.3.1.5b
Study Drug Related TEAEs by Primary SOC and PT – Safety 
Population
Table
14.3.1.6b
TEAEs by Maximum Severity by Primary SOC and PT – Safety 
Population 
Table
14.3.1.7b
Treatment-Emergent Adverse Events OFFXUULQJLQRISubjects 
by MedDRA System Organ Class and Preferred Term - Safety 
Population
Table
14.3.1.8b
Overview of Number of Subjects with Treatment-Emergent 
Adverse Events of Special Interest (AESI) – Safety Population
Table
14.3.1.9b
Adverse Events of Special Interest (AESI) by MedDRA System 
Organ Class and Preferred Term – Safety Population
14.3.2
Listings of Deaths, Other Serious and Significant Adverse 
Events
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Table
14.3.2.1b
Listing of Deaths – Safety Population
Table
14.3.2.2b
Listing of SAEs – Safety Population
Table
14.3.2.3b
Listing of Discontinuations Due to AE – Safety Population
14.3.4
Laboratory value
Table
14.3.4.1b
Laboratory Parameters – Hematology – Safety Population
Table
14.3.4.2b
Laboratory Parameters – Biochemistry – Safety Population
Table
14.3.4.4.1b
Laboratory Parameters – Urinalysis (Quantitative Parameters) –
Safety Population
Table
14.3.4.4.2b
Laboratory Parameters – Urinalysis Categorical – Safety 
Population
Table
14.3.4.5b
Tests of Growth, Precocious Puberty and Thyroid Function –
Safety Population
Table
14.3.4.6b
Epilepsy Genotype Panel – Safety Population
14.4.1
Vital Signs
Table
14.4.1.1b
Vital Signs Parameters – Safety Population
14.4.4
Tanner Staging
Table
14.4.4.1b
Tanner Staging by Age Group for Boys – Safety Population
Table
14.4.4.2b
Tanner Staging by Age Group for Girls – Safety Population
14.4.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
Table
14.4.5.1b
Columbia Suicide Severity-Rating Scale (C-SSRS) - Number of
Subjects with Suicidal Ideation, Suicidal Behavior, and Self-
Injurious Behavior without Suicidal Intent based on the C-SSRS  – 
Safety Population
Table
14.4.5.2b
Columbia Suicide Severity-Rating Scale (C-SSRS) - Shift Table of 
Changes in C-SSRS Categories During Treatment - Safety 
Population 
14.4.6
Brief Rating Inventory of Executive Function- (BRIEF)
Table
14.4.6.1b
Brief Rating Inventory of Executive Function Preschool Version 
(BRIEF-P) – Safety Population 
Table
14.4.6.2b
Brief Rating Inventory of Executive Function (BRIEF) – Safety 
Population
16.2
Subject data listing
16.2.1 
Subject disposition and discontinuation
Listing
16.2.1.1b
Subject Completion/Discontinuation
16.2.2
Protocol deviations
Listing
16.2.2b
Major Protocol Deviations
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16.2.3
Subjects excluded from analysis
Listing
16.2.3.1b
Subjects Excluded from the Per Protocol Population
Listing
16.2.3.2b
Subject Allocation to Trial Populations 
16.2.4 
Demographic data and other baseline characteristics
Listing
16.2.4.1.1b
Demographic and Baseline Characteristic Data 
Listing
16.2.4.1.2b
Percentage Change from Baseline in Weight and BMI
Listing
16.2.4.2b
Medical History 
Listing
16.2.4.3b
Prior and Concomitant Medications and Therapies/Treatments 
Listing
16.2.4.4b
Prior and Concomitant Anti-Epileptic Drugs (AEDs)
Listing
16.2.4.5b
Rescue Medications
16.2.5
Treatment exposure and compliance
Listing
16.2.5.1b
IMP Intake per Day during Treatment 
Listing
16.2.5.2b
IMP Intake – Self Reported % Compliance
Listing
16.2.5.3b
Drug Accountability and Compliance to Study Treatment by Visit
16.2.6
Efficacy data
Listing
16.2.6.1b
Convulsive Seizure – Duration and Number of Occurrences per 
Subject (Diary data) 
Listing
16.2.6.2b
Non-Convulsive Seizure – Duration and Number of Occurrences 
per Subject (Diary data) 
Listing
16.2.6.3b
Longest Interval between Convulsive Seizures during T+M, and 
Convulsive Seizure Free Days during Baseline, M and T
Listing
16.2.6.4b
Percent Change in Convulsive Seizure Frequency from Baseline 
Listing
16.2.6.5b
Clinical Global Impression – Improvement Rating as Assessed by 
the Parent/Caregiver and Investigator
Listing
16.2.6.6b
Quality of Life in Childhood Epilepsy Scale
Listing
16.2.6.7b
Quality of Life of the Parent/Caregiver using EQ-5D-5L Scale
Listing
16.2.6.8.1b
Pediatric Quality of Life Inventory (Peds QL) - for TODDLERS 
(age 2-4 years)
Listing
16.2.6.8.2b
Pediatric Quality of Life Inventory (Peds QL) - for Young Children
(age 5-7 years)
Listing
16.2.6.8.3b
Pediatric Quality of Life Inventory (Peds QL) - for Children (age 8-
12 years)
Listing
16.2.6.8.4b
Pediatric Quality of Life Inventory (Peds QL) - for TEENS (age 13-
18 years)
Listing
16.2.6.8.5b
Pediatric Quality of Life Inventory (Peds QL) – Family Impact 
Module
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Listing
16.2.6.9b
Sleep Quality and Meal Time Behavior
Listing
16.2.6.10b
Karolinska Sleepiness Scale
Listing
16.2.6.11b
Hospitalization and Other Healthcare Resource Utilization to Treat 
Seizure
16.2.7 
Adverse events
Listing
16.2.7.1b
Adverse Events
Listing
16.2.7.2b
Adverse Events of Special Interests (AESI)
16.2.8
Laboratory data
Listing
16.2.8.1.1b
Laboratory Data: Hematology Parameters
Listing
16.2.8.1.2b
Extreme Value Laboratory Parameters - Hematology
Listing
16.2.8.2.1b
Laboratory Data: Biochemistry Parameters
Listing
16.2.8.2.2b
Extreme Value Laboratory Parameters - Biochemistry
Listing
16.2.8.3b
Laboratory Data: Coagulation Parameters
Listing
16.2.8.4.1b
Laboratory Data: Urinalysis Parameters
Listing
16.2.8.4.2b
Extreme Value Laboratory Parameters - Urinalysis
Listing
16.2.8.5b
Tests of Growth, Precocious Puberty and Thyroid Function
Listing
16.2.8.6b
Urine Pregnancy Test 
Listing
16.2.8.7b
Urine Cannabinoid Panel
Listing
16.2.8.8b
Whole Blood Cannabidiol
16.2.9
Other Safety Data
Listing
16.2.9.1.1b
Vital Signs 
Listing 
16.2.9.1.2b
Most Extreme Abnormal Vital Signs Data
Listing 
16.2.9.1.3b
Subjects with Weight Decreases >5% During Treatment
Listing
16.2.9.2b
Listing of Items on Columbia-Suicide Severity Rating Scale
Listing
16.2.9.3.1b
Behavior Rating Inventory of Executive Function – Preschool 
Version (BRIEF-P) – Individual Questions
Listing
16.2.9.3.2b
Behavior Rating Inventory of Executive Function (BRIEF) –
Individual Questions
Listing
16.2.9.4b
Tanner Staging
Listing
16.2.9.5b
Physical Examination 
Listing
16.2.9.6b
Neurological Examination
Listing
16.2.9.7b
Epilepsy Genotype Panel
Listing
16.2.10.1b
Individual Subject Drug Concentrations for Background AED
Listing
16.2.10.2b
Individual Subject Drug Concentrations for ZX008
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