An Open-label, Single-arm Study to Assess the Safety, Pharmacokinetics, and Efficacy of Adjunctive Cannabidiol Oral Solution (GWP42003-P) in Participants With Tuberous Sclerosis Complex (Age 1 Month to < 2 Years of Age), Dravet Syndrome (1 Year to < 2 Years of Age), or Lennox-Gastaut Syndrome (1 Year to < 2 Years of Age) Who Experience Inadequately-controlled Seizures
Phase: PHASE3
Conditions: Seizure in Participants With Tuberous Sclerosis Complex, Seizure in Participants With Dravet Syndrome, Seizure in Participants With Lennox-Gastaut Syndrome
Sponsor: Jazz Pharmaceuticals

Jazz P har mace uticals Researc h U K Li mite d  
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C O N FI D E N TI A L  
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A N O P E N -L A B E L , SI N G L E-A R M  S T U D Y T O A S S E S S T H E S A F E T Y, 
P H A R M A C O KI N E TI C S, A N D E F FI C A C Y O F A D J U N C TI V E C A N N A BI DI O L 
O R A L S O L U TI O N ( G W P 4 2 0 0 3 -P) I N P A R TI CI P A N T S WI T H T U B E R O U S 
S C L E R O SI S C O M P L E X ( 1 M O N T H T O <  2 Y E A R S O F A G E ), D R A V E T 
S Y N D R O M E ( 1 Y E A R T O < 2 Y E A R S O F A G E), O R L E N N O X -G A S T A U T 
S Y N D R O M E ( 1 Y E A R T O < 2 Y E A R S O F A G E)  W H O E X P E RI E N C E 
I N A D E Q U A T E L Y-C O N T R O L L E D S EI Z U R E S.  
St u d y C o de: G W E P 1 7 0 0 5  
E U C T R N u m ber: 2 0 2 3 -5 0 5 8 5 1 -3 3 -0 0  
C LI NI C A L P R O T O C O L  
J azz P h ar m ace utic als Rese arc h U K Li mite d  
B uil di n g 7 3 0 , Ke nt Scie nce P ar k  
Sitti n g b o ur ne  
Ke nt  
U nite d Ki n g d o m , M E 9 8 A G 
Tel: + 4 4 8 0 8 1 8 9 0 3 8 7  
F a x: + 4 4 ( 0) 1 2 2 3 2 3 5 6 6 7  
C o nfi de nti alit y St ate me nt  
T his d oc u me nt c o ntai ns c o nfi de ntial i nf or mati o n of Jazz P har mace uticals Researc h 
U K L imite d  (Jazz) t hat m ust n ot be discl ose d t o a n y o ne ot her t ha n t h e reci pie nt st u d y 
staff a n d me m bers of t he i nstit uti o nal re vie w b oar d or i n de pe n de nt et hics c o m mittee. 
T his  i nf or mati o n ca n n ot be use d f or a n y p ur p ose ot her t ha n t he e v al uati o n or c o n d uct 
of t he cli nical i n vesti gati o n wit h o ut t he pri or writte n c o nse nt of J azz. 

Jazz P har mace uticals Researc h U K Li mite d  
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I n vesti g at or A gree me nt 
I h a ve rea d t he attac he d cli nical pr ot oc ol title d “A n O pe n -la bel, Si n gle -Ar m St u d y t o 
Assess t he Safet y, P har m ac o ki netics, a n d Efficac y of A dj u ncti ve Ca n na bi di ol Oral 
S ol uti o n ( G W P 4 2 0 0 3 -P) i n Partici pa nts wit h T u ber o us Scler osis C o m ple x ( 1  M o nt h 
t o <  2 Years of A ge ), Dra vet S y n dr o me ( 1 Year t o < 2 Years of A ge), or  
Le n n o x -Gas ta ut S y n dr o me ( 1 Year t o < 2 Years of A ge)  w h o E x perie n ce 
I n a de q uat el y-c o ntr olle d Seiz ures ” a n d a gree t o a bi de b y a ll pr o visi o ns set f ort h 
t herei n. 
I a gree t o c o m pl y wit h a p plica ble re g ulat or y re q uire me nt(s); t he U nite d St ates ( U S ) 
F o o d a n d Dr u g A d mi nistrati o n ( F D A) re g ulati o ns relati n g t o g o o d cli nical practice 
( G C P) a n d cli nical st u dies, a n d s u bse q ue nt a p plica ble re g ulat or y/stat ut or y 
i nstr u me nts, or t he I nt er nati o nal C o u ncil f or Har m o nisati o n Tri partite G ui deli nes f or 
G C P w here t h e E U Cli nical Trials  Re gister  a n d E U G C P Directi ve d o n ot a p pl y, a n d 
t o c o m plete F or m F D A 1 5 7 2, if re q uire d. I acce pt res p o nsi bilit y f or t he o verall 
me dical care of p artici pa nts d uri n g t he st u d y a n d f or all st u d y-relate d m e dical 
decisi o ns.  
I a m n ot a ware that a n y c o nflicts of i nterest, fi na ncial or ot her wise, e xist f or m yself, 
m y s p o use [ or le gal part ner] a n d d e pe n d e nt c hil dre n a n d a gree t o c o nfir m t his i n 
writi n g if re q uire d a n d u p date as necessar y.  
I a gree t o e ns ure t hat t he c o nfi de ntial i nf or mati o n c o ntai ne d i n t his d oc u me nt will n ot 
be use d f or a n y p ur p ose ot her t ha n t he e v al uati o n or c o n d uct of t he cli nical 
i n vesti gati o n wit h o ut t he pri or writte n c o nse nt of t he s p o ns or. 
Site N o:  
 
  
 
 
 
  
 
Pri nt na me:   
 Date:   
 
Pri nci pal i n vesti gat or 
 
  
( D D M o nt h Y Y Y Y)  
Si g nat ure:  
 
  
 
 
S p o ns or si g nat or y  
Pri nt na me:   
 Date:   
 
Cli nical p h ysicia n  
 
  
( D D M o nt h Y Y Y Y) 
Si g nat ure:  
 
 
 
  
 

Jazz P har mace uticals Researc h U K Li mite d  
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A me n d me nt 6  
O ver all R ati o n ale f or t he A me n d me nt:  
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n 
Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t h e C o u ncil of 
t he E ur o pea n U ni o n a n d E U Re g ulati o n N o 53 6/ 2 0 1 4 . Alt h o u g h t here is n o 
si g nifica nt i m pact o n  t he safet y or p h ysical/ me ntal i nte grit y of partici pa nts n or t he 
scie ntific val ue of t h e st u d y, as t he a d diti o nal ne ur o de vel o p me nt al assess m e nt ha ve 
bee n a d d e d u n der t he pri mar y e n d p oi nt  al o n g wit h t he ot her mi n or c ha n g es, t he 
a me n d me nt has bee n classifie d as s u bsta ntial .  
S pecific u p dates i nc or p orate d i nt o A me n d me nt 6. 0  are liste d bel o w.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
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Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
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C O N FI D E N TI A L  
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Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
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A b bre viati o ns: C B D -O S = ca n na bi di ol oral s ol uti o n; C GI C = C li nicia n Gl o bal I m pressi o n of C ha n ge; 
C GI S = Cli nicia n Gl o bal I m pressi o n of Se verit y; C O VI D -1 9 = C or o na vir us disease 2 0 1 9 ; E O T = e n d 
of treat me nt; E U  =  E ur o pea n U ni o n; E U  C T R  =  E ur o pea n U ni o n Cli nical Trial Re gister; G W  =  G W 
Researc h Lt d ; I T Q O L =  I nfa nt a n d T o d dler Q ualit y of Life Q uesti o n naire; S A P = statistic al a nal ysis 
pla n; S U S A R  =  seri o us u ne x pecte d seri o us a d verse reacti o n; T S C = t u ber o us scler osis c o m ple x ; 
V E E G  = vi de o electr oe nce p hal o gra m ; U K = U nite d Ki n g d o m. 

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1.  
P R O T O C O L S Y N O P SI S  
St u d y  Title  
A n O pe n -la bel, Si n gle -ar m St u d y  t o Assess t he Safet y, 
P har mac o ki netics, a n d Efficac y of A dj u ncti ve Ca n na bi di ol Oral 
S ol uti o n ( G W P 4 2 0 0 3 -P) i n Partici pa nts wit h T u ber o us Scler osis 
C o m ple x ( A ge 1 M o nt h t o <  2 Years of A ge ), Dra vet S y n dr o me 
( 1 Year t o < 2 Years of A ge), or Le n n o x -Gasta ut S y n dr o me ( 1  Year t o 
< 2 Years of A ge)  w h o E x perie nce I na de q uatel y -c o ntr olle d Seiz ures  
Cli nical St u d y  
T y pe  
P hase 3  
I n dicati o n 
Seiz ures i n partici pa nts wit h tu ber o us scler osis co m ple x ( T S C), Dra vet 
sy n dr o me  ( D S), or Le n n o x -Gasta ut  s y n dr o me ( L G S) 
O bjecti ves a n d 
E n d p oi nts  
Pri m ar y O bjecti ve s  
Pri m ar y E n d p oi nt s 
T o e val uate t he safet y 
a n d t olera bilit y of 
a dj u ncti ve G W P 4 2 0 0 3 -P 
assesse d d uri n g t he 
5 2 -wee k treat me nt 
peri o d.  
T he safet y pr ofile of a dj u ncti ve 
G W P 4 2 0 0 3 -P will be assesse d b y 
meas uri n g:  
•  
A d verse e ve nts ( A Es ) 
(fre q ue nc y, t y pe, a n d se verit y). 
•  
Vital si g ns.  
•  
P h ysical e xa mi nati o n.  
•  
1 2 -lea d electr ocar di o gra m 
(E C G ). 
•  
Cli nicall y si g nifica nt c ha n ges i n 
la b orat or y para meters.  
•  
E mer ge nce of ne w seiz ure t y pes  
as rec or de d b y A E re p orti n g. 
•  
C o m pre he nsi ve 
n e ur o de vel o p me nt al assess me nt . 
T o i n vesti gate t he 
e x p os ure of 
G W P 4 2 0 0 3 -P a n d its 
maj or meta b olites 
f oll o wi n g m ulti ple d oses 
of G W P 4 2 0 0 3 -P.  
Tr o u g h, 3 -h o ur a n d 6 -h o ur p ost d ose 
plas ma c o nce ntrati o ns of  G W P 4 2 0 0 3 -P 
a n d its maj or meta b olites f oll o wi n g 
m ulti ple d oses of G W P 4 2 0 0 3 -P.  
T o e val uate t he 
efficac y of 
G W P 4 2 0 0 3 -P i n 
re d uci n g t he 
fre q ue nc y of 
i n dicati o n-s pecific 
c o u nta ble 
seiz ures.  
Perce nta ge c ha n ge fr o m baseli ne i n 
i n dicati o n-s pecific * c o u nta ble seiz ures 
(a vera ge per 2 8 da ys) as rec or de d b y 
care gi vers i n seiz ure diaries at Wee k  1 2, 
e ver y 4  wee ks t hereafter, a n d d uri n g t he 
4 -wee k peri o d pri or t o e n d of treat me nt 
( E O T). 
* F ocal/ ge neralise d seiz ures ( T S C), dr o p 
seiz ures ( L G S), or c o n v ulsi ve seiz ures 
( D S). 
Sec o n d ar y 
O bjecti ves  
Sec o n d ar y E n d p oi nts  

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T o e val uate t he efficac y  
of G W P 4 2 0 0 3 -P  in  
re d uci n g t he fre q ue nc y 
of t otal c o u nta ble 
seiz ures. 
Meas ure me nts of t otal c o u nta ble 
seiz ures (a vera ge per 2 8 da ys) as 
rec or de d b y care gi vers o n seiz ure diaries 
at Wee k 1 2, e ver y 4  wee ks t hereafter, 
a n d d uri n g t he 4 -wee k peri o d pri or t o 
E O T  will be use d t o deter mi ne t he 
f oll o wi n g e n d p oi nts: 
•  
N u m ber a n d p erce nta ge of 
partici pa nt s c o nsi dere d 
treat me nt res p o n ders, defi ne d as 
t h ose wit h a ≥ 5 0 % re d ucti o n 
fr o m baseli ne i n t otal c o u nta ble 
seiz ures .  
•  
Cate g orical perce nta ge c ha n ge 
fr o m baseli ne t o E O T i n t otal 
c o u nta ble seiz ures  as f oll o ws:  
 >  2 5 % (i ncrease); 
 ≥ 0 % t o ≤ 2 5 % (i ncrease) ; 
 >  – 2 5 % t o <  0 % ( re d ucti o n);  
 >  – 5 0 %  t o ≤ – 2 5 % 
(re d ucti o n); 
 >  – 7 5 % t o ≤ – 5 0 % 
(re d ucti o n); 
 ≤ – 7 5 % (re d ucti o n) . 
•  
Seiz ure free d o m, defi ne d as 
1 0 0 % re d ucti o n fr o m baseli ne i n 
t otal c o u nta ble seiz ures.  
T o assess t he rete nti o n 
of pa rtici pa nts recei vi n g 
G W P 4 2 0 0 3 -P . 
Perce nta ge of pa rtici pa nts still ta ki n g 
G W P 4 2 0 0 3 -P at Wee k  1 2  a n d e ver y 
4  wee ks t hereafter.  
E x pl or at or y  O bjecti ve s  E x pl or at or y  E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

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St u d y  Desi g n  
•  
T his is a p hase 3, m ulti ce ntre , o pe n-la bel, si n gle-ar m  st u d y t o 
e val uate t he safet y, P K, efficac y, a n d e x pl orat or y Q o L  of 
a dj u ncti ve G W P 4 2 0 0 3 -P  i n partici pa nts <  2 years of a ge wit h 
T S C, D S, or L G.  E nr o lme nt will be stratifie d via t he 
Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt ( R T S M) t o 
e ns ure t he st u d y i ncl u des at least 5  partici pa nts eac h (a ge d 1  t o 
<  2  years of a ge) wit h L G S a n d D S a n d 8  partici pa nts 
( 4 partici pa nts < 1 year of a ge a n d 4  partici pa nts a ge d 1 t o 
<  2  years of a ge) wit h T S C  i n or der t o ac hie ve 1 8 e val ua ble 
partici p a nts. 
•  
T he st u d y d urati o n will be u p t o a p pr o xi matel y 6 2  wee ks, 
i ncl u di n g a 4-wee k scree ni n g/ baseli ne peri o d, a 5 2 -wee k d ose 
o pti misati o n peri o d ( w hic h i ncl u des a fi xe d 2 -wee k titrati o n 
peri o d  f oll o we d b y fle xi ble d ose o pti misati o n ), a 1 0 -da y  ta per 
peri o d, a n d a safet y f oll o w -u p peri o d ( 4  wee ks after t he 
e n d-of -ta per visit). T hr o u g h o ut t he st u d y, partici pa nts s h o ul d 
c o m plete all visits  a n d assess me nts as o utli ne d i n t he S c he d ule 
o f A cti vities ( S o A) . After t he i nf or me d c o nse nt f or m (I C F) has 
be e n si g ne d b y t he pare nt(s)/ le gall y a ut h orise d re prese ntati ve 
(L A R ), partici pa nts  will be c o nsi dere d e nr olle d a n d e nter t he 
scree ni n g/ baseli ne peri o d ( Visit 1 a n d Visit 2  [ p h o ne visit]). 
Partici pa nts ca n be rescree ne d o nce , at t he discreti o n of t he 
i n vesti gat or a n d f oll o wi n g a p pr o val fr o m t he me dical m o nit or. 
Rescree ne d partici pa nts will be assi g ne d a ne w partici pa nt 
n u m ber a n d all scree ni n g assess me nts will be re peate d.  
•  
F oll o wi n g e nr ol me nt, d ose a dj ust me nts t o c o nc o mita nt 
a ntiseiz ure me dicati o ns ( A S Ms ) s h o ul d n ot be ma de wit h o ut 
pri or  disc ussi o n  wit h a n d a p pr o val b y t he me dical m o nit or. All 
A S M d ose a dj ust me nts m ust be ca pt ure d wit hi n t he electr o nic 
case re p ort f or m  (e C R F). 
•  
Starti n g at Visit 3, partici pa nts w h o c o nti n ue t o meet eli gi bilit y 
criteria will i nitiate t he 5 2 -wee k treat me nt peri o d wit h t he 
st u d y i nter ve nti o n ( G W P 4 2 0 0 3-P)  as a dj u ncti ve t hera p y ( i.e., 
i n a d diti o n t o t heir c urre nt A S M re gi me n ). T he st u d y 
i nter ve nti o n will be ta ke n orall y or wit h a gastric or 
nas o gastric t u be ( G -or N G -t u be) t wice a da y ( b.i. d.) (e. g., 
m or ni n g a n d e ve ni n g) at a b o ut t he sa me ti me eac h da y, 
c o nsiste ntl y wit h or wit h o ut f o o d . T he ti me of G W P 4 2 0 0 3 -P  
a d mi nistrati o n i n relati o n t o  f o o d s h o ul d be ke pt c o nsiste nt 
t hr o u g h o ut t he st u d y. D uri n g t he first 2 wee ks of treat me nt 
(i.e., t he fi xe d titrati o n peri o d), partici pa nts s h o ul d be gi n 
titrati n g G W P 4 2 0 0 3 -P  at a rate of 5 m g/ k g/ wee k, reac hi n g t he 
tar get d ose le vel of 1 0 m g/ k g/ da y  ( u nless t he partici pa nt 
ca n n ot t olerate t his d ose) . 

Jazz P har mace uticals Researc h U K Li mite d  
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C O N FI D E N TI A L  
Pa ge 1 0  of 1 2 1  
•
Starti n g at Visit 5, after titrati n g t o t he tar get d ose le vel
( 1 0 m g/ k g/ da y), i n vesti gat ors will ha ve t he o pti o n t o titrate a
partici pa nt’s  d ose  n o m ore ra pi dl y t ha n 5  m g/ k g ( ≤ 2. 5  m g/ k g
b.i. d.) e ver y 7 da ys, u p t o a ma xi m u m d ose of 2 0  m g/ k g/ da y
(f or L GS  a n d D S) or 2 5  m g/ k g/ da y (f or T S C), as
rec o m me n de d i n Secti o n  8. 1. 2  a n d base d o n t he partici pa nt’ s
i n di vi d ual res p o nse a n d t olera bilit y. T he i n vesti gat or will
deter mi ne if a d diti o nal d ose a dj ust me nts are warra nte d d uri n g
sc he d ule d or u nsc he d ule d visits t hr o u g h o ut t he re mai n der of
t he 5 2-wee k treat me nt peri o d.
•
If a partici pa nt e x perie nces t olera bilit y iss ues relate d t o t he
st u d y i nter ve nti o n or a n A E occ urs a t a n y ti me d uri n g t he
5 2 -wee k treat me nt peri o d, t he i n vesti gat or ma y c o nsi der
te m p oraril y or per ma ne ntl y re d uci n g t he c urre nt d osa ge,
f oll o wi n g disc ussi o n wit h t he me dical mo nit or. D ose s ma y be
decrease d  bel o w  t he tar get d ose le vel (i.e., < 1 0  m g/ k g/ da y )
base d o n safet y a n d t olera bilit y (refer t o Secti o n  8. 1. 2 ). W here
p ossi ble, partici pa nt s s h o ul d be e nc o ura ge d t o ret ur n t o t he
tar get d ose le vel ( 1 0 m g/ k g/ da y). I n vesti gat ors s h o ul d
re g ularl y m o nit or a partici pa nt’s res p o nse t o treat me nt a n d
re-e val uate t he nee d f or a dj ust me nts t o d osa ge (i.e., i ncrease,
mai ntai n, or decrease) at t he ne xt st u d y visit, if a p plica ble.
•
I n ge neral, doses s h o ul d n ot be a dj uste d wit hi n t he 3  da ys pri or
t o P K st u d y visits (as s pecifie d i n t he Sc he d ule of Acti vities
(S o A ; A P P E N DI X  1 ), u nless cli nicall y i n dicate d f or safet y. If
a d ose a dj ust me nt is nee de d d uri n g t he 3  da ys pri or t o a P K
st u d y visit, t he P K st u d y visit s h o ul d be resc he d ule d t o occ ur
> 3  da ys after t he d ose a dj ust me nt. D oses ma y be a dj uste d
d uri n g P K st u d y visits after all P K sa m ples ha ve bee n
c ollecte d. T he rati o nale f or a n y d osa ge c ha n ges will be
d oc u me nte d i n t he a p pr o priate e C R F.
•
Partici pa nts will c o nti n ue st u d y i nter ve nti o n treat me nt u ntil t he
E O T visit, after w hic h t he y will i nitiate a ta per peri o d t o titrate
off t he st u d y i nter ve nti o n at h o me. T he ta per peri o d will last
1 0 da ys a n d e n d wit h t he en d -of -ta per visit. A safet y foll o w -u p
visit ( p h o ne call  or visit ) will occ ur 4 wee ks after t he en d -of -
ta per visit (i.e., 4 wee ks after t he last d ose of t he G W P 4 2 0 0 3 -
P ).
•
If a partici pa nt disc o nti n ues t he st u d y i nter ve nti o n or st u d y
pre mat urel y (i.e., bef ore t h e E O T visit), t he partici pa nt s h o ul d
be e nc o ura ge d t o c o m plete a n earl y ter mi nati o n ( E T ) visit as
s o o n as p ossi ble, f oll o we d b y a 1 0-da y ta per peri o d if
cli nicall y i n dicate d (i.e., u nless t he partici pa nt m ust
disc o nti n ue treat me nt d ue f or reas o ns relate d t o safet y a n d
t olera bilit y). A safet y foll o w -u p visit ( p h o ne call  or visit, if
nee de d ) will occ ur 4 wee ks after t he partici pa nt’s last d ose of
G W P 4 2 0 0 3 -P .
Sa m ple Size  
U p t o  2 7  partici pa nts will be assi g ne d t o recei ve t he st u d y i nter ve nti o n  
i n or der t o ac hie ve 1 8  e val ua ble  partici pa nts .  
S u m mar y of 
Partici pa nt  
I ncl usi o n Criteri a 
F or i ncl usi o n i n t he st u d y, partici pa nts m ust f ulfil A L L of t he 
f oll o wi n g criteria: 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1  of 1 2 1  
Eli gi bilit y 
Criteria  
6. 1. 1  
Partici pa nts  wit h T S C ( 1  m o nt h t o <  2  years of a ge), or D S 
( 1 year t o <  2  years of a ge), or L G S ( 1  year t o <  2  years of 
a ge) wit hi n t he s pecifie d a ge ra n ge at t he ti me of i nitial 
i nf or me d c o nse nt. 
6. 1. 2  
Partici pa nts wit h T S C m ust ha ve a dia g n osis per t he 
2 0 1 2  I nter nati o nal T u ber o us Scler osis C o m ple x C o nse ns us 
C o nfere nce ( A P P E N DI X  3 )(N ort hr u p 2 0 1 3 ). Partici pa nts 
wit h L G S or D S m ust ha ve a dia g n osis t hat is c o nsiste nt 
wit h I nter nati o nal Lea g ue A gai nst E pile ps y (I L A E) 
g ui deli nes a n d c o nfir me d b y E S CI (S pecc hi o 2 0 2 2 , Z u beri 
2 0 2 2 ). 
6. 1. 3  
Partici pa nts w h o ha ve u nc o ntr olle d seiz ures, a n d w h o are 
c urre ntl y recei vi n g 1 or m ore A S Ms.  
6. 1. 4  
Pare nt(s)/ L A R  is/are willi n g a n d a ble t o gi ve i nf or me d 
c o nse nt f or partici pati o n i n t he st u d y. 
6. 1. 5  
Pare nt(s)/ L A R  is/are willi n g a n d a ble (i n t he i n vesti gat or’s 
o pi ni o n) t o c o m pl y wit h all st u d y re q uire me nts (i ncl u di n g 
acc urate electr o nic patie nt re p orte d o utc o me [e P R O] dia r y 
c o m pleti o n). 
6. 1. 6  
Care gi ver c o m pletes at least 7 5 % of e P R O a n d pa per 
seiz ure diar y e ntries d uri n g t he 2 8 da ys of t he 
scree ni n g/baseli ne peri o d ( ≥ 2 1 da ys of e ntries).  
6. 1. 7  
A s uita ble V E E G , as a vaila ble i n t he me dical rec or ds, 
wit hi n 1 year of Visit 1. W he n a hist orical V E E G is n ot 
a vaila ble, a n d if cli nicall y i n dicate d a n d a p pr o priate ( d ue 
t o u ncertai nties or ne w seiz ures), a V E E G will be 
c o m plete d a n d rea d t o c o nfir m dia g n osis pri or t o Visit  3. 
All V E E Gs are t o be rea d at baseli ne b y t he i n vesti gat or 
a n d b y a n i nde pe n de nt re vie wer.  
•  
A s uita ble V E E G meets all t he f oll o wi n g criteria:  
i. M ultic ha n nel ( mi ni m u m 8 -c ha n nel) 
ii. Pr ol o n ge d c o nti n u o us rec or di n g u p t o 
2 4  h o urs  
iii. C o m plete d wit hi n 1 year of Visit  1  
i v. C o nsiste nt wit h t he partici pa nt ’s c urre nt 
seiz ures (i n t he i n vesti gat or’s o pi ni o n) 
v.  Ca n be re vie we d b y t he i n vesti gat or a n d a n 
i n de pe n de nt revie wer  pri or t o Visit  3  
vi.  C o nsiste nt wit h a dia g n osis of 
i na de q uatel y -c o ntr olle d seiz ures  
6. 1. 8  
C urre ntl y ta ki n g ≥ 1 A S M s at a d ose t hat re mai ns sta ble 
2  wee ks pri or t o Visit 3 a n d d uri n g t he treat me nt peri o d. 
W here re q uire d f or partici pa nt  safet y, a dj ust me nts of 
c o nc o mita nt A S M (s) or a d diti o n of ne w A S M  ma y be 
per mitte d f oll o wi n g disc ussi o n wit h t he me dical m o nit or.  
•  
A dre n oc ortic otr o pic h or m o ne ( A C T H ) or hi g h d ose 
c ortic oster oi ds f or t he treat me nt of i nfa ntile /e pile ptic 
s pas ms (I S/ E S) are c o u nte d as A S M s. 
6. 1. 9  
Has seiz ures t hat are n ot a de q uatel y c o ntr olle d t hr o u g h 
t heir c urre nt AS M s, defi ne d as ≥ 1 seiz ure re p orte d o n t he  
seiz ure diar y d uri n g t he scree ni n g/baseli ne peri o d.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 2  of 1 2 1  
6. 1. 1 0  Pare nt(s)/ L A R  is/are willi n g t o all o w t he res p o nsi ble 
a ut h orities t o be n otifie d of partici pati o n i n t he st u d y, if 
ma n date d b y l ocal la w.  
6. 1. 1 1  Pare nt(s)/ L A R  is/are willi n g t o all o w t he partici pa nt ’s 
pri mar y care practiti o ner (if t he y ha ve o ne)  a n d c o ns ulta nt 
(if t he y ha ve o ne) t o be n otifie d of partici pati o n i n t he 
st u d y if t he pri mar y care practiti o ner/c o ns ulta nt is differe nt 
fr o m t he i n vesti gat or. 
E xcl usi o n Criteri a  
T he partici pa nt  ma y n ot e nter t he st u d y if A N Y of t he f oll o wi n g a p pl y: 
6. 2. 1  
Has cli nicall y si g nifica nt u nsta ble me dical c o n diti o n ot her 
t ha n e pile ps y. 
6. 2. 2  
Has ha d cli nicall y si g nifica nt s y m pt o ms or a cli nicall y 
si g nifica nt ill ness wit hi n t he 4 wee ks pri or t o Visit  1 , ot her 
t ha n e pile ps y, w hic h i n t he o pi ni o n of t he i n vesti gat or 
c o ul d affect seiz ure fre q ue nc y.  
6. 2. 3  
Has u n der g o ne ge neral a naest hesia  wit hi n  4 wee ks pri or t o 
Visit 1 .  
6. 2. 4  
Has u n der g o ne s ur ger y f or e pile ps y wit hi n 6 m o nt hs pri or 
t o Visit 1  or has pla ns t o u n der g o s ur ger y f or e pile ps y 
d uri n g t he st u d y . 
6. 2. 5  
H as ta ke n fel ba mate f or < 1 year pri or t o Visit  1 . 
6. 2. 6  
Is <  1 year of a ge  a n d ta ki n g val pr oic aci d . 
6. 2. 7  
Has t u m ou r gr o wt h w hic h, i n t he o pi ni o n of t he 
i n vesti gat or, c o ul d affect partici pa nt  safet y. 
6. 2. 8  
Has cli nicall y si g nifica nt a b n or mal la b orat or y val ues, i n 
t he i n vesti gat or’s o pi ni o n, at scree ni n g/ baseli ne. 
6. 2. 9  
Has cli nicall y si g nifica nt a b n or malities i n t he E C G 
meas ure d at scree ni n g / baseli ne. 
6. 2. 1 0  Has a n y c o nc urre nt car di o vasc ular c o n diti o ns  t hat will, i n 
t he i n vesti gat or’s o pi ni o n, i nterfere wit h t he a bilit y t o 
assess t heir E C Gs.  
6. 2. 1 1  Has a n y k n o w n or s us pecte d h y perse nsiti vit y t o 
ca n na bi n oi ds or a n y of t he e xci pie nts of t he st u d y 
i nter ve nti o n s uc h as sesa me see d oil. 
6. 2. 1 2  Has si g nifica ntl y i m paire d he patic f u ncti o n pri or t o 
Visit  3 , defi ne d as: 
•  
Ser u m ala ni ne a mi n otra nsferase ( A L T ) or  as partate 
a mi n otra nsferase ( A S T ) >  3  × u p per li mit of n or mal 
(U L N ) a n d  (t otal bilir u bi n [T B L ] >  2  ×  U L N or  
i nter nati o nal n or malise d rati o [I N R] > 1. 5).  
•  
Ser u m A L T or A S T >  5  ×  U L N . 
•  
Ser u m A L T or A S T >  3  ×  U L N  wit h t he prese nce of 
fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or 
te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) . 
•  
Ele vate d A L T or A S T s h o ul d be disc usse d wit h t he 
me dical m o nit or pri or t o Visit 3 ; t he me dical m o nit or 
ma y all o w f or a c o nfir mat or y re dra w pri or t o Visit  3 . 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 3  of 1 2 1  
6. 2. 1 3  Has rec ei ve d a n ot her st u d y i nter ve nti o n wit hi n 4  wee ks 
pri or t o Visit 1  or pla ns t o ta ke a n ot her st u d y i nter ve nti o n 
d uri n g t he st u d y . 
6. 2. 1 4  Care gi ver is c urre ntl y gi vi n g or has gi ve n recreati o nal or 
me dici nal ca n na bis, ca n na bi n oi d -base d me dicati o ns 
(i ncl u di n g Sati ve x) or ca n na bi di ol ( C B D ; i ncl u di n g 
E pi di ole x / E pi d y ole x [ G W P 4 2 0 0 3-P]) t o t he partici pa nt 
wit hi n t he 4  wee ks pri or t o Visit 1 or  is un willi n g t o 
a bstai n fr o m d oi n g s o f or t he d urati o n of t he st u d y. 
6. 2. 1 5  M ot her (if breastfee di n g) is c urre ntl y usi n g or has use d 
recreati o nal or me dici nal ca n na bis, ca n na bi n oi d-base d 
me dicati o ns (i ncl u di n g Sati ve x) or C B D (i ncl u di n g 
E pi di ole x / E pi d y ole x [ G W P 4 2 0 0 3-P]) wit hi n t he 4  wee ks 
pri or t o Visit  1  or  is u n willi n g t o a bstai n fr o m d oi n g s o f or 
t he d urati o n of t he st u d y. 
6. 2. 1 6  Has a n y ot her cli nicall y si g nifica nt disease or dis or der 
w hic h, i n t he o pi ni o n of t he i n vesti gat or, ma y eit her p ut 
t he partici pa nt , ot her partici pa nts, or site staff at ris k 
beca use of partici pati o n i n t he st u d y, ma y i nfl ue nce t he 
res ult of t he st u d y, or ma y affect t he partici pa nt ’s a bilit y t o 
ta ke part i n t he st u d y. 
6. 2. 1 7  A n y cli nicall y si g nifica nt a b n or malities i de ntifie d 
f oll o wi n g a p h ysical e xa mi nati o n of t he partici pa nt t hat, i n 
t he o pi ni o n of t he i n vesti gat or, w o ul d je o par dize t he safet y 
of t he partici pa nt if t he y t o o k part i n t he st u d y. 
6. 2. 1 8  Has pre vi o usl y bee n e nr olle d i nt o t his st u d y. 
6. 2. 1 9  Has pla ns t o tra vel o utsi de t heir c o u ntr y of resi de nce 
d uri n g t he st u d y, u nless t he partici pa nt has c o nfir mati o n 
t hat t he st u d y i nter ve nti o n is per mitte d i n t he desti nati o n 
c o u ntr y,  a n d all st o ps al o n g t he wa y.  
Criteria f or 
Wit h dra wal  
Disc o nti n ue  St u d y I nter ve nti o n:  
•  
Pare nt(s)/ L A R  ma y decli ne t o c o nti n ue partici pati n g i n st u d y 
i nter ve nti o n a n d/ or ot her pr ot oc ol-re q uire d t hera pies or 
pr oce d ures at a n y ti me d uri n g t he st u d y.  
•  
Pare nt(s)/ L A R  w h o c h o ose t o disc o nti n ue partici pati o n i n 
st u d y i nter ve nti o n a n d/ or ot her pr ot oc ol-re q uire d t hera pies or 
pr oce d ures s h o ul d n ot be a ut o maticall y re m o ve d fr o m t he 
st u d y. W he ne ver safe a n d feasi ble, a n d i n a gree me nt wit h t he 
s p o ns or, t he partici pa nts s h o ul d re mai n i n t he st u d y t o e nsure 
safet y s ur veilla nce a n d/ or c ollecti o n of o utc o me data. 
•  
T he i n vesti gat or is t o disc uss wit h t he partici pa nt’s 
pare nt(s)/ L A R  t he a p pr o priate pr ocesses f or disc o nti n uati o n 
fr o m st u d y i nter ve nti o n or ot her pr ot oc ol-re q uire d t hera pies. 
T hese partici pa nts s h o ul d c o m plete a n earl y ter mi nati o n ( E T) 
visit f oll o we d b y 1 0 -da y ta per peri o d if cli nicall y i n dicate d 
(i.e., if n o safet y reas o ns pr o hi bit c o nti n ue d treat me nt; refer t o 
Secti o n  8. 1. 2 ). A safet y f oll o w-u p visit s h o ul d be c o n d ucte d 
4  wee ks after t he partici pa nt’s last d ose of G W P 4 2 0 0 3 -P . T he 
i n vesti gat or m ust disc uss wit h t he partici pa nt’s pare nt(s)/ L A R  
t he p ossi bilities f or c o nti n uati o n of acti vities descri be d i n t he 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 4  of 1 2 1  
S o A  (A P P E N DI X  1 ) a n d m ust d oc u me nt t his decisi o n i n t he 
e C R F. 
Reas o ns f or re m o val fr o m st u d y i nter ve nti o n or pr oce d ural 
assess me nts i ncl u de a n y of t he f oll o wi n g:  
•  
Decisi o n b y t he i n vesti gat or . 
•  
Decisi o n b y sp o ns or .  
•  
Decisi o n b y re g ulat or y a ut h orit y. 
•  
Wit h dra wal of pare nt(s)/ L A R  c o nse nt. 
•  
C ha n ge i n c o m plia nce wit h a n y i ncl usi o n/e xcl u si o n criteri o n 
t hat is cli nicall y rele va nt a n d affects partici pa nt  safet y, as 
deter mi ne d b y t he i n vesti gat or ( or desi g nee).  
•  
Pr ot oc ol de viati o n t hat is c o nsi dere d t o p ote ntiall y 
c o m pr o mise t he safet y of t he pa rtici pa nt. 
•  
N o nc o m plia nce wit h st u d y i nter ve nti o n . 
•  
N o nc o m plia nce wit h a n y of t he st u d y assess me nts.  
•  
A n y cli nicall y rele va nt si g n or s y m pt o m t hat i n t he o pi ni o n of 
t he i n vesti gat or ( or desi g nee) warra nts partici pa nt re m o val 
fr o m st u d y i nter ve nti o n. 
•  
Li ver C he mistr y - Disc o nti n uati o n of st u d y i nter ve nti o n f or 
a b n or mal li ver tests is re q uire d b y t he i n vesti g at or w he n a 
partici pa nt meets o ne of t he f oll o wi n g c o n diti o ns o utli ne d or i n 
t he prese nce of a b n or mal li ver c he mistries n ot meeti n g 
pr ot oc ol -s pecifie d st o p pi n g r ules if t he i n vesti gat or belie ves 
t hat it is i n best i nterest of t he partici pa nt . 
 A L T or A S T >  3 × U L N wit h t he a p peara nce of 
fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or 
te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %).  
 A L T or A S T >  8 × U L N.  
 A L T or A S T > 5 × U L N f or m ore t ha n 2 wee ks.  
 A L T or  A S T > 3 × U L N a n d  ( T B L > 2 × U L N or  
I N R >  1. 5).  
N ote: Pri or t o treat me nt disc o nti n uati o n f or t he tra nsa mi nase ele vati o ns 
n ote d a b o ve, t he i n vesti gat or ma y c h o ose t o c o nfir m t he tra nsa mi nase 
ele vati o ns b y re peati n g t he f oll o wi n g la b orat or y tests, tests wit hi n 
2 4  t o 4 8 h o urs: A L T, A S T, T B L, I N R, % e osi n o p hils, 
ga m ma -gl uta m yl tra nsferase ( G G T ) a n d al kali ne p h os p hatase  (als o 
refer t o Secti o n  1 2. 7 ). S h o ul d t he a b o ve tr a ns a mi n ase ele v ati o n 
criteri a be c o nfir me d, t he p artici p a nt m ust per m a ne ntl y 
disc o nti n ue t he st u d y i nter ve nti o n. I n c ases w here tr a ns a mi n ase 
ele v ati o n wit h dr a w al criteri a  are n ot met or c o nfir me d, t he d ose of 
st u d y i nter ve nti o n or a c o nc o mit a nt me dic ati o n wit h k n o w n 
he p at ot o xicit y m a y be re d uce d f oll o wi n g disc ussi o n wit h t he 
me dic al m o nit or. T he fi n al decisi o n re g ar di n g d ose a dj ust me nts 
s h o ul d be t a ke n b y t he i n vesti g at or.  
•  
Disease pr o gressi o n t hat c o m pr o mises t he a bilit y of t he 
partici pa nt t o safel y c o nti n ue st u d y i nter ve nti o n. 
•  
Partici pa nts w h o are wit h dra w n f or n o n dr u g  relate d reas o ns 
ma y be re place d f oll o wi n g disc ussi o n bet wee n t he i n vesti gat or 
a n d t he s p o ns or. Partici pa nts wit h dra w n as a res ult of A Es 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 5  of 1 2 1  
t h o u g ht t o be relate d t o st u d y i nter ve nti o n, as deter mi ne d b y 
t he i n vesti gat or, will ge nerall y n ot be re place d. T he decisi o n 
re gar di n g t he re place me nt of pa rtici pa nts will be d oc u me nte d.  
T he partici pa nt  ma y als o be  per ma ne ntl y disc o nti n ue d fr o m treat me nt 
f or a n y of t he f oll o wi n g: 
•  
Partici pa nt  or pare nt(s)/ L A R  n o nc o m plia nce.  
•  
A n A E (i ncl u di n g cli nicall y si g nifica nt la b orat or y res ult) 
w hic h, i n t he o pi ni o n of t he i n vesti gat or, w o ul d c o m pr o mise 
t he c o nti n ue d safe participati o n of t he partici pa nt  i n t he st u d y. 
•  
N ot meeti n g  eli gi bilit y criteria. 
•  
A n y e vi de nce of dr u g a b use or dr u g di versi o n.  
•  
Disease pr o gressi o n t hat c o m pr o mises t he a bilit y of t he 
partici pa nt  t o safel y c o nti n ue partici pati n g i n t he st u d y. 
P artici p a nt  Disc o nti n u ati o n/ Wit h dr a w al Fr o m t he St u d y:  
•  
A partici pa nt ’s pare nt(s)/L A R  ma y  deci de t o  wit h dra w  t he 
partici pa nt fr o m t he st u d y at a n y ti me at t heir o w n re q uest or 
t he partici pa nt ma y be wit h dra w n at a n y ti me at t he discreti o n 
of t he i n vesti gat or or s p o ns or f or safet y, be ha vi ou ral, or 
c o m plia nce reas o ns.  
•  
T he partici pa nt  will be per ma ne ntl y disc o nti n ue d b ot h fr o m 
t he st u d y i nter ve nti o n a n d fr o m t he st u d y at t hat ti me. 
•  
If a partici pa nt  is wit h dra w n fr o m t he st u d y, t he st u d y m o nit or 
will be i nf or me d i m me diatel y. If t here is a me dical reas o n f or 
wit h dra wal, t he partici pa nt  will be f oll o we d u p b y t he 
i n vesti gat or u ntil satisfact or y healt h has ret ur ne d. 
•  
At t he ti me of disc o nti n ui n g fr o m t he st u d y, all eff orts m ust be 
ma de t o c o m plete a n d re p ort t he o bser vati o ns as t h or o u g hl y as 
p ossi ble u p t o t he date of wit h dra wal. If p ossi ble, a n E T  visit 
s h o ul d be c o n d ucte d, f oll o we d b y a 1 0-da y ta per peri o d if 
cli nica ll y i n dicate d (refer t o Secti o n  8. 1. 2 ). A safet y f oll o w -u p 
visit s h o ul d be c o m plete d 4  wee ks after t he partici pa nt’s last 
d ose of G W P 4 2 0 0 3 -P. See  t he S o A (A P P E N DI X  1 ) f or data t o 
be c ollecte d at t he ti me of st u d y disc o nti n uati o n a n d f oll o w -u p 
a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d.  
•  
If t he partici pa nt ’s pare nt(s)/L A R  wit h dra ws c o nse nt f or 
discl os ure of f ut ure i nf or mati o n, t he s p o ns or ma y retai n a n d 
c o nti n ue t o use a n y data c ollecte d bef ore s uc h a wit h dra wal of 
c o nse nt. 
•  
If a partici pa nt  wit h dra ws fr o m t he st u d y, her/ his 
pare nt(s)/ L A R  ma y re q uest destr ucti o n of a n y sa m p les ta ke n 
a n d n ot teste d, a n d t he i n vesti gat or m ust d oc u me nt t his i n t he 
site st u d y rec or ds. 
Reas o ns f or re m o val of a partici pa nt  fr o m t he st u d y are: 
•  
Decisi o n b y t he i n vesti gat or . 
•  
Decisi o n b y s p o ns or . 
•  
Decisi o n b y re g ulat or y a ut h orit y.  
•  
Wit h dra wal of pare nt( s)/L A R  c o nse nt. 
•  
Deat h.  
•  
L ost t o f oll o w -u p.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 6  of 1 2 1  
•  
Partici pa nt  or pare nt(s)/ L A R(s)  n o nc o m plia nce  wit h st u d y 
sc he d ule. 
•  
Partici pa nt  or pare nt(s)/ L A R  n o nc o m plia nce wit h st u d y 
i nter ve nti o n a d mi nistrati o n . 
St u d y 
I nter ve nti o n: 
F or m ulati o n, 
M o de of 
A d mi nistrati o n, 
D ose a n d 
Re gi me n  
T he st u d y i nter ve nti o n is G W P 4 2 0 0 3 -P  oral s ol uti o n ( 1 0 0  m g/ m L 
C B D diss ol ve d i n t he e xci pie nts sesa me oil a n d a n h y dr o us et ha n ol 
[ 1 0 % v/ v], wit h s weete ner [s ucral ose] , a n d stra w berr y fla v ou ri n g). 
M o de of a d mi nistrati o n: t o be ta ke n orall y b.i. d. ( m or ni n g a n d 
e ve ni n g) usi n g t he s yri n ge(s) pr o vi de d. I n partici pa nt s wit h G- or 
N G -t u bes b ut w here oral d osi n g of G W P 4 2 0 0 3 -P  is p ossi ble, oral 
d osi n g is prefera ble. O nl y i n partici pa nt s w here oral d osi n g is n ot 
p ossi ble, a n d f oll o wi n g c o ns ultati o n wit h t he me dical m o nit or, s h o ul d 
G W P 4 2 0 0 3 -P  be a d mi nistere d via G - or N G -t u bes ma de fr o m silic o n 
o nl y (fee di n g t u bes m ust be fl us he d wit h 1 5 t o 3 0  m L of water bef ore 
a n d after G W P 4 2 0 0 3 -P  d osi n g a n d als o fl us he d aft er a d mi nistrati o n of 
c o nc o mita nt me dicati o ns t o be ta ke n bef ore G W P 4 2 0 0 3 -P  [ v ol u me of 
water ma y be m o difie d i n partici pa nt s wit h fl ui d restricti o ns]). T he 
v ol u me of G W P 4 2 0 0 3 -P  will be deter mi ne d b y partici pa nt ’s wei g ht 
a n d assi g ne d d ose.  
T he G W P 4 2 0 0 3 -P  s h o ul d be ta ke n at a b o ut t he sa me ti me eac h da y 
c o nsiste ntl y wit h or wit h o ut f o o d . T he ti me of G W P 4 2 0 0 3 -P  
a d mi nistrati o n i n relati o n t o f o o d s h o ul d be ke pt c o nsiste nt t hr o u g h o ut 
t he st u d y. 
O n Da y 1 of treat me nt  wit h t he G W P 4 2 0 0 3 -P , partici pa nts will be gi n  
d osi n g wit h 5  m g/ k g/ da y  ( 2. 5 m g/ k g b.i. d.). O n Da y  8 ( ±  3  da ys), t he 
d ose will be i ncrease d t o 1 0  m g/ k g/ da y ( 5  m g/ k g b.i. d.). Partici pa nts 
will be o bser ve d o n Da y 1 5 a n d , s u bse q ue ntl y, t he d ose ma y be 
escalate d f urt her base d o n i n di vi d ual cli nical res p o ns e a n d t olera bilit y; 
d oses ma y i ncrease u p t o a ma xi m u m of 2 0  m g/ k g/ da y ( 1 0 m g/ k g 
b.i. d .) f or L G S a n d D S or 2 5 m g/ k g/ da y ( 1 2. 5  m g/ k g b.i. d.)  f or T S C . If 
cli nicall y i n dicate d f or safet y, partici pa nts ma y decrease t heir d ose at 
a n y ti me.  
Partici pa nts disc o nti n ui n g G W P 4 2 0 0 3 -P  treat me nt at t he e n d of t he 
st u d y, or at a n y ot her ti me if t he y disc o nti n ue treat me nt earl y, s h o ul d 
u n der g o a 1 0 -da y ta per peri o d  if cli nicall y i n dicate d (i.e., if n o safet y 
reas o ns pr o hi bit c o nti n ue d treat me nt).  
Pr oce d ures  
Scree ni n g/ B aseli ne Peri o d Assess me nts  
Starti n g a t Visit 1, after c o m pleti o n of t he I C F, t he f oll o wi n g 
assess me nts will be perf or me d: eli gi bilit y criteria will be re v ie we d, 
al o n g wit h de m o gra p hics, me dical hist or y, a n d pri or a n d c o nc o mita nt 
me dicati o ns . Partici pa nts will u n der g o f ull p h ysical e xa mi nati o n s 
(i ncl u di n g hei g ht/le n gt h, b o d y wei g ht , a n d hea d circ u mfere nce ); vital 
si g ns, E C G, a n d V E E G  will als o be re vie we d . Cli nical la b orat or y 
sa m ples will be c ollecte d, i ncl u di n g c he mistr y, hae mat ol o g y , a n d 
uri nal ysis ( w he n p ossi ble). P artici pa nts’ seiz ures will be classifi e d, a n d 
the f oll o wi n g f or ms s h o ul d be c o m plete d a n d s u b mitte d t o t he E pile ps y 
St u d y C o ns orti u m ( E S CI) : t he Seiz ure I de ntificati o n  F or m ( SI F ) (f or 
T S C)  or t he Seiz ure I de ntificati o n a n d Dia g n ostic Re vie w F or m 
(SI F/ D R F) ( f or L G S a n d D S) , al o n g wit h t he Ep ile ps y Diar y Refere nce 
S heet ( E D R F)  (f or all partici pa nts).  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 7  of 1 2 1  
Care gi vers will be trai ne d t o use pa per a n d e P R O seiz ure diar ies, a n d 
diar y e ntries will be re vie we d .  
Tre at me nt Peri o d  Assess me nts  
Partici pa nts w h o c o nti n ue t o satisf y all i ncl usi o n criteria , a n d n o ne  of 
t he e xcl usi o n criteria, will recei ve t he st u d y i nter ve nti o n, w hic h will be 
dis pe nse d a n d c ollecte d , wit h c o m plia nce re vie we d , at ti me p oi nts 
s pecifie d i n t he So A ( A P P E N DI X  1 ). Partici pa nts will  u n der g o t he 
f oll o wi n g assess me nts as s pecifie d i n t he  S o A : a b bre viate d p h ysical 
e xa mi nati o n (i ncl u di n g hei g ht/le n gt h , b o d y wei g ht , a n d hea d 
circ u mfere nce ), ne ur o de vel o p me ntal assess me nts, C GI C/ C GI S, vital 
si g ns, a n d E C G . Co nc o mita nt me dicati o ns  a n d A Es will be rec or de d , 
a n d seiz ure t y pe(s), a n d e P R O diar y e ntries will be re vie we d. Cli nical 
la b orat or y sa m ples will be c ollecte d, i ncl u di n g c he mistr y, 
hae mat ol o g y , a n d uri nal ysis ( w he n p ossi ble). P har mac o ki netic 
assess me nts will be c o m plete d f or all partici pa nts . 
E n d -of -T a per Assess me nts : 
T he f oll o wi n g assess me nts will be perf or me d: a b bre viate d p h ysical 
e xa mi nati o n  (i ncl u di n g hei g ht/le n gt h, b o d y wei g ht , a n d hea d 
circ u mfere nce ), ne ur o de vel o p me ntal assess me nts, C GI C/ C GI S,  a n d 
vital si g ns, c o nc o mita nt me dicati o ns rec or de d, a n d A Es, seiz ure t y pes, 
a n d e P R O diar y e ntries will be re vie we d. T he st u d y i nter ve nti o n  will 
be c ollecte d, a n d c o m plia nce will be re vie we d.  
S afet y F oll o w -u p Assess me nts:  
C o nc o mita nt me dicati o ns a n d A Es will be rec or de d b y a tele p h o ne call  
or visit . 
P har mac o ki netics  P har mac o ki netic sa m ples will be c ollecte d f or all partici pa nt s. 
M or ni n g tr o u g h (i.e., ta ke n wit hi n 6 0 mi n utes pri or t o t he m or ni n g 
d ose of st u d y i nter ve nti o n), 3 -h o ur , a n d 6-h o ur p ost d ose sa m ples will 
be c ollecte d as s pecifie d i n t he S o A (A P P E N DI X  1 ).  
A dj ust me nts t o d osa ge s h o ul d be a v oi de d wit hi n  3 da ys pri or  t o P K  
visits , u nless cli nicall y i n dicate d f or safet y. If a partici pa nt’s d ose is 
a dj uste d, P K sa m ple c ollecti o n s h o ul d n ot occ ur u ntil >  3  da ys after t he 
d ose a dj ust me nt.  D ose a dj ust me nts  ma y be ma de d uri n g P K st u d y 
visits after all P K sa m ples ha ve bee n c ollecte d. 
Statistical 
C o nsi derati o ns  
N o f or mal h y p ot hesis testi n g will be perf or me d i n t h is st u d y. 
E n d p oi nts will be a nal yse d a n d re p orte d usi n g a p pr o priate s u m mar y  
statistics i ncl u di n g mea n, sta n dar d de viati o n or sta n dar d err or, me dia n, 
i nter q uartile ra n ge, mi ni m u m a n d ma xi m u m, c o u nts a n d perce nta ges. 
Details will be pr o vi de d i n a se parate st atistical a nal ysis pla n. 
Safet y 
M o nit ori n g 
C o m mittee  
( S M C) 
A n i n de pe n de nt S M C will be use d i n t his st u d y t o e val uate partici pa nt 
safet y. Details are pr o vi de d  i n t he c harter. 
S p o ns or  
Jazz P har mace uticals Researc h U K Li mite d (f or mall y k n o w n as G W 
Researc h Lt d)  
B uil di n g 7 3 0 Ke nt Scie nce Par k  
Sitti n g b o ur ne, Ke nt  
U nite d Ki n g d o m , M E 9 8 A G 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 8  of 1 2 1  
Fi g ure 1  
St u d y Sc he m a  
  
A b bre viati o ns: D = Da y; E O T = e n d of treat me nt; E T = earl y ter mi nati o n; T S C  = t u ber o us scler osis c o m ple x; V = Visit; W =  wee ks  
N ote: Visit  3 will occ ur 1 4  da ys ( +  3  da ys) after Visit  2 ( p h o ne visit occ urs 1 4  da ys after Visit  1), h o we v er, n ot earlier t ha n 2 8  da ys after Visit  1.  
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 9  of 1 2 1  
T A B L E O F C O N T E N T S  
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E  ............. 3  
1.  
P R O T O C O L S Y N O P SI S  .............................................................. 7  
LI S T O F T A B L E S  .......................................................................................... 2 3  
LI S T O F A B B R E V I A TI O N S ......................................................................... 2 4  
2.  
O BJ E C TI V E S A N D E N D P OI N T S  ............................................. 2 8  
3.  
B A C K G R O U N D A N D R A TI O N A L E  ........................................ 3 0  
3. 1.  
Disease  ......................................................................................... 3 0  
3. 2.  
Ca n na bi di ol Bac k gr o u n d  ............................................................. 3 2  
3. 3.  
Rati o nale  ...................................................................................... 3 3  
3. 3. 1.  
J ustificati o n f or D ose ................................................................... 3 3  
3. 4.  
Cli nical H y p ot hesis  ...................................................................... 3 3  
3. 5.  
Be nefit/ Ris k Assess me nt  ............................................................. 3 3  
4.  
E X P E RI M E N T A L P L A N  ........................................................... 3 5  
4. 1.  
St u d y Desi g n  ................................................................................ 3 5  
4. 2.  
N u m ber of Cli nical St u d y Sites  ................................................... 3 6  
4. 3.  
N u m ber of Partici pa nts  ................................................................ 3 6  
4. 4.  
E n d of St u d y Defi niti o n  ............................................................... 3 6  
5.  
S T U D Y I N T E R V E N TI O N  ......................................................... 3 7  
5. 1.  
Pac ka gi n g, St ora ge a n d Dr u g Acc o u nta bilit y  .............................. 3 7  
5. 1. 1.  
Pac ka gi n g a n d La b elli n g  .............................................................. 3 7  
5. 1. 2.  
St ora ge  ......................................................................................... 3 8  
5. 1. 3.  
S u p pl y a n d Ret ur n of St u d y I nter ve nti o n  .................................... 3 8  
5. 1. 4.  
St u d y I nter v e nti o n Acc o u nta bilit y  ............................................... 3 8  
5. 1. 5.  
P ost -St u d y Pr o visi o n  ................................................................... 3 9  
6.  
P A R TI CI P A N T E LI GI BI LI T Y  ................................................... 4 0  
6. 1.  
I n cl usi o n Criteria ......................................................................... 4 0  
6. 2.  
E xcl usi o n Criteria  ........................................................................ 4 1  
7.  
P A R TI CI P A N T E N R O L M E N T  .................................................. 4 3  
7. 1.  
E nr ol me nt Stratificati o n  ............................................................... 4 3  
8.  
T R E A T M E N T P R O C E D U R E S  .................................................. 4 4  
8. 1.  
St u d y I nter v e nti o n D osa ge, A d mi nistrati o n a n d Sc he d ule  .......... 4 4  
8. 1. 1.  
D ose A d mi nistrati o n  .................................................................... 4 4  
8. 1. 2.  
D ose Escalati o n a n d D os e A dj ust me nts  ...................................... 4 4  
8. 2.  
C o nc o mita nt T hera p y  .................................................................. 4 6  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 0  of 1 2 1  
8. 3.  
Pr o hi bite d T hera p y D uri n g St u d y Peri o d  .................................... 4 6  
8. 4.  
Preca uti o nar y C o nc o mita nt Me dicati o ns  ..................................... 4 7  
8. 5.  
C o m plia nce i n St u d y I nt er ve nti o n A d mi nistrati o n  ...................... 4 7  
9.  
S T U D Y P R O C E D U R E S  ............................................................. 4 8  
9. 1.  
St u d y Pr oce d ures  ......................................................................... 4 8  
9. 1. 1.  
I nf or me d C o nse nt ........................................................................ 4 8  
9. 1. 2.  
De m o gra p hics  .............................................................................. 4 8  
9. 1. 3.  
Me dical Hist or y  ........................................................................... 4 8  
9. 1. 4.  
Pri or a n d C o nc o mita nt Me dicati o n a n d T hera pies  ...................... 4 9  
9. 1. 5.  
P h ysical E xa mi nati o n  .................................................................. 4 9  
9. 1. 6.  
C o m pre he nsi ve Ne ur o de vel o p me ntal Assess me nt  ...................... 4 9  
9. 1. 7.  
Vital Si g ns  ................................................................................... 5 0  
9. 1. 8.  
1 2 -Lea d Electr ocar di o gra m  ......................................................... 5 0  
9. 1. 9.  
Vi de o Electr o e nce p h al o gra m  ....................................................... 5 0  
9. 1. 1 0.  
Bl o o d Sa m pli n g  ........................................................................... 5 0  
9. 1. 1 0. 1.  
Cli nical La b orat or y Sa m pli n g ...................................................... 5 0  
9. 1. 1 0. 2.  
P har mac o ki netic Bl o o d Sa m pli n g  ............................................... 5 2  
9. 1. 1 0. 3.  
O pti o nal Bl o o d Sa m pli n g  ............................................................ 5 2  
9. 1. 1 1.  
Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt S yste m  ............... 5 3  
9. 1. 1 2.  
Q uesti o n naires a n d Assess me nts C o m plete d at Sc he d ule d Visits
 ..................................................................................................... 5 3  
9. 1. 1 2. 1.  
C o nfir mati o n of Dia g n osis ( D S a n d L G S) a n d Sei z ure 
Class ificati o n ............................................................................... 5 3  
9. 1. 1 2. 2.  
Partici pa nt Diaries  ....................................................................... 5 5  
9. 1. 1 2. 3.  
I nfa nt a n d T o d dler Q ualit y of Life Q uesti o n nair e S h ort F or m  4 7
 ..................................................................................................... 5 6  
9. 1. 1 2. 4.  
Ne ur o de v el o p me ntal Scale –  Cli nicia n Gl o bal I m pressi o n of 
C ha n ge/ Se verit y  ........................................................................... 5 6  
9. 1. 1 3.  
St u d y I nter v e nti o n Acc o u nta bilit y  ............................................... 5 6  
9. 1. 1 4.  
A d verse E v e nts  ............................................................................ 5 7  
9. 1. 1 5.  
S pecial Circ u msta nces  ................................................................. 5 7  
1 0.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T DI S C O N TI N U A TI O N/ WI T H D R A W A L  ........ 5 9  
1 0. 1.  
Disc o nti n uati o n of St u d y I nter ve nti o n ......................................... 5 9  
1 0. 2.  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ............ 6 1  
1 0. 2. 1.  
L ost t o F oll o w -u p  ........................................................................ 6 2  
1 1.  
U R G E N T S A F E T Y M E A S U R E S  ............................................... 6 3  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 1  of 1 2 1  
1 2.  
A D V E R S E E V E N T R E P O R TI N G  ............................................. 6 4  
1 2. 1.  
A d verse E v e nt Defi niti o n  ............................................................ 6 4  
1 2. 2.  
Seri o us A d verse E v e nts  ............................................................... 6 4  
1 2. 3.  
Re p orti n g Pr oce d ures f or Seri o us A d verse E v e nts  ...................... 6 5  
1 2. 4.  
Ca usalit y Assess me nt  .................................................................. 6 6  
1 2. 5.  
Re p orti n g Pr oce d ures f or All A d verse E v e nts  ............................. 6 6  
1 2. 6.  
F oll o w -u p Pr oce d ures f or A d verse E ve nts  .................................. 6 8  
1 2. 7.  
P ote ntial Cases of Dr u g -I n d uce d Li ver I nj ur y ............................. 6 8  
1 2. 8.  
N otificati o n of Safet y I nf or mati o n t o I n v esti gat ors, Re g ulat or y 
A ut h orities, a n d I R Bs/I E Cs.  ........................................................ 6 9  
1 3.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................ 7 1  
1 3. 1.  
Sa m ple Size, P o wer a n d Si g nifica nce Le v els  .............................. 7 1  
1 3. 2.  
I nter me diate A nal ysis .................................................................. 7 1  
1 3. 3.  
A nal ysis Sets  ................................................................................ 7 1  
1 3. 4.  
Pr ot oc ol De viati o ns  ..................................................................... 7 2  
1 3. 5.  
Ge neral C o nsi derati o ns  ................................................................ 7 2  
1 3. 6.  
Acc o u nta bilit y a n d Bac k gr o u n d C haracteristics  ......................... 7 2  
1 3. 6. 1.  
E nr ol me nt a n d Dis p ositi o n  .......................................................... 7 2  
1 3. 6. 2.  
Baseli ne a n d De m o gr a p hic C haract eristics  ................................. 7 2  
1 3. 6. 3.  
Me dical Hist or y  ........................................................................... 7 2  
1 3. 6. 4.  
C o nc o mita nt Me dicati o n  ............................................................. 7 2  
1 3. 6. 5.  
Treat me nt C o m plia nce a n d E xte nt of Treat me nt E x p os ure  ........ 7 2  
1 3. 7.  
E n d p oi nts a n d Statistical Met h o ds  ............................................... 7 3  
1 3. 7. 1.  
Pri mar y Safet y a n d P har mac o ki netic E n d p oi nts  ......................... 7 3  
1 3. 7. 1. 1.  
A d verse E v e nts  ............................................................................ 7 3  
1 3. 7. 1. 2.  
Cli nical La b orat or y Data  ............................................................. 7 3  
1 3. 7. 1. 3.  
Vital Si g ns, 1 2 -Lea d Electr ocar di o gra m, P h ysical E xa mi nati o n 
a n d Ot her Safet y Data  .................................................................. 7 3  
1 3. 7. 1. 4.  
P har mac o ki netics  ......................................................................... 7 3  
1 3 . 7. 2. 
Pri mar y a n d Sec o n dar y Efficac y E n d p oi nt s ................................ 7 4  
1 3. 7. 2. 1.  
T otal C o u nta ble Seiz ures  ............................................................. 7 4  
1 3. 7. 3.  
Ot her Sec o n d ar y a n d E x pl orat or y E n d p oi nts  .............................. 7 5  
1 4.  
S A F E T Y M O NI T O RI N G C O M MI T T E E  ................................... 7 6  
1 5.  
R E G U L A T O R Y A N D E T HI C A L O B LI G A TI O N S ................... 7 7  
1 5. 1.  
Declarati o n of Helsi n ki  ................................................................ 7 7  
1 5. 2.  
I nf or me d C o nse nt ........................................................................ 7 7  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 2  of 1 2 1  
1 5. 3.  
I nstit uti o nal Re vie w B oar d .......................................................... 7 7  
1 5. 4.  
Recr uit me nt Strate g y  ................................................................... 7 7  
1 5. 5.  
Fi na ncial Discl os ur e  .................................................................... 7 8  
1 5. 6.  
Pre -st u d y D oc u me ntati o n Re q uire me nts ..................................... 7 8  
1 5. 7.  
Partici pa nt C o nfi de ntialit y  ........................................................... 7 8  
1 6.  
A D MI NI S T R A TI V E A N D L E G A L O B LI G A TI O N S  ............... 8 0  
1 6. 1.  
Pr ot oc ol A me n d me nts a n d E n d of St u d y or Ter mi nati o n  ........... 8 0  
1 6. 2.  
St u d y D oc u me ntati o n a n d St ora ge  .............................................. 8 0  
1 6. 3.  
St u d y M o nit ori n g a n d Data C ollecti o n  ........................................ 8 1  
1 6. 4.  
Electr o nic D ata C ollecte d b y Electr o nic Patie nt Re p orte d 
O utc o mes a n d Vi de o El ectr oe nce p hal o gr a m  ............................... 8 1  
1 6. 5.  
Q ualit y Ass ura nce  ........................................................................ 8 2  
1 6. 6.  
C o m pe nsati o n  .............................................................................. 8 2  
1 6. 7.  
P u blicati o n P olic y  ........................................................................ 8 2  
1 6. 8.  
I ntelle ct ual Pr o pert y Ri g hts ......................................................... 8 3  
1 6. 9.  
C o nfi de ntial I nf or mati o n  ............................................................. 8 3  
1 7.  
R E F E R E N C E S  ............................................................................ 8 4  
A P P E N DI X  1  S C H E D U L E O F A C TI VI TI E S  ............................................ 8 8  
A P P E N DI X  2  S T U D Y P E R S O N N E L  ....................................................... 1 0 9  
A p pe n di x  2. 1  I n v esti gat or Details .............................................................. 1 0 9  
A p pe n di x  2. 2  S p o ns or C o ntact Details  ...................................................... 1 0 9  
A p pe n di x  2. 3  C o ntract Researc h Or g a nisati o ns  ........................................ 1 0 9  
A p pe n di x  2. 4  Bi oa nal ytical La b orat or y  ..................................................... 1 0 9  
A p pe n di x  2. 5  Vi de o E E G Ve n d or .............................................................. 1 1 0  
A P P E N DI X  3  Q U E S TI O N N AI R E S/ A S S E S S M E N T S  ............................. 1 1 1  
A p pe n di x  3. 1  Dia g n ostic Criteria f or Cli nical Dia g n osis of T u ber o us 
Scler osis  ..................................................................................... 1 1 1  
A p pe n di x  3. 2  I nter nati o nal Lea g ue A gai nst E pile ps y Seiz ure Classificati o n
 
1 1 2  
A p pe n di x  3. 3  Et hical C o nsi derati o ns f or Cli nical Trials o n Me dici nal 
Pr o d ucts C o n d ucte d wit h Mi n ors  .............................................. 1 1 3  
A P P E N DI X  4  G E N E TI C S/ BI O M A R K E R S  ............................................. 1 1 4  
A P P E N DI X  5  P R O T O C O L A M E N D M E N T HI S T O R Y  .......................... 1 1 5  
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E  ......... 1 1 5  
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 3  of 1 2 1  
LI S T O F T A B L E S  
Ta ble 1  
F or m ulati o n of G W P 4 2 0 0 3 -P Oral S ol uti o n  ............................... 3 7  
Ta ble 2  
D ose Titrati o n  .............................................................................. 4 5  
Ta ble 3  
C he mistr y, Hae mat ol o g y, a n d Uri nal ysis  .................................... 5 1  
 
LI S T O F FI G U R E S  
Fi g ure 1  
St u d y Sc he ma  .............................................................................. 1 8  
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 4  of 1 2 1  
LI S T O F A B B R E VI A TI O N S  
7 -C O O H -C B D  
7 -car b o x y -ca n na bi di ol 
7 -O H -C B D  
7 -h y dr o x y -ca n na bi di ol 
A C T H  
A dre n oc ortic otr o pic h or m o ne  
A E  
A d verse E ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A S M  
A ntise iz ure me dicati o n 
A S T  
As partate ami n otra nsferase  
b.i. d.  
T wice a da y  
C B D  
Ca n na bi di ol  
C B D -O S  
Ca n na bi di ol oral s ol uti o n  
C B 1  
Ca n na bi n oi d rece pt or 1  
C B 2  
Ca n na bi n oi d rece pt or 2  
C F R  
C o de of Fe deral Re g ulati o ns  
C GI C  
Cli nicia n Gl o bal I m pressi o n of C ha n ge  
C GI S  
Cli nicia n Gl o bal I m pressi o n of Se verit y 
CI O M S  
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C R O  
Cli nical Researc h Or ga nisati o n  
C S R  
Cli nical St u d y Re p ort  
C TI S  
Cli nical Trials I nf or mati o n S yste m 
D R F  
Dia g n ostic Re vie w F or m  
D S  
Dra vet s y n dr o me  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
E C  
Et hics C o m mittee  
E D C  
Electr o nic data ca pt ure  
E D R S  
E pile ps y Diar y Refere nce S heet  
E E G  
Electr oe nce p hal o gra m  
E M A  
E ur o pea n Me dici nes A ge nc y  
E O T  
E n d of treat me nt  
e P R O 
Electr o nic patie nt -re p orte d o utc o me 
E S  
E pile ptic s pas ms  
E S CI  
E pile ps y St u d y C o ns orti u m  
E T  
Earl y ter mi nati o n  
E U  
E ur o pea n U ni o n  
E U C T D  
E ur o pea n U ni o n Cli nical Trial Directi ve  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 5  of 1 2 1  
E U C T R  
E ur o pea n U ni o n Cli nical Trial Re gister  
E u dra C T  
E ur o pea n U ni o n Dr u g Re g ulati n g A ut h orities Cli nical Trials Data base  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G  
Gastric  
G C P  
G o o d Cli nical Practice  
G G T  
Ga m ma -gl uta m yl tra nsferase  
G -t u be 
Gastric -t u be 
G W  
G W Researc h Lt d  
G W P 4 2 0 0 3 -P  
Ca n na bi di ol oral s ol uti o n  
I B 
I n vesti gat or’s Br oc h ure  
I C F 
I nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts 
f or H u ma n Use 
I E C 
I n de pe n de nt Et hics C o m mittee 
I L A E 
I nter nati o nal Lea g ue A gai nst E pile ps y 
I N R 
I nter nati o nal N or malise d Rati o  
I R B 
I nstit uti o nal Re vie w B oar d 
I S 
I nfa ntile s pas ms 
I T Q O L-S F 4 7  
I nfa nt a n d T o d dler Q ualit y of Life -S h ort F or m 4 7  
L A R  
Le gall y a ut h orise d re prese ntati ve 
L G S  
Le n n o x -Gasta ut s y n dr o me  
m T O R  
Ma m malia n tar get of ra pa m yci n  
N G  
Nas o gastric  
PI  
Pri nci pal i n vesti gat or  
P K  
P har mac o ki netic  
P L N  
Pac ka gi n g l ot n u m ber  
P T  
Pr ot hr o m bi n ti me  
Q o L  
Q ualit y of life  
Q Tc B  
C orrecte d Q T i nter val wit h Bazett c orrecti o n  
R T S M  
Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical a nal ysis pla n  
S C N 1 A  
S o di u m v olta ge -gate d c ha n nel al p ha s u b u nit 1  
S E  
Stat us e pile ptic us  
S E G A  
S u be pe n d y mal gia nt cell astr oc yt o ma  
S E N  
S u be pe n d y mal n o d ules  
SI F  
Seiz ure I de ntificati o n F or m  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 6  of 1 2 1  
S M C  
Safet y m o nit ori n g c o m mittee  
S o A  
Sc he d ule of Acti vities  
S O C  
S yste m Or ga n Class  
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
T B L  
T otal bilir u bi n  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
T H C  
∆9-tetra h y dr oca n na bi n ol 
T ma x  
Ti me t o ma xi m u m plas ma c o nce ntrati o n  
T S C  
T u ber o us scler osis c o m ple x  
U L N  
U K  
U p per Li mit of N or mal  
U nite d Ki n g d o m  
U S  
U nite d States  
V E E G  
Vi de o e lectr oe nce p hal o gra m 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 7  of 1 2 1  
D efi niti o n of T er m s  
Ter m  
Defi niti o n  
A dj u ncti ve t hera p y 
T hera p y a d mi nistere d i n a d diti o n t o a partici pa nt’s c urre nt A S M  
re gi me n.  
Care gi ver  
Pare nt( s) or g uar dia n(s) w h o pr o vi de a n d ma n a ge t he e ver y da y 
care f or t he partici pa nt.  
E n d of st u d y 
Last partici pa nt  last visit or last c o ntact, w hic he ver occ urs last. 
E nr olle d partici pa nt  
A n y partici pa nt  w h ose pare nt (s)/le gall y a ut h orise d re prese ntati ve 
has pr o vi de d writte n i nf or me d c o nse nt t o ta ke part i n t he st u d y. 
Inter nati o nal n or malise d 
rati o 
A calc ulati o n ma de t o sta n dar dize pr ot hr o m bi n ti me. 
I n vesti gat or 
St u d y pri nci pal i n vesti gat or or a f or mall y dele gate d st u d y 
p h ysicia n.  
Scree ni n g/ b aseli ne 
T he 2 8 -da y peri o d fr o m Visit 1 t o Visit 3 ( Da y 1).  
Stat us e pile ptic us  
A n y seiz ure lasti n g 3 0 mi n utes or l o n ger. 
St u d y inter ve nti o n  
Ter m use d t o descri be t he acti ve i n vesti gati o nal pr o d uct.  
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 8  of 1 2 1  
2.  
O B J E C TI V E S A N D E N D P OI N T S  
O bjecti ves  
E n d p oi nts  
Pri m ar y  
T o e val uate t he safet y a n d t olera bilit y 
of a dj u ncti ve G W P 4 2 0 0 3 -P assesse d 
d uri n g t he 5 2 -wee k treat me nt peri o d.  
T he safet y pr ofile of a dj u ncti ve G W P 4 2 0 0 3 -P 
will be assesse d b y meas uri n g:  
•  
A d verse e ve nts ( A Es [fre q ue nc y, t y pe, 
a n d se verit y ]). 
•  
Vital si g ns.  
•  
P h ysical e xa mi nati o n.  
•  
1 2 -lea d electr ocar di o gra m ( E C G ). 
•  
Cl i nicall y si g nifica nt c ha n ges i n 
la b orat or y para meters. 
•  
E mer ge nce of ne w seiz ure t y pes  as 
rec or de d b y A E re p orti n g. 
•  
C o m pre he nsi ve n e ur o de vel o p me nt al 
assess me nt. 
T o i n vesti gate t he e x p os ure of 
G W P 4 2 0 0 3 -P a n d its maj or 
meta b olites f oll o wi n g m ulti ple d oses 
of G W P 4 2 0 0 3 -P . 
Tr o u g h , 3-h o ur a n d 6 -h o ur p ost d ose  plas ma 
c o nce ntrati o ns of G W P 4 2 0 0 3 -P  a n d its maj or 
meta b olites f oll o wi n g m ulti ple d oses of 
G W P 4 2 0 0 3 -P.  
T o e val uat e t he efficac y of 
G W P 4 2 0 0 3 -P i n re d uci n g t he 
fre q ue nc y of i n dicati o n-s pecific 
c o u nta ble seiz ures.  
Perce nt a ge c ha n ge fr o m baseli ne i n 
i n dicati o n-s pecific*  c o u nta ble seiz ures ( a vera ge 
per 2 8 da ys) as rec or de d b y care gi ver s o n 
seiz ure diaries at Wee k 1 2, e ver y 4 wee ks 
t hereafter, a n d d uri n g t he 4-wee k peri o d pri or t o 
e n d of treat me nt ( E O T ).  
* F ocal/ ge neralise d seiz ures (t u ber o us scler osis 
c o m ple x [ T S C ]), dr o p seiz ures (Le n n o x -Gasta ut 
s y n dr o me [L G S ]), or c o n v ulsi ve seiz ures 
(D ra vet s y n dr o me [D S ]) 
Sec o n d ar y  
T o e val uate t he efficac y  of 
G W P 4 2 0 0 3 -P  i n re d uci n g t he 
fre q ue nc y of t otal c o u nta ble seiz ures. 
Meas ure me nts of t otal c o u nta ble seiz ures 
(a vera ge per 2 8 da ys) as rec or de d b y care gi vers 
o n seiz ure diaries at Wee k 1 2, e ver y 4 wee ks 
t hereafter, a n d d uri n g t he 4-wee k peri o d pri or t o 
E O T will be use d t o deter mi ne t he f oll o wi n g  
e n d p oi nts : 
•  
N u m ber a n d perce nta ge of partici pa nts 
c o nsi dere d treat me nt res p o n ders, 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 2 9  of 1 2 1  
O bjecti ves  
E n d p oi nts  
defi ne d as t h ose wit h a ≥ 5 0 % re d ucti o n 
fr o m baseli ne i n t otal c o unta ble 
seiz ures.  
•  
Cate g orical perce nta ge c ha n ge fr o m 
baseli ne t o EO T i n t otal c o u nta ble 
seiz ures as f oll o ws: 
 >  2 5 % (i ncrease) ; 
 ≥ 0 % t o ≤ 2 5 % (i ncrease) ; 
 >  – 2 5 % t o <  0 % (re d ucti o n) ;  
 >  – 5 0 % t o ≤ – 2 5 % (re d ucti o n) ; 
 >  – 7 5 % t o ≤ – 5 0 % (re d ucti o n) ; 
 ≤ – 7 5 % (re d uct i o n). 
•  
Seiz ure free d o m, defi ne d as 1 0 0 % 
re d ucti o n fr o m baseli ne i n t otal 
c o u nta ble seiz ures .  
T o assess t he rete nti o n of partici pa nts 
recei vi n g G W P 4 2 0 0 3-P . 
Perce nta ge of partici pa nts still ta ki n g 
G W P 4 2 0 0 3 -P at Wee k  1 2 a n d e ver y 4  wee ks 
t hereafter. 
E x pl or at or y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 0  of 1 2 1  
3.  
B A C K G R O U N D A N D R A TI O N A L E  
3. 1.  
Dise ase  
T u ber o us scler osis c o m ple x , L G S, a n d D S are rare, earl y-o nset e nce p h al o pat hic 
e pile psies wit h p o or pr o g n oses  a n d ass ociat e d c o m or bi dities. C urre nt o pti o ns f or 
a ntiseiz ure me dicati o ns ( A S Ms ) i n t hese c o n diti o ns ha ve  s u bsta ntial li mitati o ns, 
i ncl u di n g p har mac oresista nce lea di n g t o l o w seiz ure c o ntr ol a n d i nt olera ble si de 
effects. M ore o ver, less effecti ve sei z ure c o ntr ol is ofte n ass ociate d wit h a d diti o nal 
c o m or bi dities a n d a l o wer Q o L. T heref ore, earl y treat me nt a n d c o ntr ol of seiz ures 
ma y  be critical i n  i m pr o vi n g t he de vel o p me ntal o utc o mes  f or patie nt s wit h t hese 
c o n diti o ns  (va n der P oest Cle me nt 2 0 2 0 ). 
T u ber o us Scler osis C o m ple x  
T u ber o us scler osis c o m ple x  is a ge netic dis or d er c haract erise d b y t he f or mati o n of 
n o n mali g na nt t u m o urs (t u bers) i n m ulti ple or ga n s yste ms. T he cli nical si g ns of T S C 
arise as a res ult of i nacti vati n g m utati o ns i n t u m o ur s u p press or ge n es: T S C 1  (l ocate d 
o n c hr o m os o me 9 q 3 4. 1 3) or T S C 2  (l ocate d o n c hr o m os o me 1 6 p 1 3. 3) (E ur o pea n 
C hr o m os o me 1 6 T u ber o us Scler osis C o ns orti u m 1 9 9 3 , va n Sle gte n h orst 1 9 9 7 ). T he 
T S C 1  ge ne e nc o des t he 1 3 0  k Da pr otei n T S C 1  ( ha marti n) w hilst T S C 2  e nc o des t he 
2 0 0  k Da pr otei n T S C 2  (t u beri n) (E ur o pea n C hr o m os o me 1 6  T u ber o us Scler osis 
C o ns orti u m 1 9 9 3 , va n Sle gte n h or st 1 9 9 7). T he T S C 1  a n d T S C 2  s hare n o h o m ol o g y 
yet bi n d t o eac h ot her wit h hi g h affi nit y t o f or m a f u ncti o nal heter o di mer  (Va n 
Sle gte n h orst 1 9 9 8 ), w hic h s u p presses m T O R, a ke y re g ulat or of cell gr o wt h a n d 
pr oliferati o n  (I n o ki 2 0 0 2). T h us, i nacti vati n g m utati o ns i n T S C 1  a n d T S C 2  lea d t o 
i na de q uate s u p pressi o n of m T O R si g nalli n g, res ulti n g i n a b n or mal cell ular gr o wt h 
a n d t u m ori ge nesis  (C ha n 2 0 0 4 , H ua n g 2 0 0 8 ). T u b er o us scler osis c o m ple x  is 
tra ns mitte d i n a n a ut os o mal-d o mi na nt patter n of i n herita nce, alt h o u g h t w o -t hir ds of 
all cases are ca use d b y d e n ov o  m utati o ns  (E ur o p ea n C hr o m os o me 1 6 T u b er o us 
Scler osis C o ns orti u m 1 9 9 3 , We b b 1 9 9 6 b , J o nes 1 9 9 9). M utati o ns i n T S C 1  acc o u nt f or 
a p pr o xi matel y 1 5 % of al l cases, w hile a p pr o xi mat el y 7 0 % of all cases are d ue t o 
m utati o ns i n T S C 2 ; a p pr o xi matel y 1 5 % of patie nts ha ve n o i de ntifia ble m utati o n i n 
t he c o di n g re gi o ns of eit h er ge ne (J o nes 1 9 9 9, Da b ora 2 0 0 1 ). Ge nerall y, 
T S C 2  m utati o ns res ult i n a m ore se v ere dise ase p h e n ot y pe c o m pare d wit h 
T S C 1  m utati o ns  (J o nes 1 9 9 9, Da b ora 2 0 0 1 ). T he birt h i nci de nce of T S C is esti mate d 
t o be 1  i n 6 0 0 0, wit h a p pr o xi matel y 5 0, 0 0 0 i n di vi d uals i n t he Unite d S tates a n d 
1  milli o n i n di vi d uals w orl d wi de affecte d  (Os b or ne 1 9 9 1 , T u ber o us Scler osis Allia nce 
2 0 1 9 ). 
T u m o urs  i n patie nts wit h T S C  ca n occ ur i n a n y m aj or or ga n y et de vel o p pri maril y i n 
t he brai n, e yes, h eart, ki d ne y, s ki n, a n d l u n gs (Cri n o 2 0 0 6 ). T he ra n d o m l ocati o n, 
n u m ber, size, a n d distri b uti o n of t u m o urs res ult i n a great v ariet y of cli nical 
ma nifestati o ns, yet m ost patie nts e x hi bit der mat ol o gical, re nal a n d/ or ne ur ol o gical 
a b n or malities, w hic h a p p ear at disti nct de vel o p me ntal p oi nts  (C urat ol o 2 0 0 8 ). 
Der mat ol o gical a b n or malities ge nerall y first a p pear i n i nfa nc y or earl y c hil d h o o d a n d 
i ncl u de h y p o mela n otic mac ules, w hic h are prese nt i n m ore t ha n 9 0 % of pati e nts  wit h 
T S C , a n d facial a n gi ofi br o mas, f o u n d i n a p pr o xi matel y 7 5 % of patie nts wit h T S C  
(We b b 1 9 9 6a , We b b 1 9 9 6 b , J óz wia k 2 0 0 0). I n c o ntrast, re nal a b n or malities te n d n ot 
t o de vel o p u ntil late c hil d h o o d/a d olesce nce a n d i n cl u de a n gi o m y oli p o mas (f o u n d i n 
5 0 % t o 7 0 % of patie nts), re nal c ysts (f o u n d i n 2 5 % t o 3 5 % of patie nts) a n d, ver y 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 1  of 1 2 1  
rarel y, r e nal-cell carci n o mas (f o u n d i n 2 % t o 3 % of patie nts)  (C o o k 1 9 9 6 , 
O' Calla g ha n 2 0 0 4 , Ra k o ws ki 2 0 0 6 ). Ne ur ol o gical a b n or malities first a p pear d uri n g 
e m br y o ge nesis a n d i ncl u de cere bral c ortical t u bers a n d s ube pe n d y mal n o d ules 
(S E Ns ), eac h of w hic h are f o u n d i n 8 0 % t o 9 0 % of patie nts , as well as s u be pe n d y mal 
gia nt ce ll astr oc yt o mas ( S E G As ), w hic h are pres u me d t o deri ve fr o m S E Ns a n d are 
f o u n d i n 5 % t o 1 5 % of p atie nts (N ort hr u p 2 0 1 3 ). W hereas S E Ns a n d S E G As are 
us uall y as y m pt o matic, t he prese n ce of c ortical t u bers is wi del y belie ve d t o c o ntri b ute 
t o t he ne ur ol o gic ma nifestati o ns of T S C, w hic h i ncl u de e pile ps y, c o g niti ve disa bilit y, 
a n d a utis m  (Cri n o 2 0 0 6 , C urat ol o 2 0 0 8 , N ort hr u p 2 0 1 3 ). 
E pile ptic seiz ures are t he m ost c o m m o n cli nical ma nifestati o n of T S C, affecti n g m ore 
t ha n 7 0 % of patie nts (D a b ora 2 0 0 1 , C h u -S h ore 2 0 0 9 , Wa n g 2 0 1 4 ). Seiz ure o nset 
occ urs wit hi n t he first ye ar of life i n a p pr o xi matel y 6 0 %  of patie nts a n d wit hi n t he 
first 3 years of life i n a p pr o xi matel y 8 0 % of patie nts  (C h u -S h ore 2 0 0 9 ). T he o nset of 
e pile ps y i n T S C c o m m o nl y ma nifests as f ocal m ot or seiz ures, w hic h c o e xist wit h 
i nfa ntile s pasms ( I S) i n a p pr o xi matel y o ne-t hir d of patie nts (C h u -S h ore 2 0 0 9 ). 
I nterictal E E G rec or di n gs at o nset t y picall y s h o w h y psarr h yt h mia, c haracterise d b y 
f ocal or m ultif ocal s pi ke disc har ges a n d irre g ular sl o w-wa ve acti vit y (C urat ol o 2 0 0 2 ). 
Virt uall y all patie nts wit h  T S C w h o ha ve a hist or y of  I S a n d a p pr o xi matel y half of 
t h ose wit h o ut I S de vel o p m ulti ple seiz ure t y pes, i ncl u di n g c o m ple x f ocal s eiz ures 
( wit h or wit h o ut sec o n dar y ge neralisati o n ), ge ne ralise d t o nic-cl o nic seiz ures, at o nic 
seiz ures, a n d at y pical a bs e nces (C h u -S h ore 2 0 0 9 ). Alt h o u g h I S res ol v e wit h ti me, t he 
fre q ue n c y a n d se v erit y of ot her seiz ures te n d t o i ncreas e t hr o u g h o ut earl y c hil d h o o d, 
a n d nearl y t w o -t hir ds of patie nts wit h T S C de vel o p me dicall y i ntracta ble e pile ps y, 
i ncl u di n g L G S  (C h u -S h ore 2 0 0 9 ). C o g niti ve i m pair me nt (i ntelli ge nce/ de vel o p me ntal 
q u otie nt <  7 0) is o bser ve d i n ar o u n d 6 0 % of all patie nts wi t h T S C w h o ha ve a hist or y 
of seiz ures a n d i n a p pr o xi matel y t hree -q uarters of all patie nts  wit h T S C  wit h a hist or y 
of refract or y e pile ps y  (C h u -S h ore 2 0 0 9 ). Earl y ma na ge me nt of s eiz ures is t heref ore 
i m p orta nt i n pre ve nti n g s u bse q ue nt e pile ptic e n ce p hal o pat h y a n d i n re d u ci n g t he 
ass ociate d c o g niti ve a n d ne ur o ps yc hiatric c o nse q u e nces  (B o m bar dieri 2 0 1 0 , 
Wa n g  2 0 1 4 ). 
Le n n o x -G ast a ut Sy n dr o me  
L e n n o x-G asta ut s y n dr o me  is a rare e pile ptic e nce p hal o pat h y i n w hic h fre q u e nt a n d 
de bilitati n g seiz ures are belie ve d t o c o ntri b ute t o i ntellect ual a n d be ha vi o u ral 
disa bilit y. T he o nset of L G S s y m pt o m s us uall y  occ urs  bet wee n 3 a n d 5 y ears of a ge  
b ut ca n als o , i n rare cases, occ ur  d uri n g t he  first ye ar of life (Tre v at ha n 1 9 9 7 , 
Arzi ma n o gl o u 2 0 0 9 b ). T he disease is c h aracterise d  b y t he prese n ce of m ulti ple 
seiz ure t y pes ( pre d o mi na ntl y t o nic, at o nic, a n d at y pical a bse nce seiz ures b ut ca n 
i ncl u de g e neralise d t o nic-cl o nic, f ocal, a n d m y ocl o nic seiz ures), p ossi bl y sl o w E E G 
s pi ke wa ves ( <  3 Hz) wit h a b n or mal bac k gr o u n d acti vit y w he n a w a k e, a n d 
i ntellect ual i m pair me nt (Tre vat ha n 1 9 9 7 , Arzi ma n o gl o u 2 0 0 9 b ). H o we ver, dia g n osis 
ca n be d ela ye d b e y o n d t he o nset of seiz ures, as t he electr oe n ce p h al o gra m ( E E G ) 
fi n di n gs ofte n d o n ot f ull y de vel o p u ntil 1 t o 8 years of a ge  (Arzi ma n o gl o u 2 0 0 9 b ). 
Seiz ures i n L G S ma y pr o gress t o stat us e pile ptic us  ( S E), w hic h ma y occ ur fre q ue ntl y 
i n s o me patie nt s a n d carries great ris ks, i ncl u di n g deat h. Le n n o x −Gasta ut  s y n dr o me 
ca n be s u b di vi de d i nt o cases of k n o w n ori gi n ( ge n etic, str uct ural, meta b olic, i m m u ne, 
a n d i nfecti o us) a n d i di o p at hic cases, i n w hi c h t he fir st cli nical si g n is ofte n t he 
occ urre nce of a br u pt falls (c o m m o nl y referre d t o as dr o p attac ks/sei z ures). Dr o p 
seiz ures are c o m m o n i n L G S a n d ca n lea d t o p h ysical i nj ur y lea di n g t o i ncrease d 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 2  of 1 2 1  
m or bi dit y a n d m ortalit y. C o g niti ve i m pair me nt is a p pare nt i n ≥ 7 5 % of all patie nt s 
wit h L G S  wit hi n  5  years of disease o nset  (Arzi ma n o gl o u 2 0 0 9 b ). T h us, t he nee d f or 
treat me nt f or p atie nt s wit h L G S ofte n e mer g es earl y a n d pri or t o f or mal dia g n osis.  
Dr avet Sy n dr o me  
D ra vet s y n dr o m e, a se v ere m y ocl o nic e pile ps y i n i nfa nc y, is a rare f or m of se vere, 
treat me nt-resista nt e pile ps y wit h o nset i n earl y c hil d h o o d a n d a disti ncti ve yet 
c o m ple x electr o e nce p hal o gra p hic a n d cli nical prese ntati o n  (Sc heffer 2 0 1 2 , Dra vet 
2 0 1 3 ). It is c haracteris e d b y a variet y of treat me nt -resista nt seiz ures (fe brile a n d 
afe brile, g e neralise d , a n d u nilateral, cl o nic, or t o ni c-cl o nic) t h at occ ur i n t h e first year 
of life, wit h a p o or c o g niti ve pr o g n osis. Dra vet s y n dr o me  is ca use d b y p at h o ge nic 
varia nts i n t he  s o di u m v olta ge-gate d c ha n nel al p ha s u b u nit 1 ( S C N 1 A ) i n t he maj orit y 
( > 7 0 %) of patie nts  (Claes 2 0 0 1 , M ulle y 2 0 0 6 , S uls 2 0 0 6 , De pie n ne 2 0 0 9 , Na ka ya m a 
2 0 1 0 ). O nset us uall y occ urs bet wee n 4  a n d 8  m o nt hs of a ge a n d ma nifests t y picall y as 
a pr ol o n ge d ( >  1 5  mi n utes ) cl o nic, ge neralise d or u nilateral c o n v ulsi ve seiz ure, ofte n 
tri g gere d b y fe ver, t h at c a n e v ol ve i nt o S E (Arzi m a n o gl o u 2 0 0 9a , D ra vet 2 0 1 1, 
Dra vet 2 0 1 3 ). I n fact, t he occ urre nce of t he first seiz ure i n t he first ye ar of life is part 
of t he cri teri a f or dia g n osis of D S, w hic h ha ve bee n c o nfir me d i n a cli nical st u d y 
(Cetica 2 0 1 7 ). D ra vet s y n dr o me is e xtre mel y resista nt t o treat me nt d uri n g c hil d h o o d 
a n d patie nt s c o nti n ue t o ha ve u nc o ntr olle d s eiz ures t hr o u g h o ut t heir lifeti me. I n 
a d diti o n t o c o n v ulsi ve seiz ures, ot her seiz ure t y p es a p pear b et wee n t he a g es of 
1  a n d 4  years, i n cl u di n g m y ocl o nic seiz ures, f ocal seiz ures, at y pical a bse n ces, a n d 
o bt u n dati o n stat uses (i n w hic h c o nsci o us ness is i m paire d). I ntellect ual i m pair me nt 
affects nearl y all patie nts  a n d is se vere i n 5 0 % of cases, ofte n res ul ti n g i n de pe n de n c y 
i n a d ult h o o d d ue t o t he c hr o nic si g nifica nt disa bilit y (Ge nt o n 2 0 1 1 ). 
3. 2.  
C a n n a bi di ol B ac k gr o u n d  
G W P 4 2 0 0 3 -P ( E pi di ole x/ E pi d y ole x) is t he s u bsta nce c o d e f or t he st u d y i nt er ve nti o n, 
p urifie d G W P 4 2 0 0 3 -P, a n o n ps yc h oacti ve ca n na bi n oi d u n der de vel o p me nt b y Jazz 
P har mace uticals  Researc h U K Lt d.  f or t he treat me nt of a n u m ber of c o n diti o ns. I n t he 
U nite d States , E pi di ole x is i n dicate d f or the tr eat me nt of seiz ures ass ociat e d wit h 
L G S, D S, or T S C i n patie nts  1  year of a ge a n d ol der. E pi d y ole x  has recei v e d a p pr o val 
i n t he E ur o pea n U ni o n f or a dj u ncti ve use t o treat s eiz ures ass ociate d wit h L G S a n d 
D S , i n c o nj u ncti o n wit h cl o baza m, i n patie nts  2  y ears of a ge a n d ol d er, a n d f or 
a dj u ncti ve use t o treat seiz ures ass o ciate d wit h T S C i n p atie nts 2 years of a ge a n d 
ol der. T he pr o d u ct  has recei ve d Or p ha n Dr u g Desi g nati o n fr o m t he E ur o pea n 
Me dici nes A ge n c y ( E M A) a n d  U S  F o o d a n d Dr u g A d mi nistrati o n  (F D A ) f or t he 
treat me nt of seiz ures ass ociate d wit h L G S, D S, a n d T S C. 
G W P 4 2 0 0 3 -P is e xtracte d fr o m C a n n a bis s ativ a  L. pla nts, has a defi n e d c he mical 
pr ofile, a n d c o nt ai ns c o nsiste nt le vels of ca n na bi di ol ( C B D ) as t he pri nci pal 
p h yt oca n na bi n o i d. E xtracts fr o m t hese pla nts are pr ocesse d t o yiel d p ure ( ≥ 9 8 %) 
C B D t hat t y picall y c o ntai ns less t ha n 0. 1 0 % ( w/ w) ∆9-tetra h y dr oca n na bi n ol (T H C ). 
T he p ure C B D is s u bse q ue ntl y diss ol ve d i n e xci pie nts wit h a d de d s weet e n er a n d 
fla v ou ri n g. 
T he p har mac ol o gica l effects of p h yt oca n n a bi n oi ds are t h o u g ht t o be me diate d 
pri maril y via t heir i nteracti o n wit h t he e n d oca n n a bi n oi d s yste m, w hic h c o nsists of 
ca n na bi n oi d rece pt ors, e n d o ge n o us li ga n ds (e n d o ca n na bi n oi ds), a n d e nz y mes f or 
e n d oca n n a bi n oi d s y nt hesis a n d de gra d a ti o n. T w o G pr otei n-c o u ple d rece pt ors f or 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 3  of 1 2 1  
ca n na bi n oi ds ha ve s o far bee n i de ntifie d, desi g n ate d ca n n a bi di ol rece pt or 1 ( C B 1) a n d 
ca n na bi di ol rece pt or 2 ( C B 2) rece pt ors; C B D d oes n ot bi n d t o eit her of t hese rece pt ors 
wit h a n y great affi nit y b ut d oes m o d ulate t he meta b olisi n g e nz y mes of t he 
e n d oca n n a bi n oi d s yste m. C a n na bi di ol  als o affects i o n c ha n nel c o n d ucta nce a n d acts 
o n ot her G pr otei n -c o u ple d rece pt ors, s uc h as t he tra nsie nt rece pt or p ote nti al c ha n nel, 
T R P V 1  (Bis o g n o 2 0 0 1 ), a n d t he or p ha n G P R 5 5 (W h yte 2 0 0 9 ). Ca n na bi di ol als o  
i n hi bits a de n osi ne re u pta ke via e q uili brati ve n ucl e osi de tra ns p orter 1 , t here b y 
e n ha nci n g t he a ntic o n v ulsi ve a n d a nti -i nfla m mat or y effects of a d e n osi ne vi a a g o nis m 
of A 1 a n d A 2 A rece pt ors (Se bastiã o 2 0 0 0 , Carrier 2 0 0 6 , Ri beir o 2 0 1 2 , A m ori m 2 0 1 6 ). 
I m p ort a ntl y, i n c o ntrast t o T H C, C B D lac ks detecta ble ps yc h oacti vit y. Ca n na bi di ol 
has de m o nstrate d a ntic o n v ulsa nt, a nti ps yc h otic, a n xi ol ytic, ne ur o pr otecti ve, 
a nti o xi da nt, a n d a nti -i nfla m mat or y acti vit y (Pert wee 2 0 0 4 ). 
3. 3.  
R ati o n ale  
T he rati o nale f or t his st u d y is t o f urt her c haract eri ze t he safet y, P K, a n d efficac y  of 
G W P 4 2 0 0 3 -P  i n partici pa nts wit h T S C, D S, a n d L G S w h o are < 2 years of a ge. 
C urre nt treat me nt o pti o ns f or t hese patie nts are i n a de q uate , es peci all y beca use these 
c o n diti o ns ofte n prese nt wit hi n t he first year s of l ife a n d ca n ma nifest i n i nfa nts 
<  1 2  m o nt hs of a ge . N e w, effic aci o us p har m ace uti cal treat me nts are n ee de d f or  t he 
y o u n g est patie nts wit h t hese t y picall y refract or y e pile ps y s y n dr o mes.  
3. 3. 1.  
J ustific ati o n f or D ose  
T he rati o nale b e hi n d t he d osi n g sc he d ule is fr o m t he well -esta blis he d  cli nical 
de vel o p me nt pr o gra m me i ncl u d i n g 5 p ositi ve pi v otal st u dies t hat ha ve s u p p orte d its 
c o m merciali sati o n as a n A S M i n t he U S, E U, a n d ot he r ge o gra p hic e x p a nsi o n areas. 
C B D -O S has bee n a p pr o ve d u p t o a ma xi m u m mai nte na nce d ose of 2 0 m g/ k g/ da y f or 
t he treat me nt of D S a n d L G S, a n d u p t o a ma xi m u m mai nte na nce d ose of 
2 5  m g/ k g/ da y f or t he treat me nt of T S C. It has als o bee n pres cri be d b y p h ysi cia n s f or 
t he treat me nt of p atie nts wit h i ntracta ble e pile ps y res ulti n g fr o m a vari et y of 
aeti ol o gies as part of t h e i n vesti gat or -i nitiate d e x p a n de d access pr o gra m  wit h dail y 
d osa ges u p t o 5 0  m g/ k g/ da y. Base d o n safet y res ults fr o m pre vi o us st u dies, a n d si nce 
t he c urre nt st u d y is desi g ne d t o all o w f or i n di vi d ualise d d osi n g, a dail y ma xi m u m 
d osa ge of 2 0  m g/ k g/ da y C B D -O S f or partici pa nts wit h D S a n d L G S a n d a ma xi m u m 
d osa ge of 2 5  m g/ k g/ da y C B D -O S f or partici pa nts wit h T S C was selecte d.  
T he 5 2 -wee k treat me nt peri o d of St u d y G W E P 1 7 0 0 5 i ncl u des a fi xe d 2 -wee k titrati o n 
sc he d ule f oll o we d b y fle xi ble d ose o pti misati o n. T he o pti mal d ose will be base d o n 
t he partici pa nt’s o bser ve d efficac y, safet y, a n d t ol era bilit y per t he i n vesti gat or’s 
cli nical j u d ge me nt.  
3. 4.  
Cli nic al H y p o t hesis 
T he pri mar y cli nic al h y p ot hesis u n derl yi n g t his st u d y is t hat G W P 4 2 0 0 3-P has a 
p ositi ve ris k/ be nefit o utc o me i n t he a dj u ncti ve treat me nt of seiz ures i n partici pa nts 
wit h T S C , L G S, or D S. 
3. 5.  
Be nefit/ Ris k Assess me nt  
Ca n na bi di ol oral s ol uti o n has bee n a p pr o ve d f or use i n treat me nt of sei z ures 
ass ociate d wit h L G S, D S, a n d T S C. 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 4  of 1 2 1  
 
 
 
 
 
Partici pa nts  i n t he c urre nt st u d y ma y e x perie nce s o me i m pr o ve me nt of s y m pt o ms a n d 
will recei ve c o m pre he nsi ve cli nical e xa ms a n d cli nical m o nit ori n g ass ociate d wit h t he 
st u d y. T he ris ks of partici pati o n are pri maril y ass o ciate d wit h a d verse reacti o ns t o 
G W P 4 2 0 0 3 -P, alt h o u g h t here ma y als o be s o me disc o mf ort fr o m c ollecti o n of bl o o d 
sa m ples a n d ot her st u d y pr oce d ures. Ca n na bi di ol oral s ol uti o n c o ntai ns 7 9 m g/ m L 
et ha n ol. I n t his st u d y i n y o u n g c hil dre n, t here ma y be a p ote ntial ris k of acc u m ulati o n 
w he n C B D -O S  is c hr o ni call y c oa d mi nistere d wit h ot her me dici nes c o nt ai ni n g et ha n ol 
or ot her s u bstrates f or alc o h ol de h y dr o ge nas e (s uc h as pr o p yle ne gl yc ol).  Cli nical 
j u d g me nt s h o ul d be use d wei g h p ote ntial be nefit fr o m C B D -O S  a gai nst t his p ote ntial 
ris k. M ore i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits, ris ks, a n d reas o na bl y 
a ntici pate d A Es ass o ciate d wit h G W P 4 2 0 0 3 -P ma y be f o u n d i n t he c urre nt a p pr o ve d 
versi o n of t he I n v esti gat or’s Br oc h ure (I B) ( C B D-O S I B).  
T he m ost c o m m o nl y re p orte d si de effects i ncl u de s o m n ole nce; decreas e d a p petite; 
diarr h oea ; tra nsa mi nase ele vati o ns; fati g ue, malais e, a n d ast he nia; ras h; i ns o m nia, 
slee p dis or der, a n d p o or-q ualit y slee p; i nfecti o ns; p yre xia; a n d v o miti n g. Seri o us si de 
effects i ncl u de  he p at ocell ular i nj ur y, s o m n ole nce a n d se dati o n, s uici dal be h a vi o u r a n d 
i deati o n, a n d h y pers e nsiti vit y reacti o ns. F urt her i nf or mati o n is i ncl u de d i n t he latest 
C B D -O S I B.  
O verall, t he e xt e nsi ve cli nical safet y a n d efficac y res ults of G W P 4 2 0 0 3 -P were 
de m o n strate d acr oss 5 P hase 3 st u dies, a n o pe n-la bel st u d y, a n d t he ex pa n d e d access 
pr o gra m i n t he treat me nt of pae diatri c e pile ps y s y n dr o mes . A n d i t is belie ve d t hat 
G W P 4 2 0 0 3 -P has a fa v o u ra ble be n efit ris k pr ofile f or t he treat me nt of seiz ures 
ass ociate d wit h  T S C, D S, a n d L G S i n t he partici p a nt a ge ra n ges bei n g i n vesti gate d i n 
t his st u d y. 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 5  of 1 2 1  
4.  
E X P E RI M E N T A L P L A N  
4. 1.  
St u d y  Desi g n  
T his is a p hase 3, m ulti ce ntre, o pe n-la bel, si n gle-ar m st u d y t hat will e val uate t he 
safet y, P K , efficac y, a n d  e x pl orat or y Q o L  of a dj u ncti ve G W P 4 2 0 0 3 -P i n partici pa nts 
<  2 years of a g e  wit h T S C, L G S, or D S . E nr ol me nt will be stratifie d via t he 
Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt ( R T S M ) t o e ns ure at least 
5  partici pa nts eac h wit h D S or L G S  ( 1 t o < 2 years of a ge) a n d 8  partici p a nts wit h 
T S C ( 4  partici pa nts < 1 y ear of a ge a n d 4 partici pa nts 1 t o < 2 years of a ge) are 
i ncl u de d i n t his st u d y i n or der t o ac hie ve 1 8 e val u a ble partici pa nts. 
T he st u d y d urati o n will be u p t o a p pr o xi matel y 6 2  wee ks, i ncl u di n g a 4-wee k 
scree ni n g/ bas eli ne peri o d, a 5 2-wee k d ose o pti misati o n treat me nt peri o d (w hic h 
i ncl u des a fi xe d 2 -wee k titrati o n peri o d  f oll o we d b y fle xi ble d ose o pti misati o n ), a 
1 0 -da y  ta per peri o d, a n d a safet y f oll o w-u p peri o d ( 4  wee ks after t h e e n d-of -ta per 
visit ). T hr o u g h o ut t he st u d y, partici pa nts s h o ul d c o m plete all visits a n d assess me nts 
as o utli ne d i n t he S c he d ule of Acti vities ( S o A ) (A P P E N DI X  1 ).  
After t he i nf or me d c o nse nt f or m (I C F) h as bee n si g ne d b y t he pare nt(s)/ le gall y 
a ut h orise d re prese ntati ve (L A R ), partici pa nts will be c o nsi dere d e nr olle d a n d e nter 
t he scree ni n g/ baseli ne peri o d ( Visit 1 a n d Visit 2 [ p h o ne visit]). Partici pa nts ca n be 
rescree ne d o n ce, at t he discreti o n of t he i n vesti gat or a n d f oll o wi n g a p pr o val fr o m t he 
me dical m o nit or. Rescree ne d partici p a nts will be assi g ne d a ne w partici pa nt n u m ber 
a n d all scree ni n g assess me nts will be re peat e d. 
F oll o wi n g e nr ol me nt, d ose a dj ust me nts t o A S M s s h o ul d n ot be ma de a n d ne w A S Ms 
s h o ul d n ot be a d de d wit h o ut pri or disc ussi o n  wit h a n d a p pr o val b y t he m e dical 
m o nit or.  All A S M d ose a dj ust me nts m ust be ca pt ure d i n t he electr o nic case re p ort 
f or m (e C R F). 
Starti n g at Visit 3, partici pa nts w h o c o nti n ue t o meet all eli gi bilit y criteria will i nitiate 
t he 5 2-wee k treat me nt p eri o d  wit h t he st u d y i nter ve nti o n ( G W P 4 2 0 0 3-P)  as 
a dj u ncti ve t hera p y (i.e., i n a d diti o n t o t heir c urre nt A S M re gi me n) . T he st u d y 
i nter ve nti o n will be ta ke n orall y or wit h a gastric or nas o gastric t u be ( G -or N G -t u be) 
t wice a da y ( b.i. d.) (e. g., m or ni n g a n d e ve ni n g) at a b o ut t he sa me ti me eac h da y, 
c o nsiste ntl y wit h or wit h o ut f o o d. T he ti me of G W P 4 2 0 0 3 -P  a d mi nistrati o n i n 
relati o n t o f o o d s h o ul d be ke pt c o nsiste nt t hr o u g h o ut t he st u d y. D uri n g t he first 
2  wee ks of trea t me nt (i.e., t he fi xe d titrati o n peri o d), partici pa nts s h o ul d be gi n 
titrati n g G W P 4 2 0 0 3-P at a rate of u p t o 5  m g/ k g/ wee k , reac hi n g t he t ar get d ose le vel 
of 1 0  m g/ k g/ d a y ( u nless t he partici pa nt ca n n ot t olerate t his d ose).  
Starti n g at Visit 5, after titrati n g t o t he tar get d ose le vel  ( 1 0 m g/ k g/ da y), i n v esti gat ors 
will  ha ve t he o pti o n t o titrate a p art ici pa nt’s d ose n o m ore ra pi dl y t ha n 5  m g/ k g 
( ≤ 2. 5  m g/ k g  b.i. d .) e ver y 7 da ys , u p t o a ma xi m u m d ose of 2 0  m g/ k g/ da y (f or L G S  
a n d D S) or 2 5  m g/ k g/ da y (f or T S C), as rec o m me n de d i n Secti o n 8. 1. 2  a n d base d o n 
t he partici pa nt’s i n di vi d ual res p o nse a n d t olera bilit y. T he i n vesti gat or will deter mi ne 
if a d diti o nal  d ose a dj ust me nts are warra nte d d uri n g sc he d ule d or u ns c he d ule d visits 
t hr o u gh o ut t he re mai n der of t he 5 2 -wee k treat me nt peri o d.   
If a partici pa nt e x perie nces t olera bilit y iss ues relat e d t o t he st u d y i nter ve nti o n or a n 
A E occ urs  at a n y ti me d uri n g t he  5 2 -wee k  treat me nt peri o d, t he i n vesti gat or ma y 
c o nsi der te m p oraril y or p er ma ne ntl y re d uci n g t he partici pa nt’s d osa ge , f oll o wi n g 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 6  of 1 2 1  
disc ussi o n wit h t he me dical m o nit or. D oses ma y be  decrea s e d bel o w t he t ar get d ose 
le vel (i.e., < 1 0  m g/ k g/ da y) base d o n safet y a n d t olera bilit y  (refer t o Secti o n  8. 1. 2 ). 
W here p ossi ble, p artici pa nts s h o ul d be e nc o ura g e d t o ret ur n t o t he tar get d ose le vel 
( 1 0 m g/ k g/ da y) . I n vesti g at ors s h o ul d re g ularl y m o nit or a partici pa nt’s res p o nse t o 
treat me nt a n d re-e v al uate t he nee d f or a dj ust me nts t o d osa ge (i.e., i ncreas e, mai ntai n, 
or decrease) at t he n e xt st u d y visit, if a p plica ble.  
I n g e neral, d oses s h o ul d n ot be a dj uste d wit hi n t he 3 da ys pri or t o P K st u d y visits (as 
s pecifie d i n t he S o A [A P P E N DI X  1 ]) u nless cli nicall y i n dicate d f or safet y. If a d ose 
a dj ust me nt is nee de d d uri n g t he 3 da ys pri or t o a P K st u d y visit, t he P K st u d y visit 
s h o ul d be resc h e d ule d t o occ ur >  3 da ys after t he d ose a dj ust me nt. D oses ma y be 
a dj uste d d uri n g P K st u d y visits after all P K sa m ples ha ve bee n c ollecte d . T he 
rati o nale f or a n y d osa g e c ha n ges will be d oc u m e nte d i n t he a p pr o priat e e C R F.  
•  Partici pa nts will c o nti n ue  treat me nt wit h t he st u d y i nter ve nti o n u ntil t he 
E O T visit , after w hic h t h e y will i nitiate a ta per peri o d t o titrate off t he 
st u d y i nter ve nti o n at h o me. T he ta per peri o d will last 1 0  da ys  a n d e n d wit h  
t he en d -of -ta per visit . A safet y foll o w -u p visit ( p h o ne call or visit ) will 
occ ur 4  w ee ks after t he en d -of -ta per visit  (i.e., 4  wee ks after t he last d ose 
of G W P 4 2 0 0 3 -P ). 
If a partici pa nt disc o nti n ues t he st u d y i nter ve nti o n or st u d y pre mat urel y (i. e., bef ore 
t he E O T visit), t he partici pa nt s h o ul d be e nc o ura g e d t o c o m plete a n earl y t er mi nati o n 
(E T ) visit  as s o o n as p ossi ble , f oll o we d b y a 1 0-d a y ta per peri o d if cli nicall y i n dicate d 
(i.e., u nless t he partici p a nt m ust disc o nti n ue treat ment d ue f or reas o ns r elate d t o 
safet y a n d t olera bilit y). A safet y foll o w -u p visit ( p h o ne call  or visit , if nee de d) will 
occ ur 4  w ee ks after t he p artici pa nt’s last d ose of G W P 4 2 0 0 3 -P .  
A sc he matic  f or t he o verall st u d y desi g n is prese nte d i n Fi g ure 1 . M ore det aile d 
i nf or mati o n o n treat me nt a n d st u d y pr oce d ures is pr o vi de d i n  Secti o n  8  a n d Secti o n  9 , 
res pecti vel y. 
4. 2.  
N u m ber of Cli nic al St u d y Sites  
A p pr o xi matel y 
 cli nical trial ce ntres are e x p ecte d t o partici pate i n t his st u d y. 
A d diti o nal sites ma y be use d i n or der t o s u p ple me nt recr uit me nt.  
4. 3.  
N u m ber of P artici p a nts  
U p t o 2 7 partici pa nt s will be assi g ne d t o recei ve t h e st u d y i nter ve nti o n i n or der t o 
ac hie ve 1 8  e val ua ble p artici pa nts f or t his st u d y. A d diti o nal i nf or mati o n is  pr o vi de d i n 
Secti o n  1 3. 1 . 
4. 4.  
E n d of St u d y Defi niti o n  
A partici pa nt is c o nsi dere d t o ha ve c o m plet e d t he st u d y if t he y ha ve c o m pl ete d all 
p hases of t he st u d y, i ncl u di n g t he last sc he d ule d pr oce d ure s h o w n i n t he S o A  
(A P P E N DI X  1 ). 
T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast visit of t he last partici pa nt i n t he 
st u d y or last c o ntact, w hi c he ver occ urs last. 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 7  of 1 2 1  
5.  
S T U D Y I N T E R V E N TI O N  
Please refer t o t he se p arate p har mac y m a n ual f or m ore detaile d i nf or m ati o n a b o ut  t he 
st u d y i nter ve nti o n. 
T he st u d y i nter ve nti o n, G W P 4 2 0 0 3 -P oral s ol uti o n , c o ntai ns 1 0 0  m g/ m L C B D 
diss ol ve d i n t he e xci pie nts sesa me oil a n d a n h y dr o us et ha n ol ( 1 0 %  v/ v), wit h 
s weete ner (s ucral ose), a n d stra w berr y fla v ou ri n g (Ta ble 1 ). 
T a ble 1  
F or m ul ati o n of G W P 4 2 0 0 3 -P Or al S ol uti o n  
I n gre die nts 
Q u a ntit y  
C B D  
1 0 0  m g/ m L  
A n h y dr o us et ha n ol  
7 9  m g/ m L  
S ucral ose  
0. 5  m g/ m L  
Stra w berr y fla v ou r 
0. 2  m g/ m L  
Refi ne d sesa me oil  
ma ke u p t o 1  m L  
A b bre viati o ns: C B D = ca n na bi di ol.  
 
5. 1.  
P ac k a gi n g, St or a ge a n d Dr u g Acc o u nt a bilit y  
5. 1. 1.  
P ac k a gi n g a n d L a belli n g  
T he st u d y i nter ve nti o n will be ma n ufact ure d, pac k a ge d, la belle d, a n d/ or distri b ute d b y 
t he s p o ns or or dele g ate d c o ntract ors. T h e st u d y i nter ve nti o n will b e pres e nte d i n 
1 0 5  m L a m ber glass b ottles c o ntai ni n g 1 0 0 m L of 1 0 0 m g/ m L C B D s ol uti o n wit h 
c hil d resista nt scre w ca ps  a n d pac k e d i n cart o ns. S ufficie nt st u d y i nter ve nti o n will be 
dis pe nse d at eac h rel e va nt visit c o nsi deri n g t he d ose gr o u p a n d t he wei g ht of t he 
partici pa nt . A u ni q ue i de ntificati o n n u m ber will be use d t o i de ntif y eac h b o x a n d t he 
st u d y i nter ve nti o n it c o ntai ns. T he u ni q ue i de ntificati o n n u m ber t o get her wit h t he 
pac ka gi n g l ot n u m ber  ( P L N) w ill per mit f ull tracea bilit y of ma n ufact ur e, p ac k a n d 
la bel acti vities c o n d ucte d at or o n be half of s p o ns or a n d t he st u d y i nter ve nti o n 
i nf or mati o n hel d o n t he R T S M s yste m . T he s p o ns or will e ns ure t hat all st u d y 
i nter ve nti o n pr o vi de d is f ull y la belle d a n d pac k a ge d.  La bel te xt will i ncl u de t he 
f oll o wi n g i nf or mati o n, as a mi ni m u m: 
•  S p o ns or’s na me a n d a d dress.  
•  Pr o d uct i de ntificati o n (e. g., G W P 4 2 0 0 3 -P or C B D -O S).  
•  D ose a n d/ or p ote n c y (e. g., “ 1 0 0 m g/ m L G W P 4 2 0 0 3 -P”).  
•  St u d y  c o de n u m ber. 
•  E x pir y date.  
•  St ora ge c o n diti o ns.  
•  I nstr u cti o n: “ F or cli nical trial use o nl y”. 
•  I nstr u cti o n: “ Kee p o ut of t he si g ht a n d reac h of c hil dre n”. 
•  A n y ot her i nf or mati o n re q uire d b y l ocal r e g ulat or y a ut h orities.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 8  of 1 2 1  
Directi o ns f or us e will be pr o vi de d se paratel y t o t he partici pa nt . 
5. 1. 2.  
St or a ge  
T he st u d y i nter ve nti o n m ust be st ore d u pri g ht at r o o m te m perat ure ( <  3 0° C) a n d m ust 
n ot be refri g erat e d or fr oze n. It m ust als o be ke pt a wa y fr o m heat a n d direct s u nli g ht.  
T he st u d y i nter ve nti o n m ust be st ore d i n c o m plia nce wit h t he l ocal r e g ulati o ns f or a 
c o ntr olle d dr u g (if a p plica ble t o t he c o u ntr y). T h e s p o ns or m ust a p pr o ve t h e st ora ge 
l ocati o n a n d facilities. Te m perat ure rec or ds of t he cli nical site st ora ge l ocati o n m ust 
be mai n tai ne d (rec or di n g a mi ni m u m of M o n da y t hr o u g h Fri da y, e xcl u di n g p u blic 
h oli da ys) fr o m date of recei pt of first s hi p me nt u ntil e n d of st u d y dis pe nsi n g peri o d at 
eac h site. T h ese rec or ds m ust c o ntai n at least t he mi ni m u m a n d ma xi m u m dail y 
te m perat ur es a n d m ust be ma de a v aila ble t o t he a p pr o priate s p o ns or p ers o n nel f or 
re vie w t hr o u g h o ut t he st u d y. Te m perat ur e d uri n g tra nsit of G W P 4 2 0 0 3 -P  t o t he site 
m ust be c hec ke d o n recei pt a n d c o m plia nce/ n o nc o m plia nce t o t he mi ni m u m a n d 
ma xi m u m rec or de d.  
S h o ul d st ora ge c o n d iti o ns de viate fr o m t hes e s pecifie d re q uire m e nts, t he s p o ns or 
st u d y m o nit or m ust be c o ntacte d i m me diatel y t o c o nfir m if t he st u d y i nter ve nti o n 
re mai ns s uita ble f or us e. T he st u d y i nter ve nti o n  m ust be place d u n der q uara nti ne u ntil 
writte n c o nfir mati o n is recei ve d t hat t he st u d y i nter ve nti o n is s uita ble f or use. 
Care gi vers will be pr o vi d e d wit h i nstr ucti o ns re gar di n g h o me st ora ge re q uire me nts 
f or t he st u d y i nter ve nti o n. 
5. 1. 3.  
S u p pl y a n d Ret ur n of St u d y I nter ve nti o n  
At st u d y i nitiati o n a n d as nee de d t hereafter, t he st u d y i nter ve nti o n will be s hi p pe d t o 
t he i de ntifie d res p o nsi ble pers o n, s uc h as t he p h ar macist, at t he i n vesti gat or’s site, 
w h o will c hec k t he a m o u nt recei ve d (a g ai nst t he R T S M S hi p me nt Re q u est) a n d 
c o n diti o n of t he dr u g (i.e., i nte grit y, p h ysical a p peara nce, te m perat ure d uri n g tra nsit). 
Details of t he st u d y i nter ve nti o n recei v e d will be rec or de d i n t he st u d y i nter ve nti o n 
acc o u nta bilit y rec or d (s ee Secti o n  5. 1. 4 ). T he site will ac k n o wle d ge t he st u d y 
i nter ve nti o n recei pt via t he R T S M a n d will c o m plete a n y recei pt f or ms re q uire d. 
St u d y i nter ve nti o n  will be dis pe nse d a n d ret ur ne d as detail e d i n Secti o n  8. 5 . As 
directe d, all s u p plies, i ncl u di n g u n use d, partiall y use d, or e m pt y c o ntai ners, will be 
ret ur ne d t o t he s p o ns or or destr o ye d at a s p o ns or-a p pr o ve d site if a gree d i n writi n g b y 
t he st u d y m o nit or.  
5. 1. 4.  
St u d y I nter ve nti o n  Acc o u nt a bilit y  
T he i n vesti gat or has o verall res p o nsi bilit y f or t he acc o u nta bilit y of all use d a n d 
u n use d st u d y i nter ve nti o n. A dr u g acc o u nta bilit y rec or d f or t he st u d y i nter ve nti o n 
m ust be ke pt c urre nt a n d m ust c o ntai n:  
•  St u d y c o de. 
•  P ac k n u m ber, P L N, date of recei pt , a n d q ua ntit y of st u d y i nter ve nti o n 
recei v e d. 
•  Partici pa nt’s st u d y i de ntificati o n a n d/or treat me nt n u m ber.  
•  Date a n d q u a ntit y of st u d y i nter ve nti o n dis pe nse d.  
•  T he i nitials of t he dis pe nsi n g/ d osi n g part y.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 3 9  of 1 2 1  
•  Date a n d q u a ntit y of st u d y i nter ve nti o n ret ur ne d t o t he i n vesti gat or. 
•  St u d y i nter ve nti o n  e x pir y dates.  
Refer t o A P P E N DI X  1  f or w he n t he st u d y i nter ve nti o n will be dis pe nse d. 
Partici pa nts ’ care gi vers will be as ke d t o ret ur n all st u d y i nter ve nti o n (u n use d , partiall y 
use d , a n d e m pt y c o ntai ners ) at eac h rele va nt visit. T he site will c hec k t he ret ur ne d 
st u d y i nter ve nti o n a gai nst t he usa ge rec or de d i n t h e diar y. A n y discre pa n cies will be 
disc usse d wit h t he care gi ver  at t he ti me of t he visit a n d d oc u me nte d acc or di n gl y 
wit hi n t he partici pa nt’s s o urce d oc u m e nts. 
T he i n vesti gat or m ust i nf or m t he s p o ns or pr o m ptl y of all missi n g  or u nacc o u nta ble 
st u d y i nter ve nti o n. 
A rec or d of ret ur ne d st u d y i nter ve nti o n m ust be c o m plete d a n d i ncl u de d i n t he 
s hi p me nt of use d a n d u n use d st u d y i nter ve nti o n t o t he rele va nt dr u g distri b uti o n 
de p ot. At t he e n d of t he st u d y, a rec or d/state me nt of rec o nciliati o n m ust be c o m plete d 
a n d pr o vi de d t o t he s p o ns or. 
T hese i n ve nt ories m ust b e ma de a v aila ble f or i ns p ecti o n b y a n a ut h orise d s p o ns or 
re pres e ntati ve a n d l oc al officials or re g ulat or y a g e nc y i ns pect ors. 
Please refer t o t he se p arate p har mac y m a n ual f or m ore detaile d i nf or m ati o n o n t he 
st u d y i nter ve nti o n. 
5. 1. 5.  
P ost -St u d y  Pr o visi o n  
Partici pa nts will n ot ha ve access t o G W P 4 2 0 0 3 -P t hr o u g h a n e x p a n de d access 
pr o gra m aft er t he st u d y is c o m plete d;  partici pa nts ma y ha ve access t o t he c o m mercial 
pr o d uct  u p o n c o m pleti n g t he st u d y as per mitte d per l ocal healt h a ut h orities . 
A s u m mar y of t he res ults of t his st u d y will be ma de a vaila ble o n  
htt p:// w w w.cli nicaltrials. g o v  a n d htt ps://e ucli nicaltrials.e u /(as a p plica ble), as re q uire d 
b y U S a n d E U la w . 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 4 0  of 1 2 1  
6.  
P A R TI CI P A N T E LI GI BI LI T Y  
I n v esti gat ors are res p o nsi ble f or c o nfir mi n g partici pa nt eli gi bilit y a n d will be re q uir e d 
t o mai ntai n a l o g t hat i ncl u des li mite d i nf or mati o n a b o ut all scree ne d partici pa nts 
(e. g., i nitials, a ge, a n d se x [as all o we d p er l ocal re g ulati o ns]) a n d o utc o me of 
scree ni n g. 
6. 1.  
I ncl usi o n Criteri a 
F or i ncl usi o n i n t he st u d y p artici pa nt s m ust f ulfil A L L of t he f oll o wi n g crit eria:  
6. 1. 1  Partici pa nts  wit h T S C ( 1  m o nt h t o <  2  years of a g e ), or D S ( 1  year t o < 2  years 
of a ge), or L G S ( 1  year t o <  2  years of a g e ) wit hi n t he s pecifie d a ge ra n ge at 
t he ti me of i nitial i nf or me d c o nse nt.  
6. 1. 2  Partici pa nts wit h T S C m ust ha ve a dia g n osis per t he 2 0 1 2 I nter n ati o nal 
T u ber o us Scler osis C o m ple x C o nse ns us C o nfere n ce (N ort hr u p 
2 0 1 3 )(A P P E N DI X  3 ). Partici pa nts wit h L G S or D S m ust ha ve a dia g n osis t hat 
is c o nsiste nt wit h I nter n ati o nal Lea g ue A gai nst E pile ps y ( I L A E) g ui deli nes 
a n d c o nfir me d b y t h e E pile ps y St u d y C o ns orti u m ( E S CI ) (als o refer t o 
Secti o n  9. 1. 1 2. 1 ) (S pecc hi o 2 0 2 2 , Z u beri 2 0 2 2 ). 
6. 1. 3  Partici pa nts w h o ha ve u n c o ntr olle d seiz ures, a n d w h o are c urre ntl y recei vi n g 
1  or m ore A S Ms . 
6. 1. 4  P are nt(s)/ L A R  is/are willi n g a n d a ble t o gi ve i nf or me d c o nse nt f or 
partici pati o n i n t he st u d y. 
6. 1. 5  Pare nt(s)/ L A R  is/are willi n g a n d a ble (i n t he i n vesti gat or’s o pi ni o n) t o c o m pl y 
wit h all st u d y re q uire me nts (i ncl u di n g acc urate el ectr o nic patie nt -re p ort e d 
o utc o me [ e P R O] diar y c o m pleti o n).  
6. 1. 6  Care gi ver c o m pletes at least 7 5 % of e P R O a n d pa per seiz ure diar y e ntries 
d uri n g t he 2 8 da ys of t he baseli ne peri o d ( ≥ 2 1  d a ys of e ntries).  
6. 1. 7  A s uita ble V E E G, as a vaila ble i n t he me dical rec or ds, wit hi n 1 year of Visit 1. 
W he n a hist orical V E E G is n ot a vaila ble, a n d if cli nicall y i n dicate d a n d 
a p pr o priate d u e t o u ncertai nties or ne w seiz ures, a V E E G  will be c o m plete d 
a n d rea d t o c o nfir m dia g n osis pri or t o Visit 3. All V E E Gs are  t o be rea d at 
baseli ne b y t he i n vesti gat or a n d a n i n de pe n de nt r e vie wer . 
•  A s uita ble V E E G meets all t he f oll o wi n g criteria:  
i. 
M ultic ha n nel ( mi ni m u m 8 -c ha n nel)  
ii. 
Pr ol o n ge d c o nti n u o us rec or di n g u p t o 2 4  h o ur s 
iii. 
C o m plete d wit hi n 1 year of Visit 1  
i v. 
C o nsiste nt wit h t he partici pa nt’s c urre nt seiz ures (i n t he i n vesti gat or’s 
o pi ni o n)  
v.  
Ca n be re vie we d b y t he i n vesti gat or a n d a n i n de pe n de nt re vie wer  pri or 
t o Visit 3  
vi.  
C o nsiste nt wit h a dia g n osis of i na de q uatel y -c o ntr olle d seiz ures  
6. 1. 8  C urre ntl y ta ki n g ≥ 1 A S M s at a d ose t hat re m ai ns sta ble 2  wee ks pri or t o 
Visit  3 a n d d uri n g t he treat me nt peri o d. W here re q uire d f or partici pa nt safet y, 
a dj ust me nts of c o nc o mita nt A S M s or a d diti o n of ne w AS M  ma y be per mitte d 
f oll o wi n g disc ussi o n wit h t he me dical m o nit or. 
•  A dre n oc ortic otr o pic h or m o ne ( A C T H ) or hi g h d ose c ortic oster oi ds f or t he 
treat me nt of I S/ E S are c o u nte d as A S M s. 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 4 1  of 1 2 1  
6. 1. 9  Has seiz ures t hat are n ot a de q uatel y c o ntr olle d t hr o u g h t heir c urre nt A S M s, 
defi ne d as ≥ 1 sei z ure re p orte d o n t he seiz ure diar y d uri n g t he 
scree ni n g/ bas eli ne peri o d.  
6. 1. 1 0  Pare nt(s)/ L A R  is/are willi n g t o all o w t he res p o nsi ble a ut h orities t o be n otifie d 
of partici pati o n i n t he st u d y, if ma n date d b y l ocal l a w. 
6. 1. 1 1  Pare nt(s)/ L A R  is/are willi n g t o all o w t he partici pa nt’s pri mar y care 
practiti o ner (if t he y ha ve o ne) a n d c o ns ulta nt (if t he y ha ve o n e) t o be n otifie d 
of partici pati o n i n t he st u d y if t he pri mar y care practiti o ner/c o ns ulta nt is 
differe nt fr o m t he i n vesti gat or.  
6. 2.  
E xcl usi o n Criteri a  
T he partici pa nt  ma y n ot e nter t he  st u d y if A N Y of t he f oll o wi n g a p pl y: 
6. 2. 1  Has cli nicall y si g nifica nt u nsta ble me dical c o n diti o n ot her t ha n e pile ps y.  
6. 2. 2  Has ha d cli nicall y si g nifi ca nt s y m pt o ms or a cli nicall y si g nifica nt ill ness 
wit hi n t he 4  wee ks pri or t o Visit 1 , ot her t ha n e pile ps y, w hic h i n t he o pi ni o n 
of t he i n vesti gat or c o ul d affect seiz ure fre q ue n c y.  
6. 2. 3  Has u n der g o ne ge neral a n aest hesia wit hi n 4 wee ks pri or t o Visit 1.  
6. 2. 4  Has u n der g o ne s ur ger y f or e pile ps y wit hi n 6 m o nt hs pri or t o Visit 1  or has 
pla ns t o u n der g o s ur ger y f or e pile ps y d uri n g t he s t u d y. 
6. 2. 5  Has ta ke n fel ba mate < 1 year pri or t o Visit 1 . 
6. 2. 6  Is < 1 year of a g e a n d ta ki n g val pr oic aci d.  
6. 2. 7  Has t u m o u r gr o wt h w hic h, i n t he o pi ni o n of t he i n vesti gat or, c o ul d affect 
partici pa nt safet y. 
6. 2. 8  Has cli nicall y si g nifica nt a b n or mal la b orat or y val ues, i n t he i n vesti gat or’s 
o pi ni o n, at scree ni n g /bas eli ne.  
6. 2. 9  Has cli nicall y si g nifica nt a b n or malities i n t he E C G meas ure d at 
scree ni n g/ bas eli ne. 
6. 2. 1 0  Has a n y c o n c urre nt car di o vasc ular c o n diti o ns  t hat will, i n t he i n vesti gat or’s 
o pi ni o n, i nterfere wit h t h e a bilit y t o assess t heir E C Gs.  
6. 2. 1 1  Has a n y k n o w n or s us p ecte d h y perse nsiti vit y t o ca n na bi n oi ds or a n y of t he 
e xci pie nts of t he st u d y i nter ve nti o n s uc h as ses a me see d oil. 
6. 2. 1 2  Has si g nifica ntl y i m paire d he patic f u ncti o n pri or t o Visit 3 , defi ne d as: 
•  Ser u m ala ni ne a mi n otra nsferas e ( A L T ) or  as p artat e a mi n otra nsferase 
(A S T ) >  3  × u p p er li mit of n or mal ( U L N ) a n d (t otal bilir u bi n 
[T B L ] >  2  ×  U L N or i nter nati o nal n or malise d rati o [I N R] >  1. 5).  
•  Ser u m A L T or A S T > 5 × U L N.  
•  Ser u m A L T or A S T > 3 × U L N wit h t he prese nce of fati g ue, na us ea, 
v o miti n g, ri g ht u p per q ua dra nt pai n or te n d er ness , fe ver, ras h, a n d/ or 
e osi n o p hilia ( >  5 %).   
•  Ele vate d A L T or A S T s h o ul d be disc usse d wit h t he me dical m o nit or pri or 
t o Visit 3 ; t he me dical m o nit or ma y all o w f or a c o nfir mat or y re-dra w pri or 
t o Visit 3 . 
6. 2. 1 3  Has recei ve d a n ot her st u d y i nter ve nti o n wit hi n 4  wee ks pri or t o Visit 1  or 
pla ns t o ta ke a n ot her st u d y i nter ve nti o n d uri n g t he st u d y . 
6. 2. 1 4  Care gi ver is c urre ntl y gi vi n g or has gi ve n recreati o nal or me d ici nal ca n na bis, 
ca n na bi n oi d -bas e d me dicati o ns (i ncl u di n g Sati ve x) or C B D (i ncl u di n g 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 4 2  of 1 2 1  
E pi di ole x / E pi d y ole x [G W P 4 2 0 0 3 -P ]) t o t he parti ci pa nt wit hi n t he 4  wee ks 
pri or t o Visit 1  or  is u n willi n g t o a bstai n fr o m d oi n g s o f or t he d urati o n of t he 
st u d y. 
6. 2. 1 5  M ot her (if breastfee di n g) is c urre ntl y usi n g or has use d recreati o nal or 
me dici nal ca n na bis, ca n n a bi n oi d -base d me dicati o ns (i ncl u di n g Sati ve x) or 
C B D (i ncl u di n g E pi di ole x / E pi d y ole x [G W P 4 2 0 0 3 -P ]) wit hi n t he 4 wee ks 
pri or t o Visit 1  or  is u n willi n g t o a bstai n fr o m d oi n g s o f or t he d urati o n of t he 
st u d y. 
6. 2. 1 6  Has a n y ot her cli nicall y si g nifica nt disease or dis or der w hic h, i n t he o pi ni o n of 
t he i n vesti gat or, ma y eit her p ut t he partici p a nt, ot her pa rtici p a nts, or site staff 
at ris k beca us e of partici pati o n i n t he st u d y, ma y i nfl ue nce t he res ult of t he 
st u d y, or ma y affect t he p artici pa nt’s a bilit y t o ta ke part i n t he st u d y. 
6. 2. 1 7  A n y cli nicall y si g nifica nt a b n or malities i de ntifie d f oll o wi n g a p h ysical 
e xa mi nati o n of t he partici pa nt t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d 
je o par dize t h e safet y of t he partici pa nt if t he y t o o k part i n t he st u d y. 
6. 2. 1 8  Has pre vi o usl y be e n e nr olle d i nt o t his st u d y. 
6. 2. 1 9  Has pla ns t o tra vel o utsi d e t heir c o u ntr y of resi de n ce d uri n g t he st u d y, u nless 
t he partici pa nt has c o nfir mati o n t hat t he st u d y i nter ve nti o n is per mitte d i n t he 
desti nati o n c o u ntr y a n d all st o ps al o n g t he wa y.  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 4 3  of 1 2 1  
7.  
P A R TI CI P A N T E N R O L M E N T  
Bef ore partici pa nts ma y be e ntere d i nt o t he st u d y, t he s p o ns or re q uir es a c o p y of t he 
rele va nt site’s I nstit uti o nal Re vie w B oar d (I R B)/I n de pe n de nt Et hics C o m mittee  (I E C) 
writte n a p pr o val of t h e pr ot oc ol, I C F , a n d ot her p artici pa nt i nf or mati o n material. 
Partici pa nts will be c o nsi dere d e nr olle d i n t he st u d y fr o m t he ti me of t he 
pare nt (s)/L A R pr o vi di n g writte n i nf or me d c o ns e nt. T he partici pa nt’s p are nt(s)/ L A R 
m ust pers o nall y si g n a n d date t he I C F re g ulati o ns, pri or t o a n y pr oce d ures b e i n g 
perf or me d (refer t o Secti o n  9. 1. 1  a n d Secti o n  1 5. 2 ). 
7. 1.  
E nr ol me nt Str atific ati o n  
E nr ol me nt will be stratifie d via t he R T S M t o e ns ure t hat at least 5  p artici pa nts eac h 
wit h L G S a n d D S (1 t o <  2 years  of a ge ) a n d 8 partici pa nts  wit h T S C  (4  partici pa nts 
<  1  year of a g e a n d 4  partici pa nts a ge d 1 t o < 2 years) are i ncl u de d i n t his st u d y  i n 
or der t o ac hie ve 1 8 e val u a ble partici pa nts . All partici pa nts will recei ve o pe n -la bel 
st u d y i nter ve nti o n i n t his n o nra n d o mise d  st u d y.  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 4 4  of 1 2 1  
8.  
T R E A T M E N T P R O C E D U R E S  
8. 1.  
St u d y I nter ve nti o n  D os a ge, A d mi nistr ati o n a n d Sc he d ule  
F or details r e gar di n g st u d y i nter ve nti o n f or m ulati o ns, see Secti o n  5 . 
8. 1. 1.  
D ose A d mi nistr ati o n  
G W P 4 2 0 0 3 -P will be a d mi nistere d  as a dj u ncti ve t hera p y  (i.e., i n a d diti o n t o t he 
partici pa nt’s c urre nt A S M re gi me n)  orall y b.i. d. ( m or ni n g a n d e ve ni n g) usi n g t he 
s yri n ge(s) pr o vi de d. I n p artici pa nts wit h G - or N G -t u bes b ut w here oral d osi n g of 
G W P 4 2 0 0 3 -P is p ossi ble, oral d osi n g is prefera ble. O nl y i n partici pa nts w here oral 
d osi n g is n ot p ossi ble, a n d f oll o wi n g c o ns ultati o n wit h t he me dical m o nit or, s h o ul d 
G W P 4 2 0 0 3 -P be a d mi nistere d via G - or N G -t u bes ma de fr o m silic o n o nl y (fee di n g 
t u bes m ust be fl us he d wit h 1 5 t o 3 0 m L of water b ef ore a n d aft er G W P 4 2 0 0 3-P 
d osi n g a n d als o fl us he d after a d mi nistrati o n of c o n c o mita nt me dicati o ns t o be ta ke n 
bef ore G W P 4 2 0 0 3 -P [ v ol u me of water m a y be m o difie d f or partici pa nts wit h fl ui d 
restricti o ns]). V ol u me of G W P 4 2 0 0 3-P t o be deter mi ne d b y partici pa nt’s wei g ht a n d 
assi g ne d d ose.  
G W P 4 2 0 0 3 -P s h o ul d be ta ke n at a b o ut t he sa m e ti me eac h d a y c o nsiste ntl y wit h or 
wit h o ut f o o d. T he ti me of G W P 4 2 0 0 3 -P  a d mi nistrati o n i n relati o n t o f o o d s h o ul d be 
ke pt c o nsiste nt t hr o u g h o ut t he st u d y. 
R o ute of a d mi nistrati o n wit h G W P 4 2 0 0 3 -P ( oral or wit h G - or  N G -t u bes) s h o ul d 
re mai n c o nsiste nt t hr o u g h o ut t he st u d y. A n y c ha n ges i n t he r o ute of a d mi nistrati o n 
s h o ul d be ca pt ure d i n t he partici pa nt’s me dical rec or d s. 
8. 1. 2.  
D ose Esc al ati o n a n d D ose A dj ust me nts  
T he 5 2 -wee k treat me nt peri o d i ncl u des a fi x e d 2-wee k titrati o n sc he d ul e  f oll o we d b y 
fle xi ble d ose o pti misati o n . T he o pti mal d ose will be base d o n  t he p artici pa nt’s 
o bser ve d  effic ac y , safet y, a n d t olera bilit y  per t he i n vesti gat or’s cli nical j u d ge me nt. 
O n Da y 1  ( Visit 3) of treat me nt wit h G W P 4 2 0 0 3 -P, partici pa nt s will i nitiate t he fi xe d 
2 -wee k titrati o n of G W P 4 2 0 0 3 -P , be gi n ni n g wit h a d os e of 5  m g/ k g/ da y 
( 2. 5 m g/ k g  b.i. d.). O n Da y 8 ( ±  3 da ys), t he d ose will be i ncreas e d t o t he tar get d ose 
le vel of 1 0  m g/ k g/ da y ( 5  m g/ k g  b.i. d.). Partici pa nts will be o bser ve d o n 
Da y  1 5  ( Visit 5) . 
After D a y 1 5 ( Visit 5), t h e G W P 4 2 0 0 3 -P d ose ma y be escal ate d f urt h er bas e d o n 
i n di vi d ual cli nical res p o nse a n d t olera bilit y usi n g a fle xi ble titrati o n sc he d ule , per t he 
i n vesti gat or’s cli nical j u d ge me nt. If, i n t he i n vesti gat or’s o pi ni o n, t he parti ci pa nt is 
e x perie n ci n g a cli nicall y mea ni n gf ul i m pr o ve me nt i n seiz ures, i n vesti gat ors will ha ve 
t he o pti o n t o mai ntai n or  i ncreas e a partici pa nt’s d ose at a n y ti me d uri n g or bet wee n 
sc he d ule d visits u ntil E O T . D oses ma y be i ncreas ed  u p t o a ma xi m u m of  
2 0  m g/ k g/ da y  ( 1 0 m g/ k g b.i. d .) f or L G S a n d D S or 2 5  m g/ k g/ da y ( 1 2. 5  m g/ k g b.i. d.)  
f or T S C, i n ma xi m u m wee kl y i ncre m e nts of 5 m g/ k g/ da y ( ≤ 2. 5  m g/ k g b.i. d.) . If 
p ossi ble, c ha n ges i n d ose s h o ul d be a v oi de d d uri n g t he 3 da ys pri or t o P K visits or 
bef ore P K s a m ples ha ve bee n c ollecte d o n t he da y of P K st u d y visits (as s pecifie d i n 
A P P E N DI X  1 ) u nless cli nicall y i n dicate d f or safet y (Secti o n  9. 1. 1 0. 1  pr o vi des 
a d diti o nal details ).  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 4 5  of 1 2 1  
A  titrati o n sc he d ule (i ncl u di n g t he fi xe d 2-wee k titrati o n t o t he tar get d ose a n d a 
s u g geste d titrati o n sc he d ule u p t o t he ma xi m u m d ose) is pr o vi de d i n Ta ble 2 . P er t he 
ta ble, a partici p a nt’s d ose ma y be escalated  t o u p t o 1 5 m g/ k g/ da y ( ≤ 7. 5  m g/ k g  b.i. d.) 
o n or after Da ys 1 5, u p t o 2 0  m g/ k g/ da y ( ≤ 1 0  m g/ k g b.i. d.) o n or after Da y 2 2 , a n d u p 
t o 2 5  m g/ k g/ da y ( ≤ 1 2. 5  m g/ k g b.i. d. ; T S C o nl y) o n or after Da y  2 9.  H o we ver, t he 
titrati o n sc he d ule starti n g at Da y 1 5 i n Ta ble 2  is o pti o nal; i n vesti gat ors s h o ul d use 
t heir cli nical j u d ge me nt w he n titrati n g a partici pa nt ’s d ose. A n y a dj ust me nts t o a 
partici pa nt’s d ose will re q uire f oll o w-u p wit hi n 7  da ys via a n i n -cli nic visit or 
tele p h o ne f oll o w-u p, as deter mi ne d b y t he i n vesti g at or, t o e val uate p artici pa nt safet y . 
A n u nsc he d ule d p h o n e c o ntact ( d oc u me nte d as a n u nsc he d ule d p h o ne visit) or 
u nsc he d ule d cli nic visit m ust be rec or de d i n t he e C R F.  
 
T a ble 2  
D ose Titr ati o n  
D a ys  
D ail y D ose  
M or ni n g a n d E ve ni n g 
D ose  
Fixe d  titr ati o n t o tar get d ose  
1 t o 7  
5 m g/ k g/ da y  
2. 5 m g/ k g b.i. d.  
8 t o 1 4  
1 0 m g/ k g/ da y  
5 m g/ k g b.i. d.  
S u g geste d  titr ati o n t o t he m axi m u m d ose  
≥ 1 5  
≤ 1 5 m g/ k g/ da y  
≤ 7. 5 m g/ k g b.i. d.  
≥ 2 2  
≤ 2 0 m g/ k g/ da y  
≤ 1 0 m g/ k g b.i. d.  
≥ 2 9  
≤ 2 5 m g/ k g/ da y  ( T S C o nl y) 
≤ 1 2. 5 m g/ k g b.i. d.  
A b bre viati o n s: b.i. d. = t wice a da y ; D S = Dra vet s y n dr o me; L G S = Le n n o x −Gasta ut s y n dr o me; 
T S C  =  t u ber o us scler osis c o m ple x. 
N ote: Partici pa nts wit h T S C ma y recei ve a ma xi m u m d ose of 2 5 m g/ k g/ da y; partici pa nts wit h L G S or 
D S ma y recei ve a ma xi m u m d ose of 2 0 m g/ k g/ da y.  
 
•  If a partici pa nt re p orts a n y t olera bilit y iss ues relate d t o G W P 4 2 0 0 3 -P  or a n 
A E occ urs  at a n y ti me d uri n g t h e 5 2 -wee k  treat me nt peri o d, t he 
i n vesti gat or ma y te m p oraril y or per ma ne ntl y re d uce t he partici pa nt’s 
d osa ge , f oll o wi n g disc ussi o n wit h t he me dical m o nit or. F or partici pa nts 
wit h p o or t olera bilit y, t he dail y d ose s h o ul d be re d uce d b y 1 0  m g/ k g e ver y 
7  da ys (u nless s maller, lar ger, or m or e ra pi d d os e re d ucti o ns are cli nicall y 
i n dicate d per  t he i n v esti gat or’s o pi ni o n).  
•  At a n y ti me, t he d ose le vel ma y be decreas ed  bel o w  t he tar get d ose (i.e., 
<  1 0  m g/ k g/ da y ), base d o n safet y a n d t olera bilit y , wit h 2. 5 m g/ k g/ da y 
bei n g t he mi ni m u m d ose . W here p ossi ble, t he p artici pa nt s h o ul d be 
e nc o ura g e d t o ret ur n t o t he tar get d ose l e vel ( 1 0  m g/ k g/ da y) ; d oses ma y 
i ncreas e i n ma xi m u m wee kl y i ncre me nts of 5  m g/ k g/ da y ( ≤ 2 . 5 m g/ k g 
b.i. d .) f oll o wi n g c o ns ultati o n wit h t he me dical m o nit or. I n v esti gat ors 
s h o ul d re g ularl y m o nit or a partici pa nt’s res p o nse t o treat me nt a n d 
re-e v al uate t he n ee d f or a dj ust me nts t o d osa ge (i.e. , i ncreas e, mai ntai n, or 
decrease) at eac h st u d y visit, if a p plica ble. T he rati o nale f or a n y d os a ge 
c ha n ges will be d oc u m e nte d i n t he a p pr o priat e e C R F.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 4 6  of 1 2 1  
F oll o wi n g t he EO T  visit , d oses of G W P 4 2 0 0 3 -P  will be d o w n -titrate d at h o me 
( 1 0 % of t he fi n al d ose per da y f or 1 0 d a ys) u ntil t he en d -of -ta per visit.  
Partici pa nt s disc o nti n ui n g t he st u d y i nter ve nti o n earl y s h o ul d still c o m plete a 1 0-da y 
ta per peri o d ( u nless a c o nti n ue d d osi n g is n ot p ossi ble d ue t o a n A E  or ot h er safet y or 
t olera bilit y c o nsi derati o ns); ad diti o nal i nf or mati o n is i n Secti o n  1 0 . 
F oll o wi n g e nr o lme nt, d ose a dj ust me nts t o A S M s h o ul d n ot be  ma de wit h o ut pri or 
c o ns ultati o n wit h t he me dical m o nit or. All a dj ust me nts m ust be ca pt ure d wit hi n t he 
e C R F (refer t o  Secti o n  8. 2 ).  
8. 2.  
C o nc o mit a nt T her a p y  
It is t he oreticall y p ossi ble t hat G W P 4 2 0 0 3-P ma y m o dif y t he meta b olis m of ot her 
dr u gs (i ncl u di n g A S M s) a d mi nistere d c o nc urre ntl y a n d t here re mai ns t he p ossi bilit y 
of p h ar mac ol o gical i nteracti o ns bet wee n G W P 4 2 0 0 3 -P a n d ot her c o n c urre ntl y 
a d mi nistere d dr u gs. D oses of a n y c o nc o mita nt or n o n p har mac ol o gical A S M s m ust 
ha ve bee n sta ble f or at least 2  wee ks pri or t o Visit 3 a n d m ust re mai n sta ble f or t he 
d urati o n of t he st u d y. A n y c o nc o mita nt  me dicati o n, i ncl u di n g d ose  a dj ust me nts t o 
c o nc o mita nt  me dicati o ns, m ust be ca pt ure d wit hi n t he e C R F.  
W here re q uir e d f or p artici pa nt safet y, a dj ust me nts of c o nc o mita nt AS M s or a d diti o n 
of ne w A S M  ma y be p er mitte d f oll o wi n g disc ussi o n wit h t h e me dical m o nit or. If si de  
effects  are s us pecte d of bei n g relate d t o a n ele vati o n i n t he c o nc o mita nt AS M  
c o nce ntr ati o n, t he i n vesti gat or m ust c o ntact t he m e dical m o nit or t o disc uss best 
ma na ge me nt. D ecisi o ns s h o ul d be base d o n cli nical s y m pt o ms a n d n ot pla s ma le vels 
of A S Ms . F urt her i nf or m ati o n o n dr u g i nteracti o ns ca n be f o u n d i n t he C B D -O S I B. 
C o nc o mita nt A S M  d ose re d ucti o ns are per mitte d o n cli nical gr o u n ds (e. g., d ue t o A Es 
or tra nsa mi nase ele vati o ns n ot meeti n g  wit h dra wal criteria s pecifie d i n Secti o n  1 0 ) 
f oll o wi n g disc ussi o n wit h t he me dical m o nit or.  
T he use of resc ue m e dicati o n is all o we d w he n necessar y a n d eac h us e s h o ul d be 
rec or de d i n t he partici p a nt diar y a n d e C R F.  
8. 3.  
Pr o hi bite d T her a p y D uri n g St u d y  Peri o d  
T here are n o me di cati o ns t hat are s pecificall y pr o hi bite d. T here are 2 me dicati o ns t hat 
are e x cl usi o nar y i n s pecific circ u msta n ces f or st u d y e nr ol me nt , per t he E x cl usi o n 
Criteria ( Secti o n 6. 2 ), as f oll o ws:  
•  Fel ba mat e ta ke n < 1 year pri or t o Visit 1.  
•  Val pr oic aci d f or partici p a nts < 1 year of a g e.  
Refer t o Secti o n  6. 2  E xcl usi o n Criteria  f or a d diti o nal details. 
H o we ver, a n y partici pa nt s ta ki n g t hese me dicati o ns/t hera pies aft er Visit 3  s h o ul d n ot 
be disc o nti n ue d fr o m treat me nt u nless t here are s afet y c o ncer ns. If a p plica ble, t he 
p ossi ble effects of t hese me dicati o ns o n t he pri mar y e n d p oi nt will be c o nsi dere d 
d uri n g t he assess me nt of t he e val ua ble p eri o d (see Secti o n  1 3. 7. 1 ). 
•  T he a d diti o n of a n y ne w me dicati o ns or i nter ve nti o ns f or e pile ps y 
(i ncl u di n g ket o ge nic diet a n d va g us ner ve sti m ulati o n) are pr o hi bite d after 
t he partici pa nt has b ee n e nr olle d i n t he st u d y. W here re q uir e d f or 
partici pa nt  safet y, a dj ust me nts of c o nc o mita nt A S Ms or t he a d diti o n of 

Jazz P har mace uticals Researc h U K Li mite d  
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ne w A S M ma y be per mitte d  f oll o wi n g disc ussi o n  wit h a n d a p pr o val b y t he 
me dical m o nit or.  
Refer t o t he S m P C a n d I B f or a d diti o nal i nf or mati o n.  
8. 4.  
Prec a uti o n ar y  C o nc o mit a nt Me dic ati o ns  
A d diti o nal c are s h o ul d b e ta ke n wit h dr u gs, or t heir meta b olites, t hat are c yt oc hr o me 
P 4 5 0  2 C 1 9  s u bstrates, s uc h as N-d es met h ylcl o baza m. Care s h o ul d als o be t a ke n wi t h 
dr u gs, or t heir meta b olites, t hat are s olel y or pri maril y meta b olise d b y U G T 1 A 9 a n d 
U G T 2 B 7.  S pecificall y, care s h o ul d be ta ke n wit h t he f oll o wi n g me dicati o ns t hat ha ve 
k n o w n i nteracti o ns wit h G W P 4 2 0 0 3 -P:  
•  Sir oli m us, e ver oli m us, te msir oli m us, or tacr oli m us.  
•  Cl o baza m.  
I n a d diti o n, t he f oll o wi n g me dicatio ns are c o nsi dere d preca uti o nar y: car ba m aze pi ne, 
la m otri gi ne, l oraze p a m, p he n yt oi n, stiri pe nt ol,val pr oate, mit ota ne , m or p hi ne , 
difl u nisal , efa vire n z, t he o p h ylli ne, caffei ne, pr o p of ol , si m vastati n, fe n ofi brate, 
ge mfi br ozil, e nzal uta mi de , b u pr o pi o n , St.  J o h n’s w ort, rifa m pi n, clarit hr o m yci n, 
er yt hr o m yci n , a n d me di ci nes use d t o treat aci d refl u x (e. g. o me praz ole ). 
Ca n na bi di ol oral s ol uti o n c o ntai ns 7 9 m g/ m L et ha n ol. I n t his st u d y i n y o u n g c hil dre n, 
t here ma y be a p ote ntial ris k of acc u m ulati o n w he n C B D -O S  is c hr o nicall y 
c oa d mi nistere d wit h ot her me dici nes c o ntai ni n g et ha n ol or ot her s u bstrates f or alc o h ol 
de h y dr o ge n as e (s uc h as pr o p yle ne gl yc ol). P ote n tial effects i ncl u de ce ntral ner v o us 
s yste m effects (s uc h as dr o wsi ness, be ha vi o ur al c ha n ges , a n d at a xia) as well as 
h y p ot her mia. Cli nical j u d g me nt s h o ul d be use d t o wei g h t he p ote ntial be nefit fr o m 
C B D -O S a gai nst t his p ote ntial ris k.   
F or a d diti o nal details r e g ar di n g t h ese preca uti o nar y me dicati o ns , refer t o t h e S m P C 
a n d I B.  
8. 5.  
C o m pli a nce i n St u d y I nter ve nti o n  A d mi nistr ati o n  
T he care gi ver will rec or d t he  v ol u me of st u d y i nter ve nti o n ta ke n eac h m or ni n g a n d 
e ve ni n g o n eac h treat me nt da y i n t he partici pa nt diar y  (refer t o Secti o n 9. 1. 1 2. 2  f or 
a d diti o nal i nf or mati o n) . 
Care gi vers  s h o ul d ret ur n all st u d y i nter ve nti o n (u n use d, partiall y use d, a n d e m pt y 
c o ntai ners) at eac h visit. T he diar y-re p orte d d osi n g i nf or mati o n will be c hec ke d a n d 
a n y discre p a ncies disc uss e d wit h t he care gi ver at t he ti me of t he visit a n d d oc u me nte d 
acc or di n gl y wit hi n t he partici pa nt ’s s o urce d o c u m e nts. 
Rec or ds of st u d y i nter ve nti o n acc o u nta bilit y will be mai ntai ne d ac c or di n g t o 
Secti o n  5. 1. 4 . 
 
 

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9.  
S T U D Y  P R O C E D U R E S  
A list of t he re q uire d st u d y pr oce d ures is pr o vi de d i n t he s u bsecti o ns t hat f oll o w; als o 
refer t o t he S o A  (A P P E N DI X  1 ). Ass ess me nts or tests t hat are n ot d o ne a n d 
e xa mi nati o ns t ha t are n ot c o n d ucte d m ust be re p orte d as s uc h o n t he eC R F.  
9. 1.  
St u d y  Pr oce d ures  
9. 1. 1.  
I nf or me d C o nse nt 
T he i n vesti gat or or me di call y q ualifie d desi g ne e (c o nsiste nt wit h l ocal re q uire me nts) 
m ust o btai n d oc u me nte d c o nse nt fr o m eac h p ote ntial partici pa nt ’s pare nt(s)/L A R  
pri or t o partici pati o n i n t his st u d y. A si g ne d c o p y of t he I C F  f or m s h o ul d be gi ve n t o 
t he partici pa nt’s pare nt(s)/ L A R, a n d t he ori gi nal s h o ul d be place d i n t he p artici pa nt’s 
me dical rec or ds . T he p are nt(s)/ L A R  of mi n or partici pa nt s m ust pers o nall y si g n a n d 
date t he I R B /I E C a p pr o ve d I C F bef ore a n y st u d y s pecific pr oce d ures are p erf or me d or 
a n y partici pa nt  relate d data is rec or de d f or t he st u d y. Partici pa nts ma y be rescree n e d 
o nl y o nce, at t he discreti o n of t he i n vesti gat or a n d wit h a p pr o va l fr o m t he me dical 
m o nit or. T he rescree n e d partici pa nts will be assi g ne d a ne w partici pa nt n u m ber a n d 
all scree ni n g will be re peate d.  
F or f urt her det ails, see Secti o n  1 5. 2 . 
9. 1. 2.  
De m o gr a p hics  
T he f oll o wi n g i nf or mati o n will be o btai ne d f or eac h partici pa nt : date of birt h, se x, a n d 
race (as all o w e d per l o cal re g ulati o ns). 
9. 1. 3.  
Me dic al Hist or y  
Rele va nt, si g nifica nt me dical hist or y will be o btai ne d a n d is defi ne d as a n y c o n diti o n 
or disease t hat:  
•  Ma y affect t he c o n diti o n s u n der st u d y. I ncl u di n g c o m plete seiz ure hist or y, 
lifeti me hist or y of e pile ps y, hist or y of S E , a n d a n y h os pitalisati o ns . 
•  Is o n g oi n g u p o n e ntr y i nt o t he st u d y ( pri or t o t he i nitial d ose at Visit 3) . 
•  Has occ urre d wit hi n o ne year pri or t o s cree ni n g ( Visit 1).  
•  Hist orical vacci nati o ns.  
•  F or partici pa nts wit h T S C, t he m utati o n stat us of t he T S C 1  a n d 
T S C 2  ge nes, if k n o w n, will be o btai ne d t hr o u g h t he partici pa nt ’s me di cal 
rec or ds t o s u p p ort dia g n osis. 
•  F or partici pa nts wit h D S, t he m utati o n stat us ( p ositi ve or ne gati ve f or 
m utati o n) of t he S C N 1 A  ge ne will be deter mi ne d t hr o u g h t he partici pa nt’s 
me dical rec or ds.  
•  F or partici pa nts wit h D S a n d L G S, t he E S CI will re vie w a n d c o nfir m 
dia g n osis t o e ns ure t hat t he c orrect st u d y p o p ulati o n is e nr olle d. 
I n v esti gat ors will s u b mit a d oc u me nte d hist or y of D S or L G S directl y t o 
t he E S CI  f or c o nfir mati o n of dia g n osis. T he E S CI will als o verif y seiz ure 
t y pes f or all partici p a nts (refer t o Secti o n 9. 1. 1 2. 1 ).  

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9. 1. 4.  
Pri or a n d C o nc o mit a nt Me dic ati o n a n d T her a pies  
Details of all c urre nt a n d rece nt me di cati o n (i.e., ta ke n wit hi n t he pre vi o us 3 m o nt hs 
pri or t o Visit 3 ), a n d all A S Ms , resc ue me dicati o ns, a n d vacci n ati o ns ta ke n d uri n g t he 
partici pa nt ’s life will be rec or de d i n t he e C R F a n d re vie we d at eac h s u bse q ue nt visit. 
A n y c ha n ges i n c o nc o mita nt me dicati o ns (e. g., A S Ms , resc ue me di cati o n usa ge, 
vacci nati o ns, or ot her me dicati o ns), me dical pr o ce d ures (e. g., G -or N G -t u b e 
place me nt/re visi o n . or c h a n ges t o n o n -dr u g t hera pies d uri n g t he st u d y m ust be 
disc usse d wit h t he m e dic al m o nit or a n d rec or de d o n t he e C R F (als o r efer t o 
Secti o n  8. 2 ).  
9. 1. 5.  
P h ysic al E x a mi n ati o n  
P h ysical e xa mi nati o ns will i ncl u de le n gt h ( hei g ht ), b o d y wei g ht , a n d hea d 
circ u mfere nce  meas ure m e nts.  A f ull p h ysical e xa mi nati o n will be c o m plete d at 
Visit  1; a n a b bre viate d p h ysical e xa mi nati o n ma y be c o m plete d at eac h s u bse q ue nt 
visit , as cli nicall y i n dicate d. 
A n y fi n di n gs relate d t o ( ne ur o)de v el o p me ntal  or  gr o wt h iss ues c o nsi dere d t o 
re pres e nt a n A E m ust be d oc u me nte d o n t he e C R F. 
9. 1. 6.  
C o m pre he nsi ve Ne ur o de vel o p me nt al  Assess m e nt  
I n a d diti o n t o sta n dar d p h ysical e xa mi nati o ns, a f or malize d ne ur o de vel o p me ntal 
e xa mi nati o n will be perf or me d at Visit s 3 , 1 3, a n d E O T. T he sta n dar d  p h ysical 
e xa mi nati o n will i ncl u de ma n y of t he  f oll o wi n g c o m p o ne nts a n d d u plicati o n is n ot 
necessar y. Visits wit h ne ur o de vel o p me ntal ass ess me nts  s h o ul d i ncl u de rec or di n g of 
t he f oll o wi n g as pects: 
•  Pae diatric  n e ur ol o gical exa m i nati o n 
− I n cl u di n g me ntal stat us (le vel of alert ness, atte nti o n, e ye c o ntact, etc .) 
cra nial ner ve e xa mi nati o n  I-XII , m ot or e xa mi nati o n (t o ne, p ost ure, 
stre n gt h, i n v ol u ntar y m o ve me nts), se ns or y e xa mi nati o n, c o or di nati o n, 
dee p te n d o n refle x es, de v el o p me ntal / pri miti ve refl e xes, gait (if a g e 
a p pr o priate)  
− I n cl u di n g h eari n g a n d visi o n  testi n g 
− H ei g ht, w ei g ht, a n d hea d circ u mfere nce  rec or de d d uri n g t he  p h ysical 
e xa mi nati o n (Secti o n  9. 1. 5 ) 
•  D e vel o p me ntal milest o nes  assess me nt  
− I n cl u di n g rec or di n g de vel o p me ntal i nter ve nti o ns/e d ucati o nal ser vice 
(i.e., earl y i nter ve nti o n ser vices i nc l u di n g s peec h, occ u pati o nal, 
p h ysical, de vel o p me ntal  t hera pies)  
− I n cl u di n g fee di n g/slee p c o ncer ns a n d milest o nes  
•  Rec or di n g of o n g oi n g healt h c o n diti o ns  as detaile d i n Secti o n  9. 1. 1 2. 2  
•  L o n git u di nal m o nit ori n g of ne ur o de v el o p me nt via Cli nicia n Gl o bal 
I m pr essi o n of C ha n ge/ Se verit y ( C GI C/C GI S) f or se ns or y, m ot or, 
c o g niti o n, e m oti o nal/ be ha vi o u ral healt h, c o m m u nicati o n, s ocial, a n d 
a da pti ve f u ncti o ni n g  

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•  Q ualit y of life assess me nts via I nfa nt a n d T o d dler Q ualit y of Life 
Q uesti o n naire S h ort F or m 4 7 (I T Q O L -4 7) as det aile d i n Secti o n  9. 1. 1 2. 3  
(P erf or me d at Baseli ne, Visit 3 , a n d E O T)  
9. 1. 7.  
Vit al Si g ns  
Vital si g n meas ure me nts ( bl o o d press ure, p ulse rat e , res pirati o n rate, b o d y 
te m perat ur e), i ncl u di n g bl o o d press ure ta ke n i n a s u pi ne p ositi o n at rest f or 5 mi n utes,  
will be c o m plete d al o n gsi de t he p h ysical e xa mi nati o n. Bl o o d press ure m ust be 
rec or de d usi n g t he sa me ar m t hr o u g h o ut t he st u d y, w here p ossi ble. 
9. 1. 8.  
1 2 -Le a d Electr oc a r di o gr a m  
A 1 2 -lea d E C G will be p erf or me d after 5 mi n utes i n a s u pi ne  p ositi o n. A p h ysicia n 
m ust re vie w t he E C G i m me diatel y (a n n otate d, si g ne d , a n d date d), a n d a n y cli nicall y 
si g nifica nt a b n or mal fi n di n gs c o nsi dere d t o i n dicate si g nifica nt me dical hist or y or 
A E s m ust be rec or de d a p pr o priatel y o n t he e C R F. A d diti o nal E C G meas ure me nts ca n 
be ta ke n at a n y ti me d uri n g t he st u d y, if cli nicall y i n dicate d. 
9. 1. 9.  
Vi de o Electr oe nce p h al o gr a m  
Pr ol o n ge d m ultic ha n nel ( mi ni m u m 8 -c ha n nel) V E E G  rec or di n g of  u p t o 2 4 h o urs will 
be perf o r me d. Pri or t o Visit 3, a s uita ble V E E G  m ust be re vie we d b y t he i n vesti gat or 
a n d a n i n de pe n d e nt re vie wer t o esta blis h a bas eli ne V E E G f or t he partici pa nt a n d  
c o nfir m partici pa nt  eli gi bilit y (i.e., a VE E G patter n c o nsiste nt wit h a dia g n osis of 
i na de q uatel y-c o ntr olle d s eiz ures). See Secti o n  6. 1  f or defi niti o n of a s uita bl e V E E G. 
A n y V E E G fi n di n gs c o nsi dere d t o re prese nt a n A E m ust be d oc u me nte d o n t he e C R F.  
9. 1. 1 0.  
B l o o d S a m pli n g  
F or all bl o o d sa m ples, th e ma xi m u m a m o u nt of bl o o d ta ke n at a n y si n gle ti me will n ot 
e xcee d 1 % of t otal bl o o d v ol u me a n d t he c u m ulati ve ma xi m u m a m o u nt of bl o o d 
ta ke n i n a n y 4-w ee k peri o d will n ot e xcee d 3 % of t otal bl o o d v ol u me as per rele va nt 
E U g ui da nce o n et hical c o nsi derati o ns f or cli nical st u dies o n me dici nal pr o d ucts 
c o n d ucte d wit h mi n ors ( A p pe n di x  3 .3 ). W h ere re q uire d b y t he site’s I R B/I E C, t he 
v ol u me of all  bl o o d c ollecte d fr o m t he partici pa nt d uri n g t heir partici pati o n i n  t he 
st u d y will be rec or de d o n a bl o o d dra w rec or d s heet. W here t he re q uire d bl o o d dra w 
v ol u me f or st u d y sa m ples e xcee ds g ui d a nce at a partic ular visit, safet y p ara meters 
(c he mistr y a n d hae mat ol o g y ) s h o ul d be pri oritise d . 
T he care gi ver m ust be a d vise d t hat it ma y n ot be safe f or partici p a nts t o u n derta ke 
f urt her bl o o d tests wit hi n 1 m o nt h of a n y st u d y-rel ate d bl o o d dra ws a n d t o i nf or m t he 
i n vesti gat or if t he y s uffere d a n y bl o o d l oss d uri ng t he 1 -m o nt h peri o d lea di n g u p t o a 
pla n ne d bl o o d dra w.  
9. 1. 1 0. 1.  Cli nic al L a b or at or y S a m pli n g  
T he i n vesti gat or s h o ul d use t heir j u d g me nt a n d k n o wle d ge of t he p artici pa nt  t o 
deter mi ne w he n b est t o c ollect t he bl o o d a n d uri ne sa m ples i n or der t o miti gate t he 
ris k t hat i n vasi ve pr oce d ures ma y ca use t he partici pa nt  t o bec o me stresse d, t here b y 
affecti n g t he res ults of ot her assess me nts.  
D ue t o t he y o u n g a ge a n d l o w b o d y wei g ht of t he partici pa nt s bei n g st u die d, a n d t o 
e ns ure c o m plia n ce wit h bl o o d dra w li mits ( A p pe n di x  3 .3 ), it will be necessar y t o use 

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l ocal la b orat ories f or t he cli nical la b orat or y as pects of t he st u d y. T he esse ntial 
para meters  i n Ta ble 3  s h o ul d be pri oritise d , a n d t he a d diti o nal para m eters s h o ul d o nl y 
be c ollecte d w here p ossi ble base d o n bl o o d dra w li mits o utli ne d i n A p pe n di x  3 .3 . 
La b orat or y tests will i ncl u de hae mat ol o g y , c h e mistr y, a n d uri nal ysis ( pr o vi de d 
e n o u g h uri ne ca n be o btai ne d).   
T he i n vesti gat or a n d st u d y m o nit or will be pr o vi de d wit h a list of t he n or mal ra n ges 
use d b y t he site’s l ocal la b orat or y f or all varia bles assa ye d d uri n g t he st u d y a n d a 
state me nt of accre ditati o n ( or si milar) f or t he l a b orat or y. Cli nical la b orat or y sa m ple 
para meters are detaile d i n Ta ble 3 . A d diti o nal det ails will be pr o vi de d i n a se parat e 
la b orat or y ma n u al. 
T a ble 3  
C he mistr y, H ae m at ol o g y , a n d Uri n al ysis 
C he mistr y ( Ser u m)  
H ae m at ol o g y  ( W h ole 
Bl o o d)  
Uri n al ysis ( Uri ne) e  
Esse nti al P ar a meters a 
Ala ni ne a mi n otra nsferase  
Hae mat ocrit  
Gl uc ose  
Al kali ne p h os p hatase  
Hae m o gl o bi n  
Nitrites  
As partate a mi n otra nsferase  
Mea n c or p usc ular 
hae m o gl o bi n  
p H  
Creati ni ne  
Platelet c o u nt  
Pr otei n  
Ga m ma -gl uta m yl tra nsferase  
Re d bl o o d cell c o u nt  
W hite bl o o d cells  
P otassi u m  
W hite bl o o d cell c o u nt wit h 
a ut o mate d differe ntial c 
Hae m o gl o bi n  
( bl o o d) 
Pr ot hr o m bi n ti me/ I nter nati o nal 
N or malise d Rati o  ( P T/I N Rb ) 
( plas ma) 
 
 
S o di u m  
 
 
T otal bilir u bi n  
 
 
Tri gl yceri des  
 
 
Urea ( bl o o d urea nitr o ge n)  
 
 
A d diti o n al P ar a meters d 
Al b u mi n  
Mea n c or p usc ular v ol u me  
 
Calci u m  
 
 
Creati ni ne cleara nce  
 
 
T otal pr otei n  
 
 
C hl ori de  
 
 
A b bre viati o ns: eC R F  = electr o nic case re p ort f or m; I N R = inter nati o nal n or malise d rati o; 
P T  =  pr ot hr o m bi n ti me.  
a A nal yse d as a pri orit y.  
b B ot h P T a n d I N R will be rec or de d i n t he eC R F.  
c I ncl u di n g a bs ol ute c o u nts a n d perce nt f or ne utr o p hils, l y m p h oc ytes, m o n oc ytes, e osi n o p hils, a n d 
bas o p hils.  
d A nal yse d i n a d diti o n t o t he esse ntial para meters, w here ver p ossi ble. 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 5 2  of 1 2 1  
e W here p ossi ble, uri ne sa m ples f or bi oc he mistr y will be a nal yse d at t he site’s l ocal la b orat or y b y use 
of a di pstic k wit h a n y rele v a nt fi n di n gs bei n g se nt f or f urt her uri nal ysis ( uri nal ysis, micr osc o p y, 
c ult ure, a n d se nsiti vit y, as a p plica ble).  
 
All la b orat or y res ults will be re vie we d, a n d t he re p orts si g ne d a n d date d b y a n 
i n vesti gat or. A n y res ults c o nsi dere d t o be of cli nical si g nifica nce m ust be d oc u me nte d 
as A E s a n d f oll o we d u p as cli nicall y a p pr o pri ate.  
All la b orat or y res ults c o nsi dere d t o re prese nt a n A E m ust be d oc u me nte d o n t he 
e C R F. F or re p orti n g a n d f oll o w -u p of p ote ntial cases of dr u g -i n d uce d li ver i nj ur y, see 
Secti o n  1 2. 6 . 
Re peat sa m ples will be ta ke n, if re q uir e d, f or cli nical f oll o w -u p or if t h e sa m ple is l ost 
or da ma ge d. A n y a b n or m al E O T  cli nical la b orat or y res ult of cli nical  si g nifica nce 
m ust be re peat e d at re g ul ar i nter vals u ntil it ret ur ns t o n or mal, or u ntil a n i n vesti gat or 
is satisfie d t hat t he a b n or malit y is n ot relate d t o t he st u d y i nter ve nti o n a n d nee ds n o 
f urt her i n vesti gati o n. 
9. 1. 1 0. 2.  P h ar m ac o ki netic Bl o o d S a m pli n g  
P har mac o k i netic sa m ples will be c ollecte d fro m  all partici pa nt s. 
M or ni n g tr o u g h (i.e., ta k e n wit hi n 6 0 mi n utes pri or t o t he m or ni n g d ose of 
G W P 4 2 0 0 3 -P ) P K sa m ples will be c ollecte d al o n g wit h  3 -h o ur , a n d 6-h o ur p ost d ose 
sa m ples d uri n g cert ai n st u d y visits as s pecifie d i n t he S o A  (A P P E N DI X  1 ). A  
mi ni m u m i nter val of at least 2 h o urs bet wee n eac h of t he bl o o d sa m pli n g ti me p oi nts  
m ust be mai ntai n e d. T he P K  sa m ples will be use d t o deter mi ne c o nce ntrati o ns of 
G W P 4 2 0 0 3 -P a n d its mai n meta b olites  (refer t o S ecti o n 1 3. 7. 1. 4  f or a d diti o nal 
details ). 
If p ossi ble, a n y c h a n ges i n d ose s h o ul d be a v oi de d d uri n g t he 3 da ys pri or t o P K 
visits , u nless cli nicall y i n dicate d f or safet y. If a p artici pa nt’s d ose is a dj uste d, P K 
sa m ple c ollecti o n s h o ul d n ot occ ur u ntil > 3 da ys after t he d ose a dj ust me nt. D oses 
ma y be a dj uste d d uri n g a P K st u d y visit after all P K sa m ples ha ve b ee n c oll ecte d o n 
t he da y of t he P K st u d y visit.  
A nal ysis of all P K sa m ples will be c o n d ucte d at a ce ntral bi oa n al ytical la b orat or y. 
Bl o o d sa m ple v ol u me re q uire me nts a n d pr ocessi n g pr oce d ures will als o be detaile d i n 
a se parate la b orat or y ma n ual; t he ma xi m u m a m o u nt of bl o o d ta ke n f or P K a nal y ses 
d uri n g t he st u d y will n ot  e xcee d li mits s pecifie d i n A p pe n di x  3 .3 .  
T he care gi ver will rec or d t he ti mi n g a n d c o nte nt of meals d uri n g t he 2 4 h o urs pri or t o 
P K sa m ple c ollecti o n (refer t o Secti o n  9. 1. 1 2. 2 ). T hese data will be i ncl u de d i n a n 
e x pl orat or y a n al ysis al o n g wit h t he d ose ti me a n d P K s peci me ns t o f urt her u n dersta n d 
t he P K pr ofile of G W P 4 2 0 0 3-P i n t his p o p ulati o n.  
9. 1. 1 0. 3.  O pti o n al  Bl o o d S a m pli n g  
T he f oll o wi n g sa m ples are o pti o nal a n d will o nl y be c ollecte d fr o m partici pa nts 
w h ose pare nt (s)/ L A R ha ve c o nsente d t o partici pate  i n t hese a nal yses.  
Partici pati o n is o pti o nal. Partici pa nts w h ose pare nt(s)/ L A R d o n ot wis h t o partici pate 
i n t hese a nal yses ma y still partici pate i n t he  st u d y.  
Sa m ples c ollecte d will b e wit hi n t he li mits s pecifie d i n A p pe n di x  3 .3 .  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 5 3  of 1 2 1  
Partici pa nt c o nfi de ntialit y will be mai ntai ne d at all ti mes b y t he bli n di n g of sa m ples.  
A d diti o nal i nf or mati o n is pr o vi de d i n  A P P E N DI X 4 . Details, i ncl u di n g t he pr ocesses 
f or c ollecti o n a n d h a n dli n g of bi ol o gical sa m ples, as well as s hi p me nt a n d destr ucti o n 
of t hese sa m ples, are pr o vi de d i n t he la b orat or y m a n ual. Res ults of t hese a n al yses will 
be re p ort e d se paratel y.  
9. 1. 1 0. 3. 1.  P h ar m ac o ge n o mics  
O pti o nal b l o o d sa m ples ma y be c ollecte d  fr o m partici pa nts w h o se pare nt(s)/ L A R 
ha ve c o nse nt e d t o partici pate i n t he ge netic  a nal ysis c o m p o ne nt of t he st u d y as 
o utli ne d  i n t he S o A (A P P E N DI X  1 ). 
•  Bl o o d s a m ples will be a nal yse d t o detect p ol y m or p his ms i n s pecific ge nes 
a n d deter mi ne if u ni q u e si n gle n ucle oti de p ol y m or p his ms or m ore 
c o m ple x Me n delia n fact ors mi g ht be a c o ntri b uti n g fact or i n a p artici pa nt’s 
res p o nse t o G W P 4 2 0 0 3 -P .  
9. 1. 1 0. 3. 2.  E x pl or at or y Bi o m ar ker s 
O pti o nal  plas ma sa m ples ma y be c ollecte d fr o m p artici pa nts w h ose pare nt(s)/ L A R  
ha ve c o nse nt e d t o partici pate i n t he e x pl orat or y bi o mar ker  a nal ysis  as s pecifie d i n t he 
S o A  (A P P E N DI X  1 ). 
 
 
 
 
 
9. 1. 1 1.  
R a n d o mis ati o n a n d Tri al S u p pl y M a n a ge me nt S yste m  
T he R T S M will be use d f or e nr ol me nt stratificati o n (refer t o Secti o n  7. 1 ) a n d t o 
ma na ge st u d y i nter ve nti o n s u p pl y. T he R T S M s yste m will be i nte grate d wit h 
electr o nic d ata ca pt ure ( E D C) . St u d y site pers o n nel m ust re gister i n E D C i n or der t o: 
•  O btai n a partici pa nt ’s n u m ber. 
•  O btai n dis pe nsi n g i nf or mati o n.  
•  Pr o vi de c o m pleti o n/ta per/ pre mat ure ter mi nati o n i nf or mati o n.  
•  Trai ni n g will be gi ve n t o all trial ce ntres pri or t o t he start o f t he st u d y. 
9. 1. 1 2.  
Q uesti o n n aires a n d Assess m e nts C o m plete d at Sc he d ule d Visits  
Q uesti o n naires a n d diaries s h o ul d be c o m plete d b y t he mai n care gi ver w h o has 
recei v e d trai ni n g o n c o m pleti o n of st u d y assess me nts, as a p pr o priate. I n sit uati o ns 
w here t his is n ot p os si ble d uri n g a sc he d ule d visit, t he q uesti o n naire s h o ul d be 
c o m plete d wit hi n 3  da ys of sc he d ule d visit. T he sa me pers o n s h o ul d c o m plete t he 
q uesti o n naires a n d diar y assess me nts i n or der t o mai ntai n c o nsiste nc y.  
9. 1. 1 2. 1.  C o nfir m ati o n of Di a g n osis  ( D S a n d L G S) a n d Se iz ure Cl assific ati o n  
F or partici pa nts wit h D S or L G S o nl y, t he E S CI will c o nfir m dia g n osis d uri n g t he 
scree ni n g / bas eli ne peri o d. Partici pa nts wit h D S or L G S w h ose dia g n osis ca n n ot be 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 5 4  of 1 2 1  
c o nfir me d b y t he E S CI m ust disc o nti n ue t he st u d y (refer t o Secti o n  6. 2 , I n cl usi o n 
Crit eria).  
I n a d diti o n, to pr o m ote acc urat e a n d c o nsiste nt re p orti n g of I L A E seiz ures ass ociate d 
wit h L G S , D S, or T S C f or t his st u d y (A P P E N DI X  3 ) (F o u n d ati o n 2 0 1 7 ), t he E S CI 
will verif y t he I L A E s eiz ure t y pes of scree ne d partici pa nts  d uri n g t he 
scree ni n g/ bas eli ne peri o d .  
D uri n g Visit  1, i n vesti gat ors will c ollect a detaile d me dical hist or y re gar di n g t he 
partici pa nt’s seiz ure hist or y usi n g t he f oll o wi n g f or ms pr o vi de d :  
•  T he Seiz ure I de ntificati o n F or m ( SI F ; f or T S C) 
•  T he SI F/  Dia g n ostic Re vie w F or m ( D R F ; f or L G S a n d D S) 
•  T he  E pile ps y Diar y Refere nce S heet ( E D R S ; f or all partici pa nts)  
T he i n vesti gat or will s u b mit t he se f or ms directl y t o t he E S CI,  al o n g wit h t h e 
f oll o wi n g s u p p orti n g i nf or mati o n f or c o nfir m ati o n of dia g n osis (f or D S a n d L G S) a n d 
verificati o n of s eiz ure t y pes  (f or all partici pa nts) wit hi n 2 4 h o urs ( 1 b usi ness da y) of 
Visit 1 :  
•  I nter-Ictal-E E G s u m mar y re p orts  (f or all partici p a nts) 
•  Ictal-E E G s u m mar y ( f or all partici pa nts, w here a v aila ble)  
•  Ne ur oi ma gi n g s u m mar y (f or L G S  a n d D S)  
T he E S CI ma y as k t he i n vesti gat or f or a d diti o nal i nf or mati o n t o assist i n t heir 
decisi o n. T he E S CI will pr o vi de writte n c o nfir mati o n of dia g n osis (f or D S a n d L G S ) 
a n d writte n c o nfir m ati o n of seiz ure t y p es (f or all partici pa nts) d uri n g t he 
scree ni n g/ b as eli ne peri o d.  
Als o d uri n g Visit 1, t he i n vesti gat or will re vie w a n d trai n t he care gi ver t o i de ntif y, 
c o u nt, a n d re p ort t he partici pa nt ’s e x pecte d seiz ures i n t he pa per (scree ni n g/ b aseli ne 
peri o d o nl y) a n d e P R O d ail y seiz ure diar y(ies) usi n g t he E D R S . C are gi vers will be gi n 
dail y trac ki n g of t he i n vesti gat or-classifie d seiz ure t y pes i n b ot h t he pa per s eiz ure 
diar y a n d t he e P R O seiz ure diar y.  
After t he E S CI has pr o vi de d writte n c o nfir m ati o n of seiz ure t y p es , t he i n vesti gat or 
m ust c o ntact t he care gi ver i m me diatel y if a n y seiz ure t y pe was misclassifi e d b y t he 
i n vesti gat or d uri n g t he i nitial trai ni n g. If a seiz ure t y pe was misclassifie d, t he 
i n vesti gat or m ust retrai n t he care gi ver an d s u b mit a n u p date d  E D R S  t o E S CI f or 
re vie w a n d a p pr o val .  
T he care gi ver will c o nti n ue dail y trac ki n g of t h e E S CI -a p pr o ve d sei z ure t y p es i n b ot h 
t he pa per s eiz ure di ar y a n d t he e P R O seiz ure diar y, usi n g t he E S CI -a p pr o ve d E D R S , 
t hr o u g h t he re mai n der of t he scree ni n g/ baseli ne peri o d. At Visit 3 , t he care gi ver will 
ret ur n t o t he trial c e ntre wit h t he pa per sei z ure di ar y  a n d e P R O sei z ure diar y f or 
re vie w.  
After Visit 3 , care gi vers will o nl y use t he e P R O seiz ure diar y f or d ail y seiz ure 
re p orti n g d uri n g t he re mai ni n g c o urse of t he st u d y.  
N ote: If a ne w seiz ure t y pe occ urs d uri n g t he st u d y t hat was n ot pre vi o usl y a p pr o ve d b y 
E S CI, t he i n vesti gat or m ust c o m plete a Ne w Seiz ure F or m a n d s u b mit t his f or m t o E S CI 
f or re vie w a n d ap pr o val.  W here a gree d wit h t he E S CI a n d me dical m o nit or, t he SI F or 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 5 5  of 1 2 1  
SI F/ D R F ( as a p plica ble ) a n d E D R S ma y be u p dat e d t o i ncl u de t he ne w s eiz ure 
t y pe(s). Ne w seiz ure t y pes ma y  als o meet t he defi niti o n of a n A E (refer t o 
Secti o n  1 2. 1 ). 
O nl y seiz ures t h at are rec o g nis a ble a n d c o u nt a ble will be re p orte d b y c are gi vers 
f or t his st u d y. T he f oll o wi n g I L A E seiz ure s u bt y pes ass ociate d wit h L G S, D S, or 
T S C will be c ollecte d i n t he e P R O diar y  (S pecc hi o 2 0 2 2 , Z u beri 2 0 2 2 ): 
•  F ocal sei z ures  
− F ocal m ot or sei z ures  ( wit h or wit h o ut i m pair me nt of  c o nsci o us ness or 
a ware ness)  
− F ocal sei z ures w hic h e v ol ve t o bilateral c o n v ulsi ve seiz ures  
•  Ge neralise d seiz ures: 
− T o nic  
− Cl o nic  
− T o nic -cl o nic  
− At o nic  
•  Ot her ge neralise d or f ocal seiz ures:  
− M y ocl o nic  
− A bse nce  
− F ocal n o n -m ot or  ( wit h or wit h o ut i m pair me nt of  c o nsci o us ness or 
a ware ness)  
− I nfa ntile/epile ptic s pas ms  
− Ot her  
Details of t he c o m p ositi o n a n d sta n dar d o perati n g pr oce d ures of E S CI  will be 
pr o vi de d i n a se parate c h arter.  
9. 1. 1 2. 2.  P artici p a nt Di aries  
At Visit 1 a n d t hr o u g h o ut t he st u d y, care gi vers will c o m plete t he e P R O diar y t o 
rec or d i nf or mati o n dail y. D uri n g t he scree ni n g/ baseli ne peri o d o nl y, care gi vers will 
als o use a pa p er diar y f or tra c ki n g seiz ures t o s u p ple me nt t he e P R O seiz ure diar y  
(refer t o Secti o n 9. 1. 1 2. 1 ). Care gi ver trai ni n g o n diar y c o m pleti o n will be pr o vi de d at 
as o utli ne d i n A P P E N DI X  1 . Care gi vers will be as ke d t o rec or d t he f oll o wi n g 
i nf or mati o n i n t he e P R O diar y: 
•  Seiz ures  
•  C ha n ges i n partici pa nt’s healt h (e. g., p ossi ble A E s) 
•  St u d y i nter ve nti o n  usa ge, i ncl u di n g d ose ti me a n d v ol u me  
•  C ha n ges i n c o nc o mita nt me dicati o ns, i ncl u di n g resc ue me dicati o n usa g e  
•  Details of eac h meal c o ns u me d b y t he partici pa nt wit hi n 2 4 h o urs pri or t o 
P K  c ollecti o n, i ncl u di n g t he start ti me, e n d ti me a n d meal t y pe:  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 5 6  of 1 2 1  
− Hi g h fat meal ( breast mil k, f or m ula mil k, or meat)  
− Sta n dar d meal (fr uit or ve geta ble)  
− Ot her (if n ot fitti n g i nt o o ne of t he cate g ories a b o ve)  
Care gi vers s h o ul d be i nstr ucte d t o i m me diatel y c o nt act t he i n vesti gat or b y p h o ne t o 
disc uss a n y A E s (i ncl u di n g w orse ni n g of seiz ures as descri be d i n  Secti o n 1 2. 1 ) or 
c ha n ges i n c o n c o mita nt A S Ms  (i ncl u di n g use of resc ue me dicati o n).  
All diar y e ntries will be re vie we d a n d disc usse d wit h care gi vers f or verificati o n, a n d 
w here n ecess ar y, rec or de d wit hi n t he a p plica ble secti o ns of t he e C R F b y site staff. 
A n y c ha n ges i n c o nc o mita nt A S Ms s h o ul d be disc usse d wit h a n d a p pr o ve d b y t he 
me dical m o nit or. A n y e ntries of A E s s h o ul d be re p orte d acc or di n g t o A E re p orti n g 
pr oce d ures o utli ne d i n  Secti o n 1 2 . 
9. 1. 1 2. 3.  I nf a nt a n d T o d dler Q u alit y of Life  Q uesti o n n aire S h ort  F or m  4 7  
Care gi vers will be i nstr ucte d o n h o w t o rec or d a n d c o m plete t he I T Q O L -S F 4 7 . Ra w 
sc ores o btai ne d i n t he qu esti o n naire  will be tra nsf or me d t o a val ue  fr o m 0 ( w orst 
healt h) t o 1 0 0 ( best he alt h). T he I T Q O L -S F 4 7 will be c o m plete d at t he site b y t he 
care gi v er o n a n electr o ni c cli nical o utc o mes ass ess me nt  de vice  (Healt h Act C H Q 
2 0 1 7 ).  
9. 1. 1 2. 4.  Ne ur o de ve l o p me nt al Sc ale –  Cli nic ia n Gl o b al I m pressi o n of 
C h a n ge/ Se verit y   
Cli nicia ns will be i nstr ucte d o n h o w t o rec or d a n d c o m plete t he Cli nicia n  Gl o bal  
I m pr essi o n of C ha n ge/ Se verit y (C GI C/ S ) c o veri n g critical ne ur o de vel o p me ntal 
d o mai ns. T his is a 2 -q uesti o n s ur ve y f or eac h d o m ai n a n d will be c o m plete d b y t he 
cli nicia n as part of t h e c o m pre he nsi ve n e ur o de vel o p me ntal assess me nt at  V isits 3, 1 3, 
a n d E O T. Eac h partici p a nt s h o ul d ha ve t heir C GI C / S perf or me d b y t he s a me cli nicia n 
t hr o u g h o ut t he st u d y a n d re p orte d i nt o E D C.  
T he C GI C/ S d o mai ns i ncl u de  t he f oll o wi n g: 
•  
S e ns or y (e. g., visi o n, t o uc h, heari n g, tast e, s mell)  
•  
M ot or  (e. g., fi ne a n d gr oss m ot or)  
•  
C o g niti o n  (e. g., u n dersta n di n g, reacti n g , reas o ni n g, pr o ble ms s ol vi n g ) 
•  
E m oti o nal/ b e ha vi o u ral healt h (e. g., e m oti o nal re g ulati o n, self-s o ot hi n g) 
•  
C o m m u nicati o n  (e. g., rece pti ve a n d e x pressi ve  s kills) 
•  
S ocial (e. g., s ocial i nteracti o ns, res p o n di n g) 
•  
A da pti ve f u ncti o ni n g  (e. g., self-hel p s kills s uc h as fee di n g self, ai di n g i n 
dressi n g , etc.)  
9. 1. 1 3.  
St u d y I nter ve nti o n  Acc o u nt a bilit y  
Rec or ds of st u d y i nter ve nti o n acc o u nta bilit y will be mai ntai ne d acc or di n g t o 
Secti o n  5. 1. 4 . 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 5 7  of 1 2 1  
9. 1. 1 4.  
A d verse E ve nts  
A ll A E s a n d seri o us a d v erse e ve nts (S A Es ) will be c ollecte d fr o m t he start of 
i nter ve nti o n u ntil t he safet y f oll o w-u p visi t, as s pecifie d i n A P P E N DI X  1 . 
Me dical occ urre n ces t hat be gi n bef ore t he start of st u d y i nter ve nti o n b ut after 
o btai ni n g i nf or me d c o nse nt will be rec or de d as me dical hist or y n ot as A E s. 
N ote: All S A Es t hat occ ur after t h e  c o nse nt f or m is si g ne d b ut bef ore st u d y 
i nter ve nti o n is i nitiate d m ust be re p orte d b y t he i n vesti gat or if t he y ca us e t he 
partici pa nt t o be e x cl u de d fr o m t he st u d y or are t he res ult of a pr ot oc ol -s pecifie d 
i nter ve nti o n, i ncl u di n g b ut n ot li mite d t o was h o ut or disc o nti n uati o n of us ual t hera p y, 
diet, place b o treat me nt, or a pr oce d ure.  
All S A Es  m ust be re p orte d t o t he s p o ns or or desi g nee i m me diatel y a n d wit hi n 
2 4  h o urs of first k n o wle d ge of t he e v e nt, as i n dicat e d i n Secti o n  1 2 . T he i n vesti gat or 
will s u b mit a n y u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of it bei n g a vaila ble.  
I n v esti gat ors are n ot o bli gate d t o acti vel y se e k i nf or mati o n o n A E s or S A Es after 
c o ncl usi o n of t he st u d y partici pati o n. H o we v er, if t he i n vesti gat or lear ns of a n y S A E, 
i ncl u di n g a deat h, at a n y ti me after a p artici pa nt h as bee n disc h ar ge d fr o m t he st u d y, 
a n d he/s he c o nsi ders t he e ve nt t o be reas o na bl y r elate d t o t he st u d y i nter ve nti o n or 
st u d y partici pati o n, t he i n vesti gat or s h o ul d pr o m ptl y n otif y t he s p o ns or. 
Refer t o Secti o n  1 2  f or d efi niti o ns, pr oce d ures a n d f urt her i nf or m ati o n o n A E 
re p orti n g. 
9. 1. 1 5.  
S peci al Circ u mst a nces  
D uri n g s pecial cir c u msta nces (e. g., C or o na vir us disease 2 0 1 9  [C O VI D -1 9 ] 
pa n de mic), t he s p ecific g ui d a nce fr o m l ocal p u blic healt h a n d ot her c o m pete nt 
a ut h orities re gar di n g t he pr otecti o n of i n di vi d uals’ welfare m ust be a p plie d. I n cases 
w here p artici pa nt s are n ot a ble t o perf or m all pr ot oc ol-defi ne d assess me nts d ue t o 
s pecial cir c u msta nces, t h e i n vesti gat or m ust disc uss wit h t he me dical m o nit or 
p ote ntial miti gati o n a p pr oac hes.  
F or t he d urati o n of s uc h s pecial cir c u msta nces, t h e f oll o wi n g meas ures m a y be 
i m ple me nte d f or e nr olle d partici pa nt s: 
•  Safet y f oll o w -u p ma y be d o ne b y a tele p h o n e call, ot her mea ns of  virt u al 
c o ntact or h o me visit, if a p pr o priate.  
•  Partici pa nt  a n d/ or cli nici a n -rat e d o utc o mes assess me nts ma y be d o ne b y 
vi de oc o nfere nce, tele p h o ne call, ot her mea ns of virt ual c o ntact, if p ossi ble.  
•  A n alter nati ve a p pr oac h f or st u d y i nter ve nti o n dis pe nsi n g, sec ure deli ver y, 
a n d c ollecti o n ma y be s o u g ht.  
•  Visits ma y ta ke place i n a differe nt l ocati o n t ha n defi ne d i n t he pr ot oc ol. If 
t his is n ot feasi ble, t he n t he visit ma y ta ke place virt uall y wit h t he mea ns 
of c o m m u nicati o n d oc u me nt e d (e. g., p h o ne call or vi deoc o nfere n ce).  
•  Bi ol o gical sa m ples ma y be c ollecte d a n d a nal ys e d at a differe nt l ocati o n 
t ha n defi ne d i n t he pr ot o c ol. Bi ol o gical sa m ples s h o ul d n ot be c ollecte d if 
t he y ca n n ot be pr o cesse d i n a ti mel y ma n ner or a p pr o priatel y st ore d u ntil 
s hi p pi n g/ pr ocessi n g. 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 5 8  of 1 2 1  
•  If des pite best eff orts it is n ot p ossi ble t o c ollect t he bi ol o gical sa m ples or 
safet y assess me nts (e. g., E C G, vital si g ns) wit hi n t he i nter val pre d efi ne d i n 
t he pr ot oc ol (see A P P E N DI X  1 ), t he n t he i nter val ma y be e xte n de d u p t o a 
ma xi m u m le n gt h of ±  7 da ys.  
•  If des pite best eff orts a s afet y assess m e nt ca n n ot be perf or me d, t he 
i n vesti gat or m ust re vie w t he be nefit-ris k f or part ici pa nt c o nti n uati o n i n t he 
st u d y a n d rec or d t his i n t he me dical r ec or ds. 
T he rati o nale (e. g., t he s p ecific reas o ns be hi n d t he c ha n ges) a n d o utc o me of t he 
disc ussi o n wit h t he me dical m o nit or will be d oc u me nte d i n t he me dical r ec or d s. 
I nf or mati o n o n h o w each visit was perf or me d will be rec or de d i n t he e C R F.  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 5 9  of 1 2 1  
1 0.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T  DI S C O N TI N U A TI O N/ WI T H D R A W A L  
T he p artici pa nt s’ pare nt(s)/ L A R ha ve t he ri g ht t o wit h dra w t he partici pa nt fr o m st u d y 
i nter ve nti o n a n d/ or ot her pr ot oc ol -re q uir e d t hera pies, pr ot oc ol pr oce d ures, or t he 
st u d y as a w h ole at a n y ti me a n d f or a n y reas o n wit h o ut prej u dice t o t he partici pa nt’s 
f ut ure me dical care b y t h e p h ysicia n or at t he i nstit uti o n. 
T he i n vesti gat or a n d/ or s p o ns or ca n deci de t o wit h dr a w a p artici pa nt (s) fr o m st u d y 
i nter ve nti o n, a n d/ or ot her pr ot oc ol-re q uir e d t hera pies, pr ot oc ol pr oce d ures, or t he 
st u d y as a w h ole at a n y ti me pri or t o st u d y c o m pleti o n f or t he reas o ns liste d i n 
Secti o n  1 0. 1  a n d Secti o n  1 0. 2 . 
1 0. 1.  
Disc o nti n u ati o n of St u d y I nter ve nti o n  
•  Pare nt(s)/ L A R  ma y decli ne t o c o nti n ue partici pati n g i n st u d y i nter ve nti o n 
a n d/ or ot her pr ot oc ol -re q uire d t hera pi es or pr oce d ures at a n y ti me d uri n g 
t he st u d y. 
•  Pare nt(s)/ L A R  w h o c h o ose t o disc o nti n ue partici p ati n g i n st u d y 
i nter ve nti o n a n d/ or ot her pr ot oc ol-re q uir e d t hera pies or pr oce d ures s h o ul d 
n ot be a ut o maticall y re m o ve d fr o m t he st u d y. W h e ne ver safe a n d feasi ble, 
a n d i n a gree me nt wit h t he s p o ns or, t he partici p a nt s s h o ul d re mai n i n t he 
st u d y t o e ns ure safet y s ur veilla nce a n d/ or c ollecti o n of o utc o me data. 
•  T he i n vesti gat or is t o disc uss wit h t he partici pa nt ’s pare nt(s)/L A R  t he 
a p pr o priate pr ocess es f or disc o nti n uati o n fr o m st u d y i nter ve nti o n or ot her 
pr ot oc ol -re q uir e d t hera pies. T he i n vesti gat or m ust disc uss wit h t he  
partici pa nt’s pare nt(s)/ L A R t he p ossi bilities f or c o nti n uati o n of acti vities 
descri be d i n t he S o A ( A P P E N DI X  1 ) a n d m ust d o c u me nt t his decisi o n i n 
t he e C R F.  
•  T hese p artici p a nts s h o ul d c o m plete a n E T visit f oll o we d b y  1 0 -da y t a per 
peri o d if cli nicall y i n dicate d (i.e., if n o safet y reas o ns pr o hi bit c o nti n ue d 
treat me nt; refer t o Secti o n 8. 1. 2 ). A safet y f oll o w-u p visit  s h o ul d be 
c o n d ucte d 4 w ee ks after t he  partici pa nt’s  last d ose of G W P 4 2 0 0 3 -P . 
Re mai ni n g assess me nt visits a n d acti vit ies as deter mi ne d b y t he 
i n vesti gat or ca n still pr ocee d as pla n n e d.  
Reas o ns f or re m o val fr o m st u d y i nter ve nti o n or pr oce d ural assess me nts i n cl u de a n y 
of t he f oll o wi n g:  
•  Decisi o n b y t he i n vesti gat or .  
•  Decisi o n b y s p o ns or .  
•  D ecisi o n b y re g ulat or y a ut h orit y.  
•  Wit h dra wal of p are nt(s)/ L A R  c o nse nt . 
•  C ha n ge i n c o m plia nce wit h a n y i ncl usi o n/e xcl usi o n criteri o n t hat is 
cli nicall y rele va nt a n d affects partici p a nt  safet y, as deter mi ne d b y t he 
i n vesti gat or ( or desi g ne e). 
•  Pr ot oc ol de viati o n t hat is c o nsi dere d t o p ote ntiall y c o m pr o mise t he safet y 
of t he partici pa nt . 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 6 0  of 1 2 1  
•  N o nc o m plia nce wit h st u d y i nter ve nti o n.  
•  N o nc o m plia nce wit h a n y of t he st u d y assess me nts.  
•  A n y cli nicall y rele v a nt si g n or s y m pt o m t hat i n t he o pi ni o n of t he 
i n vesti gat or ( or desi g ne e) warra nts partici pa nt  re m o val fr o m st u d y 
i nter ve nti o n. 
•  Li ver C he mistr y –  Disc o nti n uati o n of st u d y i nter ve nti o n f or a b n or mal li ver 
tests is re q uire d b y t he i n vesti gat or w he n a p artici pa nt  meets o ne of t he 
f oll o wi n g c o n diti o ns o utli ne d or i n t he prese n ce of a b n or mal li ver 
c he mistries n ot meeti n g pr ot oc ol-s pecifi e d st o p pi n g r ules if t he 
i n vesti gat or belie ves t hat it is i n best i nterest of t he partici pa nt . 
− A L T or A S T > 3 × U L N wit h t he a p peara nce of fati g ue, na usea, 
v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or 
e osi n o p hilia ( > 5 %).  
− A L T or A S T >  8 × U L N.  
− A L T or A S T > 5 × U L N f or m ore t ha n 2 wee ks.  
− A L T or  A S T > 3 × U L N a n d  ( T B L > 2 × U L N or  I N R >  1. 5).  
N ote: Pri or t o treat me nt disc o nti n uati o n f or t he tr a nsa mi nase el e vati o ns n ote d 
a b o ve, t he i n vesti gat or m a y c h o ose t o c o nfir m t he tra nsa mi nase el e vati o ns b y 
re peati n g t he f oll o wi n g la b orat or y tests, tests wit hi n 2 4 t o 4 8 h o urs: A L T, 
A S T, T B L, I N R, % e osi n o p hils, ga m ma -gl uta m yl tra nsferase ( G G T ), a n d 
al kali ne p h os p hatase  (als o refer t o Secti o n 1 2. 7 ). S h o ul d t he a b o ve 
tr a ns a mi n ase ele v ati o n criteri a be c o nfir me d, t he p artici p a nt  m ust 
per m a ne ntl y disc o nti n ue t he st u d y i nter ve nti o n. I n c ases w here 
tr a ns a mi n ase ele v ati o n wit h dr a w al criteri a are n ot met or c o nfir me d, t he 
d ose of st u d y i nter ve nti o n or a c o nc o mit a nt me dic ati o n wit h k n o w n 
he p at ot o xicit y m a y be re d uce d f oll o wi n g disc ussi o n wit h t he me dic al 
m o nit or. T he fi n al decisi o n re g ar di n g d ose a dj ust me nts s h o ul d  be t a ke n 
b y t he i n vesti g at or.  
•  Disease pr o gressi o n t hat c o m pr o mises t he a bilit y of t he partici pa nt  t o 
safel y c o nti n ue st u d y i nter ve nti o n t o t he partici pa nt  i n t he st u d y. 
•  Partici pa nt s w h o are wit h dra w n f or n o n dr u g relate d reas o ns ma y b e 
re place d f oll o wi n g disc ussi o n bet wee n t he i n vesti gat or a n d t he s p o ns or. 
Partici pa nt s wit h dra w n as a res ult of A Es t h o u g ht t o be relate d t o st u d y 
i nter ve nti o n, as deter mi n e d b y t he i n vesti gat or, will generall y n ot be 
re place d. T he d ecisi o n re gar di n g t he re pl ace me nt of partici pa nt s will be 
d oc u me nte d.  
T he partici pa nt  ma y als o be per ma n e ntl y disc o nti n ue d fr o m treat me nt f or a n y of t he 
f oll o wi n g: 
•  Partici pa nt  or pare nt(s)/ L A R  n o nc o m plia nce.  
•  A E (i ncl u di n g cli n icall y si g nifica nt la b orat or y res ult) w hic h, i n t he o pi ni o n 
of t he i n vesti gat or, w o ul d c o m pr o mise t he c o nti n ue d safe p artici pati o n of 
t he partici pa nt  i n t he st u d y. 
•  Di d n ot meet eli gi bilit y criteria.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 6 1  of 1 2 1  
•  A n y e vi de nce of dr u g a b use or dr u g di versi o n.  
•  Disease pr o gressi o n th at c o m pr o mises t he a bilit y of t he partici pa nt  t o 
safel y c o nti n ue p artici pati n g i n t he st u d y. 
1 0. 2.  
P artici p a nt  Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y  
•  A partici pa nt ’s pare nt(s)/ L A R  ma y deci de t o wit h dra w t he partici pa nt 
fr o m t he st u d y at a n y ti me at t heir o w n re q uest , or  t he partici pa nt ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or or s p o ns or f or 
safet y, be h a vi ou ral, or c o m plia nce reas o ns. 
•  T he partici pa nt  will be p er ma ne ntl y disc o nti n ue d b ot h fr o m t he  st u d y 
i nter ve nti o n a n d fr o m t he st u d y at t hat ti me. 
•  If a partici pa nt  is wit h dra w n fr o m t he st u d y, t he st u d y m o nit or will be 
i nf or me d i m me diatel y. If t here is a me dical reas o n f or wit h dra wal, t he 
partici pa nt  will be f oll o w e d u p b y t he i n vesti gat or u ntil sa tisfact or y healt h 
has ret ur ne d.  
•  At t he ti me of disc o nti n ui n g fr o m t he st u d y, all eff orts m ust be ma de t o 
c o m plete a n d re p ort t he o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he 
date of wit h dra wal. If p ossi ble, a n E T  visit s h o ul d be c o n d ucte d , f oll o we d 
b y a 1 0-da y ta p er peri o d if cli nicall y i n dicate d ( refer t o Secti o n  8. 1. 2 ). A 
safet y f oll o w-u p visit s h o ul d be c o m plete d 4 wee ks after t he p artici pa nt’s 
last d ose of G W P 4 2 0 0 3 -P . See  t he S o A (A P P E N DI X  1 ) f or data t o be 
c ollecte d at t he ti me of st u d y disc o nti n uati o n a n d f oll o w -u p a n d f or a n y 
f urt her e v al uati o ns t hat n ee d t o be c o m plet e d. 
•  If t he partici p a nt ’s pare nt(s)/L A R  wit h dra ws c o ns e nt f or discl os ure of 
f ut ure i nf or mati o n, t he s p o ns or ma y retai n a n d c o nti n ue t o use a n y data 
c ollecte d bef ore s u c h a wit h dra wal of c o ns e nt. 
•  If a partici pa nt  is wit h dra w n fr o m t he st u d y, her/his  pare nt(s)/ L A R  ma y 
re q uest destr u cti o n of a n y sa m ples ta ke n a n d n ot t este d, a n d t he 
i n vesti gat or m ust d oc u me nt t his i n t he site st u d y rec or ds. 
Reas o ns f or re m o val of a partici pa nt  fr o m t he st u d y are: 
•  Decisi o n b y t he i n vesti gat or .  
•  Decisi o n b y s p o ns or . 
•  Decisi o n b y re g ulat or y a ut h orit y . 
•  Wit h dra wal of p are nt(s)/ L A R  c o nse nt.  
•  Deat h.  
•  L ost t o f oll o w -u p.  
•  P are nt(s)/L A R  n o nc o m plia nce  wit h st u d y sc he d ul e.  
•  P are nt(s)/L A R  n o nc o m plia nce wit h st u d y i nter ve nti o n a d mi nistrati o n . 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 6 2  of 1 2 1  
1 0. 2. 1.  
L ost t o F oll o w -u p  
A partici pa nt  will be c o nsi dere d l ost t o f oll o w -u p if he or s he re peate dl y fails t o ret ur n 
f or sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he trial ce ntre. 
T he f oll o wi n g acti o ns m ust be ta ke n if a p artici pa nt  fails t o ret ur n t o t he cli nic f or a 
re q uire d st u d y visit: 
•  T he site m ust atte m pt t o c o ntact t he partici pa nt ’s pare nt(s)/ L A R a n d 
resc he d ul e t he misse d visit as s o o n as p ossi ble a n d c o u nsel t he 
pare nt(s)/ L A R  o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule a n d ascertai n w het her or n ot t he p are nt(s)/ L A R  wis hes t o a n d/ or 
s h o ul d ha ve t he partici p a nt c o nti n ue i n t he st u d y.  
•  Bef ore a p artici pa nt  is de e me d l ost t o f oll o w-u p, t he i n vesti gat or or 
desi g nee m ust ma ke e v er y eff ort t o re gai n c o ntact wit h t he partici pa nt ’s 
pare nt(s)/ L A R ( w here p ossi ble, 3 t ele p h o ne calls a n d, if necessar y, a 
certifie d letter t o t he parti ci pa nt ’s last k n o w n maili n g a d dress or l ocal 
e q ui vale nt met h o ds). T hese c o ntact atte m pts s h o ul d be d oc u me nte d i n t he 
partici pa nt ’s me dic al rec or ds. 
•  S h o ul d t he partici pa nt ’s pare nt(s)/ L A R c o nti n ue t o  be u nreac ha ble, t h e n 
t he partici pa nt will be c o nsi dere d t o ha ve wit h dra w n fr o m t he st u d y.  
Site pers o n nel, or a n i n de pe n de nt t hir d part y, ma y atte m pt t o c ollect t he vital stat us of 
t he partici pa nt  wit hi n le g al a n d et hical b o u n d aries f or all partici pa nt s ra n d o mise d, 
i ncl u di n g t h ose w h o di d n ot get st u d y i nter ve nti o n. P u blic s o urces ma y be searc h e d 
f or vital stat us i nf or mati o n. If vital stat us is deter mi ne d as decease d, t his will be 
d oc u me nte d a n d t h e p arti ci pa nt  will n ot be c o nsi dere d l ost t o f oll o w -u p. S p o ns or 
pers o n nel will n ot be i n v ol ve d i n a n y atte m pts t o c ollect vital stat us i nf or mati o n.  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 6 3  of 1 2 1  
1 1.  
U R G E N T S A F E T Y M E A S U R E S  
T he s p o ns or a n d i n vesti g at or ma y ta ke a p pr o priat e ur ge nt safet y meas ures i n or der t o 
pr otect t he partici pa nt s of a cli nical st u d y a g ai nst a n y i m me diate hazar d t o t heir healt h 
or safet y. If s uc h me as ur es are t a ke n b y t he i n vesti gat or, t he y m ust n otif y t he s p o ns or 
i m me diatel y or at least wit hi n 2 4 h o urs of a ware ness  (s p o ns or c o ntact det ails are 
pr o vi de d i n t he trial ce ntr e file [A P P E N DI X  2 ]). T he s p o ns or  will re p ort ur ge nt safet y 
meas ures t o r e g ulat or y a ut h orities b y tele p h o ne wit hi n 2 4  h o urs of a ware ness, 
w here v er p ossi ble, a n d will pr o vi de a writte n re p ort t o t he re g ulat or y a ut h orities a n d 
I R B/I E C wit hi n 3  da ys.  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 6 4  of 1 2 1  
1 2.  
A D V E R S E E V E N T R E P O R TI N G  
1 2. 1.  
A d verse E ve nt D efi niti o n 
F or t he p ur p os es of t his st u d y, a n A E is defi ne d as  a n y u nt o war d me dical o cc urre nce 
i n a cli nical st u d y partici pa nt, te m p orall y ass ociat e d wit h t he use of st u d y 
i nter ve nti o n, w het her or n ot c o nsi dere d relate d t o t he st u d y i nter ve nti o n. 
A n A E ca n t h eref ore b e a n y u nfa v ou ra bl e a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e xacer bate d) te m p orall y ass ociate d 
wit h t he use of st u d y i nter ve nti o n . 
T he partici pa nt’s e x pecte d seiz ure t y pes d o n ot r o uti nel y re q ui re d oc u m e ntati o n as 
A Es. H o we ver, a n y w ors e ni n g, i ncl u di n g ne w seiz ure t y pes a n d c ha n ge i n t he patter n 
or se verit y of e xisti n g seiz ure t y pes, s h o ul d be d oc u me nte d i n t he e C R F if d ee me d t o 
meet t he defi niti o n of a n A E, i n t he i n vesti gat or’s o pi ni o n.  
As part of t he o n g oi n g safet y re vie w, a n i n de pe n d e nt Safet y M o nit ori n g C o m mittee 
(S M C ) will m o nit or a n y w orse ni n g of seiz ures, i n cl u di n g e mer ge n ce of ne w seiz ure 
t y pes or c ha n g e i n t he patter n or se verit y of e xisti n g seiz ure t y pes. Ne w sei z ure t y pes 
s h o ul d be disc usse d wit h t he me dical m o nit or a n d t he E S CI , a n d a Ne w Seiz ure F or m 
s h o ul d be s u b mitte d t o t he E S CI F or re vie w a n d a p pr o val (refer t o  Secti o n 9. 1. 1 2. 1 ).  
S ur gical/ in vesti gati o nal pr oce d ures are n ot A Es. T he me dical r eas o n f or t he pr oce d ure 
is t he A E. Electi ve h os pitalisati o ns f or pre-st u d y e xisti n g c o n diti o ns or electi ve 
pr oce d ures are n ot A Es. T he e xce pti o n ma y be if t he partici pa nt  has a n A E d uri n g 
h os pit alisati o n t hat pr ol o n gs t heir sc he d ule d h os pital sta y , i n w hic h case it w o ul d be 
c o nsi dere d a S A E (refer t o Secti o n  1 2. 2 ). 
T he n u m ber of i n patie nt h os pitalisati o ns t hat are, i n t he i n vesti gat or’s o pi ni o n, d ue t o 
e pile ps y will be rec or de d i n t he partici pa nt’s e C R F a n d t hr o u g h t he S A E re p orti n g 
pr ocess.  
If re p orti n g a fatal e ve nt, t he S A E ter m s h o ul d be t he u n derl yi n g ca us e of th e deat h 
(e. g., disease or me dic al c o n diti o n lea di n g t o deat h). 
1 2. 2.  
Seri o us A d verse E ve nts  
D uri n g cli nical i n vesti gati o ns, A Es ma y occ ur w hi c h, if s us pecte d t o be st u d y 
i nter ve nti o n-relat e d, mi g ht be si g nifica nt e n o u g h t o lea d t o i m p orta nt c ha n g es i n t he 
wa y t he st u d y i nter ve nti o n is de vel o pe d (e. g., c ha n ge i n d ose, p o p ulati o n, m o nit ori n g 
nee d, c o nse nt f or ms). T his is partic ularl y tr ue f or e ve nts t hat t hreate n life or f u ncti o n. 
S uc h S A Es will be re p ort e d pr o m ptl y t o re g ulat or y a ut h orities, a p plica ble I R Bs /I E Cs, 
a n d i n vesti gat ors (e x p e dite d re p orti n g) b y t he s p o ns or. 
A n A E m ust o nl y be classe d as seri o us, i.e., a S A E, w he n t he e v e nt falls i nt o o ne of 
t he f oll o wi n g criteria: 
•  Res ults i n d eat h. 
•  Is life-t hreate ni n g *. 
•  Re q uires i n patie nt h os pitalisati o n or pr ol o n gati o n of e xisti n g 
h os pitalisati o n . 
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y.  

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•  Is a c o n ge nital a n o mal y/ birt h defect. 
•  Is me di call y si g nifica nt * *. 
* T he ter m “life -t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h 
t he partici pa nt  was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n 
e ve nt w hic h, h y p ot heticall y, mi g ht ha ve ca use d deat h if it were m or e se vere.  
* * Me dical a n d sci e ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E 
re p orti n g is a p pr o priat e i n ot her sit uati o ns. I m p ort a nt me dical e ve nts ma y n ot be 
i m me diatel y life-t hreat e ni n g or res ult i n deat h or h os pitalisati o n b ut ma y je o par dize 
t he partici p a nt or ma y re q uire i nter ve nti o n t o pre v e nt o ne of t he ot her o utc o mes liste d 
i n t he defi niti o n a b o ve. T hese s h o ul d als o us uall y be c o nsi dere d seri o us. E x a m ples of 
s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me f or aller gic 
br o nc h os pas m,  bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisati o n , 
de vel o p me nt of dr u g d e p e n de nc y , or dr u g a b us e.  
T he s p o ns or  c o nsi ders all c o n v ulsi ve a n d n o n -c o n v ulsi ve S E  e ve nts t o be 
me dic all y si g nific a nt e ve nts t h at s h o ul d be re p orte d t o t he s p o nsor as me dic all y 
si g nific a nt S A Es. St at us e pile ptic us is defi ne d as a n y seiz ure l asti n g 3 0  mi n utes 
or l o n ger . 
1 2. 3.  
Re p orti n g Pr oce d ures f or Seri o us A d verse E ve nts  
All S A Es occ urri n g d uri n g t he st u d y m ust be re p orte d t o t he s p o ns or wit h a n y ot her 
s u p p orti n g i nf ormati o n a n d rec or de d i n t he A E secti o n of t he e C R F. A n y o n g oi n g 
S A Es s h o ul d be f oll o we d u p u ntil res ol uti o n w here ver p ossi ble. F or all deat hs, t he 
w or ki n g dia g n osis or ca use of deat h as state d o n a deat h certificate, a vaila bl e a ut o ps y 
re p orts a n d rele va nt me di cal re p orts s h o ul d be se nt t o t he s p o ns or pr o m ptl y.  
All S A Es m ust be rec or de d i n t he e C R F i m me di atel y a n d wit hi n 2 4  h o urs of 
disc o ver y or n otific ati o n of t he e ve nt . T he s p o ns or  will be a ut o maticall y n otifie d 
t hat a n S A E has bee n rec or de d. A n y a d diti o nal i nf or mati o n re q uire d f or a case 
(f oll o w-u p or c orrecti o ns t o t he ori gi nal case) will be re q uest e d b y t he s p o ns or 
t hr o u g h e C R F q ueries. T he i n vesti gat or will s u b mit a n y u p date d S A E data t o t he 
s p o ns or wit hi n 2 4 h o urs of it bei n g a vaila ble.  
T he i n vesti gat or is n ot o bli ge d t o acti vel y m o nit or f or a n y ne w S A Es t hat occ urre d 
after t he s afet y f oll o w-u p visit . H o we ver, if t he i n vesti gat or lear ns of a n y S A E, 
i ncl u di n g a deat h, at a n y ti me after a p artici pa nt h as bee n disc h ar ge d fr o m t he st u d y, 
a n d he/s he c o nsi ders t he e ve nt t o be reas o na bl y r elate d t o t he st u d y i nter ve nti o n or 
st u d y partici pati o n, t he i n vesti gat or s h o ul d pr o m ptl y n otif y t he s p o ns or. 
After t he p artici pa nt c o m pletes t he safe t y f oll o w-u p visit, a n y ot her pr o ble m 
disc o vere d t hat is de e me d t o be a n u ne x pecte d safet y iss ue a n d li kel y t o ha ve a n 
i m pact o n ot her st u d y partici pa nt s m ust be treate d as a n S A E a n d re p orte d t o t he 
s p o ns or. S uc h p ostst u d y S A Es d o n ot nee d t o be rec or de d o n t h e partici p a nt ’s e C R F if 
e diti n g ri g hts t o t he e C R F ha ve b ee n re m o ve d d ue t o fi nal st u d y data l oc k. T he 
s p o ns or ma y re q uest safet y f oll o w -u p i nf or mati o n after t he s afet y f oll o w-u p  visit i n 
or der t o i n vesti gate a p ot e ntial safet y iss ue.  
C o ntact details f or S A E re p orti n g  are pr o vi de d i n t he trial ce ntr e file. 

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1 2. 4.  
C a us alit y Assess me nt  
Ca usalit y assess me nt is re q uire d f or all A Es a n d S A Es. Ca usalit y assess me nt m ust 
o nl y be assi g ne d b y t he i n vesti gat or. All cases j u d ge d as ha vi n g a reas o n a ble 
s us pecte d ca usal rel ati o ns hi p t o t he st u d y i nter ve nti o n m ust be re p orte d as s uc h. T he 
e x pressi o n “re as o n a ble c a us al rel ati o ns hi p ”  is mea nt t o c o n ve y i n ge neral t hat t here 
are facts ( e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p.  
T he f oll o wi n g q uesti o n w hic h m ust be a ns were d b y t he i n vesti gat or f or all A Es is 
use d t o ca pt ure t h e reas o na ble ca us al relati o ns hi p of a n e ve nt t o t he st u d y 
i nter ve nti o n: 
“I n y o ur o pi ni o n is t here a pl a usi ble rel ati o ns hi p t o t he st u dy i nterve nti o n? ” T he 
a ns wer is eit her “ yes ” or “ n o”.  
E ve nts t hat start bef ore t he first d ose of st u d y i nter ve nti o n ( pre-treat me nt) s h o ul d be 
c o nsi dere d as n ot ca usall y relate d. W h ere a pre -tr eat me nt e ve nt w orse ns i n se verit y 
f oll o wi n g t he first d ose of st u d y i nter ve nti o n, a ne w e ve nt rec or d s h o ul d be e ntere d 
i nt o t he e C R F. 
C o nsi deri n g t he e x pla nati o n gi ve n a b o ve, i n vesti gat ors are str o n gl y e nc o ura ge d t o 
e x press t heir o pi ni o n o n w hat t he ca us e of a n A E mi g ht be. F or i n di vi d ual 
partici pa nt s, t he i n vesti gat or is us uall y i n t he best p ositi o n t o assess t he u n derl yi n g 
s us pecte d ca use of a n A E. F or all A Es a n d es peciall y S A Es, it is i m p orta nt t hat t he 
i n vesti gat or assess n ot o nl y t he p ossi ble r ole of t he st u d y i nter ve nti o n b ut als o ot her 
p ote ntial c o ntri b uti n g fact ors. Fact ors f or c o nsi d erati o n of t he u n derl yi n g ca use ma y 
i ncl u de: 
•  Me dical a n d disease hist or y.  
•  Lac k of effic ac y/ w ors e ni n g of treate d c o n diti o n.  
•  C o nc o mita nt or pre vi o us treat me nt.  
•  St u d y i nter ve nti o n  disc o nti n uati o n.  
•  Pr ot oc ol -relate d pr oce d ure. 
1 2. 5.  
Re p orti n g Pr oce d ures f or All A d verse E ve nts  
All A Es (i ncl u di n g S A Es) occ urri n g d uri n g t he st u d y will be re p orte d o n t h e r u n ni n g 
l o gs i n t he A E secti o n of t he e C R F. T his i ncl u des all e ve nts fr o m t he ti me f oll o wi n g 
t he i nitiati o n of st u d y i nter ve nti o n ( Visit 3 ) u p t o a n d i ncl u di n g t he safet y f oll o w-u p 
visit, w het her or n ot attri b ute d t o st u d y i nter ve nti o n a n d o bser ve d b y t h e i n vesti gat or 
or partici pa nt ’s care gi ver. 
T he f oll o wi n g i nf or mati o n will nee d t o be pr o vi de d f or all A Es:  
A.  A d verse E ve nt ( Di a g n osis or S y n dr o me if K n o w n, or Si g ns a n d S y m pt o ms)  
W here t h e i n vesti gat or ca n n ot deter mi ne a di a g n o sis, si g ns or s y m pt o ms s h o ul d be 
rec or de d i n t he A E secti o n of t he e C R F. O nce a di a g n osis has bee n d eter mi ne d t he 
A E secti o n of e C R F m ust be u p date d t o reflect t he dia g n osis i n re place me nt of t he 
ori gi nal s y m pt o ms. I n cir c u msta nces w h ere o nl y a pr o visi o nal  dia g n osis is p ossi ble 
( w or ki n g dia g n osis), t he e C R F m ust be u p date d t o reflect t he pr o visi o nal dia g n osis i n 
re place me nt of t he ori gi n al s y m pt o ms. I n s o me cir c u msta nces it ma y be rel e va nt f or 
t he i n vesti gat or t o i ncl u de t he s y m pt o ms al o n gsi de t he dia g n osis i n t he ver bati m e ve nt 

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descri pti o n. H o we v er, t h e dia g n osis (f ull or pr o visi o nal) s h o ul d be clearl y state d, 
(e. g., hea d ac h e a n d fe ver d ue t o p ne u m o nia) . 
B.  A d verse E ve nt St art D ate a n d St o p D ate  
T he start a n d st o p dates of t he e ve nt m ust be pr o vi de d. All A Es r e q uir e t hes e fiel ds t o 
be c o m plete d i n f ull. Partial dates or missi n g dates are n ot n or mall y acce pta ble a n d 
si g nifica nt eff ort m ust be u n derta ke n t o o btai n a n y u n k n o w n i nf or mati o n. If a precis e 
date is n ot k n o w n a n esti mate d date s h o ul d be pr o vi de d i nstea d . W he n a c o m plete 
date ca n n ot b e gi ve n, rec or d as m uc h i nf or mati o n as p ossi ble (i.e., m o nt h a n d year or, 
i n e xce pti o nal circ u msta nces, j ust year). W he n t h e act ual start date bec o mes k n o w n 
t he e C R F m ust be u p date d t o re place t h e pre vi o usl y rec or de d date. 
C.  O u tc o me 
T he o utc o me of t he e ve nt m ust be rec or de d acc uratel y a n d classifie d i nt o o ne f or t he 
f oll o wi n g cate g ories: 
•  Rec o vere d/ Res ol ve d.  
•  Rec o vere d/ Res ol ve d wit h se q uelae.  
•  Rec o veri n g/ Res ol vi n g.  
•  N ot rec o vere d/ N ot r es ol ve d.  
•  Fatal.  
D.  Se verit y  
W he n descri bi n g t he se v erit y of a n A E t he t er ms mil d, m o derate, or se vere s h o ul d be 
use d. Cli nical j u d g me nt s h o ul d be use d w he n d eter mi ni n g w hic h se verit y a p plies t o 
a n y A E.  
If t he se verit y of a n A E fl uct uates da y-t o-d a y, e. g., a hea d ac he or c o nsti pati o n, t he 
c ha n ge i n se v erit y s h o ul d n ot be rec or de d eac h ti m e; i nstea d, o nl y t he w orst o bser ve d 
se verit y s h o ul d be rec or de d wit h A E start a n d st o p dates relati n g t o t he o verall e ve nt 
d urati o n, re gar dless of se verit y.  
A  se vere A E is n ot t he sa me as a S A E. F or e x a m ple, a partici p a nt  ma y  ha ve se vere 
v o miti n g, b ut t he e ve nt d oes n ot res ult i n a n y of t h e S A E criteria a b o ve. T h eref ore, it 
s h o ul d n ot be classe d as seri o us. 
T he se verit y of a n A E will be rec or de d as o ne of t he f oll o wi n g:  
•  Mil d: easil y t olerate d, d oes n ot i nterfere wit h n or mal dail y acti vities, d oes 
n ot re q uire i nter ve nti o n  
•  M o der ate: ca uses s o me i nterfere nce wit h dail y acti vities; mi ni mal, l ocal, 
or n o ni n vasi ve i nter ve nti o n i n dicate d  
•  Se vere: d ail y acti vities li mite d or c o m pletel y halte d; i nter ve nti o n 
i n dicate d. 
E.  C a us alit y  
See Secti o n  1 2. 4  a b o ve.  
F.  Acti o n T a ke n wit h St u d y  Me dic ati o n  

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T his q uesti o n refers t o t h e acti o n ta ke n wit h t he st u d y i nterve nti o n  d ue t o a n A E. T he 
acti o n wit h t he st u d y i nter ve nti o n m ust be classe d as:  
•  D ose I ncreas e d.  
•  D ose N ot C ha n ge d.  
•  D ose re d u ce d.  
•  Dr u g i nterr u pte d.  
•  Dr u g Wit h dra w n.  
•  N ot A p plica ble.  
1 2. 6.  
F oll o w -u p Pr oce d ures f or A d verse E ve nts  
T he i n vesti gat or ma y be as ke d t o pr o vi de f oll o w -u p i nf or mati o n t o t he s p o ns or f or 
a n y re p ort e d A Es or d uri n g t he i n vesti gati o n of p ote ntial safet y iss ues. S uc h re q uests 
f or a d diti o nal safet y i nf or mati o n ma y occ ur after t he safet y f oll o w-u p visit  (i.e., after 
t he st u d y). 
A d verse e ve nts c o nsi dere d relate d t o t he st u d y i nter ve nti o n b y t he i n vesti gat or or t he 
s p o ns or s h o ul d be f oll o we d u p u ntil res ol uti o n or t he e ve nt is c o nsi dere d sta ble.  
It will be left t o t he i n vesti gat or’s cli nical j u d g me nt w het her a n A E is of s ufficie nt 
se verit y t o re q uir e t he partici pa nt ’s re m o val fr o m treat me nt. A partici pa nt  ma y als o 
v ol u ntaril y wit h dra w fr o m treat me nt d ue t o w hat he or s he percei v es as a n i nt olera ble 
A E. F urt her details of wit h dra wal are prese nte d i n Secti o n  1 0 . If eit her of t hese 
occ urs, t he p artici pa nt  s h o ul d pr ocee d t o a n E T visit a n d be gi ve n a p pr o pri ate care 
u n der me dical s u p er visi o n u ntil s y m pt o ms cease or t he c o n diti o n bec o mes sta ble. If a 
safet y c o n cer n is i de ntifi e d f oll o wi n g wit h dra wal of a partici p a nt , t he s p o ns or ma y 
c o ntact t he i n vesti gat or f or a d diti o nal f oll o w -u p i nf or m ati o n. 
1 2. 7.  
P ote nti al C ases of Dr u g -I n d uce d Li ver I nj ur y 
All i n vesti gati o nal sites are re q uir e d t o s u b mit t o t he s p o ns or t he la b orat or y res ults f or 
a n y partici pa nt  after ra n d o misati o n t hat meets t he criteria f or t he selecte d la b orat or y 
para meters as f oll o ws:  
•  A L T or A S T >  3  ×  U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, 
ri g ht u p per q ua dra nt pai n or te n der ness, fe v er, ras h, a n d/ or e osi n o p hilia 
( > 5 %).  
•  A L T or A S T >  8  ×  U L N.  
•  A L T or A S T >  5  ×  U L N f or m ore t ha n 2  wee ks.  
•  A L T or  A S T >  3  ×  U L N a n d  ( T B L > 2  ×  U L N  or I N R >  1. 5).  
T hese re p orts m ust be se nt t o t he s p o ns or via e mail f or S A E re p orti n g wit hi n 2 4  h o urs 
of bec o mi n g a w are of t he res ults. I n a d diti o n, please se n d a c o p y of t he partici pa nt ’s 
baseli ne la b orat or y res ults wit h all re p orts t o t he s p o ns or. S p o ns or c o ntact details are  
pr o vi de d i n t he trial ce ntr e file (A P P E N DI X  2 ). 
A b n or mal val ues i n A S T a n d/ or A L T c o n c urre nt wit h a b n or mal ele vati o ns i n T B L 
t hat meet t he criteri a o utli ne d a b o ve are c o nsi d ere d p ote ntial cases of dr u g-i n d uce d 
li ver i nj ur y a n d will be c o nsi dere d as pr ot o c ol-defi ne d criteria f or wit h dra wal a n d 

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i m p orta nt me dical e ve nts. T he i n vestigat or will arra n ge f or t h e partici pa nt  t o ret ur n t o 
t he i n vesti gati o nal site as s o o n as p ossi ble ( wit hi n 2 4  h o urs of n otice of a b n or mal 
res ults) f or re peat assess me nt of A L T, A S T, T B L, I N R, % e osi n o p hils, al kali ne 
p h os p hatase , a n d G G T le vels, detaile d hist or y, a n d p h ysical e xa mi nati o n. Partici pa nt s 
s h o ul d be f oll o we d i n t his wa y u ntil all a b n or malities ha ve n or malise d (i n t he 
i n vesti gat or’s o pi ni o n) or ret ur ne d t o t he b aseli ne state. H o we ver, if t he a b o ve 
tra nsa mi nase el e vati o n criteria are c o nfir me d b y t he first set of f oll o w-u p la b orat or y 
tests, t he partici pa nt  m ust per ma ne ntl y disc o nti n ue t he st u d y i nter ve nti o n. 
Ele vati o ns i n A L T or  A S T >  3  ×  U L N o r  T B L >  2  ×  U L N al o n e are n ot c o nsi dere d 
p ote ntial cases of dr u g -i n d uce d li ver i nj ur y, b ut will be f oll o we d as detaile d a b o ve, 
wit hi n 7 2  h o urs’ n otice of a b n or mal r es ults. If t he partici pa nt  ca n n ot ret ur n t o t he 
i n vesti gati o nal site, re peat assess me nts ma y be d o ne at a l ocal la b orat or y a n d t he 
res ults se nt t o t he s p o ns or. 
1 2. 8.  
N otific ati o n of S afet y I nf or m ati o n t o I n vesti g at ors, 
Re g ul at or y A ut h orities, a n d I R Bs /I E Cs. 
I n acc or da n ce wit h t he R e g ulati o n ( E U) 5 3 6/ 2 0 1 4 , rele va nt parts of t he F D A C o de of 
Fe deral Re g ulati o ns  a n d a n y nati o nal re g ulati o ns, t he s p o ns or will i nf or m 
i n vesti gat ors, re g ulat or y a ut h orities, a n d rele va nt I R Bs/I E Cs of all rele va nt safet y 
i nf or mati o n. T his will i ncl u de t he re p orti n g of rel e va nt S A Es a n d all S us pecte d 
U ne x pect e d Seri o us A d v ers e Reacti o ns ( S U S A Rs ). I n t he E U, su b missi o n of 
e x pe dite d safet y re p orts t o E u dra vi gila nce will be perf or me d vi a E 2 B . 
T his i nf or mati o n will be pr o vi de d t hr o u g h 2  s o urces: 
1.  In v esti gat or’s Br oc h ure : a c o m pilati o n of t he cli nical a n d n o n-cli nical safet y 
data a v aila ble o n t h e st u d y i nter ve nti o n t hat is rele va nt t o t he trial. T he 
In v esti gat or’s B r oc h ure is u p date d a n n uall y or w h e n i m p orta nt ne w safet y 
i nf or mati o n bec o mes a v aila ble. 
2.  C o u ncil f or I nter nati o nal Or ga nizati o ns of M e dical Scie nces ( CI O M S ) re p orts: 
t hese re p orts are iss ue d e ver y ti me a S U S A R is re p orte d t o t he s p o ns or. T h e y 
pr o vi de i nf or mati o n o n i n di vi d ual case re p orts a n d are se nt t o all t he 
re g ulat or y a ut h orities, t h e rele va nt ce ntr al I R B/I E C t hat ha ve a p pr o ve d t he 
trial a n d i n vesti gat ors. As re q uire d, t he i n vesti gat or s h o ul d n otif y t heir 
re gi o nal I R Bs/I E Cs of S A Es or S U S A Rs occ urri n g at t heir site a n d ot her A E 
re p orts, i.e., CI O M S re p orts a n d a n y a d diti o nal safet y d oc u me ntati o n recei v e d 
fr o m t he s p o ns or, i n acc or da nce wit h l ocal pr oce d ures.  
I n t he Unite d S tates, i n vesti gat ors are n or mall y re q uire d t o re p ort pr o m ptl y t o t heir 
I R Bs/I E Cs all u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o partici pa nt s, or ot hers, 
i ncl u di n g A Es t hat s h o ul d be c o nsi dere d u na ntici pate d pr o ble ms. Base d o n c urre nt 
F D A g ui da n ce t he f oll o wi n g clarificati o n is pr o vi d e d i n deter mi ni n g w hat c o nstit utes 
a n u na ntici pate d pr o bl e m:  
I n g e neral, a n A E o bs er ve d d uri n g t he c o n d uct of a st u d y s h o ul d be c o nsi dere d a n 
u na ntici pate d pr o ble m i n v ol vi n g ris k t o partici pa nt s a n d re p orte d t o t he I R B/I E C, o nly  
if it were u ne x p ecte d, s eri o us, a n d w o ul d ha ve i m plicati o ns f or t he c o n d uct of t he 
st u d y (e. g., re q uiri n g a si g nifica nt, a n d us uall y safet y-relat e d, c ha n g e i n t he pr ot oc ol 
s uc h as re visi n g i ncl usi o n/e xcl usi o n criteria or i ncl u di n g a ne w m o nit ori n g 
re q uire me nt, i nf or me d c o nse nt, or I B). A n i n di vi d ual A E occ urre n ce or di n arily  d oes 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 0  of 1 2 1  
n ot meet t hese criteria beca use, as a n is olate d e v e nt, its i m plicati o ns f or t he st u d y 
ca n n ot be u n derst o o d.  
T he F D A g ui da nce states t hat, acc or di n gl y, t o satisf y t he i n vesti gat or’s o bli gati o n t o 
n otif y t he I R B /I E C of u na ntici pate d pr o ble ms, a n y i n vesti gat ors partici pati n g i n a 
m ulti ce ntre st u d y ma y rel y o n t he s p o ns or’s assess me nt a n d pr o vi de t o t he I R B /I E C a 
re p ort of t he u n a ntici pate d pr o ble m pre pare d b y t h e s p o ns or. 
T he s p o ns or will i nf or m i n vesti gat ors, re g ulat or y a ut h orities a n d rele va nt I R Bs /I E Cs 
of a n y safet y iss ues or case re p orts t hat are c o nsi d ere d t o be u na ntici pate d a n d pr o vi de 
s uc h re p orts as m e nti o ne d a b o ve. It s h o ul d be n ot e d t hat a si n gle S U SA R re p ort 
n otifie d t o i n vesti gat ors i n t he st u d y d oes n ot necessaril y c o nstit ute a n u na ntici pate d 
pr o ble m u nless i de ntifie d b y t he s p o ns or i n t he s u b missi o n c o ver letter. 
As a mi ni m u m, t he reci pie nt will be se nt all of t he a b o ve a n d rele va nt u p d ates 
bet wee n t he p eri o d fr o m et hical a p pr o v al a n d fi nal data base l oc k.  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 1  of 1 2 1  
1 3.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
F urt her details of t he pr o p ose d statistical a nal ysis will be d oc u me nte d i n t he Statistical 
A nal ysis Pla n ( S A P ), w hic h will be fi nalise d pri or t o a n y descri pti ve a n al ys is of data 
pertai ni n g t o St u d y  G W E P 1 7 0 0 5 . A n y de viati o ns fr o m t he S A P will be descri be d i n 
t he fi nal cli nical st u d y re p ort. 
1 3. 1.  
S a m ple Size, P o wer a n d Si g nific a nce Le vels  
U p t o  2 7 partici pa nts  will be assi g ne d t o recei ve t h e st u d y i nter ve nti o n  i n or der t o 
ac hie ve 1 8  e val ua ble p artici pa nts , w hic h the  P ae di atric I n vesti gati o n al Pla n f or 
G W P 4 2 0 0 3 -P c o nsi ders s ufficie nt t o c haracterize P K i n c hil dre n <  2 years of a ge.  
E nr ol me nt will be stratifie d t o e ns ure t hat at least 5  partici pa nts eac h wit h L G S a n d 
D S ( 1  t o <  2 years of a ge)  a n d 8 partici p a nts wit h T S C ( 4 partici pa nts < 1  y ear of a ge 
a n d 4 partici pa nts a g e d 1  t o <  2 years) are i ncl u de d i n t his st u d y . T he S A P will 
de scri be t he d efi niti o n of a n e val ua bl e partici pa nt i n greater d etail. 
T here will be n o f or mal t esti n g of statistical h y p ot heses i n t his  st u d y. 
N ote : Partici pa nts are c o nsi dere d “e nr olle d” w he n t heir pare nt(s)/ L A R has/ ha ve 
si g ne d t he I C F (refer t o Secti o n 9. 1. 1 ). 
1 3. 2.  
I nterme di ate  A n al ysis  
E x pl orat or y i nter me diate a nal yses ma y be c o n d uct e d d uri n g t he st u d y t o e xa mi ne, f or 
e xa m ple, baseli ne d ata distri b uti o n, part ici pa nt dis p ositi o n, treat me nt e x p os ure, or a 
s u bset of effic ac y a n d safet y o utc o mes, u p o n s pecific re q u est. Res ults fr o m t hese 
a nal yses ma y als o s u p p ort p u blicati o n o bjecti ves ( descri be d else w here) or i nter nal 
e val uati o n of tre n ds. T h e j ustificati o n a n d t he details of a n y i nter me diate a n al ysis will 
be d oc u me nte d i n a s e parate  S A P  c o veri n g i nter m e diate re p orti n g . 
1 3. 3.  
A n al ysis Sets  
S creeni n g  A n al ysis Set  
All partici pa nt s w h o are e nr olle d will be i ncl u de d.  T his a nal ysis set will be use d t o 
descri be a d mi nistrati ve as pects of st u d y e nr o lme nt, i ncl u di n g reas o ns f or s cree ni n g 
fail ure. 
S afet y A n al ysis Set  
All e nr olle d partici pa nt s w h o recei ve at least 1 d ose of G W P 4 2 0 0 3 -P  will be i ncl u de d.  
T his a nal ysis set will  be use d t o esti mate rete nti o n a n d all safet y -relate d e n d p oi nts. 
Effic ac y  A n al ysis Set  
All e nr olle d partici pa nt s w h o recei ve at least 1 d ose of G W P 4 2 0 0 3 -P  a n d at least 
1  p ost -baseli ne efficac y meas ure me nt (s eiz ure diar y or I T Q O L -S F 4 7) . T his a nal ysis 
set will be use d t o esti mate all efficac y-relate d e n d p oi nts. 
•  If warra nte d, a Per -Pr ot oc ol A n al ysis Set  ma y be a d diti o nall y defi ne d, i n 
w hic h partici pa nts wit h i m p orta nt pr ot oc ol de viati o ns t hat c o m pr o mise 
effic ac y ass ess me nts are e xcl u de d.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 2  of 1 2 1  
P K A n a l ysis Set 
All e nr olle d partici pa nt s w h o recei ve at least 1 d ose of G W P 4 2 0 0 3 -P , ha v e at least 
1  p ost d ose  P K meas ure m e nt o n Visit 9 or t he E O T/ E T visit, a n d ha ve n ot e x perie nce d 
a n y i nterc urre nt e v e nts  t hat c o ul d i m pact e x p os ure. Interc urre nt e v e nts i ncl u de a n A E 
of v o miti n g t hat occ urs wit hi n 2  ti mes t he me di a n ti me t o ma xi m u m plas ma 
c o nce ntr ati o n ( T ma x ). T his a nal ysis set will be use d f or all P K-rel ate d e n d p oi nts.  
1 3. 4.  
Pr ot oc ol De vi ati o ns  
All pr ot oc ol de viati o ns will be liste d.  
1 3. 5.  
Ge ner al C o nsi der ati o ns  
U nless state d ot her wise, c o nti n u o us varia bles will be s u m marise d s h o wi n g t he 
n u m ber of n o n -missi n g val ues ( n), mea n, sta n dar d de viati o n  or sta n dar d err or , 
me dia n, i nter q uartile ra n ge, mi ni m u m a n d ma xi m u m . Cate g orical vari a bles will be 
s u m marise d s h o wi n g t he n u m ber a n d perce nt a ge of partici pa nt s i n eac h cate g or y. 
S u m maries  will be prese nte d b y i n dicati o n a n d o v erall , u nless ot her wise s p ecifie d.  
F or cli nic visit -base d e n d p oi nts ( u nless ot her wise s pecifie d), baseli ne is defi ne d as t he 
last rec or d or meas ur e c ollecte d pri or t o t he first d ose of G W P 4 2 0 0 3 -P . 
1 3. 6.  
Acc o u nt a bilit y a n d B ac k gr o u n d C h ar acteristics  
1 3. 6. 1.  
E nr ol m e nt a n d Dis p ositi o n  
All e nr olle d partici pa nt s (scree ne d, pre mat urel y ter mi nate d st u d y i nter ve nti o n, etc.) 
will be acc o u nte d f or i n t he e nr ol m e nt a n d dis p ositi o n s u m mar y ta bles.  
1 3. 6. 2.  
B aseli ne a n d De m o gr a p hic C h ar acteristics  
A ge, se x, race (as per l ocal data pr otecti o n la ws i n eac h s pecific c o u ntr y) a n d a n y 
ot her de m o gra p hi c or bas eli ne c haracteristics will be s u m marise d usi n g a p pr o priate 
s u m mar y statistics. 
1 3. 6. 3.  
Me dic al Hist or y  
Pre vi o us a n d c urre nt me dical c o n diti o ns (i ncl u di n g details of T S C , L G S, or D S a n d 
ot her c o m or bi d dis or ders) will be s u m marise d b y S yste m Or ga n Class  ( S O C). 
1 3. 6. 4.  
C o nc o mit a nt Me dic ati o n  
C o nc o mita nt me dicati o ns (i ncl u di n g A S Ms  a n d a ntiseiz ure t hera pies) ta ke n pri or t o 
a n d d uri n g t he st u d y will be s u m marise d se paratel y; details will be s pecifie d i n t he 
S A P.  
1 3. 6. 5.  
Tre at me nt C o m pli a nce a n d E xte nt of Tre at me nt E x p os ure  
E x p os ure t o t he st u d y i nter ve nti o n o verall a n d at eac h d ose le vel, e x presse d i n d osi n g 
da ys, i n a d diti o n t o treat me nt c o m plia nce will be s u m marise d. 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 3  of 1 2 1  
1 3. 7.  
E n d p oi nts a n d St atistic al Met h o ds  
1 3. 7. 1.  
Pri m ar y S afet y a n d P h ar m ac o ki netic E n d p oi nts  
A nal ysis a n d re p orti n g of t he pri mar y safet y a n d P K e n d p oi nt para met ers will i ncl u de 
descri pti ve statistical s u m maries of eac h ele m e nt at baseli ne a n d f oll o w -u p st u d y 
visits w here c ollecti o n w as perf or me d.   
1 3. 7. 1. 1.  A d verse E ve nts  
A d verse eve nt s will be c ollecte d as s pecifie d i n  Secti o n 9. 1. 1 4 1 4 , are d efi n e d i n 
Secti o n  1 2. 1 , a n d will be c o de d acc or di n g t o t he M e dical Dicti o nar y f or Re g ulat or y 
Acti vities dicti o nar y.  
Descri pti ve prese ntati o ns of A Es will be gi ve n b y preferre d t er m a n d S O C f or t he 
safet y a n al ysis set. T he n u m ber of partici p a nt s re p orti n g at least 1 A E will be 
pr o vi de d . A d vers e e v ents  will be s u m marise d i n ter ms of t he n u m ber of p artici pa nt s 
wit h at least 1 e ve nt ( N) a n d t he perce nta ge of partici pa nt s wit h at least 1 e ve nt ( %). 
T he f oll o wi n g s u m maries will be pr o d uce d as a mi ni m u m:  
•  All -ca usalit y A Es.  
•  Treat me nt -relate d A Es. 
•  All -ca usalit y A Es b y ma xi mal se verit y. 
•  All -ca usalit y seri o us A Es.  
•  Treat me nt -relate d s eri o us A Es. 
•  T he A Es re p orte d as le a di n g t o per ma ne nt cess ati o n of st u d y i nter ve nti o n. 
•  Fatal A Es.  
1 3. 7. 1. 2.  Cli nic al L a b or at or y D at a  
Cli nical la b orat or y data will be s u m marise d at scree ni n g / baseli ne a n d at eac h ti me 
p oi nt d uri n g t he treat me nt peri o d usi n g a p pr o priat e s u m mar y statistics. Cate g orical 
s hift ta bles will be prese nte d, s h o wi n g t he n u m bers of partici pa nt s wit h val ues o utsi de 
t he n or mal ra n g e. C ha n g e fr o m baseli ne will als o be s u m marise d b y visit.  
1 3. 7. 1. 3.  Vit al Si g ns, 1 2 -Le a d Electr o c ar di o gr a m, P h ysic al E x a mi n ati o n a n d 
Ot her S afet y D at a  
Vital si g ns, E C G, p h ysical e xa mi nati o n , a n d ne ur o de vel o p me ntal assess m e nt  data will 
be s u m marise d, at scree ni n g/ baseli ne a n d at eac h ti me p oi nt d uri n g t he treat me nt 
peri o d usi n g a p pr o priat e s u m mar y statistics. C ha n ges i n t he vital si g ns fr o m baseli ne 
will als o be s u m marise d. 
1 3. 7. 1. 4.  P h ar m ac o ki netics  
Plas ma c o nce ntr ati o ns f or C B D a n d its maj or meta b olites (7 -h y dr o x y -ca n n a bi di ol 
[7 -O H -C B D ] a n d 7 -car b o x y -ca n na bi di ol [ 7 -C O O H -C B D ]) will be s u m marise d b y 
n o mi nal ti me, partici pa nt, a n d d ose le vel . P har m ac o ki netic d ata c ollect e d i n t his st u d y 
will be c o m bi ne d  wit h data fr o m ot her st u dies t o esti mate P K para meters vi a a 
p o p ulati o n P K a nal ysis ; res ults of t h is a nal ysis  will be re p orte d s e paratel y.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 4  of 1 2 1  
1 3. 7. 2.  
Pri m ar y a n d Sec o n d ar y Effic ac y E n d p oi nt s 
A nal ysis a n d re p orti n g of t he pri mar y a n d sec o n dar y efficac y e n d p oi nts will i ncl u de 
descri pti ve statistical s u m maries of seiz ure fre q u e nc y, perce nt c ha n ge fr o m  baseli ne, 
a n d perce nt c ha n g e fr o m baseli ne cat e g ories (i.e., i ncreas e or re d ucti o n, as s pecifie d 
i n Secti o n 2 ). Beca use G W P 4 2 0 0 3-P d ose le vels are n ot fi xe d d uri n g  t he st u d y, 
s u m maries as well as 9 5 % c o nfi de n ce i nter vals f or perce nt c ha n g e fr o m b aseli ne will 
be re p ort e d b y i n dicati o n a n d o verall. A ncillar y ta bles s u m marisi n g efficac y 
e n d p oi nts b y seiz ure t y pe, base d o n i n dicati o n, will als o be pr o vi de d.  
1 3. 7. 2. 1.  T ot al C o u nt a ble Seiz ures  
All m eas ure me nts of t otal c o u nta ble seiz ures  (a v era ge per 2 8 da ys) will be deter mi ne d 
as rec or de d b y care gi vers o n seiz ure diaries at Wee k 1 2, e ver y 4  wee ks t hereafter, a n d 
d uri n g t he 4 -wee k peri o d pri or t o E O T.  
Pri m ar y Effic ac y E n d p oi n t 
T he perce nta g e c ha n g e fr o m baseli ne i n i n dicati o n-s pecific c o u nta ble sei z ures * will 
be s u m marise d usi n g des cri pti ve statistics a n d i ncl u di n g t he l o wer a n d u p per 
q uartiles.  
* I n dic ati o n-s pecific seiz ures are defi n e d as f oll o ws:  
•  D S : C o n v ulsi ve seiz ures, defi ne d as t o nic-cl o nic, t o nic, cl o nic, or at o nic.  
•  L G S : Dr o p seiz ures, d efi ne d as a n attac k or s pell (at o nic, t o nic, or 
t o nic-cl o nic) i n v ol vi n g t he e ntire b o d y, tr u n k, or h ea d t hat le d or c o ul d 
ha ve le d t o a fall, i nj ur y, sl u m pi n g i n a c hair, or hitti n g t he partici pa nt’s 
hea d o n a s urface.  
•  T S C: F ocal m ot or seiz ures wit h o ut i m pair me nt of c o nsci o us ness or 
a ware ness; f ocal seiz ures wit h i m pair me nt of c o nsci o us ness or a ware n ess; 
f ocal seiz ures e v ol vi n g t o bilateral ge neralise d c o n v ulsi ve sei z ures a n d 
ge neralise d s eiz ures (t o nic-cl o nic, t o nic, cl o nic, or at o nic) t hat are 
c o u nta ble.  
A d diti o nal seiz ure cate g ories i ncl u de  ot her g e neralise d or f ocal s eiz ures ( m y ocl o nic, 
a bse nce, f ocal n o n -m ot or, I S/ E S, ot her) a n d S E  (c o n v ulsi ve a n d n o n-c o n v ulsi ve 
seiz ures lasti n g 3 0 mi n utes or l o n ger) t h at are rec o g nis a ble a n d c o u nt a ble . 
Sec o n d ar y Effic ac y E n d p oi nts  
•  T he n u m ber a n d p erce nta ge of partici p a nt s c o nsi dere d tr eat me nt 
res p o n ders (i.e., wit h a ≥ 5 0 % re d ucti o n i n t otal c o u nta ble seiz ures) will be 
s u m marise d usi n g descri pti ve statistics a n d i ncl u di n g t he l o wer a n d u p per 
q uartiles . 
•  T he cate g orical perce nta ge c ha n g e fr o m bas eli ne t o E O T i n t otal c o u nta ble 
seiz ures will be s u m marise d, wit h cate g ories defi n e d as f oll o ws : 
− >  2 5 % (i ncreas e)  
− ≥ 0 % t o ≤ 2 5 % (i ncrease)  
− >  – 2 5 % t o <  0 % (re d u cti o n)  
− >  – 5 0 % t o ≤ – 2 5 % (re d u cti o n)  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 5  of 1 2 1  
− >  – 7 5 % t o ≤ – 5 0 % (re d u cti o n)  
− ≤ – 7 5 % (re d u cti o n)  
•  Seiz ure free d o m, defi ne d as 1 0 0 % re d u cti o n fr o m baseli ne i n t otal 
c o u nta ble seiz ures, will be s u m marise d. 
1 3. 7. 3.  
Ot her Sec o n d ar y a n d E x pl or at or y E n d p oi nts  
T o assess treat me nt rete nti o n, t he perce nta ge of partici pa nts still ta ki n g G W P 4 2 0 0 3 -P  
at Wee k 1 2 a n d e v er y 4 wee ks t hereaft er will be esti mate d  usi n g t he Ka pl a n -Meier 
met h o d . Ti me at ris k will be gi n o n t he date of first d ose. Partici pa nts d isc o nti n ui n g 
st u d y treat me nt f or a n y reas o n will be classifie d as a fail ure as of t heir last k n o w n 
treat me nt date. Partici pa nts w h o wit h dra w fr o m t he st u d y or are l ost t o f oll o w-u p f or 
n o n -treat me nt-relate d reas o ns will be c o nsi dere d ce ns ore d as of t heir last k n o w n 
treat me nt date. 
E n d p oi nts relate d t o V E E G -rec or de d s eiz ures (liste d i n Secti o n 2 ) will be s u m marise d 
i n a ma n ner si milar t o t h ose relate d t o sei z ures rec or de d i n e P R O diaries . W here 
p ossi ble, m ultic ha n nel V E E G -rec or de d s eiz ures will be c orrelate d wit h t he seiz ure 
fre q ue n c y rec or de d b y i n vesti gat ors a n d care gi vers i n e P R O diaries . 
Res ults of t he I T Q O L-S F 4 7 a n d c ha n g e fr o m bas eli ne will be s u m marise d f or eac h 
st u d y ti me p oi nt. 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 6  of 1 2 1  
1 4.  
S A F E T Y M O NI T O RI N G C O M MI T T E E  
A n i n de pe n de nt S M C will be use d i n t his st u d y t o e val uate p artici pa nt  safet y. Details 
of t he c o m p ositi o n a n d sta n dar d o perati n g pr oce d ures of t he S M C will be detaile d i n a 
se parat e c harter. 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 7  of 1 2 1  
1 5.  
R E G U L A T O R Y A N D  E T HI C A L O B LI G A TI O N S  
1 5. 1.  
Decl ar ati o n of Helsi n ki  
T he i n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n f ull c o nf or mit y wit h t he 
c urre nt v ersi o n a n d s u bse q ue nt a me n d me nts of t he Declarati o n of Helsi n ki, t he 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u m a n Use ( I C H) Tri partite G ui deli ne f or G C P T o pic E 6( R 2), 
Re g ulati o n ( E U) 5 3 6/ 2 0 1 4, t he E U G C P Directi ve a n d t he cli nical trial r e g ulati o ns 
a d o pti n g E ur o pea n C o m missi o n Directi ves i nt o nati o nal le gislati o n.  
1 5. 2.  
I nf or me d C o nse nt 
•  T he i n vesti gat or or t heir re pres e ntati ve will e x plai n t he nat ure of t h e st u d y 
t o t he partici pa nt’s pare nt (s) or L A R  a n d a ns wer all q uesti o ns re gar di n g 
t he st u d y. 
Partici pa nt’s p are nt(s) or L A R  m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y. 
Partici pa nt’s p are nt(s) or L A R will be re q uire d t o si g n a state me nt of i nf or me d 
c o nse nt t hat meets t he re q uire me nts of 2 1 C F R 5 0, l ocal re g ulati o ns, I C H g ui deli nes, 
Re g ulati o n ( E U) 5 3 6/ 2 0 1 4, t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act of 
1 9 9 6  re q uire me nts ( w here a p plica ble), Re g ulati o n ( E U) 2 0 1 6/6 7 9  Ge n eral Data 
Pr otecti o n Re g ulati o n re q uire me nts ( w here a p plica ble), a n d t he I R B/ I E C or trial 
ce ntre ’ e xisti n g p o p ulati o n data base , a n d/ or t hr o u g h referrals , a n d/ or ot her materials 
(e. g., fl yers, p atie nt a d v o cac y gr o u p n e wsletters, s ocial me dia etc.) w hic h w o ul d be 
a p pr o ve d b y t he I R B/ I E C. 
1 5. 3.  
I nstit uti o n al Re vie w B o ar d 
A c o p y of t he pr ot o c ol, pr o p ose d I C F, mast er I C F, ot her partici pa nt  i nf or mati o n 
material, a n y p r o p os e d a d vertisi n g material a n d a n y f urt her d oc u me ntati o n re q ueste d 
m ust be s u b mitte d t o t he I R B /IE C  f or writte n a p pr o val. T he s p o ns or  m ust recei ve a 
c o p y of t he writte n a p pr o val of t he a p pr o priate versi o n of t he pr ot oc ol a n d I C F bef ore 
recr uit me nt of p ar tici pa nts i nt o t he st u d y a n d s hi p me nt of t he st u d y i nter ve nti o n. 
T he i n vesti gat or m ust s u b mit a n d, w here necessar y, o btai n a p pr o val fr o m t he 
I R B/IE C  f or all s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n g es t o t he i nf or me d 
c o nse nt d oc u me nt. T he i n vesti gat or m ust n otif y t he I R B /IE C  of de viati o ns fr o m t he 
pr ot oc ol, S A Es occ urri n g at t he site a n d ot her A E re p orts recei ve d fr o m t he s p o ns or, 
i n acc or da nce wit h l ocal pr oce d ures. 
T he i n vesti gat or will be res p o nsi ble f or o btai ni n g a n n ual/ o n g oi n g I R B /IE C  
a p pr o val/re n e wal t hr o u g h o ut t he d urati o n of t he st u d y. C o pies of t he i n vesti gat or’s 
re p orts a n d t he I R B/IE C  c o nti n ua nce of a p pr o val m ust be se nt t o t he s p o ns or. 
T he i n vesti gat or will be res p o nsi ble f or p r o vi di n g o versi g ht of t he c o n d uct of t he 
st u d y at t he site a n d a d here nce t o re q uire m e nts of 2 1 C F R, I C H g ui deli nes, 
Re g ulati o n ( E U) 5 3 6/ 2 0 1 4, t he I R B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical 
st u dies, a n d all ot her a p plica ble l ocal r e g ulati o ns. 
1 5. 4.  
Recr ui t me nt Str ate g y 
T he st u d y will utilize vari o us t o ols f or recr uit me nt , i ncl u di n g b ut n ot li mite d t o fl yers, 
patie nt a d v ocac y o utreac h, we bsite, a n d s ocial me dia . 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 8  of 1 2 1  
1 5. 5.  
Fi n a nci al Discl os ure  
I n v esti gat ors a n d s u b-i n v esti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate 
fi na ncial i nf or mati o n as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m plete a n d 
acc urate fi n a ncial certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y 
a ut h orities. I n v esti gat ors are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na n cial 
i nterests d uri n g t he c o urs e of t he st u d y a n d f or 1 year after c o m pleti o n of t he st u d y. 
1 5. 6.  
Pre -st u d y D oc u me nt ati o n Re q uire me nts  
T he i n vesti gat or is res p o nsi ble f or f or war di n g t he f oll o wi n g d oc u me nts t o t he s p o ns or 
f or re vie w bef ore all o wi n g a n y partici pa n ts t o c o ns e nt f or e ntr y i nt o t he st u d y: 
•  Si g ne d a n d date d pr ot oc ol si g nat ure pa ge.  
•  C o p y of I R B /IE C  a p pr o ve d I C F (i n cl u di n g versi o n n u m ber a n d date) a n d 
ot her partici pa nt  i nf or mati o n material. 
•  C o p y of t he I R B /IE C  a p pr o val of t he pr ot oc ol, I C F f or ms (i ncl u di n g 
versi o n n u m ber a n d d ate) a n d ot her partici pa nt  i nf or mati o n material. 
•  U p t o date c urric ula vitae a n d me dical lice ns es (as per l ocal r e g ulati o ns) of 
t he pri nci pal i n vesti gat or ( PI ) a n d all s u b -i n vesti g at ors. 
•  T h e I R B /IE C  c o m p ositi o n a n d/ or writte n state me nt of t he I R B /IE C  i n 
c o m plia nce wit h t he F D A re g ulati o ns relati n g t o G C P a n d cli nical st u dies, 
Re g ulati o n ( E U) 5 3 6/ 2 0 1 4, t he E U G C P Directi ve,  or t he I C H Tri partite 
G ui deli nes  f or G C P T o pic E 6( R 2) w here t he Re g ul ati o n ( E U) 
5 3 6/ 2 0 1 4 a n d E U G C P Directi ve d o n ot a p pl y.  
•  Si g ne d a n d date d la b orat or y n or mal ra n g es a n d d o c u me ntati o n of 
la b orat or y certificati o n ( or e q ui vale nt) u nless usi n g ce ntral la b orat or y 
arra n g e d b y t he s p o ns or. 
•  Si g ne d a n d date d cli nical st u d y a gree me nt (i n cl u di n g 
partici pa nt /i n vesti gat or i n de m nit y i ns ura nce a n d fi na ncial a gree me nt). 
•  F or m F D A 1 5 7 2, if re q uire d.  
•  Dr u g E nf orce me nt A d mi nistrati o n Re gistrati o n (as re q uire d).  
•  C o m plete d fi na ncial discl os ure state me nts f or t he PI a n d all 
s u b-i n vesti gat ors, if rele va nt. 
T he s p o ns or  will e ns ure t hat t he site is i nf or me d of w he n scree ni n g of p arti ci pa nt s ca n 
c o m me nce.  
1 5. 7.  
P artici p a nt  C o nfi de nti alit y  
T he i n vesti gat or m ust e ns ure t hat t he partici p a nt ’s a n o n y mit y is maintai ne d. I n t he 
e C R Fs a n d wit hi n data bases use d t o c ollect t he st u d y data  or ot her d oc u me nts 
s u b mitte d t o t he s p o ns or, partici pa nt s s h o ul d be i de ntifie d b y t heir st u d y partici pa nt 
n u m ber o nl y. D oc u me nts t hat are n ot f or s u b missi o n t o t he s p o ns or (e. g., si gne d I C F ) 
s h o ul d be ke pt i n strict c o nfi de nce b y t he i n v esti gat or. 
I n c o m plia nce wit h t he F D A re g ulati o ns relati n g t o G C P a n d cli nical st u dies, a n d t he 
E U C T R /I C H Tri partite I nte grate d A d d e n d u m t o I C H E 6( R 1): G ui deli ne f or G C P 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 7 9  of 1 2 1  
E 6( R 2), it is re q uire d t hat t h e i n vesti gat or a n d i nstit uti o n per mit a ut h orise d 
re pres e ntati ves of t he c o m pa n y, t he re g ulat or y a ut h orities a n d t he I R B/IE C  ha ve 
direct access t o re vie w t h e partici pa nt ’s ori gi nal me dical rec or ds f or verifi cati o n of 
st u d y-relate d pr oce d ures a n d data. Dir ect access i n cl u des e xa mi ni n g, a nal ysi n g , 
verif yi n g, a n d re pr o d uci n g a n y rec or ds a n d re p orts t hat are i m p orta nt t o t he e val uati o n 
of t he st u d y. T he i n vesti gat or is o bli gate d t o i nf or m t he partici pa nt  t hat his/ her 
st u d y-relate d rec or ds will be re vie we d b y t he a b o v e-na me d re prese ntati ves wit h o ut 
vi olati n g t he c o nfi de ntialit y of t he partici pa nt . 
All i nf or mati o n c o ncer ni n g t he st u d y i nter ve nti o n a n d s p o ns or o perati o ns s uc h as 
pate nt a p plicati o ns, f or m ulae, ma n ufact uri n g pr ocesses, basic sci e ntific dat a or 
f or m ulati o n i nf or mati o n s u p plie d t o t he i n vesti gat or b y t he s p o ns or a n d n ot pre vi o usl y 
p u blis he d is c o nsi dere d c o nfi de ntial b y t he s p o ns or a n d s hall re mai n t he s ol e pr o pert y 
o f t he s p o ns or. T he i n vesti gat or will a gree t o use t his i nf or mati o n o nl y i n 
acc o m plis hi n g t he st u d y a n d will n ot use it f or a n y ot her p ur p oses wit h o ut t he writte n 
c o nse nt of t he s p o ns or. 
T he c o ntract bet wee n t he s p o ns or a n d trial ce ntr es s pecifies t he res p onsi bilities of t he 
parties’ relate d data pr otecti o n, i ncl u di n g ha n dli n g of data sec urit y breac hes a n d 
res pecti ve c o m m u nicati o n a n d c o o perati o n of t he parties. 
I nf or mati o n tec h n ol o g y s yste ms use d t o c ollect, pr ocess, a n d st ore st u d y-rel ate d data 
are sec ure d  b y t ec h nic al a n d or ga nisati o nal  sec urit y meas ures desi g ne d t o pr otect s uc h 
data a gai nst acci de ntal or u nla wf ul l oss, alterati o n, or u na ut h orise d  discl os ure or 
access.  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 0  of 1 2 1  
1 6.  
A D MI NI S T R A TI V E A N D L E G A L O B LI G A TI O N S  
1 6. 1.  
Pr ot oc ol A me n d me nts a n d E n d of St u d y  or Ter mi n ati o n  
Pr ot oc ol a me n d me nts m ust be ma de o nl y wit h t he pri or a p pr o val of s p o ns or. 
A gree me nt fr o m t he i n vesti gat or m ust be o btai ne d f or all pr ot oc ol a me n d m e nts a n d 
a me n d me nts t o t he i nf or me d c o nse nt d oc u me nt. T he I R B/IE C  a n d re g ulat or y 
a ut h orities m ust be i nf or me d of all a me n d me nts a n d gi ve a p pr o val f or a n y s u bsta ntial 
a me n d me nts. A me n d me nts f or a d mi nistrati o nal c ha n ges ca n b e s u b mitte d t o t he 
I R B/IE C  f or i nf or mati o n o nl y. T he i n vesti gat or m ust  se n d a c o p y of t he ap pr o val 
letter fr o m t he I R B/IE C  t o t he s p o ns or. 
B ot h t he s p o ns or a n d t he i n vesti gat or reser ve t he ri g ht t o ter mi nate t he st u d y, 
acc or di n g t o t he cli nical st u d y a gree me nt. T h e i n vesti gat or m ust n otif y t he I R B /IE C  
i n writi n g of t he st u d y’s c o m pleti o n or E T a n d se n d a c o p y of t he n otificati o n t o t he 
s p o ns or. 
1 6. 2.  
St u d y  D oc u me nt ati o n a n d St or a ge  
T he i n vesti gat or m ust mai ntai n a list of a p pr o priat el y q ualifie d pers o ns t o w h o m 
he/s he has dele g ate d st u d y d uties.  
S o urce d oc u me nts are ori gi nal d oc u m e nts, data a n d rec or ds c o ntai ni n g all 
pr ot oc ol -s pecifi e d i nf or mati o n fr o m w hic h t he p artici pa nt ’s e C R F d ata are o btai ne d. 
T hese i ncl u de, b ut are n ot li mite d t o, h os pital rec or ds, cli nical a n d office c h arts, 
la b orat or y a n d p h ar mac y rec or ds, diaries, electr onic data ca pt ure d b y e P R O , 
micr ofic hes, V E E G rec or di n gs, ra di o gra p hs, a n d c orres p o n de n ce.  
T he i n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d 
ce ntralise d fili n g s yste m of all st u d y-relate d, esse ntial d oc u me ntati o n (as o utline d i n 
t he I C H Tri partite G ui deli nes f or G C P T o pic E 6[ R 2], Secti o n  8. 2 ), s uita ble f or 
i ns pecti o n at a n y ti me b y s p o ns or re prese ntati ves a n d/ or a p plica ble re g ulat or y 
a ut h orities. Ele me nts s h o ul d i ncl u de:  
•  Partici pa nt  files c o ntai ni n g c o m plete d e C R Fs, I C F f orms a n d s u p p orti n g 
c o pies of s o urce d oc u me ntati o n.  
•  St u d y  files c o ntai ni n g t he pr ot oc ol wit h all a me n d me nts, I B, c o pies of 
pre -st u d y d oc u me ntati o n (see Secti o n  1 5. 6 ) a n d all c orres p o n d e nce t o a n d 
fr o m t he I R B/IE C  a n d t he s p o ns or. 
•  E nr o lme nt l o g of all partici pa nt s w h o c o nse nte d t o ta ke part i n t he st u d y. 
•  Scree ni n g a n d recr uit me nt l o g of all partici pa nt s scree n e d a n d w het her or 
n ot t he y were recr uite d i nt o t he st u d y (i.e., d ose d wit h G W P 4 2 0 0 3 -P ). 
•  Pr o of of recei pt, st u d y i nter ve nti o n acc o u nta bilit y rec or d, ret ur n of st u d y 
i nter ve nti o n f or destr u cti o n, fi nal st u d y i nter ve nti o n rec o nciliati o n 
state me nt a n d all dr u g relate d c orres p o n de n ce.  
I n a d diti o n, all ori gi nal s o urce d oc u m e nts s u p p orti n g e ntries i n t he e C R Fs, diar y data 
a n d electr o ni c data ca pt ure d b y e P R O m ust be mai ntai ne d a n d be rea d il y a vaila ble. 
F oll o wi n g c o m pleti o n or ter mi nati o n of a cli nical st u d y, t he s p o ns or will i nitiate 
pr o per arc hi ve of cli nical st u d y-relate d d oc u m e ntati o n a n d electr o nic rec or ds 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 1  of 1 2 1  
ge nerat e d b y t he i n vesti g at or a n d/ or t he s p o ns or. U nless l ocal re q uir e me nts re q uire 
arc hi vi n g f or a l o n ger p eri o d, t he s p o ns or a n d t he i n vesti gat or s hall arc hi v e t he 
c o nte nt of t he cli nical tri al master file f o r at least 2 5 years after t he e n d of t he cli nical 
trial. H o we ver, t he me dical files of partici p a nts s hall be arc hi v e d i n acc or da nce wit h 
nati o nal la w.  T hese d o c u me nts m ust be retai ne d f or a l o n ger p eri o d, h o we ver, if 
re q uire d b y t he a p plica bl e re g ulat or y re q uir e me nts or if nee de d b y t he s p o ns or. 
T he s p o ns or  will i nf or m t he i n vesti gat ors f or eac h site i n writi n g of t he nee d f or 
rec or d rete nti o n. N o st u d y d oc u me nt ma y be destr o ye d wit h o ut pri or writte n 
a gree m e nt bet wee n t he s p o ns or a n d t he i n vesti gat or. S h o ul d t he i n vesti gat or wis h t o 
assi g n t he st u d y rec or ds t o a n ot her part y or m o ve t he m t o a n ot her l ocati o n, he/s he 
m ust n otif y t he s p o ns or i n writi n g of t he ne w res p o nsi ble pers o n a n d/ or t he ne w 
l ocati o n. 
1 6. 3.  
St u d y  M o nit ori n g a n d D at a C ollecti o n  
T he s p o ns or re present ati ve a n d re g ul at or y a ut h orit y i ns pect ors are res p o nsi ble f or 
c o ntacti n g a n d visiti n g t he i n vesti gat or f or t he p ur p ose of i ns pecti n g t he facilities a n d, 
u p o n re q uest, i ns pecti n g t he vari o us rec or ds of t he st u d y (e. g., e C R Fs a n d ot her 
perti ne nt data ) pr o v i de d t hat partici pa nt  c o nfi de ntialit y is res pecte d.  
T he s p o ns or st u d y m o nit or, or desi g ne e, is res p o nsi ble f or i ns pecti n g ( o n -site or 
re m otel y) t he e C R Fs a n d a vaila ble e P R O/ diar y d ata at re g ular i nter vals t hr o u g h o ut 
t he st u d y t o verif y a d here nce t o t he pr ot oc ol, c o m plete ness, acc urac y a n d c o nsiste nc y 
of t he data a n d a d here nce t o l ocal re g ulati o ns o n t he c o n d uct of cli nical res earc h. T h e 
st u d y m o nit or m ust ha ve ( direct or re m ote) access t o partici pa nt  me dical r ec or ds a n d 
ot her st u d y-relat e d rec or ds nee de d t o verif y t he e ntries o n t he e C R Fs.  
T he i n vesti gat or a grees t o c o o perat e wit h t he st u d y m o nit or t o e ns ure t hat a n y 
pr o ble ms detecte d i n t he c o urse of t hes e m o nit ori n g visits are res ol ve d.  
T o e ns ure t he q u alit y of cli nical data acr oss all partici pa nt s a n d sites, a cli nical data 
ma na ge me nt re vie w will be perf or me d o n partici pa nt  data recei ve d at t he s p o ns or or a  
Cli nical Researc h Or ga nisati o n (C R O ). D uri n g t his re vie w, partici pa nt  data will be 
c hec k e d f or c o nsiste nc y, o missi o ns, a n d a n y a p pare nt discre pa n cies. I n a d diti o n, t he 
data will be re vie we d f or a d here n ce t o t he pr ot oc ol a n d F D A re g ulati o ns, I C H 
Tri partite G ui deli nes f or G C P T o pic E 6( R 2) a n d all ot her a p plica ble re g ulat or y 
re q uire me nts. T o  res ol ve a n y q uesti o ns arisi n g fr o m t he cli nical data ma na ge me nt 
re vie w pr ocess, dat a q ueries a n d/ or site n otificati o ns will be se nt t o t he site f or 
c o m pleti o n a n d t he n ret ur ne d t o t he s p o ns or or t he C R O, as a p plica ble.  
1 6. 4.  
Electr o nic D at a C olle cte d b y Electr o nic P atie nt Re p orte d 
O utc o mes a n d Vi de o Electr oe nce p h al o gr a m  
S o urce data f or t he ass ess me nts c ollecte d via e P R O a n d V E E G will be ma na ge d b y 
t he ser vice pr o vi ders i n acc or da n ce wit h I C H Tri partite G ui deli nes f or G C P T o pic 
E 6( R 2) a n d i n a d here nce t o a q ualit y ma na ge me nt s yste m. All data will be st ore d i n a 
sec ure (e. g., re d u n da nt h ar d ware, pass w or d c o ntr ol, li mite d p h ysical access t o 
ser vers), f ull y a u dit-traile d e n vir o n me nt wit h a p pr o priate i n d ustr y sta n dar d bac k u p 
a n d offsite st ora g e practice s. 
W here a p plica ble, access f or partici pa nt s pr o vi di n g assess me nts a n d i n vesti gat ors will 
be a ut he nticate d a n d meet i n d ustr y sta n dar ds a n d c o m pl y wit h t he re q uire m e nts 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 2  of 1 2 1  
o utli ne d i n t he F D A C o d e of Fe deral Re g ulati o ns Title 2 1, Part 1 1, S u b part B 
( Electr o nic Rec or ds) . 
After dat a base l oc k, all i n vesti gat ors will recei v e a certifi e d c o p y of all e P R O/ E D C 
assess me nt data. T hes e d ata will be i n a n a gree d, rea d -o nl y f or m at wit h a c o veri n g 
letter e x plai ni n g t he c o nt e nt of t he data, a q ualit y state me nt fr o m t he e P R O/E D C 
pr o vi der a n d t he i n v esti gat or’s res p o nsi bilities.  
Re g ulat or y a n d s p o ns or a u dit ors will ha ve t he a bilit y t o re vie w, b ut n ot m o dif y, 
e P R O/ E D C data via a n a gree d mea ns of access.  
1 6. 5.  
Q u alit y Ass ur a nce  
I n acc or da n ce wit h t he F D A re g ulati o ns E U C T R /I C H Tri partite G ui deli nes f or G C P 
t he s p o ns or’s a u dit pla ns, re pres e ntati ves fr o m t he s p o ns or’s Cli nical Q ualit y 
Ass ura nce De p art me nt ma y select t his st u d y f or a u dit. I ns pecti o n of site facilities, 
e. g., p har mac y, dr u g st ora ge areas, la b orat ories, a n d re v ie w of st u d y-relate d rec or ds 
will occ ur t o e val uat e t he st u d y c o n d uct a n d c o m plia nce wit h t he pr ot oc ol, t he E U 
C T R  ( w he n a p plica ble)/I C H Tri partite G ui deli nes f or G C P T o pic E 6( R 2) a n d 
a p plica ble re g ulat or y re q uire me nts.  
T he s p o ns or st u d y m o nit or, or desi g n ee, is res p o nsi ble f or i ns pecti n g ( o n -site or 
re m otel y) t he e C R Fs a n d a vaila ble electr o nic diar y data at re g ul ar i nter vals 
t hr o u g h o ut t he st u d y t o verif y a d h ere n ce t o t he pr ot oc ol, c o m plete ness, acc urac y, a n d 
c o nsiste nc y of t he dat a a n d a d here n ce t o l ocal re g ulati o ns o n t he c o n d uct of cli nical 
researc h. T h e st u d y m o nit or m ust ha ve ( direct or re m ote) access t o partici pa nt  
me dical rec or ds a n d ot her st u d y-relate d rec or ds nee de d t o verif y t h e e ntries o n t he 
e C R Fs.  
1 6. 6.  
C o m pe ns ati o n  
T he s p o ns or  will i n de m nif y t he i n v esti gat or a n d t he trial ce ntr e i n t he e ve nt of a n y 
clai m i n res pect of p ers o nal i nj ur y arisi n g d ue t o a partici pa nt ’s i n v ol ve me nt i n t he 
st u d y, pr o vi di n g t hat t he st u d y pr ot oc ol has bee n a d here d t o. T his w o ul d i ncl u de 
clai ms arisi n g o ut of or relati n g t o t he a d mi nistrati o n of t he st u d y i nter ve nti o n or a n y 
cli nical i nter ve nti o n or pr oce d ure pr o vi de d f or or re q uire d b y t he pr ot o c ol t o w hic h 
t he cli nical st u d y partici p a nt  w o ul d n ot ot her wise ha ve bee n e x p ose d, pr o vi di n g t here 
is n o e vi de nce of ne gli ge nce o n beh alf of t he i n vesti gat or or t heir tea m. T h e s p o ns or  
will n ot be lia ble f or a n y clai ms arisi n g fr o m ne gli ge nce o n t he part of t he i n vesti gat or 
or t heir tea m.  
1 6. 7.  
P u blic ati o n P olic y  
As t he s p o ns or of t he st u d y, Jazz P har m ace uticals. is s olel y res p o nsi ble f or discl osi n g 
res ults o n Cli nical Trials. g o v, E U C T R, a n d ot her p u blic re gistries i n acc or da nce wit h 
a p plica ble gl o bal la ws a n d re g ulati o ns. B y si g ni n g t his pr ot oc ol, t he i n vesti gat or 
ac k n o wle d g es t hat all p osti n g re q uire me nts are s olel y t he re s p o nsi bilit y of t he s p o ns or 
a n d a grees n ot t o s u b mit a n y i nf or mati o n a b o ut t h e st u d y or its res ults.  
T he s p o ns or  rec o g nises t hat t here is a res p o nsi bilit y u n der t he re g ul at or y g ui deli nes t o 
e ns ure t hat res ults of scie ntific i nterest arisi n g fr o m t his cli ni cal st u d y are 
a p pr o priatel y p u blis he d a n d disse mi nate d. T he y will c o or di nate t his disse mi nati o n 
a n d ma y s olicit i n p ut a n d assista nce fr o m t he c hief/ P Is.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 3  of 1 2 1  
A s u m mar y of t he res ults of t his st u d y will be ma de a vaila ble o n 
htt p:// w w w.cli nicaltrials. g o v  a n d htt ps://e ucli nicaltrials.e u /(as a p plica ble), as re q uire d 
b y U S a n d E U la w . 
A n y p u blicati o n of t he st u d y data will be ma de i n acc or da nce wit h t he ter ms of t he 
Cli nical Trial A gree me nt.  
All p u blicati o ns, e. g., ma n uscr i pts, a bstracts, or al/sli de prese ntati o ns, or b o o k c ha pters 
base d o n t his trial, m ust be s u b mitte d t o t he s p o ns or a n d f or c or p orate re vie w bef ore 
releas e. T o e ns ur e a de q u ate ti me f or t he s p o ns or t o ma ke c o m me nts a n d s u g gesti o ns 
w here p erti ne nt, all s uc h material s h o ul d be s u b mitte d t o t he m at least 6 0  da ys pri or t o 
t he date f or s u b missi o n f or p u blicati o n, p u blic disse mi nati o n, or re vie w b y a 
p u blicati o n c o m mittee. T he PIs  m ust t he n i nc or p orate all  reas o na ble c o m me nts ma de 
b y t he s p o ns or i nt o t he p u blicati o n. 
T he s p o ns or  als o res er ves t he ri g ht t o dela y t he s u b missi o n of s uc h i nf or mati o n b y a 
peri o d of u p t o 6  m o nt hs fr o m t he date of first s u b missi o n t o t he m i n or der t o all o w 
t he m t o ta ke ste ps t o pr otect pr o priet ar y i nf or mati o n w here a p plica ble. 
1 6. 8.  
I ntellect u al Pr o pert y Ri g hts 
All i ntellect ual pr o pert y ri g hts o w ne d b y or lice nse d t o eit her t he s p o ns or or t he P Is, 
ot her t ha n t h ose arisi n g fr o m t he cli nical st u d y, will re mai n t heir pr o pert y. All 
i ntellect ual pr o pert y ri g hts arisi n g o ut of t he cli nical st u d y will vest i n or be 
e xcl usi vel y lice nse d t o t h e s p o ns or a n d, as s u c h, t he PI m ust pr o m ptl y discl ose all 
k n o wle d ge t o t he s p o ns or a n d refrai n fr o m usi n g s uc h k n o wle d ge wit h o ut t he pri or 
writte n c o nse nt o f t he s p o ns or. 
1 6. 9.  
C o nfi de nti al I nf or m ati o n  
T he s p o ns or  a n d t he PI m ust e ns ure t hat o nl y pers o n nel directl y c o ncer ne d wit h t he 
st u d y are part y t o c o nfi de ntial i nf or mati o n a n d t hat a n y i nf or mati o n c o mi n g t o eit her 
part y a b o ut t he ot her d uri n g t he c o urse of t he st u d y m ust be ke pt strictl y c o nfi de ntial 
a n d m ust n ot be discl ose d t o a n y t hir d part y or ma de use of wit h o ut t he pri or writte n 
c o nse nt of t he ot her.  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 4  of 1 2 1  
1 7.  
R E F E R E N C E S  
A m ori m B O, Ha ma ni C, Ferreira E, et al. ( 2 0 1 6). Effects of A 1 rece pt or 
a g o nist/a nta g o nist o n s p o nta ne o us seiz ures i n pil ocar pi ne -i n d uce d e pile ptic rats. 
E pile ps y & Be ha vi or: E & B. 6 1, 1 6 8 -7 3.  
Arzi ma n o gl o u A ( 2 0 0 9 a). Dra vet s y n dr o m e: fr o m electr ocli nical c haracteristics t o 
m olec ular bi ol o g y. E pile psia. 5 0 S u p pl 8, 3 -9.  
Arzi ma n o gl o u A, Fre n c h J, Bl u me W T, et al. ( 2 0 0 9 b). Le n n o x -Gasta ut s y n dr o me: a 
c o nse ns us a p pr o ac h o n dia g n osis, assess me nt, ma na ge me nt, a n d trial met h o d ol o g y. 
T he La ncet Ne ur ol o g y. 8( 1), 8 2 -9 3.  
Bis o g n o T, Ha n us L, De Petr ocellis L, et al. ( 2 0 0 1). M olec ular tar gets f or ca n na bi di ol 
a n d its s y nt hetic a nal o g u es: effect o n va nill oi d V R 1 rece pt ors a n d o n t he cell ular 
u pta ke a n d e n z y matic h y dr ol ysis of a na n da mi de. Britis h J o ur nal of P har mac ol o g y. 
1 3 4( 4), 8 4 5 -5 2.  
B o m bar dieri R, Pi nci M, M oa ver o R, Cer mi nar a C, C urat ol o P ( 2 0 1 0). Earl y c o ntr ol 
of seiz ures i m pr o ves l o n g -ter m o utc o me i n c hil dre n wit h t u ber o us scler osis c o m ple x. 
E ur o pea n J o ur n al of Pae diatric Ne ur ol o g y: EJ P N : official j o ur nal of t he E ur o pea n 
Pae diatric Ne ur ol o g y S ociet y. 1 4( 2), 1 4 6 -9.  
Carrier E J, A u c ha m pa c h J A, Hillar d CJ ( 2 0 0 6). I n hi biti o n of a n e q uili brati ve 
n ucle osi de tra ns p ort er b y ca n na bi di ol: a mec h a nis m of ca n na bi n oi d 
i m m u n os u p pressi o n. Pr ocee di n gs of t he Nati o nal Aca de m y of S cie nces of t he U nite d 
States of A merica. 1 0 3( 2 0), 7 8 9 5 -9 0 0.  
Cet ica V, C hiari S, Mei D, et al. ( 2 0 1 7). Cli nical a n d ge netic fact ors pre di cti n g Dra vet 
s y n dr o me i n i nfa nts wit h S C N 1 A  m utati o ns. Ne ur ol o g y. 8 8( 1 1), 1 0 3 7 -4 4.  
C ha n J A, Z ha n g H, R o berts P S, et al. ( 2 0 0 4). Pat h o ge nesis of t u ber o us scl er osis 
s u be pe n d y mal gia nt cell astr oc yt o mas: biallelic i nacti vati o n of T S C 1 or T S C 2 lea ds 
t o m T O R acti vati o n. J o ur nal of Ne ur o pat h ol o g y & E x peri me ntal Ne ur ol o g y. 6 3( 1 2), 
1 2 3 6 -4 2.  
C h u -S h ore CJ, Maj or P, M o nte ne gr o M, T hiele E ( 2 0 0 9). C yst -li ke t u bers are 
ass ociate d wit h T S C 2 a n d e pil e ps y i n t u ber o us scl er osis c o m ple x. Ne ur ol o g y. 7 2( 1 3), 
1 1 6 5 -9.  
Claes L, Del -Fa ver o J, Ce ule ma ns B, et al. ( 2 0 0 1). De n o v o m utati o ns i n t he 
s o di u m-c ha n nel ge n e S C N 1 A ca us e se vere m y ocl o nic e pile ps y of i nfa n c y. T he 
A merica n J o ur nal of H u ma n Ge netics. 6 8( 6), 1 3 2 7 -3 2.  
C o o k J, Oli ver K, M ueller R, Sa m ps o n J ( 1 9 9 6). A cr oss secti o nal st u d y of re nal 
i n v ol ve me nt i n t u ber o us scler osis. J o ur nal of Me dical Ge netics. 3 3( 6), 4 8 0-4.  
Cri n o P B, Nat ha ns o n K L, He ns ke E P ( 2 0 0 6). T h e t u ber o us scler osis c o m pl e x. T he 
Ne w E n gla n d  J o ur n al of Me dici ne. 3 5 5( 1 3), 1 3 4 5-5 6.  
C urat ol o P, B o m bar dieri R, J oz wia k S ( 2 0 0 8). T u ber o us scler osis. L a ncet. 3 7 2( 9 6 3 9), 
6 5 7 -6 8.  
C urat ol o P, Ver decc hia M, B o m bar dieri R ( 2 0 0 2). T u ber o us scl er osis c o m ple x: a 
re vie w of ne ur ol o gical as pects. E ur o pea n J o ur nal of Pae diatric Ne ur ol o g y: EJ P N 
: official j o ur nal of t he E ur o pea n Pae di atric Ne ur ol o g y S ociet y. 6( 1), 1 5-2 3.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 5  of 1 2 1  
Da b ora S L, J oz wia k S, Fra nz D N, et al. ( 2 0 0 1). M utati o nal a nal ysis i n a c o h ort of 
2 2 4  t u ber o us scler osis patie nts i n dicates i ncreas e d se verit y of T S C 2, c o m pare d wit h 
T S C 1, disease i n m ulti ple or ga ns. T he A merica n J o ur nal of H u ma n Ge neti cs. 6 8( 1), 
6 4 -8 0.  
De pie n ne C, Tr o uillar d O, Sai nt -Marti n C, et al. ( 2 0 0 9). S pectr u m of S C N 1 A ge ne 
m utati o ns ass ociate d wit h Dra vet s y n dr o m e: a nal ysis of 3 3 3 patie nts.  J o ur nal of 
Me dical Ge n etics. 4 6( 3), 1 8 3 -9 1.  
Dra vet C ( 2 0 1 1). Dra v et s y n dr o me hist or y. De vel o p me ntal Me dici ne & C hil d 
Ne ur ol o g y. 5 3 S u p pl 2, 1 -6.  
Dra vet C, O g u ni H ( 2 0 1 3). Dra v et s y n dr o me (se v ere m y ocl o nic e pile ps y i n i nfa nc y). 
Ha n d b o o k of Cli nical Ne ur ol o g y. 1 1 1, 6 2 7 -3 3.  
E ur o pea n C hr o m os o me 1 6 T u ber o us Scler osis C o ns orti u m ( 1 9 9 3). I de ntifi cati o n a n d 
c haracteri zati o n of t he t u ber o us scler osis ge n e o n c hr o m os o me 1 6. Cell. 7 5( 7), 
1 3 0 5 -1 5.  
E pile ps y F o u n dati o n 2 0 1 7 Re vise d Classificati o n of Seiz ures. ( 2 0 1 7). A v aila ble fr o m: 
htt ps:// w w w.e pile ps y.c o m/article/ 2 0 1 6/ 1 2/ 2 0 1 7 -re vise d-classificati o n -seiz ures. 
(accesse d 2 4 Marc h 2 0 2 1). 
Ge nt o n P, Velizar o va R, Dra vet C ( 2 0 1 1). Dra v et s y n dr o me: t he l o n g -ter m o utc o me. 
E pile psia. 5 2 S u p pl 2, 4 4 -9.  
I T Q O L: I nfa nt T o d dler Q ualit y of Life Q uesti o n naire. ( 2 0 1 7). A vaila ble fr o m: 
htt ps:// w w w. healt hactc h q.c o m/s ur ve y/it q ol. (accesse d 2 0 Se pte m ber 2 0 2 1).  
H ua n g J, Ma n ni n g B D ( 2 0 0 8). T he T S C 1 -T S C 2 c o m ple x: a m olec ular s wit c h b oar d 
c o ntr olli n g cell gr o wt h. Bi oc he mical J o ur nal. 4 1 2( 2), 1 7 9 -9 0.  
I n o ki K, Li Y, Z h u T, W u J, G ua n K-L ( 2 0 0 2). T S C 2 is p h os p h or ylate d a n d i n hi bite d 
b y A kt a n d s u p presses m T O R si g nalli n g. Nat ure Cell Bi ol o g y. 4( 9), 6 4 8 -5 7.  
J o nes A C, S h ya ms u n dar M M, T h o mas M W, et al. ( 1 9 9 9). C o m pre he nsi ve m utati o n 
a nal ysis of T S C 1 a n d T S C 2 - a n d p he n ot y pic c orrelati o ns i n 1 5 0 fa milies wit h 
t u ber o us scler osis. T he A merica n J o ur nal of H u ma n Ge netics. 6 4( 5), 1 3 0 5-1 5.  
J óz wia k S, Sc h wartz R A, Ja n ni ger C K, Bielic ka-C y mer ma n J ( 2 0 0 0). Us ef ul ness of 
dia g n ostic criteria of t u ber o us scler osis c o m p le x i n pe diatric patie nts. J o ur nal of C hil d 
Ne ur ol o g y. 1 5( 1 0), 6 5 2 -9.  
M ulle y J C, Nels o n P, G uerrer o S, et al. ( 2 0 0 6). A ne w m olec ular m ec ha nis m f or 
se vere m y o cl o nic e pile ps y of i nfa nc y: e x o ni c deleti o ns i n S C N 1 A. Ne ur ol o g y. 6 7( 6), 
1 0 9 4 -5.  
Na ka ya m a T, O gi wara I, It o K, et al. ( 2 0 1 0). Deleti o ns of S C N 1 A 5′ ge n o mic re gi o n 
wit h pr o m oter acti vit y i n Dra vet s y n dr o m e. H u ma n M utati o n. 3 1( 7), 8 2 0 -9.  
N ort hr u p H, Kr u e ger D A, R o ber ds S, et al. ( 2 0 1 3). T u ber o us scler osis c o m ple x 
dia g n ostic criteria u p d ate: rec o m me n dati o ns of t he 2 0 1 2 I nt er nati o nal T u ber o us 
Scler osis C o m ple x C o nse ns us C o nfere n ce. Pe diatric Ne ur ol o g y. 4 9( 4), 2 4 3 -5 4.  
O' Calla g ha n FJ, N o a kes MJ, Mart y n C N, Os b or ne J P ( 2 0 0 4). A n e pi de mi ol o gical 
st u d y of re nal pat h ol o g y i n t u ber o us scler osis c o m ple x. BJ U Int er nati o nal. 9 4( 6), 
8 5 3 -7.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 6  of 1 2 1  
Os b or ne J P, Fr yer A, We b b D ( 1 9 9 1). E pi de mi ol o g y of t u ber o us scler osis. A n nals of 
t he Ne w Y or k Aca de m y of Scie nces. 6 1 5( 1), 1 2 5-7.  
Pert wee R G ( 2 0 0 4). T he P har mac ol o g y a n d T hera pe utic P ote ntial of Ca n na bi di ol, i n: 
Di Marz o, V ( E d. ) Ca n na bi n oi ds. Kl u wer Aca d e mic/ Ple n u m P u blis hers, Ne w Y or k, 
U S A, p p. 3 2 -8 3.  
Ra k o ws ki S, Wi nter k or n E, Pa ul E, et al. ( 2 0 0 6). Re nal ma nifestati o ns of t u ber o us 
scler osis c o m ple x: I nci de nce, pr o g n osis, a n d pre di cti ve fact ors. Ki d ne y I nter nati o nal. 
7 0( 1 0), 1 7 7 7 -8 2.  
Ri beir o A, Ferraz -de -Pa ula V, Pi n heir o M L, et al. ( 2 0 1 2). Ca n na bi di ol, a n o n -
ps yc h otr o pic pla nt -deri ve d ca n n a bi n oi d, decreases i nfla m mati o n i n a m uri ne m o del of 
ac ute l u n g i nj ur y: r ole f or t he a de n osi ne A( 2 A) rece pt or. E ur o p ea n J o ur nal of 
P har mac ol o g y. 6 7 8( 1 -3), 7 8 -8 5.  
Sc heffer I E ( 2 0 1 2). Dia g n osis a n d l o n g -ter m c o urse of Dra vet s y n dr o me. E ur o pea n 
J o ur nal of Pae diatri c Ne ur ol o g y: EJ P N : official j o ur nal of t he E ur o p ea n Pae diatric 
Ne ur ol o g y S ociet y. 1 6 S u p pl 1, S 5 -8.  
Se bastiã o A M, Ri beir o J A ( 2 0 0 0). Fi n e -t u ni n g ne ur o m o d ulati o n b y a de n osi ne. Tre n ds 
i n P har mac ol o gical Scie n ces. 2 1( 9), 3 4 1-6.  
S pecc hi o N, Wirrell E C, Sc heffer I E, et al. ( 2 0 2 2). I nter nati o nal Lea g ue A gai nst 
E pile ps y classificati o n a n d defi niti o n of e pile ps y s y n dr o mes wit h o nset i n c hil d h o o d:  
P ositi o n pa per b y t he I L A E Tas k F orce o n N os ol o g y a n d Defi niti o ns. E pile psia. 
6 3( 6), 1 3 9 8 -4 4 2.  
S uls A, Clae ys K G, G o osse ns D, et al. ( 2 0 0 6). Mi cr o deleti o ns i n v ol vi n g t he S C N 1 A 
ge ne ma y be c o m m o n i n S C N 1 A -m utati o n -ne gati ve S M EI p atie nts. H u ma n M utati o n. 
2 7 ( 9), 9 1 4-2 0.  
Tre vat ha n E, M ur p h y C C, Year gi n -Alls o p p M ( 1 9 9 7). Pre vale nce a n d d escri pti ve 
e pi de mi ol o g y of Le n n o x -Gasta ut s y n dr o me a m o n g Atla nta c hil dre n. E pile psia. 
3 8( 1 2), 1 2 8 3 -8.  
W hat is T S C? - T u ber o us Scler osis Allia nce. ( 2 0 1 9). A vaila ble fr o m: 
htt ps:/ / w w w.tscallia nce. or g/a b o ut-tsc/ w hat-is-tsc/. (accesse d 2 0 Se pte m ber 2 0 2 1). 
va n der P oest Cle me nt E, Ja nse n F E, Br a u n K PJ, Peters J M ( 2 0 2 0). U p dat e o n Dr u g 
Ma na ge me nt of Refract or y E pile ps y i n T u ber o us Scler osis C o m ple x. Pae diatric 
Dr u gs. 2 2( 1), 7 3 -8 4.  
va n Sle gte n h orst M, de H o o gt R, Her ma ns C, et al. ( 1 9 9 7). I de ntificati o n of t he 
t u ber o us scler osis ge n e T S C 1 o n c hr o m os o me 9 q 3 4. Scie nce. 2 7 7( 5 3 2 7), 8 0 5-8.  
Va n Sle gte n h orst M, Nellist M, Na gel ker ke n B, et al. ( 1 9 9 8). I nteracti o n bet wee n 
ha marti n a n d t u beri n, t he T S C 1 a n d T S C 2 ge ne pr o d ucts. H u ma n M olec ular Ge netics. 
7( 6), 1 0 5 3 -7.  
Wa n g S, Falla h A ( 2 0 1 4). O pti mal ma na ge me nt of seiz ures ass o ciate d wit h t u ber o us 
scler osis c o m ple x: c urre nt a n d e mer gi n g o pti o ns. Ne ur o ps yc hiatric Diseas e a n d 
Treat me nt. 1 0, 2 0 2 1 -3 0.  
W e b b D, Car ke A, F yer A, Os b or ne J ( 1 9 9 6a). T h e c uta ne o us feat ur es of t u ber o us 
scler osis: a p o p ulati o n st u d y. Britis h J o ur nal of Der mat ol o g y. 1 3 5( 1), 1-5.  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 7  of 1 2 1  
We b b D W, Fr yer A E, Os b or ne J P ( 1 9 9 6 b). M or bi dit y ass ociate d wit h t u ber o us 
scler osis: a p o p ulati o n st u dy. De vel o p me ntal Me dici ne & C hil d Ne ur ol o g y. 3 8( 2), 
1 4 6 -5 5.  
W h yte L S, R y ber g E, Si ms N A, et al. ( 2 0 0 9). T h e p utati ve ca n n a bi n oi d rece pt or 
G P R 5 5 affects oste o clast f u ncti o n i n vitr o a n d b o ne mass i n vi v o. Pr ocee di n gs of t he 
Nati o nal Aca d e m y of Sci e nces of t h e U nite d States of A merica. 1 0 6( 3 8), 1 6 5 1 1 -1 6.  
Z u beri S M, Wirrell E, Y oza witz E, et al. ( 2 0 2 2). I L A E classificati o n a n d d efi niti o n of 
e pile ps y s y n dr o mes wit h o nset i n ne o nates a n d i nf a nts: P ositi o n state me nt b y t he 
I L A E Tas k F orce o n N os ol o g y a n d Defi nitio ns. E pile psia. 6 3( 6), 1 3 4 9 -9 7.  
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 8  of 1 2 1  
A P P E N DI X  1  
S C H E D U L E O F A C TI VI TI E S  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
Ge ner al St u d y Acti vities  
I nf or me d 
C o nse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I C F m ust b e 
si g ne d pri or t o 
a n y st u d y -
relate d 
acti vities, 
i n cl u di n g t he 
c ollecti o n of a 
s uita ble V E E G 
fr o m t h e 
partici p a nt’s 
me dical rec or ds.  
I/ E Criteria  
X  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rec hec k 
eli gi bilit y 
bef ore first d ose 
of G W P 4 2 0 0 3 -
P . 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 8 9  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
De m o gra p h y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical 
Hist or y  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•  Cli nical 
c o n diti o n:  
C o m plete 
seiz ure, 
e pile ps y 
(lifeti me), 
Stat us 
E pile ptic us, 
h os pital -
isati o ns; 
dia g n osis per 
i n vesti gat or 
a n d as 
defi n e d b y 
I L A E/T S C 
C o nse ns us 
C o nfere nce 
( 2 0 1 2). 
•  Dia g n ostic:  
1) T S C: 
I ma gi n g 
(e. g., 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 0  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
ultras o u n d, 
M RI, C T 
sca n); 
2)  L G S/ D S: 
E E G  
•  Ge netic: 
T S C 1/ T S C 2  
ge netic 
m utati o n 
stat us f or 
T S C; 
S C N 1 A  f or 
D S ( w here 
k n o w n)  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 1  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
Pri or 
Me dicati o ns  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A n y 
me dicati o ns 
ta ke n i n 
3  m o nt hs pri or 
t o Visit 3. 
A d diti o nall y, all 
pri or/c urre nt 
A S Ms, resc ue 
me dicati o ns, 
a n d 
vacci n ati o ns 
(fr o m birt h t o 
prese nt)  
(Secti o n  9. 1. 4 ). 
St u d y I nter ve nti o n  
Stratificati o n  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 2  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
Dis pe nse 
St u d y 
I nter ve nti o n 
 
 
X  
 
X  
 
X  
 
X  
X  
 
X  
 
X  
 
X  
 
 
•  S ufficie nt 
G W P 4 2 0 0 3 -
P  will be 
dis pe nse d t o 
last u ntil t h e 
ne xt 
dis pe nsi n g 
visit.  
•  At Visit  3, 
partici p a nts 
will ta ke 
t h eir first 
d ose of 
G W P 4 2 0 0 3 -
P  i n t h e 
cli nic.  
•  G W P 4 2 0 0 3 -
P  will be 
a d mi nistere d 
i n t he cli nic 
o n da ys 
w here P K 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 3  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
sa m ples are 
c ollecte d. 
•  I n cases 
w here 
partici p a nts 
are n ot a ble 
t o atte n d 
st u d y visits 
d ue t o 
s pecial 
circ u msta nce
s (e. g., 
C O VI D -1 9 
pa n de mic), 
t h e 
i n vesti gat or 
will disc uss 
wit h t he 
s p o ns or 
p ote ntial 
miti g ati o n 
a p pr oac hes 
f or 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 4  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
G W P 4 2 0 0 3 -
P  
dis pe nsi n g, 
sec ure 
deli ver y, a n d 
c ollecti o n. 
C ollect St u d y 
I nter ve nti o n/ 
C o m plia nce 
Re vie w  
 
 
 
 
X  
 
X  
 
X  
X  
 
X  
 
X  
 
X  
X  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 5  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
S afet y a n d T oler a bilit y  
P h ysical 
E x a mi n ati o n  
X  
 
X  
 
X  
 
X  
 
X  
X  
 
X  
 
X  
 
X  
X  
 
•  Eac h visit:  
Hei g ht/  
le n gt h, 
wei g ht , a n d 
hea d circ u m -
fere nce 
•  Visit  1:  f ull 
p h ysical 
e xa mi n ati o n 
•  S u bse q ue nt 
cli nic visits: 
a b bre viate d 
p h ysical 
e xa mi n ati o n 
(as nee de d/ 
cli nicall y 
i n dicate d) 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 6  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
C o m pre -
he nsi ve 
ne ur o de -
vel o p me ntal 
assess me nt  
 
 
X  
 
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
Secti o n  9. 1. 6  
C GI C/ S  
 
 
X  
 
 
 
 
 
 
 
 
X  
 
 
 
X  
 
 
Secti o n  9. 1. 1 2. 4  
Vital Si g ns  
X  
 
X  
 
X  
 
X  
 
X  
X  
 
X  
 
X  
 
X  
X  
 
Secti o n  9. 1. 7 7  
E C G  
X  
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
 
Hae mat ol o g y  
X  
 
X  
 
 
 
X  
 
X  
 
 
X  
 
X  
 
X  
 
 
Baseli ne res ults 
t o be re vie we d 
b y a p h ysicia n 
pri or t o Visit  3 
(Secti o n 
9. 1. 1 0 1 0 ).  
C he mistr y  
X  
 
X  
 
X  
 
X  
 
X  
X  
 
X  
 
X  
 
X  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 7  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
Uri nal ysis  
X  
 
 
 
 
 
X  
 
 
X  
 
X  
 
X  
 
X  
 
 
•  C o m plete 
w he n 
p ossi ble.  
•  Baseli ne 
res ults t o be 
re vie we d b y 
a p h ysicia n 
pri or t o 
Visit  3.  
•  Uri ne 
sa m ples will 
be se nt f or 
f urt h er 
a nal ysis o nl y 
if t h e l ocal 
la bs i d e ntif y 
rele va nt 
fi n di n gs. 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 8  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
O pti o nal 
Bl o o d Sa m ple  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o m plete w he n 
p ossi ble; refer 
t o 
Secti o n  9. 1. 1 0. 3  
O pti o nal 
Plas ma 
Sa m ple  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
A d verse 
E v e nt  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
•  A Es will be 
c ollecte d 
fr o m t h e 
start of st u d y 
i nter ve nti o n 
u ntil t h e 
safet y 
f oll o w-u p 
visit, 
w het h er or 
n ot 
attri b ute d t o 
st u d y 
i nter ve nti o n 
a n d 
o bser ve d b y 
t h e 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 9 9  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
i n vesti gat or 
or care gi v er.  
•  I ncl u des 
w orse ni n g of 
seiz ures. 
•  Refer t o 
Secti o n   
9. 1. 1 4 1 4  (f or 
A Es) a n d 
Secti o n   
9. 1. 1 2. 1  (f or 
seiz ure 
class-
ificati o n). 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 0  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
C o nc o mita nt 
Me dicati o ns  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A n y 
me dicati o ns ( or 
c ha n ges t h ere of) 
o n or after 
Visit  3 a n d 
t hr o u g h o ut 
st u d y 
partici p ati o n, 
i n cl u di n g 
A S Ms, resc ue 
me dicati o ns, 
a n d 
vacci n ati o ns 
(Secti o n  9. 1. 4 ).  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 1  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
P h ar m ac o ki netics  
P K  
 
 
X  
 
X  
 
X  
 
X  
 
 
 
 
 
 
X  
 
 
•  At all 
i n dicate d P K 
visits , 
sa m ples are 
t o be 
c ollecte d 
wit hi n 
6 0  mi n utes 
pri or t o 
m or ni n g 
G W P 4 2 0 0 3 -
P  d ose (i.e., 
tr o u g h 
c ollecti o n)  
•  At Visit  9 
a n d Visit  2 0 , 
3 -h o ur a n d 
6 -h o ur 
p ost d ose 
sa m ples 
( ≥ 2  h o urs 
bet wee n 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 2  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
eac h 
sa m pli n g 
ti me p oi nt) 
are als o t o be 
c ollecte d .  
•  Care gi v ers 
m ust rec or d 
t h e 
partici p a nt’s 
meals 
(ti mi n g a n d 
c o nte nt) 
d uri n g t h e 
2 4  h o urs 
pri or t o 
sa m ple 
c ollecti o n 
(Secti o n  
9. 1. 1 2. 2 ). 
•  D oses 
a dj ust me nts 
s h o ul d be 
a v oi d e d 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 3  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
wit hi n t h e 3 
da ys pri or t o 
P K visits. 
P K sa m ple 
c ollecti o n 
s h o ul d n ot 
occ ur u ntil 
>  3  da ys 
f oll o wi n g 
a n y d ose 
a dj ust me nt. 
D oses ma y 
be a dj uste d 
o n P K vis its 
after all P K 
sa m ples 
ha ve bee n 
c ollecte d 
(Secti o n  
9. 1. 1 0. 2 ).  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 4  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
Effic ac y  
Se n d 
I nf or mati o n 
t o E S CI  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•  C o m plete 
a n d s u b mit 
pr o vi d e d 
f or ms ( SI F 
f or T S C, 
SI F/ D R F f or 
D S a n d 
L G S, a n d 
E D R S f or all 
partici p a nts) 
a n d 
s u p p orti n g 
i nf or mati o n 
wit hi n 
2 4  h o urs of 
Visit  1.  
•  A n y ne w 
seiz ure t y pes 
after i nitial 
E S CI 
a p pr o val 
m ust b e 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 5  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
re p orte d via 
t h e Ne w 
Seiz ure 
F or m f or 
E S CI re vie w 
a n d 
a p pr o val. 
•  Refer t o 
Secti o n  
9. 1. 1 2. 1 . 
Seiz ure 
Classificati o n  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Care gi v ers m ust 
be c o ntacte d 
i m me diatel y f or 
retrai ni n g if t he 
E S CI i d e ntifies 
a n y 
misclassifie d 
seiz ures 
(Secti o n  
9. 1. 1 2. 1 ). 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 6  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
e P R O/ Pa per 
Seiz ure Diar y 
Trai ni n g  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
•  T h e  pa per 
seiz ure diar y 
is o nl y 
re q uire d 
d uri n g t h e 
scree ni n g/ b a
seli ne 
peri o d.  
•  Care gi v ers 
m ust b e 
c o ntacte d 
i m me diatel y 
f or retrai ni n g 
if t h e E S CI 
i d e ntifies 
a n y 
misclassifie d 
seiz ures 
bef ore 
Visit  3.  
•  Refer t o 
Secti o n  
9. 1. 1 2. 1 . 
e P R O/ Pa per 
Seiz ure Diar y 
C o m pleti o n   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
e P R O/ Pa per 
Seiz ure Diar y 
Re vie w  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 7  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
V E E G  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
•  Baseli ne 
V E E G will 
be o btai ne d 
fr o m t h e 
me dical 
rec or ds (if 
a vaila ble a n d 
ta ke n wit hi n 
1  year of 
Visit  1); 
ot h er wise, 
m ust b e 
c o m plete d 
a n d rea d b y 
a n 
i n vesti gat or 
a n d 
i n de pe n de nt 
re vie wer 
pri or t o 
Visit  3.  
•  A d diti o nal 
V E E G 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 8  of 1 2 1  
Sc he d ule of Acti vities  
St u d y Peri o d  
Visit  
Scree ni n g/  
B aseli ne 
Peri o d  
( 4 wee ks) 
Tre at me nt Peri o d ( 5 2 wee ks)  
E n d of 
T a per b  
S afet y
F oll o w
-u p c 
N otes  
 
Fi xe d  
Fle xi ble D ose O pti mis ati o n  
E O T
/ E Ta 
Visit 
N u m ber  
1  
2 d  
3
e 
4 d  
5  
6 d  
7  
8 d  
9  
1 0  
1 1 d , 
1 2 d  
1 3  
1 4 d , 
1 5 d  
1 6  
1 7 d , 
1 8 d , 
1 9 d  
2 0  
2 1  
2 2 d  
D a y  
−2
8  
−1 4  
1  
8  
1 5  
2 2  
2 9  
3 6  
5 7  
8 5  
1 1 3
, 
1 4 1  
1 6 9  
1 9 7, 
2 2 5  
2 5 3  
2 8 1, 
3 0 9, 
3 3 7  
3 6 5  
3 7 5  
4 0 3  
Wi n d o w 
( d a ys) 
± 3  
+ 3  
± 3  
± 7  
+ 3  
± 3  
criteria are 
pr o vi d e d i n 
Secti o n  6. 1 .  
Q ualit y of 
Life  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
Secti o n  9. 1. 1 2. 3  
A b bre viati o ns:  A E = a d verse e v e nt; A S M = antiseiz ure me dicati o n, C GI C/ S = Cli nicia n Gl o bal I m pressi o n of C ha n ge/ Se verit y; C O VI D -1 9 = c or o na vir us disease -1 9; 
C T  =  c o m p uterise d t o m o gra p h y; D R F  = Dia g n ostic Re vie w F or m; D S = Dra vet s y n dr o me; E C G  =  electr ocar di o gra m; E D R S = E pile ps y Diar y Refere n ce S heet; E E G = 
electr oe n ce p hal o gra m; E O T = e n d of tr eat me nt; e P R O =  electr o nic patie nt -re p orte d o utc o me; E S CI = E pile ps y St u d y C o ns orti u m; E T  =  earl y ter mi nati o n; I C F = i nf or me d 
c o nse nt f or m; I/E  =  i ncl usi o n/e xcl usi o n; I L A E =  I nter nati o nal Lea g ue A gai nst E pile ps y; L G S = Le n n o x-Gasta ut s y n dr o me; M RI  =  m a g netic res o na nce i ma gi n g ; 
P K  =  p har mac o ki netic; S C N 1 A  =  s o di u m v olta ge-gate d c ha n nel al p ha s u b u nit 1; SI F = Seiz ure I de ntificati o n  F or m; T S C = t u ber o us scler osis c o m ple x;  V E E G = v i de o 
electr oe n ce p hal o gra m.  
a Partici pa nts w h o disc o nti n ue pri or t o Visit  2 0  s h o ul d atte n d a n E T visit as s o o n as p ossi ble ( Secti o n  1 0 ). 
b A 1 0 -da y ta per peri o d f oll o ws t he E O T/ E T visit ( u nless n ot p ossi ble f or safet y reas o ns).  
c Occ urs 4  wee ks after t he e n d -of -ta per visit or last d ose (as a p plica ble; see Secti o n  1 0 ). 
d P h o ne Visit  
e  Visit  3 occ urs 1 4  da ys ( +  3  da ys) after Visit  2, b ut n ot <  2 8  da ys after Visit  1.  
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 0 9  of 1 2 1  
A P P E N DI X  2  
S T U D Y  P E R S O N N E L  
A p pe n di x  2 .1  
I n vesti g at or Det ails 
At t he ti me of pr ot oc ol pr o d ucti o n, t he partici pati n g i n vesti gat ors ha ve n ot bee n 
c o nfir me d. A list of all i n vesti gat ors will be mai ntai ne d wit hi n t he s p o ns or’s master 
files (electr o nicall y a n d a d de d t o t he trial master file at t he e n d of t he st u d y). 
A p pe n di x  2 .2  
S p o ns or C o nt act Det ails  
S p o ns or:  
Jazz P har mace uticals Researc h U K 
Li mite d  
B uil di n g 7 3 0 , Ke nt Scie nce Par k  
Sitti n g b o ur ne , Ke nt  
U nite d Ki n g d o m , M E 9 8 A G 
Tel:  + 4 4 8 0 8 1 8 9 0 3 8 7  
Fa x:  + 4 4 ( 0) 1 2 2 3 2 3 5 6 6 7  
Me dical A d vis or, 2 4 -h o ur E mer ge nc y C o ntact 
details , P har mac o vi gila nce De part me nt (f or S A E 
re p orti n g), a n d Cli nical Pr oject Ma na ger:  
Please refer t o t he S p o ns or a n d Relate d 
C o ntact Details f or m i n t he trial ce ntre  
file. 
Cli nical Trial S u p plies:  
G -P har m Lt d  
Tel:  + 4 4 ( 0) 1 7 9 5 4 3 5 0 2 9  
Fa x:  + 4 4 ( 0) 1 7 9 5 4 7 5 4 3 9  
A p pe n di x  2 .3  
C o ntr act Rese arc h Or g a nis ati o ns  
Pre mier Researc h E ur o p e  
1st Fl o or, R u bra 2  
M ul berr y B usi ness Par k  
Fis h p o n ds R oa d  
W o ki n g ha m, R G 4 1 2 G Y  
U nite d Ki n g d o m  
Tel: +  4 4 1 1 8 9 3 6 4 0 0 0  
A p pe n di x  2 .4  
Bi o a n al ytic al L a b or at or y  
C o va nce La b orat ories Li mite d  
Otle y R oa d  
Harr o g ate, N ort h Y or ks hire, H G 3 1 P Y  
U nite d Ki n g d o m  
Tel: +  4 4 -1 4 2 -3 5 0 -0 0 1 1  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 0  of 1 2 1  
A p pe n di x  2 .5  
Vi de o E E G Ve n d or  
Lifeli nes Ne ur o C o m pa n y, L L C  
4 1 1 E d war ds ville R oa d  
Tr o y, I L 6 2 2 9 4  
U nite d States  
Te l: + 1-8 6 6 -8 8 9 -6 5 0 5  
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 1  of 1 2 1  
A P P E N DI X  3  
Q U E S TI O N N AI R E S/ A S S E S S M E N T S  
A p pe n di x  3 .1  
Di a g n ostic Criteri a f or Cli nic al Di a g n osis of 
T u ber o us Scler osis  
T he f oll o wi n g dia g n ostic criteria were a da pte d fr o m t he 2 0 1 2 I nter nati o nal T S C 
C o nse ns us C o nfere nce (N ort hr u p 2 0 1 3 ). 
Ge netic Di a g n ostic Crit eri a f or Defi nite  T S C  
T he i de ntificati o n of eit h er a T S C 1  or T S C 2  pat h o ge nic m utati o n i n D N A fr o m 
n or mal tiss ue is s ufficie nt t o ma ke a defi nite di a g n osis of T S C.  
A pat h o ge nic m utati o n is defi ne d as a m utati o n t hat clearl y i nacti vates t he f u ncti o n of 
t he T S C 1  or T S C 2  pr otei ns (e. g., o ut -of -fra m e i n del or n o nse nse m utati o n), pre ve nts 
pr otei n s y nt hesis (e. g., lar ge ge n o mic del eti o n), or is a misse nse m utati o n w h ose 
effect o n pr otei n f u n cti o n has bee n est a blis he d b y f u ncti o nal assess me nt. Ot her 
T S C 1  or T S C 2  varia nts w h ose effect o n f u n cti o n is less certai n d o n ot meet t hese 
criteria a n d are n ot s ufficie nt t o ma ke a defi nite di a g n osis of T S C.  
N ote:  T e n perce nt t o 2 5 % of patie nts wit h T S C ha ve n o m utati o n i de ntifie d b y 
c o n ve nti o nal ge netic testi n g, a n d a n or ma l r es ult d oes n ot e xcl u de T S C, or ha ve a n y 
effect o n t he use of cli nic al dia g n ostic criteria t o di a g n ose T S C.  
Cli nic al Di a g n ostic Criteri a f or T S C  
M aj or Fe at ures  
Mi n or Fe at ures  
H y p o mela n otic mac ules ( ≥ 3, at least 5 -m m 
dia meter)  
“ C o nfetti” s ki n lesi o ns 
A n gi ofi br o mas ( ≥ 3) or fi br o us ce p halic pla q ue  
De ntal e na mel pits (  > 3)  
U n g ual fi br o mas ( ≥ 2)  
I ntra oral fi br o mas ( ≥ 2)  
S ha gree n patc h  
Reti nal ac hr o mic patc h  
M ulti ple reti nal ha mart o mas  
M ulti ple re nal c ysts  
C ortical d ys plasias *  
N o nre nal ha mart o mas  
S u be pe n d y mal n o d ules  
 
S u be pe n d y mal gia nt cell astr oc yt o ma  
 
Car diac r ha b d o m y o ma  
 
L y m p ha n gi olei o m y o mat osis ( L A M) †  
 
A n gi o m y oli p o mas ( ≥ 2) †  
 
*I ncl u des t u bers a n d cere bral w hite matter ra dial mi grati o n li nes.  
† A c o m bi nati o n of t he t w o maj or cli nical feat ures ( L A M a n d a n gi o m y oli p o mas) wit h o ut ot her feat ures 
d oes n ot meet criteria f or a defi nite dia g n osis.  
 
Defi nite Di a g n osis:  T w o maj or feat ur es or  1 maj or feat ur e wit h ≥ 2 mi n or feat ures  
P ossi ble Di a g n osis:  Eit her 1 maj or feat ur e or ≥ 2 m i n or feat ures 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 2  of 1 2 1  
A p pe n di x  3 .2  
I nter n ati o n al Le a g ue A g ai nst E pile ps y Seiz ure 
Cl assific ati o n  
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 3  of 1 2 1  
A p pe n di x  3 .3  
Et hic al C o nsi der ati o ns f or Cli nic al Tri als o n 
Me dici n al Pr o d ucts C o n d ucte d wit h Mi n ors  
Preter m a n d ter m n e o nat es ha ve ver y li mite d bl o o d v ol u me a n d, w he n sic k, are oft e n 
a nae mic d u e t o fre q u e nt r o uti ne sa m pli n g. Micr o -met h o ds o n dr y s p ots a n d sca ve n ge d 
bl o o d re m na nts s h o ul d be use d w he n e ver p ossi ble, si nce t he y re d u ce trial -relate d 
bl o o d l oss. O p p ort u nistic, p o p ulati o n, or s parse sa m pli n g, or ot her i n n o vati ve met h o ds 
c o ul d als o re d uce t he fre q ue nc y a n d v ol u me of bl o o d sa m pli n g. Alt h o u g h n ot 
e vi de nce b ase d, t he f oll o wi n g rec o m me n dati o ns ca n be ma de: p er i n di vi d ual, t he 
researc h relate d bl o o d l oss (i ncl u di n g a n y waste) as a ge neral r ule s h o ul d n ot e xcee d 
3 % of t he t otal bl o o d v ol u me o ver a p eri o d of f o ur wee ks, a n d s h o ul d n ot e xcee d 1 % 
at a n y si n gle ti me. T his rec o m me n dati o n lea ds t o t h e all o wa ble sa m ple v ol u mes, 
i n dicate d i n t he ta ble bel o w. R o uti ne healt h care ma y re q uire si g nifica nt bl o o d 
sa m pli n g (rec or de d i n i nfa nts a n d ne o nates), a n d t he i n dicate d researc h relate d bl o o d 
v ol u mes ma y e ve n be e x cessi ve, es peciall y i n ( preter m ne w b or n)  i nfa nts. T his mea ns 
t hat i n i n di vi d ual cases, acce pta bl e res earc h relat e d bl o o d l oss ma y be l o wer t ha n 
i n dicate d i n t he ta ble bel o w. Researc h rel ate d bl o o d sa m pli n g a n d v ol u mes s h o ul d 
al wa ys be j ustifie d i n t he pr ot oc ol a n d e x plai ne d i n t he patie nt i nf or m ati o n material. 
Bl o o d tra nsf usi o ns ( or ir o n or er yt hr o p oieti n s u p ple me ntati o n) s h o ul d n ot be use d as a 
c o n ve nie nce t o j ustif y i ncreas e d v ol u me or fre q ue nc y of bl o o d sa m pli n g  as per 
rele va nt E U g ui d a nce o n et hical c o nsi derati o ns f or cli nical trials o n me dici nal 
pr o d ucts c o n d ucte d wit h mi n ors . 
 
A da pte d fr o m: C ha pter V: Et hical c o nsi derati o ns f or cli nical trials o n me dici nal 
pr o d ucts c o n d ucte d wit h t he p ae diatric p o p ul ati o n ( E u dra L e x –  V ol u me 1 0) .  

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 4  of 1 2 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 5  of 1 2 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 6  of 1 2 1  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 7  of 1 2 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 8  of 1 2 1  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 1 9  of 1 2 1  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 2 0  of 1 2 1  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Jazz P har mace uticals Researc h U K Li mite d  
Pr ot oc ol G W E P 1 7 0 0 5  
G W P 4 2 0 0 3 -P  
Pr ot oc ol A me n d me nt 6. 0  
 
 
C O N FI D E N TI A L  
Pa ge 1 2 1  of 1 2 1  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 

Si g nat ure Pa ge f or Pr ot oc ol A me n d me nt G W E P 1 7 0 0 5- 0 6 - P u blis he d
V V- C LI N- 0 2 3 0 9 0
Si g nat ure Pa ge f or Pr ot oc ol A me n d me nt G W E P 1 7 0 0 5- 0 6 - P u blis he d
V V- C LI N- 0 2 3 0 9 0
A p pr o val Tas k - A p pr o val of D oc u me nt
Si g ni n g Ver dict/ Reas o n: I A p pr o ve d T his D oc u me nt
2 4-Ja n- 2 0 2 4 2 1: 4 3: 4 1 G M T + 0 0 0 0