Clinical trial NCT03283371
Conditions: Epilepsy, Focal Seizures, Partial Seizures
Keywords: Drug Resistant Focal Epilepsy, Natalizumab, Seizure
Sponsor: Biogen
Start date: 2018-03-20; Completion date: 2020-11-18
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary efficacy objective of the study is to determine if adjunctive therapy of natalizumab 300 mg intravenous (IV) every 4 weeks reduces the frequency of seizures in adult participants with drug-resistant focal epilepsy. The secondary efficacy objective is to assess the effects of natalizumab versus placebo in drug-resistant focal epilepsy on additional measures of seizure frequency.

Detailed description:

Arms: arm 1: Participants will undergo a prospective baseline period of 6 weeks (Weeks -6 to 0) followed by placebo controlled phase to receive natalizumab 300 mg intravenous (IV) infusion every 4 weeks from Week 0 to Week 24. Participants will continue to receive natalizumab 300 mg IV infusion every 4 weeks for up to an additional 24 weeks in open label phase. arm 2: Participants will undergo a prospective baseline period of 6 weeks (Weeks -6 to 0) followed by placebo controlled phase to receive natalizumab matching placebo intravenous (IV) infusion every 4 weeks from Week 0 to Week 24. Participants will then receive natalizumab 300 mg IV infusion every 4 weeks for 24 weeks in open label phase.
Interventions: intervention 1: Natalizumab intervention 2: Placebo
Intervention descriptions: intervention 1: As specified in the treatment arm. intervention 2: As specified in treatment arms.

Protocol documents:
Prot_000.pdf: 




Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3
T A B L E O F C O N T E N T S
S P O N S O R SI G N A T U R E P A G E ....................................................................................................2
1. 
S Y N O P SI S ................................ ...................................................................................8
2. 
LI S T O F A B B R E VI A TI O N S................................ .....................................................1 2
3. 
S P O N S O R I N F O R M A TI O N .....................................................................................1 4
4. 
I NT R O D U C TI O N ......................................................................................................1 5
4. 1. 
O ver vie w of E pile ps y................................................................................................. 1 5
4. 2. 
C urre nt T hera pies f or E pile ps y ...................................................................................1 6
4. 3.  
Pr ofile of Pre vi o us E x perie nce Wit h Nataliz u ma b................................ .....................1 6
4. 3. 1. 
N o ncli nical E x perie nce ...............................................................................................1 6
4. 3. 2.  
Cli nical E x perie nce................................ .....................................................................1 6
4. 4. 
St u d y  Rati o nale...........................................................................................................1 7
4. 4. 1. 
D ose Rati o nale ............................................................................................................1 8
5. 
S C H E D U L E O F A C TI VI TI E S ..................................................................................1 9
6. 
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S................................ ..............................2 5
7. 
S T U D Y D E SI G N .......................................................................................................2 8
7. 1. 
St u d y  D urati o n f or S u bjects........................................................................................2 9
7. 2. 
St u d y  St o p pi n g R ules .................................................................................................2 9
7. 3. 
E n d of St u d y ...............................................................................................................2 9
8. 
S E L E C TI O N O F S U BJ E C T S.................................................................................... 3 0
8. 1. 
I ncl usi o n Criteria........................................................................................................ 3 0
8. 2. 
E xcl usi o n Criteria .......................................................................................................3 1
9. 
S C R E E NI N G A N D R A N D O M I Z A TI O N .................................................................3 4
9. 1. 
Scree ni n g ....................................................................................................................3 4
9. 2. 
Ra n d o mizati o n ............................................................................................................3 4
9. 3. 
Bli n di n g Pr oce d ures ....................................................................................................3 4
1 0. 
DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D W I T H D R A W A L 
O F S U BJ E C T S F R O M T H E S T U D Y ........................................................................3 6
1 0. 1. 
Disc o nti n uati o n of St u d y Treat me nt ...........................................................................3 6
1 0. 2. 
L ost t o F oll o w -U p .......................................................................................................3 7
1 0. 3. 
Wit h dra wal of S u bjects Fr o m t he St u d y .....................................................................3 7
1 1. 
S T U D Y T R E A T M E N T U S E .....................................................................................3 8


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o n tai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4
1 1. 1. 
Re gi me n ...................................................................................................................... 3 8
1 1. 2. 
M o dificati o n of D ose .................................................................................................. 3 8
1 1. 3. 
Preca uti o ns .................................................................................................................. 3 8
1 1. 4. 
C o m plia nce ................................................................................................................. 3 8
1 1. 5. 
C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................................ 3 8
1 1. 5. 1. 
C o nc o mita nt T hera p y ................................................................................................. 3 8
1 1. 5. 1. 1. 
M o dificati o n of A E Ds
................................................................................................ 3 9
1 1. 5. 1. 2. 
Disall o we d C o nc o mita nt T hera p y .............................................................................. 3 9
1 1. 5. 2. 
C o nc o mita nt Pr oce d ures ............................................................................................. 4 0
1 1. 6. 
C o nti n uati o n of Treat me nt .......................................................................................... 4 0
1 2. 
S T U D Y T R E A T M E N T M A N A G E M E N T ................................................................ 4 1
1 2. 1. 
Nataliz u ma b ................................................................................................................ 4 1
1 2. 1. 1. 
Nataliz u ma b Pre parati o n ............................................................................................ 4 1
1 2. 1. 2. 
Nataliz u ma b St ora ge ................................................................................................... 4 1
1 2. 1. 3. 
Nataliz u ma b Ha n dli n g a n d Dis p osal .......................................................................... 4 2
1 2. 1. 4. 
Nataliz u ma b Acc o u nta bilit y ....................................................................................... 4 2
1 2. 2. 
Place b o ........................................................................................................................ 4 2
1 3. 
E F FI C A C Y, 
 
A S S E S S M E N T S ......................................................................................................... 4 3
1 3. 1. 
Cli nical Efficac y  Assess me nts.................................................................................... 4 3
4 3
4 4
4 4
4 4
4 4
1 4. 
S A F E T Y A S S E S S M E N T S ................................ ........................................................4 6
1 4. 1. 
Cli nical Safet y  Assess me nts....................................................................................... 4 6
1 4. 2. 
La b o rat or y Safety Assess me nts .................................................................................. 4 7
1 4. 3. 
Nataliz u ma b -S pecific Safet y  Assess me nts................................................................. 4 7
1 5. 
S A F E T Y D E FI NI TI O N S, R E C O R DI N G, R E P O R TI N G , A N D 
R E S P O N SI BI LI T I E S ................................................................................................. 4 9
1 5. 1. 
Defi niti o ns................................ ..................................................................................4 9
1 5. 1. 1. 
A d verse E ve nt .............................................................................................................4 9


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o n tai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5
1 5. 1. 2. 
Seri o us A d verse E ve nt ................................................................................................4 9
1 5. 1. 3. 
Presc he d ule d or Electi ve Pr oce d ures or R o uti nel y  Sc he d ule d Treat me nts................5 0
1 5. 2. 
Safet y  Classificati o ns..................................................................................................5 0
1 5. 2. 1. 
I n vesti gat or Assess me nt of E ve nts .............................................................................5 0
1 5. 2. 2. 
Relati o ns hi p of E ve nts t o St u d y  Treat me nt................................................................5 0
1 5. 2. 3. 
Se verit y  of E ve nts.......................................................................................................5 1
1 5. 2. 4. 
E x pecte d ness of E ve nts ..............................................................................................5 1
1 5. 3. 
M o nit ori n g a n d Rec or di n g E ve nts ..............................................................................5 1
1 5. 3. 1. 
A d verse E ve nts ...........................................................................................................5 1
1 5. 3. 2. 
Seri o us A d verse E ve nts ..............................................................................................5 2
1 5. 3. 3.  
I m me diate Re p orti n g of Seri o us A d verse E ve nts................................ .......................5 2
1 5. 3. 3. 1. 
Deat hs .........................................................................................................................5 3
1 5. 3. 4. 
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns ....................................................5 3
1 5. 4. 
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns ...............................................................5 3
1 5. 4. 1. 
Pre g na nc y ...................................................................................................................5 3
1 5. 4. 2. 
O ver d ose .....................................................................................................................5 4
1 5. 4. 3. 
Me dical E mer ge nc y ....................................................................................................5 4
1 5. 4. 3. 1. 
U n bli n di n g f or Me dical E mer ge nc y ...........................................................................5 4
1 5. 5.  
C o ntrace pti o n Re q uire me nts ................................ ......................................................5 4
1 5. 6. 
Safet y  Res p o nsi bilities................................................................................................ 5 6
1 5. 6. 1. 
T he I n vesti gat or ..........................................................................................................5 6
1 5. 6. 2. 
Bi o ge n .........................................................................................................................5 7
1 6. 
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F S A M P L E SI Z E ...........5 8
1 6. 1. 
Efficac y .......................................................................................................................5 8
1 6. 1. 1. 
A nal y sis P o p ulati o n ....................................................................................................5 8
1 6. 1. 2. 
Ge neral Met h o ds of A nal ysis .....................................................................................5 8
1 6. 1. 2. 1. 
A nal y sis of t he Pri mar y E n d p oi nt...............................................................................5 8
1 6. 1. 2. 2. 
A nal y sis of t he Sec o n dar y E n d p oi nts.........................................................................5 9
1 6. 1. 2. 3. 
A nal y sis of A d diti o nal E n d p oi nts...............................................................................6 0
1 6. 2. 
P har mac o ki netics ........................................................................................................6 0
1 6. 2. 1. 
A nal y sis P o p ulati o n ....................................................................................................6 0
1 6. 2. 2. 
Met h o ds of A nal ys is...................................................................................................6 0


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o n tai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6
................................................................................................... 6 0
.................................................................................................... 6 0
................................................................................................... 6 1
6 1
1 6. 5. 
Safet y .......................................................................................................................... 6 1
1 6. 5. 1. 
A nal y sis P o p ulati o n .................................................................................................... 6 1
1 6. 5. 2. 
Met h o ds of A nal ys is................................................................................................... 6 1
1 6. 5. 2. 1. 
A d verse E ve nts ........................................................................................................... 6 1
1 6. 5. 2. 2. 
Cli nical L a b orat or y Res ults........................................................................................ 6 1
1 6. 5. 2. 3. 
Vital Si g ns .................................................................................................................. 6 2
1 6. 5. 2. 4. 
e C-S S R S/ C -S S R S ....................................................................................................... 6 2
1 6. 6. 
I m m u n o ge nicity ( A nti -Nataliz u ma b A nti b o dies) ....................................................... 6 2
1 6. 7. 
I nteri m A nalys es ......................................................................................................... 6 2
1 6. 8. 
Sa m ple Size C o nsi derati o ns ....................................................................................... 6 2
1 7. 
E T HI C A L  R E Q UI R E M E N T S ................................................................................... 6 4
1 7. 1. 
Declarati o n of Helsi n ki ...............................................................................................6 4
1 7. 2. 
Et hics C o m mittee ........................................................................................................ 6 4
1 7. 3. 
S u bject I nf or mati o n a n d C o nse nt ............................................................................... 6 5
1 7. 4. 
S u bject Data Pr otecti o n ..............................................................................................6 5
1 7. 5. 
C o m pe nsati o n f or I nj ur y ............................................................................................. 6 5
1 7. 6. 
C o nflict of I nterest ...................................................................................................... 6 5
1 7. 7. 
Re gistrati o n of St u d y a n d Discl os ure of St u d y R es ults .............................................. 6 6
1 8. 
A D MI NI S T R A TI V E P R O C E D U R E S ....................................................................... 6 7
1 8. 1. 
St u d y  Site I nitiati o n....................................................................................................6 7
1 8. 2. 
Q ualit y  C o ntr ol a n d Q ualit y Ass ura nce......................................................................6 7
1 8. 3. 
M o nit ori n g of t he St u d y................................ ..............................................................6 7
1 8. 4. 
St u d y  F u n di n g.............................................................................................................6 8
1 8. 5. 
P u blicati o ns ................................................................................................................. 6 8
1 9. 
F U R T H E R R E Q UI R E M E N T S A N D G E N E R A L I N F O R M A T I O N........................ 6 9
1 9. 1. 
E xter nal C o ntract Or ga nizati o ns ................................................................................. 6 9
1 9. 1. 1. 
C o ntract Researc h Or ga nizati o n ................................................................................. 6 9
1 9. 1. 2. 
I nteracti ve Res p o nse Tec h n ol o g y............................................................................... 6 9


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o n tai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
7
1 9. 1. 3. 
Electr o ni c Data Ca pt ure ..............................................................................................6 9
1 9. 1. 4. 
Ce ntral La b orat ories f or La b orat or y  Assess me nts .....................................................6 9
1 9. 2. 
St u d y  C o m mittees.......................................................................................................6 9
1 9. 2. 1. 
A d vis or y C o m mittee ...................................................................................................6 9
1 9. 2. 2. 
I n de pe n de nt E pile psy Re vie w C o m mittee ..................................................................7 0
1 9. 2. 3. 
Dr u g Safet y M o nit ori n g C o m mittee ...........................................................................7 0
1 9. 2. 4. 
I n de pe n de nt Safety M o nit or .......................................................................................7 0
1 9. 3. 
C ha n ges t o Fi nal St u d y  Pr ot oc ol ................................................................................7 0
1 9. 4. 
Et hics C o m mittee N otificati o n of St u d y  C o m pleti o n or Ter mi nati o n........................ 7 1
1 9. 5. 
Rete nti o n of St u d y  Data..............................................................................................7 1
1 9. 6. 
St u d y  Re p ort Si g nat or y...............................................................................................7 1
2 0. 
R E F E R E N C E S ...........................................................................................................7 2
2 1. 
SI G N E D A G R E E M E N T O F T H E S T U D Y P R O T O C O L .........................................7 4
LI S T O F T A B L E S
Ta ble 1: 
Sc he d ule of Acti vities f or St u d y  1 0 1 E P 2 0 1...............................................................2 0
LI S T O F FI G U R E S
Fi g ure 1: 
St u d y  Desi g n Sc he matic.............................................................................................2 9


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o n tai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
8
1. 
S Y N O P SI S
Pr ot oc ol Title 
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d, P hase 2 St u d y  
E x pl ori n g t he Efficac y , Safety, a n d T olera bilit y  of Nataliz u ma b 
( B G 0 0 0 0 2) as A dj u ncti ve T hera py i n A d ult S u bjects Wit h 
Dr u g -Resista nt F ocal E pile ps y
Pr ot oc ol N u m ber 
1 0 1 E P 2 0 1
Versi o n N u m ber 
2
Na me of St u d y 
Treat me nt
B G 0 0 0 0 2 ( nataliz u ma b; T y sa bri ® )
St u d y  P hase 
2
St u d y  In dicati o n 
F ocal e pile ps y
St u d y  Rati o nale 
E vi de nce fr o m b ot h e x peri me ntal m o dels of e pile ps y  a n d h u ma n 
patie nts wit h e pile ps y  s u g gest a r ole f or i nfla m mati o n, i ncl u di n g 
i ncrease d e x pressi o n of c yt o ki nes a n d i nfla m mat or y me diat ors a n d 
bl o o d -brai n barrier brea k d o w n.  Bl oc ki n g α 4 -p ositi ve le u k oc y tes wit h 
nataliz u ma b i n s u bjects wit h dr u g- resista nt f ocal e pile ps y ma y i m pr o ve 
seiz ure c o ntr ol b y re d uci n g le u k oc yte vasc ular i nteracti o ns a n d 
s u p pressi n g i nfla m mat or y acti vit y at t he disease site.
St u d y  O bjecti ves 
a n d E n d p oi nts
T he pri mar y  efficac y o bjecti ve of t he st u d y is t o deter mi ne if a dj u ncti ve 
t hera py of nataliz u ma b 3 0 0 m g i ntra ve n o us (I V) i nf usi o n e ver y 
4 wee ks re d uces t he fre q ue nc y  of seiz ures i n a d ult s u bjects wit h 
dr u g -resista nt f ocal e pile ps y.  T he pri mar y efficac y e n d p oi nt is t he 
c ha n ge fr o m B aseli ne i n l o g-tra nsf or me d seiz ure fre q ue nc y ( n u m ber of 
seiz ures per 2 8 da y s) d uri n g Wee ks 8 t o 2 4 of treat me nt.
Seiz ures i ncl u de d i n efficac y  a nal yses are f ocal a ware seiz ures 
( pre vi o usly ter me d “si m ple partial seiz ures”) wit h m ot o r si g ns, f ocal 
i m paire d a ware ness seiz ures ( pre vi o usl y ter me d “c o m ple x partial 
seiz ures”), a n d f ocal t o bilateral t o nic-cl o nic seiz ures ( pre vi o usl y 
ter me d “ partial o nset wit h sec o n dar y ge neralizati o n”).  F ocal a ware 
seiz ures wit h o ut m ot or si g ns will n ot be i ncl u de d.
Seiz ure cl usters ( w here i n di vi d ual seiz ures ca n n ot be disti n g uis he d) 
will be c o u nte d as 1 seiz ure per cl uster o n eac h da y  t hat t he y are 
prese nt .
T he sec o n dar y  efficac y o bjecti ve is t o assess t he effects of nataliz u ma b 






Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o n tai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 1
a 1: 1 rati o.  T he ra n d o mizati o n will be stratifie d , as m uc h as p ossi ble,
base d o n t he prese nce or a bse nce of str uct ural eti ol o g y  f or f ocal 
e pile ps y, a n d base d o n t he prese nce or a bse nce of a hi g h seiz ure 
fre q ue nc y (≥2 4 seiz ures) d uri n g t he 6 -wee k pr os pecti ve baseli ne 
peri o d.
All s u bjects will recei ve 1 d ose of st u d y  treat me nt at Wee k 0 acc or di n g 
t o t heir ra n d o mizati o n i nt o 1 of t he f oll o wi ng 2 treat me nt gr o u p s wit h 
d osi n g e ver y  4 wee ks f or 2 4 wee ks:

Nataliz u ma b 3 0 0 m g I V i nf usi o n i n a p pr o xi matel y 
3 5 s u bjects

Place b o I V i nf usi o n i n a p pr o xi matel y 3 5 s u bjects
I n t he o pe n-la bel p hase of t he st u d y, all s u bjects will be assi g ne d 
nataliz u ma b 3 0 0 m g I V i nf usi o n e ver y 4 wee ks f or 2 4 wee ks.
D urati o n of 
Treat me nt a n d 
F oll o w - u p:
St u d y  d urati o n f or eac h s u bject will be a p pr o xi matel y 7 4 wee ks f or 
s u bjects c o m pleti n g t he place b o-c o ntr olle d, o pe n-la bel, a n d f oll o w- u p 
p hases :

6 - wee k pr os pecti ve baseli ne peri o d

8 -wee k d o u ble - bli n d, place b o-c o ntr olle d acti ve r u n-i n peri o d

1 6 -wee k d o u ble -bli n d, place b o -c o ntr olle d efficac y peri o d

2 4 -wee k o pe n -la bel acti ve treat me nt peri o d ( o pe n-la bel p hase)

1 2 -wee k p ost -treat me nt f oll o w-u p peri o d (e q uates t o 1 6 wee ks 
after t he last d ose of st u d y treat me nt)

F oll o w -U p Safet y  P h o ne Call ( 2 4 wee ks after t he last d ose of 
st u d y treat me nt)


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 2
2. 
LI S T O F A B B R E VI A TI O N S
A E
a d verse e ve nt
A E D
a ntie pile ptic dr u g
A L T
ala ni ne a mi n otra nsferase
A N C
a bs ol ute ne utr o p hil c o u nt
A S T
as partate a mi n otra nsferase
A U C ta u
area u n der t he ser u m c o nce ntrati o n- ti me c ur ve f or a d osi n g i nter val
B B B
bl o o d -brai n barrier
C D
Cr o h n ’s disease
CI
c o nfi de nce i nter val
C ma x
ma xi m u m ser u m c o nce ntrati o n
C N S
ce ntral ner v o us s ys te m
C R F
case re p ort f or m
C R O
c o ntract researc h or ga nizati o n
C- S S R S
C ol u m bia -S uici de Se verit y  Rati n g Scale
D H A
Directi o ns f or Ha n dli n g a n d A d mi nistrati o n
D N A
de o x yri b o n ucleic aci d
D S M C
d ata safet y mo nit ori n g co m mittee
e C O A
electr o nic Cli nical O utc o me Assess me nt
E C o G
electr oc ortic o gra m
e C-S S R S
electr o nic C ol u m bia-S uici de Se verit y Rati n g Scale
E T
Earl y Ter mi nati o n
F D A
U nite d States F o o d a n d Dr u g A d mi nistrati o n
G C P
G o o d Cli nical Practice
I CF
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
I E R C
i nde pe n de nt e pile ps y re vie w c o m mittee
I R T
i nteracti ve res p o nse tec h n ol o g y
I S M
I n de pe n de nt S afet y M o nit or
I T T
i nte nt-t o-treat
I V
intra ve n o us
J C V
J o h n C u n ni n g ha m vir us
M M R M
mi xe d m o del f or re peate d meas ures
M RI
ma g netic res o na nce i ma gi n g
M S
m ulti ple sc ler osis
P K
p har mac o ki netic(s)
P M L
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y
P R N
as nee de d
R N A
ri b o n ucleic aci d


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 3
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
U S
U nite d States
V C A M - 1
vasc ular cell a d hesi o n m olec ule- 1
W B C
w hite bl o o d cell


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 4
3. 
S P O N S O R I N F O R M A TI O N
Bi o ge n is res p o nsi ble f or t he st u d y .
Bi o ge n M A I nc.
2 2 5 Bi n ne y  Street
Ca m bri d ge, M A  0 2 1 4 2
U nite d States
Bi o ge n I dec Researc h Li mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d, Ber ks hire 
S L 6 4 A Y
U nite d Ki n g d o m
F or ur ge nt me dical iss ues i n w hic h t he st u d y  Me dical Direct or s h o ul d be c o ntacte d, please refer 
t o t he St u d y  C o ntact List f or c o m plete c o ntact i nf or mati o n.
Bi o ge n ma y  tra nsfer a n y or all of its st u d y-relate d res p o nsi bilities t o a c o ntract researc h 
or ga nizati o n ( C R O) a n d ot her t hir d parties; h o we ver, Bi o ge n retai ns o verall acc o u nta bilit y f or 
t hese acti vities.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 5
4. 
I N T R O D UC TI O N
Nataliz u ma b is a rec o m bi na nt h u ma nize d m o n ocl o nal a nti b o d y  a p pr o ve d i n t he U nite d States 
( U S), t he E ur o pea n U ni o n, a n d m ulti ple c o u ntries i n t he rest of t he w orl d f or t he treat me nt of 
rela psi n g f or ms of m ulti ple scler osis ( M S).  I n t he U S, it is als o a p pr o ve d f or t he treat me nt of 
m o derate -t o-se vere Cr o h n’s disease ( C D) i n patie nts wit h e vi de nce of i nfla m mati o n w h o ha ve 
ha d i na de q uate res p o nses t o, or are u na ble t o t olerate, c o n ve nti o nal C D t hera pies.
Nataliz u ma b is pr o d uce d i n a m uri ne m yel o ma cell li ne ( N S 0) a n d bi n ds t o t he α 4 s u b u nit of 
h u ma n i nte gri n, w hic h is e x presse d at hi g h le vels o n all circ ulati n g h u ma n le u k oc y tes e xce pt 
p ol y m or p h o n uclear le u k oc y tes.  Nataliz u ma b bi n di n g bl oc ks t he i nteracti o n of α 4 β 1 i nte gri n 
(als o k n o w n as ver y late a nti ge n-4) o n le u k oc y tes wit h its c o u nter rece pt or, vasc ular cell 
a d hesi o n m olec ule-1 ( V C A M -1) a n d fi br o necti n, l ocate d o n e n d ot helial cells.  L i ke wise, 
nataliz u ma b bl oc ks t he i nteracti o n of α 4 β 7 i nte gri n e x presse d o n le u k oc y tes wit h m uc osal 
a d dressi n cell a d hesi o n m olec ule -1.  Disr u pti o n of t hese cell a d hesi o n m olec ule i nteracti o ns 
pre ve nts traffic ki n g of m o n o n uclear le u k oc y tes acr oss t he e n d ot heli u m a n d i nt o pare nc h ymal 
tiss ue.
I n a d diti o n, α 4 i nte gri ns bi n d a d diti o nal li ga n ds i n tiss ues, i ncl u di n g oste o p o nti n an d fi br o necti n.  
A f urt her mec ha nis m of nataliz u ma b ma y  be t o s u p press o n g oi n g i nfla m mat or y reacti o ns i n 
disease d tiss ues b y i n hi biti o n of bi n di n g of α 4 -p ositi ve le u k oc y tes wit h t hese li ga n ds.  T h us, 
nataliz u ma b ma y  act t o s u p press e xisti n g i nfla m mat or y acti vit y prese nt at t he disease site, al o n g 
wit h i n hi biti n g f urt her recr uit me nt of i m m u ne cells i nt o i nfla me d tiss ue b y  i nteracti o n wit h 
V C A M - 1 ( Nataliz u ma b I n vesti gat or’s Br oc h ure 2 0 1 6).  T his is belie ve d t o be t he basis of its 
efficac y i n M S a n d C D.
Bi o ge n c o nti n ues t o e val uate nataliz u ma b f or t he treat me nt of M S i n cli nical st u dies w orl d wi de.  
T his is t he first cli nical st u d y  of nataliz u ma b i n s u bjects wit h e pile ps y.
4. 1. 
O ver vie w of E pile ps y
E pile ptic seiz ures are par o x y s mal e pis o des res ulti n g fr o m a b n or mally disc har gi n g ne ur o ns t hat 
ma y  be detecte d t hr o u g h electr oe nce p hal o gra p hic or cli nical mea ns, wit h t he partic ular site of t he 
brai n affecte d i nfl ue nci n g cli nical e x pressi o n.  E pile ptic seiz ures f u n da me ntall y  arise fr o m a n 
i m bala nce i n t he basic e xcita bilit y of ne ur o ns t hat ma y  be relate d t o t he ne ur o nal me m bra ne or 
e xcitat or y a n d i n hi bit or y pr ocesses [Br o w ne a n d H ol mes 2 0 0 4 ].  E pile ps y  is c o nce pt ually 
defi ne d as a dis or der of t he brai n c haracterize d b y a n e n d uri n g pre dis p ositi o n t o ge nerate 
e pile ptic seiz ures a n d b y t he ne ur o bi ol o gic, c o g niti ve, ps yc h ol o gical, a n d s ocial c o nse q ue nces of 
t his c o n diti o n [Fis her 2 0 0 5 ]. A rece nt re vie w of t he pre va le nce a n d i nci de nce of e pile psy 
re p orte d a lifeti me pre vale nce of 7. 6 per 1 0 0 0 pers o ns a n d a n n ual c u m ulati ve i nci de nce of 6 7. 7 7 
per 1 0 0, 0 0 0 pers o ns [Fiest 2 0 1 7 ].


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 6
4. 2. 
C urre nt T her a pies f or E pile ps y
T he mai nsta y  of t hera py f or patie nts wit h e pile psy re mai ns a ntie pile pti c dr u gs ( A E Ds), a n d it is 
esti mate d t hat a p pr o xi matel y  7 0 % of patie nts ac hie ve g o o d seiz ure c o ntr ol wit h A E D t hera py.  
Patie nts w h o fail a de q uate trials of 2 ( or m ore) t olerate d a n d a p pr o priately c h ose n a n d use d 
A E Ds are defi ne d as ha vi n g dr u g- resista nt e pile ps y [K wa n 2 0 1 0 ].  F or t hese patie nts, ot her 
t hera pies are c o nsi dere d i ncl u di n g e pile ps y s ur ger y, ne ur osti m ulati o n de vices, s pecialize d diets, 
be ha vi oral t hera pies, a n d ot her e x per i me ntal treat me nts.
A E Ds t y picall y  w or k t hr o u g h m o d ulati o n of v olta ge-de pe n de nt or li ga n d -gate d i o n c ha n nels or 
t hr o u g h effects o n i n hi bit or y or e xcitat or y ne ur otra ns mitter s yste ms.  C urre ntl y, t here are o ver 
2 0 A E Ds a vaila ble c o m merciall y.  Des pite t he la u nc h of ma n y ne wer A E Ds i n rece nt ye ars, b ot h 
ne w a n d ol d dr u gs re mai n ge nerall y e q uall y effecti ve i n ma na gi n g e pile ps y, a n d it is still rare f or 
pri or dr u g -resista nt e pile ps y patie nts t o bec o me seiz ure free wit h t he ne wer t hera pies
[E n gel 2 0 0 7 ].
4. 3. 
Pr ofile of Pre vi o us E x perie nce Wit h N at aliz u m a b
See t he I n vesti gat or’s Br oc h ure f or detaile d i nf or mati o n o n rele va nt n o ncli nical a n d cli nical 
st u dies.
4. 3. 1. 
N o ncli nic al E x perie nce
T he p har mac ol o g y , p har mac o ki netics ( P K), a n d t o xic ol o g y of nataliz u ma b ha ve bee n 
c haracterize d i n n o ncli nical i n vitr o a n d i n vi v o e x peri me ntal s y ste ms.  N o ncli nical st u dies are 
o utli ne d i n t he acc o m pa n yi n g I n vesti gat or’s Br oc h ure f or nataliz u ma b.
4. 3. 2. 
Cli nic al E x perie nce
Nataliz u ma b has bee n us e d e xte nsi vel y i n t he setti n g of rela psi n g re mitti n g M S a n d C D, b ot h i n 
cli nical st u dies as well as i n t he p ost mar keti n g setti n g.  As o f 07 A u g ust 2 0 1 7 , a p pr o xi matel y 
4 0 2 7 s u bjects ha d recei ve d nataliz u ma b f or M S i n cli nical st u dies, a n d a p pr o xi matel y 
1 7 1 ,6 3 0 s u bjects ha d recei ve d nataliz u ma b f or M S i n t he p ost mar keti n g setti n g.  A p pr o xi matel y 
1 6 3 9 a n d 1 6 8 8 s u bjects ha d recei ve d nataliz u ma b f or C D i n cli nical st u dies a n d i n t he 
p ost mar keti n g setti n g, res pecti vel y .  I n t he P hase 3 st u dies, nataliz u ma b was a dmi nistere d e ver y  
4 wee ks at a 3 0 0 m g fi xe d d ose f or a mi ni m u m of 6 m o nt hs , a n d t he a p pr o ve d d ose is 3 0 0 m g 
e ver y 4 wee ks.  T heref ore, t he safet y  of nataliz u ma b w he n gi ve n as a 3 0 0 m g i ntra ve n o us (I V) 
i nf usi o n e ver y 4 wee ks has bee n well c haracterize d i n t h ese s pecific s u bject p o p ulati o ns.  In 
a d diti o n, 2 3 1, 2 1 0 , a n d 6 s u bjects ha ve recei ve d nataliz u ma b i n cli nical st u dies f or r he u mat oi d 
art hritis, ac ute isc he mic str o ke, a n d m ulti ple m y el o ma, res pecti vel y.  
T he efficac y  of nataliz u ma b i n s u bjects wit h rela psi n g f or ms of M S has bee n esta blis he d i n 
3 c o ntr olle d st u dies: a P hase 2 d ose -c o m paris o n st u d y as well as 2 P hase 3 efficac y  a n d safety 
st u dies.  In b ot h P hase 3 st u dies, treat me nt wit h nataliz u ma b dela y e d t he ti me t o s ustai ne d 
pr o gressi o n i n disa bilit y , su bsta ntiall y  re d uce d t he fre q ue nc y of rela pses, a n d mar ke dly 
atte n uate d brai n ma g netic res o na nce i ma gi n g ( M RI ) meas ures of i nfla m mati o n a n d tiss ue 


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 7
destr ucti o n i n s u bjects wit h rela psi n g f or ms of M S.  Nataliz u ma b as m o n ot hera p y si g nifica ntl y 
re d uce d t he risk of disa bilit y  pr o gressi o n b y 4 2 % relati ve t o place b o.
Nataliz u ma b has als o bee n e val uate d i n a P hase 2a st u d y  t hat assesse d s u bjects wit h ac ute 
isc he mic str o ke.  Alt h o u g h t he pri mar y efficac y a nal ysis de m o nstrate d t hat nataliz u ma b di d n ot 
decrease ac ute i nfarct v ol u me gr o wt h defi ne d b y M RI, nataliz u ma b treat me nt was ass ociate d 
wit h i m pr o ve d cli nical o utc o mes i n pres pecifie d sec o n dar y  a n d tertiar y cli nical e n d p oi nts.  M ore 
rece ntly, a P hase 2 b st u d y di d n ot meet pri mar y a n d sec o n dar y efficac y e n d p oi nts, a n d f urt her 
de vel o p me nt of nataliz u ma b i n ac ute isc he mic str o ke is n ot bei n g p urs ue d.
A f ull o utli ne of a d verse dr u g reacti o ns is a vaila ble i n t he acc o m pa n y i n g I n vesti gat or’s Br oc h ure 
f or nataliz u ma b.  O verall, nataliz u ma b has bee n well t olerate d i n s u bjects wit h M S, wit h si milar 
i nci de nces of c o m m o n a d verse e ve nts ( A Es) a n d si milar pr o p orti o ns of s u bjects disc o nti n ui n g 
t he st u d y d ue t o a n A E i n nataliz u ma b a n d place b o treat me nt gr o u ps.  Seri o us a d verse e ve nts 
( S A Es) occ urre d sli g htl y less fre q ue ntly i n natal iz u ma b-treate d s u bjects wit h M S ( 1 5. 5 %) t ha n i n 
s u bjects wit h M S w h o recei ve d place b o ( 1 8. 9 %), wit h M S rela pse c o ntri b uti n g si g nifica ntly t o 
t he i nci de nce.  T he m ost n ota ble c o m plicati o n of treat me nt wit h nataliz u ma b is t he ris k of 
pr o gressi ve m ultif ocal l e u k oe nce p hal o pat h y ( P M L).  P M L is a n o p p ort u nistic viral i nfecti o n of 
t he ce ntral ner v o us sys te m ( C N S) ca use d by t he J o h n C u n ni n g ha m vir us (J C V).  A m o n g t he 
s u bjects w h o de vel o pe d P M L, nataliz u ma b e x p os ure ra n ge d fr o m 8 t o 1 3 4 m o nt hs, wit h t he 
maj orit y  ha vi n g recei ve d > 2 4 m o nt hs of treat me nt.  T hree esta blis he d ris k fact ors f or t he 
de vel o p me nt of P M L  ha ve bee n i de ntifie d: t he prese nce of a nti -J C V a nti b o dies, l o n ger treat me nt 
d urati o n of nataliz u ma b (es peciall y ≥2 ye ars), a n d i m m u n os u p pressa nt use pri or t o recei vi n g 
nataliz u ma b.  A P M L  ris k al g orit h m is l ocate d i n t he acc o m pa n yi n g I n vesti gat or’s Br oc h ure f or 
nataliz u ma b.
Base d o n acc u m ulate d cli nical e x perie nce i n t he treat me nt of M S a n d C D, t he P M L  ris k esti mate 
wit h ne gati ve a nti b o d y stat us, p ositi ve a nti b o d y stat us wit h o ut i n de x val ue, or a nti b o d y 
i n de x ≤0. 9 is 0. 1/ 1 0 0 0 d uri n g 1 t o 1 2 m o nt hs of nataliz u ma b e x p os ure.  T he P M L  ris k wit h 
a nti b o d y i n de x > 1. 5 is 0. 2/ 1 0 0 0 d uri n g 1 t o 1 2 m o nt hs of nataliz u ma b e x p os ure a n d i n s u bjects 
pre vi o usl y  treate d wit h a n i m m u n os u p pressa nt dr u g, t he P M L ris k is 0. 3/ 1 0 0 0 d uri n g 1 t o 
1 2 m o nt hs of nataliz u ma b e x p os ure.  Ot her ris ks of nataliz u ma b tr eat me nt i ncl u de 
h y perse nsiti vit y  reacti o ns, i nfecti o ns, a n d he patic i nj ur y.  Seri o us h yperse nsiti vit y  reacti o ns (e. g., 
a na p h yl a xis) ha ve occ urre d at a n i nci de nce of < 1 %.  A p pr o xi matel y  6 % of s u bjects i n cli nical 
st u dies de vel o pe d persiste nt a nti b o dies t o nataliz u ma b t hat were ass ociate d wit h a decrease i n t he 
effecti ve ness of nataliz u ma b.
4. 4. 
St u d y R ati o n ale
T here is a hi g h u n met nee d t o de vel o p t hera pies t hat i m pr o ve seiz ure c o ntr ol or eli mi nate 
seiz ures i n dr u g-resista nt e pile ps y.  Tar geti n g t he p ote ntial r ole of t he i m m u ne s yste m a n d 
i nfla m mati o n i n t he pat h o ge nesis of e pile psy re prese nts a n u n dere x pl ore d area i n A E D 
de vel o p me nt a n d cli nical st u dies.  E vi de nce fr o m b ot h e x peri me ntal m o dels of e pile psy a n d 
h u ma n patie nts wit h e pile ps y  s u g gest a r ole f or i nfla mmati o n.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 8
Precli nical data ha ve de m o nstrate d a n i nfla m mat or y  res p o nse after i n d uce d seiz ures, i ncl u di n g 
e x pressi o n of c yt o ki nes a n d i nfla m mat or y me diat ors [Vezza ni a n d Gra nata 2 0 0 5 ] a n d 
m o d ulati o n of ne ur o nal firi n g b y bl o o d - brai n barrier (B B B) brea k d o w n [Marc hi 2 0 1 2 ].  
F urt her m ore, i n a pil ocar pi ne -i n d uce d e pile psy m o use m o del, ac ute seiz ure acti vit y  i ncrease d 
vasc ular e x pressi o n of le u k oc y te a d hesi o n m olec ules i ncl u di n g V C A M-1 a n d e n ha nce d 
le u ko c y te a d hesi o n t o C N S vessels i n vi v o.  Treat me nt of t he pil ocar pi ne-i njecte d mice wit h 
α 4 i nte gri n-s pecific mo n ocl o nal a nti b o d y or a nti b o dies t o V C A M - 1 after stat us e pile ptic us 
s h o we d mar ke d re d ucti o n of s p o nta ne o us c o n v ulsi o ns d uri n g t he c hr o nic peri o d. W he n 
a nti b o dies t o α 4 i nte gri n were gi ve n 2 h o urs bef ore pil ocar pi ne i njecti o n, it c o m pletel y  pre ve nte d 
c o n v ulsi o ns [Fa be ne 2 0 0 8 ].
I n h u ma n patie nts, st u dies s ho w hist o pat h ol o gical e vi de nce of i ncrease d B B B per mea bilit y  i n 
s ur gical s peci me ns fr o m refract or y e pile ps y patie nts [Ra vizza 2 0 0 8 ; va n Vliet 2 0 0 7 ].  Ele vate d 
brai n le u k oc y te n u m bers ha ve bee n see n i n h u ma n c ortical C N S tiss ue fr o m s u bjects wit h 
e pile ps y c o m pare d t o c o ntr ol s u bjects wit h o ut e pile ps y [Fa be ne 2 0 0 8 ].  F urt her m ore, 
si g nifica ntly hi g her c o nce ntrati o ns of V C A M -1 i n ser u m a n d cere br os pi nal fl ui d ha ve bee n 
detecte d i n patie nts wit h dr u g- refract or y e pile psy t ha n i n t h ose wit h ne w dia g n osis a n d 
dr u g -res p o nsi ve e pile psy [L u o 2 0 1 4 ].  Fi nall y, a case re p ort descri be d a s u bsta ntial be nefit i n t he 
re d ucti o n of seiz ures after i nitiati n g t hera py wit h nataliz u ma b f or M S [S ot gi u 2 0 1 0 ].  T heref ore, 
bl oc ki n g α 4 -p ositi ve le u k oc y tes wit h nataliz u ma b i n patie nts wit h dr u g-resista nt f ocal e pile psy 
ma y  i m pr o ve seiz ure c o ntr ol b y re d uci n g le u k oc yt e- vasc ular i nteracti o ns a n d s u p pressi n g 
i nfla m mat or y acti vit y at t he disease site.
4. 4. 1. 
D ose R ati o n ale
T his P hase 2 st u d y  will e val uate t he effect of a dj u ncti ve t hera p y of nataliz u ma b 3 0 0 m g I V 
i nf usi o n e ver y 4 wee ks o n seiz ure c o ntr ol i n a d ult s u bjects wit h dr u g -resista nt f ocal e pile psy.  
T his is t he a p pr o ve d d ose a n d sc he d ule of a d mi nistrati o n f or t he tre at me nt of M S gl o ball y a n d 
C D i n t he U S, a n d t he safet y  pr ofile at t his d ose has bee n well esta blis he d i n t hese i n dicati o ns.  
Nataliz u ma b has bee n a d mi nistere d i ntra ve n o usly i n si n gle d oses as well as i n m o nt hl y re peate d 
d oses at 3. 0 m g/ k g a n d 6. 0 m g/ k g i n cli nical st u dies i n healt h y v ol u nteers a n d i n M S a n d C D 
s u bjects.  Efficac y a n d safet y res ults fr o m P hase 2 st u dies i n dicate d n o statisticall y  si g nifica nt 
differe nces bet wee n m o nt hl y  d oses at 3. 0 m g / k g a n d 6. 0 m g/ k g.  I n a d diti o n, t he α 4 i nte gri n 
sat urati on o n peri p heral bl o o d m o n o n uclear cells was deter mi ne d i n se veral st u dies after si n gle 
a n d m ulti ple d oses.  T he fi xe d 3 0 0 m g d ose use d i n P hase 3 st u dies s h o we d t hat a 7 0 % sat urati o n 
was mai ntai ne d o ver a 4 - wee k d osi n g i nter val i n s u bjects wit h ne gati ve res ults f or 
a nti-nataliz u ma b a nti b o dies.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 9
5. 
S C H E D U L E O F A C TI VI TI E S
T he sc he d ule of acti vities f or St u d y 1 0 1 E P 2 0 1 be gi ns o n t he ne xt pa ge.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of Bi o ge n M A  I nc.
2 0
T a ble 1 :  
Sc he d ule of Acti vities f or St u d y 1 0 1 E P 2 0 1
St u d y Visits/ Wee k s Scree ni n g 
Visi t
Wee k - 6
Visit 1
B aseli ne
Wee k 0
Visit 2
Wee k 4
Visit 3
Wee k 8
Visit 4
Wee k 1 2
Visit 5
Wee k 1 6
Visit 6
Wee k 2 0
Visit 7
Wee k 2 4 1
Visit 8
Wee k 2 8
Visit 9
Wee k 3 2
Visit 1 0
Wee k 3 6
Visit 1 1
Wee k 4 0
Visit 1 2
Wee k 4 4
Visit 1 3
Wee k 4 8
or E T 
Visit 2
E n d of 
St u d y Visit
Wee k 6 0 
or 
F oll o w -u p 
Visit f or 
E T 
S u bjects
( 1 6 wee k s 
after l ast 
d ose of 
st u d y 
tre at me nt3)
F oll o w - u p
S afet y 
P h o ne C all
Wee k 6 8 
( 2 4 wee k s 
after t he 
l ast d ose of 
st u d y 
tre at me nt)4
P h ase of St u d y  
Scree ni n g
Pl ace b o -C o ntr olle d P h ase
O pe n -L a bel P h ase
P ost -Tre at me nt 
F oll o w -U p
St u d y D a ys
D a y -4 2
+ 1 d a y 5
D a y 1
+ 5 d a y s5
D a y 2 8
± 5 d a ys
D a y 5 6
± 5 d a ys
D a y 8 4
± 5 d a ys
D a y 1 1 2
± 5 d a ys
D a y 1 4 0
± 5 d a ys
D a y 1 6 8
± 5 d a ys
D a y 1 9 6
± 5 d a ys
D a y 2 2 4
± 5 d a ys
D a y 2 5 2
± 5 d a ys
D a y 2 8 0
± 5 d a ys
D a y 3 0 8
± 5 d a ys
D a y 3 3 6
± 5 d a ys
D a y 4 2 0
± 5 d a ys
D a y 4 7 6
± 5 d a ys
I nf or me d C o nse nt 
X
Re vie w I ncl usi o n 
a n d E xcl usi o n 
Criteria
X   
X
De m o gra p hics a n d 
Me dical Hist or y 
I ncl u di n g Seiz ure 
a n d A ntie pile ptic 
Me dicati o n Hist or y
6
X
P h ysical a n d 
Ne ur ol o gical 
E xa mi nati o n 7
X
X
X   
X
Vital Si g ns 8
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
M RI  brai n sca n9
X
Pre g na nc y Test 1 0
X   
X
Ra n d o mizati o n
X


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of Bi o ge n M A  I nc.
2 1
St u d y Visits/ Wee k s Scree ni n g 
Visi t
Wee k - 6
Visit 1
B aseli ne
Wee k 0
Visit 2
Wee k 4
Visit 3
Wee k 8
Visit 4
Wee k 1 2
Visit 5
Wee k 1 6
Visit 6
Wee k 2 0
Visit 7
Wee k 2 4 1
Visit 8
Wee k 2 8
Visit 9
Wee k 3 2
Visit 1 0
Wee k 3 6
Visit 1 1
Wee k 4 0
Visit 1 2
Wee k 4 4
Visit 1 3
Wee k 4 8
or E T 
Visit 2
E n d of 
St u d y Visit
Wee k 6 0 
or 
F oll o w -u p 
Visit f or 
E T 
S u bjects
( 1 6 wee k s 
after l ast 
d ose of 
st u d y 
tre at me nt3)
F oll o w - u p
S afet y 
P h o ne C all
Wee k 6 8 
( 2 4 wee k s 
after t he 
l ast d ose of 
st u d y 
tre at me nt)4
P h ase of St u d y  
Scree ni n g
Pl ace b o -C o ntr olle d P h ase
O pe n -L a bel P h ase
P ost -Tre at me nt 
F oll o w -U p
St u d y D a ys
D a y -4 2
+ 1 d a y 5
D a y 1
+ 5 d a y s5
D a y 2 8
± 5 d a ys
D a y 5 6
± 5 d a ys
D a y 8 4
± 5 d a ys
D a y 1 1 2
± 5 d a ys
D a y 1 4 0
± 5 d a ys
D a y 1 6 8
± 5 d a ys
D a y 1 9 6
± 5 d a ys
D a y 2 2 4
± 5 d a ys
D a y 2 5 2
± 5 d a ys
D a y 2 8 0
± 5 d a ys
D a y 3 0 8
± 5 d a ys
D a y 3 3 6
± 5 d a ys
D a y 4 2 0
± 5 d a ys
D a y 4 7 6
± 5 d a ys
St u d y Treat me nt 
A d mi nistrati o n 1 1
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
Distr i b ute Seiz ure 
Diar y 1 2
X
Re vie w Seiz ure 
Diar y 1 2
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
He mat ol o g y a n d 
Bl o o d C he mistr y 1 3 , 1 4
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
Uri nal ysis
X   
X   
X   
X   
X   
X   
X   
X
X
X
Bl o o d Sa m ple f or 
He patitis B a n d C 
Ser ol o gies 
X
Bl o o d Sa m ple f or 
A nti -Nataliz u ma b 
A nti b o dies 1 3
X
X
X
X
Bl o o d Sa m ple f or 
A nti -J C V A nti b o d y
I n de x
X
X
X


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of Bi o ge n M A  I nc.
2 2
St u d y Visits/ Wee k s Scree ni n g 
Visi t
Wee k - 6
Visit 1
B aseli ne
Wee k 0
Visit 2
Wee k 4
Visit 3
Wee k 8
Visit 4
Wee k 1 2
Visit 5
Wee k 1 6
Visit 6
Wee k 2 0
Visit 7
Wee k 2 4 1
Visit 8
Wee k 2 8
Visit 9
Wee k 3 2
Visit 1 0
Wee k 3 6
Visit 1 1
Wee k 4 0
Visit 1 2
Wee k 4 4
Visit 1 3
Wee k 4 8
or E T 
Visit 2
E n d of 
St u d y Visit
Wee k 6 0 
or 
F oll o w -u p 
Visit f or 
E T 
S u bjects
( 1 6 wee k s 
after l ast 
d ose of 
st u d y 
tre at me nt3)
F oll o w - u p
S afet y 
P h o ne C all
Wee k 6 8 
( 2 4 wee k s 
after t he 
l ast d ose of 
st u d y 
tre at me nt)4
P h ase of St u d y  
Scree ni n g
Pl ace b o -C o ntr olle d P h ase
O pe n -L a bel P h ase
P ost -Tre at me nt 
F oll o w -U p
St u d y D a ys
D a y -4 2
+ 1 d a y 5
D a y 1
+ 5 d a y s5
D a y 2 8
± 5 d a ys
D a y 5 6
± 5 d a ys
D a y 8 4
± 5 d a ys
D a y 1 1 2
± 5 d a ys
D a y 1 4 0
± 5 d a ys
D a y 1 6 8
± 5 d a ys
D a y 1 9 6
± 5 d a ys
D a y 2 2 4
± 5 d a ys
D a y 2 5 2
± 5 d a ys
D a y 2 8 0
± 5 d a ys
D a y 3 0 8
± 5 d a ys
D a y 3 3 6
± 5 d a ys
D a y 4 2 0
± 5 d a ys
D a y 4 7 6
± 5 d a ys
Bl o o d Sa m ples f or 
P K 1 3
X 1 6
X   
X   
X   
X
X 1 6
X   
X   
X   
X   
X
X 1 6
X
e C-S S R S/ C -S S R S 1 8
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
A Es a n d S A Es 1 9
Rec or d as detaile d i n Secti o n 1 5. 3
C o nc o mita nt 
T hera pies/ Pr oce d ures
Rec or d as detaile d i n Secti o n 1 1. 5




Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of Bi o ge n M A  I nc.
2 4
f ocal e pile ps y.  3 T M RI sca n ni n g is preferre d w here ver p ossi ble.  S u bjects wit h o ut a n M RI of t he brai n wit hi n 4 8 m o nt hs pri or t o scree ni n g a n d wit h a n a bs ol ute c o ntrai n dicat i o n 
t o M RI will be c o nsi dere d o n a case-b y -case basis.  
1 0 Re q uire d o nl y f or w o me n of c hil d beari n g p ote ntial (f or defi niti o n, see Secti o n 1 5. 5 ).  A ser u m pre g na nc y test s h o ul d be perf or me d at t he Scree ni n g Visit ( Wee k -6), a n d a uri ne 
pre g na nc y test s h o ul d be perf or me d at Wee k 0 pri or t o ra n d o mizati o n.  T he uri ne pre g na nc y testi n g will be perf or me d l ocall y pri or t o ra n d o mizati o n.  F oll o w - u p pre g na nc y 
testi n g t hr o u g h o ut t he st u d y will be d o ne at t he discreti o n of t he I n vesti gat or or as re q uire d b y l ocal la w.
1 1 S u bjects m ust be o bser ve d f or 1 h o ur after c o m pleti o n of i nf usi o n.
1 2 S u bjects ( or t heir care gi vers) m ust rec or d t heir seiz ure t y pe a n d fre q ue nc y dail y fr o m Scree ni n g Visit ( Wee k - 6) t hr o u g h E n d of St u d y Visit ( Wee k 6 0), or f or s u bjects w h o 
ter mi nate t he st u d y earl y t hr o u g h t he F oll o w-u p Visit 1 6 wee ks after t heir last d ose of st u d y treat me nt.  S u bjects m ust bri n g t heir seiz ure diar y wit h t he m t o eac h st u d y visit.
1 3 Bl o o d sa m ples s h o ul d be c ollecte d pri or t o st u d y treat me nt a d mi nistrati o n at Wee k 0 t h r o u g h Wee k 4 4.  T he ti me of c ollecti o n, al o n g wit h t he start a n d st o p ti mes f or t he st u d y 
treat me nt i nf usi o n, m ust be rec or de d i n t he s u bject’s s o urce data a n d o n t he s u bject’s C R F.
1 4 W B C ( ot her t ha n a bs ol ute ne utr o p hil c o u nt) data will be re vie we d b y a n I n de pe n de nt Safet y M o nit or (see Secti o n 1 9. 2. 4 ).
1 6 B ot h pre d ose a n d p ost d ose bl o o d sa m ples are t o be c ollecte d f or P K a t Wee k
0 , Wee k
2 0 , a n d Wee k 4 4 .  T he p ost d ose sa m ple m ust be c ollecte d wit hi n 1 h o ur after c o m pleti o n 
of st u d y treat me nt i nf usi o n.  T he ti me of c ollecti o n, al o n g wit h t he start a n d st o p ti mes f or t he st u d y treat me nt i nf usi o n, m ust be rec or de d i n t he s u bjec t’s s o urce data a n d o n t he 
s u bject’s C R F.
1 8 T he “ baseli ne/scree ni n g” e C -S S R S/ C - S S R S m ust be c o m plete d at t he Scree ni n g Visit ( Wee k - 6); at all ot her visits, t he “si nce last visit” e C -S S R S/ C -S S R S m ust be use d.
1 9 S A E re p orti n g f or P M L or ne w ne ur ol o gical s y m pt o ms i n dicati ve of P M L (e. g., ne w or s u d de n c ha n ge i n t hi n ki n g, visi o n, bala nce, or stre n gt h persisti n g o ver se veral da ys) m ust 
c o nti n ue fr o m t he E n d of St u d y Visit ( Wee k 6 0) t hr o u g h t he F oll o w -U p Safet y P h o ne Call .  Ot her wise, after t he E n d of St u d y Visit or F oll o w- u p Visit f or E T s u bjects, S A Es 
s h o ul d be re p orte d o nl y if t he I n vesti gat or c o nsi ders t he S A E t o be relate d t o st u d y treat me nt.  
2 0 S u bjects s h o ul d be c o ntacte d b y p h o ne 2 4 wee ks after t he last d ose of st u d y treat me nt t o disc uss if t here has bee n a n y ne w de vel o p me nt of a n y ne w ne ur ol o gical s y m pt o ms.  
P M L or ne w ne ur ol o gical s y m pt o ms i n dicati ve of P M L (e. g., ne w or s u d de n c ha n ge i n t hi n ki n g, visi o n, bala nce, or stre n gt h persisti n g o ver se veral da ys) m ust be i m me diatel y 
re p orte d as a n S A E.








Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
2 8
7. 
S T U D Y D E SI G N
T his is a 6 -m o nt h ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o assess t he efficac y, 
safety, a n d t olera bilit y of nataliz u ma b as a dj u ncti ve t hera p y i n t he treat me nt of a d ult s u bjects 
wit h dr u g -resista nt f ocal e pile ps y.
All s u bjects will c o m plete a 6 -wee k pr os pecti ve baseli ne peri o d wit h o ut st u d y  treat me nt t o 
esta blis h a baseli ne seiz ure fre q ue nc y .  After c o m pleti n g scree ni n g assess me nts a n d f ulfilli n g t he 
criteria f or st u d y e ntr y, eli gi ble s u bjects will be ra n d o ml y assi g ne d t o 1 of 2 treat me nt gr o u ps i n 
a 1: 1 rati o, a n d eac h s u bject will recei ve 1 d ose of st u d y  treat me nt at Wee k 0 wit h d osi n g e ver y  
4 wee ks f or 2 4 wee ks, acc or di n g t o 1 of t he f oll o wi n g 2 re gi me ns:  3 0 0 m g I V nataliz u ma b 
i nf use d o ver 1 h o ur or place b o I V.   T he ra n d o mizati o n will be stratifie d , as m uc h as p ossi ble, 
base d o n t he prese nce or a bse nce of str uct ural eti ol o g y  f or f ocal e pile psy a n d base d o n t he 
prese nce or a bse nce of a hi g h seiz ure fre q ue nc y  (≥2 4 seiz ures) d uri n g t he 6 -wee k pr os pect i ve 
baseli ne peri o d.  Str uct ural eti ol o g y  f or f ocal e pile ps y is defi ne d as a b n or malities visi ble o n 
str uct ural ne ur oi ma gi n g w here t he electr ocli nical assess me nt t o get her wit h t he i ma gi n g fi n di n gs 
lea d t o a reas o na ble i nfere nce t hat t he i ma gi n g a b n or malit y is t he li kel y ca use of t he s u bject’s 
seiz ures [Sc heffer 2 0 1 7 ], a n d t his assess me nt will be a dj u dicate d b y a n i n de pe n de nt e pile ps y 
re vie w c o m mittee (I E R C) [ Secti o n 1 9. 2. 2 ].
T here will be n o d ose titrati o n of nataliz u ma b. T he i nitial 8 wee ks of t he place b o -c o ntr olle d 
p hase will c o nstit ute a n acti ve r u n-i n peri o d i n or der f or nataliz u ma b t o ac hie ve a p pr o xi matel y 
7 5 % of stea d y state i n s u bjects wit h o ut a nti - nataliz u ma b a nti b o dies, base d o n pri or st u dies i n 
M S.
At t he e n d of t he place b o -c o ntr olle d p hase, s u bjects will c o nti n ue i nt o a 2 4 -wee k o pe n -la bel 
safety a n d efficac y p hase i n w hic h all s u bjects will recei ve nataliz u ma b 3 0 0 m g I V i nf usi o n 
e ver y 4 wee ks f or 2 4 wee ks.
A p ost -treat me nt f oll o w- u p visit a n d a F oll o w -U p Safet y  P h o ne Call will occ ur 1 6 wee ks a n d 
2 4 wee ks, res pecti vel y, after t he last d ose o f st u d y treat me nt.
A data base l oc k a n d a nal y sis will occ ur at t he e n d of t he place b o-c o ntr olle d p hase.
A p pr o xi matel y  7 0 s u bjects are e x pecte d t o be e nr olle d, ra n d o mize d, a n d d ose d ( ~ 3 5 s u bjects i n 
eac h treat me nt gr o u p) at a p pr o xi matel y  4 4 sites i n t he U S. T he st u d y  will ai m t o i ncl u de 
a p pr o xi matel y 2 8 s u bjects wit h a str uct ural eti ol o g y f or f ocal e pile ps y a n d a p pr o xi matel y 
2 8 s u bjects wit h a hi g h seiz ure fre q ue nc y , a n d t hese are n ot m ut uall y e xcl usi ve.
See Fi g ure 1 f or a sc he matic of t he st u d y desi g n.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
2 9
Fi g u re 1: 
St u d y Desi g n Sc he m atic
A b bre viati o n: I V = i ntra ve n o us.
7. 1. 
St u d y D ur ati o n f or S u bjects
T he t otal d urati o n of st u d y  partici pati o n f or eac h s u bject will be u p t o a p pr o xi matel y 7 4 wee ks 
f or s u bjects c o m pleti n g t he place b o-c o ntr olle d, o pe n -la bel, a n d f oll o w- u p p hases.  T his c o nsists 
of a 6 -wee k pr os pecti ve baseli ne peri o d, a 2 4 -wee k d o u ble -bli n d place b o -c o ntr olle d p hase 
c o nsisti n g of a n 8 - wee k acti ve r u n-i n peri o d a n d a 1 6-wee k efficac y peri o d , a 2 4- wee k 
o pe n -la bel p hase, a 1 2-wee k p ost -treat me nt f oll o w-u p peri o d , a n d a F oll o w -U p Safet y P h o ne 
Call ( 2 4 wee ks after t he last d ose of st u d y  treat me nt).
T he e n d of st u d y date f or a s u bject ma y be t he last st u d y visit, last pr ot oc ol -s pecifie d assess me nt, 
or if t he s u bject has o n g oi n g A Es t hat are bei n g f oll o we d - u p, t he date ma y be t he date of A E 
res ol uti o n.
7. 2. 
St u d y St o p pi n g R ules
Bi o ge n ma y  ter mi nate t his st u d y at a ny ti me after i nf or mi n g t he I n vesti gat ors.  Bi o ge n, or 
desi g nee, will n otif y  In vesti gat ors w he n t he st u d y  is t o be place d o n h ol d, c o m plete d, or 
ter mi nate d.  A n i n de pe n de nt d ata safet y m o nit ori n g co m mittee ( D S M C) will be f or me d a n d will 
re vie w efficac y a n d safet y data re g ularly.  Details of t he D S M C res p o nsi bilities will be pr o vi de d 
i n t he D S M C c harter.
7. 3. 
E n d of St u d y
T he e n d of st u d y is last s u bject, last p h o ne call f or fi nal c ollecti o n of data.  T he e n d of t he 
place b o -c o ntr olle d p hase will be after t he assess me nts are ta ke n at Wee k 2 4, bef ore st u d y 
treat me nt a d mi nistrati o n f or t he o pe n-la bel p hase.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 0
8. 
S E L E C TI O N O F S U B J E C T S
8. 1. 
I ncl usi o n Criteri a
T o be eli gi ble t o partici pate i n t his st u d y , ca n di dates m ust meet t he f oll o wi n g eli gi bilit y criteria 
at t he ti me of scree ni n g or at t he ti me p oi nt s pecifie d i n t he i n di vi d ual eli gi bilit y  criteri o n liste d, 
a n d m ust be rec o nfir me d at t he ti me of ra n d o mizati o n:
1.
A bilit y  of t he s u bject or his/ her le gall y a ut h orize d re prese ntati ve (e. g., pare nt or le gal 
g uar dia n) t o u n dersta n d t he p ur p ose a n d ris ks of t he st u d y  a n d pr o vi de si g ne d a n d date d 
i nf or me d c o nse nt a n d a ut h orizati o n t o use c o nfi de ntial healt h i nf or mati o n i n acc or da nce 
wit h nati o nal a n d l ocal s u bject pri vac y  re g ulati o ns.
2.
A ge d 1 8 t o 7 5 ye ars, i ncl usi ve, at t he ti me of i nf or me d c o nse nt or s u bject meets t he 
mi ni m u m a ge of c o nse nt i n acc or da nce wit h nati o nal re g ulati o ns ( w hic he ver is hi g her).
3.
M ust ha ve f ocal e pile ps y dia g n ose d o n cli nical gr o u n ds a n d as a p plica ble s u p p orte d b y 
electr oe nce p hal o gra m fi n di n gs [Sc heffer 2 0 1 7 ] a n d brai n i ma gi n g.  S u bjects wit h 
m ultif ocal e pile ps y  m a y  be i ncl u de d if all ot her e ntr y criteria are met.
4. 
M ust ha ve a dr u g- resista nt e pile ps y defi ne d as fail ure of a de q uate trials of 2 ( or m ore) 
t olerate d a n d a ppr o priatel y  c h ose n a n d use d A E Ds ( w het her as m o n ot hera pies or i n 
c o m bi nati o n ) [K wa n 2 0 1 0 ].
5. 
M ust ha ve ha d a M RI sca n of t he brai n wit hi n 4 8 m o nt hs of t he Scree ni n g Visit 
( Wee k -6) t o assist i n t he electr ocli nical assess me nt of a str uct ural eti ol o g y f or f ocal 
e pile ps y.  F or s u bjects n ot meeti n g t his criterio n , a n M RI m a y be o btai ne d wit hi n t he 
pr os pecti ve baseli ne peri o d.  S u bjects wit h o u t a n M RI  of t he brai n wit hi n 4 8 m o nt hs 
pri or t o scree ni n g a n d wit h a n a bs ol ute c o ntrai n dicati o n t o M RI  will be c o nsi dere d o n a 
case-b y -case basis (see Ta ble 1 ).
6.
M ust ha ve c o nfir mati o n of dia g n osis of dr u g -resista nt f ocal e pile psy b y a me m ber of t he 
I E R C [ Sectio n 1 9. 2. 2 ].  T he i n de pe n de nt re vie wer will als o a dj u dicate t he prese nce or 
a bse nce of a str uct ural eti ol o g y  f or f ocal e pile psy.  A p pr o priate dia g n ostic i nf or mati o n 
m ust be se nt t o t he re vie wer as s o o n as p ossi ble after t he Scree ni n g Visit ( Wee k - 6) b ut 
pre fera bly s h o ul d n ot be less t ha n 2 wee ks pri or t o ra n d o mizati o n.
T he st u d y  will ai m t o i ncl u de a p pr o xi matel y 2 8 s u bjects wit h a str uct ural eti ol o g y f or 
f ocal e pile psy a n d a p pr o xi matel y 2 8 s u bjects wit h a hi g h seiz ure fre q ue nc y  (≥2 4 seiz ures 
d uri n g t he 6 -wee k pr os pecti ve baseli ne peri o d), a n d t hese are n ot m ut uall y  e xcl usi ve.
7.
E x perie nces 6 or m ore seiz ures d uri n g t he 6 -wee k pr os pecti ve baseli ne peri o d a n d is n ot 
seiz ure free f or m ore t ha n 2 1 c o nsec uti ve da ys d uri n g t he pr os pecti ve baseli ne peri o d.  
Seiz ures i ncl u de d i n c o u nts are f ocal a ware seiz ures ( pre vi o usl y ter me d “si m ple partial 


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 1
seiz ures”) wit h m ot or si g ns, f ocal i m paire d a ware ness seiz ures ( pre vi o usly ter me d 
“c o m ple x partial seiz ures” ), a n d f ocal t o bilateral t o nic-cl o nic seiz ures ( pre vi o usl y 
ter me d “ partial o nset wit h sec o n dar y ge neralizati o n”).  F ocal a ware seiz ures wit h o ut 
m ot or si g ns will n ot be i ncl u de d.
8.
Sta ble re gi me n of 1 t o 5 A E Ds.  Sta ble is defi ne d as n o m o dificati o n of A E D d osi n g 
wit hi n 4 wee ks pri or t o t he Scree ni n g Visit ( Wee k - 6).  D osi n g r e gi me n m ust als o be 
sta ble t hr o u g h o ut t he 6-wee k pr os pecti ve baseli ne peri o d . Be nz o diaze pi nes use d o n a 
re g ular basis f or a ny i n dicati o n at sta ble d osi n g will be c o nsi dere d as a n A E D.  As 
nee de d (P R N ) be nz o diaze pi ne use f or occasi o nal seiz ure e xacer bati o n is all o we d a n d 
m ust be d oc u me nte d.  P R N be nz o diaze pi ne use f or a n y ot her i n dicati o n (e. g ., slee p or 
a n xiet y) m ust als o be d oc u me nte d as s uc h.  P R N be nz o diaze pi ne use f or a n y i n dicati o n 
a vera gi n g m ore t ha n t wice wee kl y ( m ore t ha n 1 2 d oses) d uri n g t he 6 -wee k pr os pecti ve 
baseli ne peri o d will be c o nsi dere d as a n A E D .  Ne ur osti m ulati o n, i ncl u di n g va g us ner ve 
sti m ulati o n a n d t he R N S S yste m, is all o we d a n d m ust be d oc u me nte d ; h o we ver, 
i m pla ntati o n m ust ha ve occ urre d at least 6 m o nt hs pri or t o t he Scree ni n g Visit ( Wee k - 6).  
D osi n g para meters f or ne ur osti m ulati o n m ust be sta ble f or 4 wee ks pri or t o e nr oll me nt 
a n d t hr o u g h o ut t he 6 - wee k pr os pecti ve baseli ne peri o d.  Pri or e pile ps y s ur ger y  is 
all o we d; h o we ver, s ur ger y m ust ha ve occ urre d at least 6 m o nt hs pri or t o t he Scree ni n g 
Visit ( Wee k - 6).  A ket o ge nic diet is all o we d a n d m ust be d oc u me nte d; h o we ver, 
i nitiati o n m ust ha ve occ urre d a n d t he patie nt m ust be at a sta ble rati o at least 4 wee ks 
pri or t o t he Scree ni n g Visit ( Wee k - 6) a n d t hr o u g h o ut t he 6 - wee k pr os pecti ve baseli ne 
peri o d .
9.
All w o me n of c hil d beari n g p ote ntial a n d all me n m ust practice hi g hl y effecti ve 
c o ntrace pti o n d uri n g t he st u d y a n d f or at least 3 m o nt hs after t heir last d ose of st u d y  
treat me nt.  F or f urt her details of c o ntrace pti ve re q uire me nts f or t his stu d y , please refer t o 
Secti o n 1 5. 5 .
8. 2. 
E xcl usi o n Criteri a
Ca n di dates will be e xcl u de d fr o m st u d y e ntr y if a n y of t he f oll o wi n g e xcl usi o n criteria e xist at 
t he ti me of scree ni n g, or at t he ti me p oi nt s pecifie d i n t he i n di vi d ual criteri o n liste d, a n d m ust be 
rec onfir me d at t he ti me of ra n d o mizati o n :
1.
F ocal a ware seiz ures wit h o ut m ot or si g ns are t he o nl y seiz ure ty pe.
2.
Dia g n osis of ge neralize d, c o m bi ne d ge neralize d a n d f ocal, or u n k n o w n e pile ps y  
[Sc heffer 2 0 1 7 ].
3.
K n o w n pr o gressi ve str uct ural C N S lesi o n.
4.
Hist or y  of seiz ures occ urri n g i n pre d o mi na ntl y cl ustere d patter ns, as deter mi ne d b y  t he 
In vesti gat or, o ver t he 1 2 m o nt hs pri or t o t he Scree ni n g Visit ( Wee k -6) or d uri n g t he 
6 - wee k pr os pecti ve baseli ne peri o d, w here i n di vi d ual seiz ures ca n n ot be c o u nte d.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 2
5.
Hist or y  of stat us e pile ptic us wit hi n t he pre vi o us 6 m o nt hs .
6.
K n o w n hist or y  or prese nce of n o n-e pile ptic seiz ures.
7.
C urre nt maj or de pressi ve e pis o de, a p ositi ve re p ort o n t he “ baseli ne/scree ni n g” e C -S S R S 
at t he Scree ni n g Visit ( Wee k -6) or o n t he “si nce last visit” e C -S S R S at Wee k
0 , or 
c o nsi dere d at ris k of s uici de or self -har m base d o n t he cli nical j u d ge me nt of t he 
I n vesti gat or ( Secti o n 1 4. 1 ).
8.
K n o w n pla n ne d e pile ps y s ur ger y or a d missi o n t o t he e pile psy m o nit ori n g u nit wit h 
i nte n de d dr u g c ha n ge wit hi n 1 2 m o nt hs of Wee k 0 .
9.
A n y  cli nicall y si g nifica nt me dical c o n diti o n t hat ma y c o ntrai n dicate t he use of 
nataliz u ma b, i m pair relia ble partici pati o n i n t he st u d y, or necessitate t he use of 
me dicati o n n ot all o we d per pr ot oc ol.
1 0. E vi de nce of si g nifica nt acti ve he patic disease i ncl u di n g ele vati o ns of as partate 
a mi n otra nsferase ( A S T) or ala ni ne a mi n otra nsferase ( A L T) a b o ve 3 ti mes t he u p per li mit 
of n or mal or bilir u bi n a b o ve 2 ti mes t he u p per li mit of n or mal.
1 1. E vi de nce of si g nifica nt acti ve re nal disease i ncl u di n g creati ni ne a b o ve 2 ti mes t he u p per 
li mit of n or mal.
1 2. E vi de nce of si g ni fica nt acti ve he mat ol o gic disease i ncl u di n g a bs ol ute ne utr o p hil c o u nt 
( A N C) < 1 0 0 0 μ L, platelet c o u nt < 8 0, 0 0 0, a bs ol ute l y m p h oc y te c o u nt < 8 0 0 cells/μ L.
1 3. K n o w n hist or y  of p ositi ve test res ult f or h u ma n i m m u n o deficie nc y vir us.
1 4. K n o w n hist or y  of p ositi ve test res ult f or he patitis C vir us a nti b o d y or he patitis B vir us 
( defi ne d as p ositi ve f or he patitis B s urface a nti ge n A N D he patitis B c ore a nti b o d y ).
1 5. Si g ns of acti ve her pes si m ple x t y pe 1 or 2 or varicella wit hi n 4 wee ks pri or t o 
ra n d o mizati o n.
1 6. S y m pt o ms of bacterial, f u n gal, or viral i nfecti o n (i ncl u di n g u p per res pirat or y  tract 
i nfecti o n) wit hin 1 4 d a y s pri or t o ra n d o mizati o n.
1 7. A cli nicall y  si g nifica nt i nfecti o us ill ness (e. g., cell ulitis, a bscess, p ne u m o nia, se ptice mia, 
t u berc ul osis) wit hi n 3 m o nt hs pri or t o ra n d o mizati o n, or P M L  or ot her o p p ort u nistic 
i nfecti o ns at a ny ti me.
1 8. Si g ns or s y m pt o ms s u g gesti ve of a n y  o n g oi n g seri o us i nfecti o n, base d o n me dical 
hist or y , p h ysical e xa mi nati o n, or la b orat or y testi n g, as c o nsi dere d b y t he I n vesti gat or.
1 9. I m m u n oc o m pr o mise d s u bjects as deter mi ne d by t he I n vesti gat or, base d o n me dical 
hist or y , p h ysical e xa mi natio n, la b orat or y  testi n g, or i m m u n os u p pressi ve or 
i m m u n o m o d ulati n g treat me nt.  Im m u n os u p pressi ve or i m m u n o m o d ulati n g treat me nt, 




Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 4
9. 
S C R E E NI N G A N D R A N D O M I ZA TI O N
9. 1. 
Scree ni n g 
S u bjects or t heir le gall y a ut h orize d re prese ntati ve (e. g., pare nt or le gal g uar dia n m ust pr o vi de 
inf or me d c o nse nt bef ore a n y scree ni n g tests are perf or me d ) [see Secti o n 1 7. 3 ].  Partici pati n g 
st u d y sites are re q uire d t o d oc u me nt all scree ne d ca n di dates i nitiall y c o nsi dere d f or i ncl usi o n i n 
t he st u d y.  
Scree n fail ures are defi ne d as s u bjects w h o si g n t h e i nf or me d c o nse nt f or m (IC F) b ut are n ot 
s u bse q ue ntl y ra n d o mize d.  If a s u bject is c o nsi dere d a scree n fail ure, t he reas o ns f or e xcl usi o n 
m ust be d oc u me nte d i n t he s u bject’s s o urce d oc u me nts a n d o n t he scree ni n g l o g.  A mi ni mal set 
of scree n fail ure i nf or mati o n is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure 
partici pa nts t o meet t he C o ns oli date d Sta n dar ds of Re p orti n g Trials p u blis hi n g re q uire me nts a n d 
t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities.  Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, 
scree n fail ure details, eli gi bilit y criteria, a n d a n y S A Es.  In di vi d uals w h o d o n ot meet t he criteria 
f or partici pati o n i n t his st u d y (i.e., a scree n fail ure) ma y  be rescree ne d o nce per In vesti gat or 
discreti o n.
9. 2. 
R a n d o miz ati o n 
S u bjects will be ra n d o mize d after all scree ni n g assess me nts ha ve bee n c o m plete d a n d after t he 
I n vesti gat or has verifie d t hat t he s u bjects are eli gi ble per criteria i n Secti o ns 8. 1 a n d 8. 2 .  
S u bjects will be assi g ne d a u ni q ue i de ntificati o n n u m ber t hat will be use d o n st u d y -relate d 
d o c u me nts pertai ni n g t o t he s u bject.  A n y s u bject i de ntificati o n n u m bers t hat are assi g ne d will 
n ot be re use d e ve n if t he s u bject d oes n ot recei ve treat me nt or c o nti n ue i n t he st u d y .
Ra n d o mizati o n will be perf or me d usi n g i nteracti ve res p o nse tec h n ol o g y  (I R T).  S u bjects will be 
ra n d o mize d t o recei ve nataliz u ma b: place b o i n a 1: 1 rati o.  T he ra n d o mizati o n will be stratifie d, 
as m uc h as p ossi ble, base d o n t he prese nce or a bse nce of str uct ural eti ol o g y f or f ocal e pile ps y 
a n d base d o n t he prese nce or a bse nce of a h i gh seiz ure fre q ue n c y  (≥2 4 seiz ures) d uri n g t he 
6 - wee k pr os pecti ve baseli ne peri o d.  I n t he o pe n-la bel p hase, all s u bjects will be assi g ne d 
nataliz u ma b.
9. 3. 
Bli n di n g Pr oce d ures
T he I n vesti gat or, st u d y site staff, a n d s u bjects will re mai n bli n de d t o t he s u bject treat me nt 
assi g n me nts t hr o u g h o ut t he st u d y.  T o mai ntai n t he st u d y bli n d, it is i m perati ve t hat s u bject 
treat me nt assi g n me nts are n ot s hare d wit h t he s u bjects, t heir fa milies, or a n y me m ber of t he 
bli n de d st u d y  tea m, b ot h at t he st u d y site a n d at Bi o ge n an d t he C R O .  T he st u d y  s p o ns or a n d 
C R O st u d y  ma na ge me nt tea m will be f ull y bli n de d f or t he place b o-c o ntr olle d p hase of t he st u d y.  
After t he place b o -c o ntr olle d p hase is c o m plete d a n d t he cli nical st u d y  data base is l oc ke d, 
desi g nate d st u d y  s p o ns or pers o n nel will be u n bli n de d t o t he place b o -c o ntr olle d data f or t he 
p ur p ose of e val uati n g t he Wee k 2 4 data.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 5
At t he e n d of t he st u d y a n d f oll o wi n g fi nalizati o n of t he cli nical st u dy re p ort, if u n bli n di n g will 
n ot je o par dize t he res ults of o n g oi n g relate d st u dies, Bi o ge n will pr o vi de t he ra n d o mizati o n 
c o des t o I n vesti gat ors, w h o t he n ca n i nf or m t heir s u bjects a b o ut t he treat me nt recei ve d.  


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 6
1 0. 
DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D 
WI T H D R A W A L O F S U B J E C T S F R O M T H E S T U D Y
1 0. 1. 
Disc o nti n u ati o n of St u d y Tre at me nt
A s u bject m ust per ma ne ntl y  disc o nti n ue st u d y treat me nt f or a n y of t he f oll o wi n g reas o ns:

T he s u bject bec o mes pre g na nt.  St u d y treat me nt m ust be disc o nti n ue d i m me diatel y.  
Re p ort t he pre g na nc y  acc or di n g t o t he i nstr ucti o ns i n Secti o n 1 5. 4. 1 .

T he s u bject wit h dra ws c o nse nt t o c o nti n ue st u d y treat me nt.

T he s u bject desires t o disc o nti n ue treat me nt u n der t his pr ot oc ol.

T he s u bject is u n willi n g or u na ble t o c o m pl y wit h t he pr ot oc ol.

T he s u bject e x perie nces a me dical e mer ge nc y  t hat necessitates per ma ne nt 
disc o nti n uati o n of treat me nt .

T he s u bject re q uires m o dificati o n of A E Ds d ue t o a cli nicall y  si g nifica nt i ncrease i n 
seiz ure fre q ue nc y or i nte nsit y or d ue t o e mer ge nce of a ne w seiz ure t y pe.

T he s u bject e x perie nces h y perse nsiti vit y  or s us pecte d aller gic reacti o n t o st u d y 
treat me nt.

T h e s u bject e x perie nces a c ha n ge i n la b orat or y  val ues t hat necessitates per ma ne nt 
disc o nti n uati o n of treat me nt i ncl u di n g t he de vel o p me nt of acti ve he patic, re nal , or 
he mat ol o gical disease.

T he s u bject misses 2 or m ore c o nsec uti ve d oses of st u d y  treat me nt or d oes n ot recei ve 
st u d y treat me nt f or a peri o d of 1 0 wee ks.

P M L  or ot her A Es/ S A Es t hat t he I n vesti gat or belie ves necessitates disc o nti n uati o n.

At t he discreti o n of t he I n vesti gat or f or me dical reas o ns, f or n o nc o m plia nce, or f or 
reas o ns liste d i n t he c urre nt prescri bi n g i nf or mati o n.
T he pri mar y  reas o n f or disc o nti n uati o n of st u d y treat me nt m ust be rec or de d i n t he s u bject’s case 
re p ort f or m ( C R F).  O nce t he s u bject disc o nti n ues st u d y treat me nt, t he s u bject will n ot be 
eli gi ble t o restart st u d y treat me nt.  All s u bjects w h o disc o nti n ue st u d y treat me nt pre mat urely 
s h o ul d re mai n i n t he st u d y a n d u n der g o a n Early Ter mi nati o n ( E T) Visit ( 4 wee ks after t he last 
st u d y d ose), F oll o w -u p Visit ( 1 6 wee ks after t he last st u d y  d ose), a n d F oll o w-u p Safet y P h o ne 
Call ( 2 4 wee ks after t he last st u d y d ose).


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 7
1 0. 2. 
L ost t o F oll o w -U p
S u bjects will be c o nsi dere d l ost t o f oll o w -u p if t he y re peate dl y  fail t o ret ur n f or sc he d ule d visits 
a n d are u na ble t o be c o ntacte d b y t he st u d y site. 
T he f oll o wi n g acti o ns m ust be ta ke n if a s u bject fails t o ret ur n t o t he st u d y site f or a re q uire d 
st u d y visit:

T he st u d y site m ust atte m pt t o c o ntact t he s u bject a n d resc he d ule t he misse d visit as s o o n 
as p ossi ble a n d c o u nsel t he s u bject 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 t he s u bject wis hes t o a n d/ or s h o ul d c o nti n ue i n t he st u d y .

I n cases i n w hic h t he s u bject is dee 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 ver y  eff ort t o re gai n c o ntact wit h t he s u bject.  T hese c o ntact atte m pts s h o ul d 
be d oc u me nt e d i n t he s u bject’s me dical rec or d.

S h o ul d t he s u bject c o nti n ue t o be u nreac ha ble, t hat s u bject 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 wit h a pri mar y  reas o n of l ost t o f oll o w- u p.
1 0. 3. 
Wit h dr a w al of S u bjects Fr o m t he St u d y
S u bjects m ust be wit h dra w n fr o m t he st u d y f or a n y o ne of t he f oll o wi n g reas o ns:

T he s u bject wit h dra ws c o nse nt.  

T he s u bject e nr olls i nt o a n ot her i nter ve nti o nal cli nical st u d y  i n w hic h a n 
i n vesti gati o nal treat me nt or a p pr o ve d t hera py f or i n vesti gati o nal use is a d mi nistere d.

T he s u b ject is u n willi n g or u na ble t o c o m ply wit h t he pr ot oc ol.
T he pri mar y  reas o n f or t he s u bject’s wit h dra wal fr o m t he st u d y m ust be rec or de d i n t he s u bject’s 
C R F.
S u bjects w h o wit h dra w fr o m t he st u d y  after ra n d o mizati o n ma y n ot be re place d.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 8
1 1. 
S T U D Y T R E A T M E N T U S E
1 1. 1. 
Re gi me n
Refer t o a n d f oll o w t he Directi o ns f or Ha n dli n g a n d A d mi nistrati o n ( D H A).
D oses s h o ul d be gi ve n wit hi n t he visit wi n d o ws pr o vi de d i n t he sc he d ule of acti vities ( Ta ble 1 ).  
I n t he e ve nt of a misse d d ose, t he d ose s h o ul d be gi ve n as s o o n as p ossi ble, as l o n g as it is at 
least 2 1 d a y s fr o m t he ne xt d ose as st u d y treat me nts m ust occ ur at least 2 1 da y s a part.  Misse d 
d oses are ot her wise n ot all o we d t o be gi ve n.
If t he s u bject misses 2 or m ore c o nsec uti ve st u d y treat me nts or d oes n ot recei ve st u d y treat me nt 
f or a peri o d of 1 0 wee ks, t he s u bject m ust per ma ne ntl y  disc o nti n ue st u d y treat me nt 
( Secti o n 1 0. 1 ).
1 1. 2. 
M o dific ati o n of D ose
T he d osa ge of nataliz u ma b ca n n ot be m o difie d.
1 1. 3. 
Prec a uti o ns
T he s u bject m ust be o bser ve d f or 1 h o ur after c o m pleti o n of t he i nf usi o n.
1 1. 4. 
C o m pli a nce
All d oses of st u d y treat me nt will be a d mi nistere d b y  t he st u d y site staff.
1 1. 5. 
C o nc o mit a nt T her a p y a n d Pr oce d ures
1 1. 5. 1. 
C o nc o mit a nt T her a p y
A c o nc o mita nt t hera p y is a n y dr u g or s u bsta nce, i ncl u di n g n o n prescri pti o n me dicati o ns or her bal 
pre parati o ns, ot her t ha n t he st u d y treat me nt a d mi nistere d bet wee n t he Scree ni n g Visit ( Wee k -6) 
a n d t he E n d of St u d y Visit ( Wee k 6 0) or t he F oll o w- u p Visit ( 1 6 wee ks after t he last d ose of 
st u d y treat me nt).  All c o nc o mita nt t hera pies m ust be rec or de d i n t he s u bject’s me dical rec or d a n d 
o n t he a p pr o priate C R F .  Gi ve n t he mec ha nis m of acti o n of nataliz u ma b, n o si g nifica nt 
dr u g -dr u g i nteracti o ns are e x pecte d wit h c o nc o mita nt A E Ds.  Fel ba mate is o nl y  all o we d if t he 
la b orat or y criteria are met a n d t he patie nt is o n sta ble d osi n g for at least 2 4 m o nt hs pri or t o t he 
Scree ni n g Visit ( Wee k -6) beca use of t he war ni n gs of a plastic a ne mia a n d he patic fail ure i n t he 
la beli n g.  Ot her disall o we d c o nc o mita nt t hera pies are liste d i n Secti o n 1 1. 5. 1. 2 .  Bi o ge n ma y be 
c o ns ulte d f or assista nce re g ar di n g w het her a s pecific me dicati o n is all o we d or disall o we d.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 9
1 1. 5. 1. 1. 
M o dific ati o n of A E Ds
S u bjects e nteri n g t he st u d y  m ust be o n a sta ble re gi me n of A E D treat me nt t hr o u g h o ut t he 6-wee k 
pr os pecti ve baseli ne peri o d a n d t hr o u g h o ut Wee k 1 2 of t he place b o -c o ntr olle d p hase .  P R N 
be nz o diaze pi ne use f or occasi o nal seiz ure e xacer bati o n is all o we d a n d m ust be d oc u me nte d.  
S u bjects w h o use P R N be nz o diaze pi nes f or reas o ns u nrelate d t o seiz ures s h o ul d n ot c ha n ge t heir 
fre q ue nc y of use fr o m t he pr os pecti ve baseli ne peri o d.
A n y s u bject re q uiri n g m o dificati o n of A E Ds d uri n g t he 6- wee k pr os pecti ve baseli ne peri o d 
c o nstit utes a scree n fail ure.  I n t he j u d ge me nt of t he I n vesti gat or, if after ra n d o mizati o n t he 
s u bject re q uires m o dificati o n of A E Ds d ue t o a cli nicall y si g nifica nt i ncrease i n seiz ure 
fre q ue nc y or i nte nsity or f or e mer ge nce of a ne w seiz ure t y pe, t he s u bject m ust per ma ne ntl y 
disc o nti n ue st u d y  treat me nt; after t he 8-wee k r u n -i n peri o d t his c o nstit utes lac k of efficac y of 
st u d y treat me nt.
I n t he j u d ge me nt of t he I n vesti gator, if after Wee k 1 2 of t he place b o -c o ntr olle d p hase t he s u bject 
re q uires m o dificati o n of A E Ds d ue t o lac k of i m pr o ve me nt or o n g oi n g seiz ures, t his m ust be 
a p pr o ve d b y a me m ber of t he I E R C ( Secti o n 1 9. 2. 2 ) pri or t o A E D t hera py c ha n ge. M o dificati o n 
of A E Ds m ust be a p pr o ve d t hr o u g h t he E n d of St u d y  Visit ( Wee k 6 0) or F oll o w-u p Visit f or E T 
S u bjects ( 1 6 wee ks after t he last d ose of st u d y treat me nt).  M o dificati o n of A E Ds m ust be 
rec or de d i n t he s u bject’s C R F.
C ha n ges i n d osi n g para meters of ne ur osti m ulati o n a n d i n ket o ge nic diet rati os are i ncl u de d as 
m o dificati o ns of A E Ds.
1 1. 5. 1. 2. 
Dis all o we d C o nc o mit a nt T her a p y
S u bjects s h o ul d be i nstr ucte d t o c o ntact t heir I n vesti gat ors bef ore ta ki n g a n y ne w me dicati o ns, 
i ncl u di n g n o n prescri pti o n dr u gs a n d her bal pre parati o ns.  C o nc o mita nt t hera p y  wit h a n y 
i n vesti gati o nal pr o d uct f or e pile psy or f or n o n -e pile ps y i n dicati o ns is n ot all o we d, wit h t he 
e xce pti o n of ca n na bi n oi d pre parati o ns starte d at sta ble d osi n g at least 4 wee ks pri or t o t he 
Scree ni n g Visit ( Wee k -6) ; i nitiati o n of ca nna bi n oi d pre parati o ns is n ot all o we d after t he 
Scree ni n g Visit ( Wee k -6) .
I nitiati o n of ne w A E Ds or c ha n ge i n A E D d osi n g ma y n ot be perf or me d after t he Scree ni n g Visit 
( Wee k -6) e xce pt as per Secti o n 1 1. 5. 1. 1 .
Ot her disall o we d c o nc o mita nt t hera pies i ncl u de, b ut are n ot li mite d t o t he f oll o wi n g:

i nterfer o n-β or i nterfer o n - α

glatira mer acetate

c ycl o p h os p ha mi de 

terifl u n omi de


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4 0

met h otre xate

di met h y l f u marate

azat hi o pri ne

cla dri bi ne 

mit o xa ntr o ne

I V i m m u n o gl o b uli n

m y c o p he n olate m ofetil

fi n g oli m o d 

nataliz u ma b (f or a n ot her i n dicati o n), dacliz u ma b, rit u xi ma b, ocreliz u ma b, 
ale mt uz u ma b, or a n y t hera pe utic m o n ocl o nal a nti b o d y

fel ba mate, u nless o n sta ble d osi n g f or at least 2 4 m o nt hs pri or t o t he Scree ni n g Visit 
( Wee k - 6)

f u maric aci d esters

c hr o nic oral or I V ster oi ds
1 1. 5. 2. 
C o nc o mit a nt Pr oce d ures
A c o nc o mita nt pr o ce d ure is a n y t hera pe utic i nter ve nti o n (e. g., s ur ger y/ bi o ps y, p h ysical t hera py) 
or dia g n ostic assess me nt (e. g., bl o o d gas meas ure me nt, bacterial c ult ures) perf or me d bet wee n 
t he Scree ni n g Visit ( Wee k -6) a n d t he E n d of St u d y Visit ( Wee k 6 0) or t he F oll o w - u p Visit 
( 1 6 wee ks after t he last d ose of st u d y  treat me nt).
1 1. 6. 
C o nti n u ati o n of Tre at me nt 
N o f urt her pr o visi o ns are ma de f or access t o t he st u d y treat me nt.  If nataliz u ma b is pr o ve n t o be 
be neficial, all re g ulat or y  re q uire me nts re gar di n g p ostst u d y access will be met.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4 1
1 2. 
S T U D Y T R E A T M E N T M A N A G E M E N T
St u d y  treat me nt will be ma n ufact ure d, ha n dle d, a n d st ore d i n acc or da nce wit h a p plica ble G o o d 
Ma n ufact uri n g Practice.
St u d y  site staff s h o ul d f oll o w t he D H A f or s pecific i nstr ucti o ns o n t he ha n dli n g, pre parati o n, 
a d mi nistrati o n, a n d dis p osal of t he st u d y treat me nt.  T he D H A s u perse des all ot her refere nces 
(e. g., pr ot oc ol).
St u d y  treat me nt m ust be dis pe nse d o nl y b y a p har macist or a p pr o priately q ualifie d staff.  St u d y 
treat me nt is t o be dis pe nse d o nl y t o s u bjects e nr olle d i n t his st u d y.  O nce st u d y treat me nt is 
pre pare d f or a s u bject, it ca n be a d mi nistere d o nl y t o t hat s u bject.  St u d y  treat me nt vials are f or 
o ne-ti me use o nl y;  d o n ot use a n y st u d y treat me nt re mai ni n g i n t he vial f or a n ot her s u bject.
1 2. 1. 
N at aliz u m a b
Nataliz u ma b is s u p plie d as a li q ui d i n 1 5 m L vials c o ntai ni n g 3 0 0 m g  of nataliz u ma b per vial.  
Nataliz u ma b c o ntai ns rec o m bi na nt h u ma nize d a nti- α 4 i nte gri n a nti b o d y a n d e xci pie nt materials 
(s o di u m p h os p hate m o n o basic m o n o h ydrate, s o di u m p h os p hate di basic he pta h y drate, s o di u m 
c hl ori de, a n d p ol ys or bate 8 0).
Nataliz u ma b is ma n ufact ure d b y Bi o ge n.
T he c o nte nts of t he nataliz u ma b la bel will be i n acc or da nce wit h all a p plica ble re g ulat or y 
re q uire me nts.  At a mi ni m u m, t he la bel will i ncl u de a st u d y refere nce c o de, st u d y treat me nt 
i de ntifier, q ua ntit y of d osa ge u nits, l ot n u m ber, a n d ot her perti ne nt i nf or mati o n i n acc or da nce 
wit h l ocal la w.  T he e x pir y  or use-b y  date is st ore d i n t he IR T s ys te m, a n d pri nta ble assi g n me nt 
re p orts are a vaila ble t o st u d y site staff.  St u d y treat me nt sh o ul d n ot be use d after t he e x pirati o n, 
e x pir y, or use-b y  date.
1 2. 1. 1.   
N at aliz u m a b Pre p ar ati o n
T he i n di vi d ual pre pari n g nataliz u ma b s h o ul d caref ull y  re vie w t he i nstr ucti o ns pr o vi de d i n t he 
D H A.
If t he pac ka gi n g is da ma ge d, or if t here is a nyt hi n g u n us ual a b o ut t h e a p peara nce or attri b utes of 
t he vials or st u d y treat me nt, d o n ot use t he st u d y treat me nt.  T he vials i n q uesti o n s h o ul d be 
sa ve d at t he st u dy site a n d t he pr o ble m i m me diatel y re p orte d t o Bi o ge n.
1 2. 1. 2. 
N at aliz u m a b St or a ge
St u d y  treat me nt m ust be st ore d i n a secure l ocati o n.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4 2
Nataliz u ma b is t o be st ore d at 2 C t o 8 C ( 3 6 F t o 4 6 F), pr otecte d fr o m li g ht i n a m o nit ore d a n d 
l oc ke d refri gerat or wit h li mite d access.  St u d y treat me nt is n ot t o be fr oze n.  F or t he m ost 
u p -t o-date st ora ge re q uire me nts, f oll o w t he i nstr uc ti o ns pr o vi de d i n t he D H A.
1 2. 1. 3. 
N at aliz u m a b H a n dli n g a n d Dis p os al
T he I n vesti gat or m ust ret ur n all use d a n d u n use d vials of nataliz u ma b as i nstr ucte d b y Bi o ge n, 
u nless a p pr o ve d f or o nsite destr ucti o n.
If a ny nataliz u ma b s u p plies are t o be destr o ye d at t he st u d y site, t he i nstit uti o n or a p pr o priate 
st u d y site staff m ust o btai n pri or a p pr o val fr o m Bi o ge n, b y  pr o vi di n g, i n writi n g, t he destr ucti o n 
p olic y  or details of t he met h o d of destr ucti o n.  After s uc h destr ucti o n, Bi o ge n m ust be n otifie d, 
i n writi n g, of t he details of t he st u d y treat me nt destr o ye d (e. g., l ot or kit n u m bers, q ua ntities), t he 
date of destr ucti o n, a n d pr o of of destr ucti o n.
1 2. 1. 4. 
N at aliz u m a b Acc o u nt a bilit y
Acc o u nta bilit y  f or st u d y treat me nt is t he res p o nsi bilit y of t he I n vesti gat or.  T he st u d y site m ust 
mai ntai n acc urate rec or ds de m o nstrati n g dates a n d a m o u nt of st u d y  treat me nt recei ve d, t o w h o m 
dis pe nse d (s u bject -b y -s u bject acc o u nti n g), a n d acc o u nts of a n y st u d y treat me nt acci de ntally or 
deli beratel y destr o ye d or l ost.
U nless ot her wise n otifie d, all vial s, b ot h use d a n d u n use d, m ust be sa ve d f or st u d y treat me nt 
acc o u nta bilit y.  B y t he e n d of t he st u d y, rec o nciliati o n m ust be ma de bet wee n t he a m o u nt of 
nataliz u ma b s u p plie d, dis pe nse d, a n d s u bse q ue ntl y destr o ye d, l ost, or ret ur ne d t o Bi o ge n.  A 
writte n e x pl a nati o n m ust be pr o vi de d f or a n y discre pa ncies.
1 2. 2. 
Pl ace b o
Place b o is s u p plie d as a li q ui d i n 1 5 m L  vials c o ntai ni n g s o di u m p h os p hate m o n o basic 
m o n o h y drate, s o di u m p h os p hate di basic he pta h y d rate, s o di u m c hl ori de, a n d p ol ys or bate 8 0.
Place b o is ma n ufact ure d b y Bi o ge n.
T he la bel will i ncl u de c o n diti o ns f or st ora ge a n d ot her perti ne nt i nf or mati o n re q uire d b y l ocal 
la w, s uc h as t he l ot/ kit n u m ber a n d ca uti o n state me nt.  Place b o s h o ul d n ot be use d after t he 
e x pirati o n date.








Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4 6
1 4. 
S A F E T Y A S S E S S M E N T S
Refer t o Ta ble 1 f or t he ti mi n g of all safety assess me nts.
Tests a n d e val uati o ns affecti n g pri mar y  e n d p oi nts a n d/ or a nalys es ma y nee d t o be re peate d if t he 
ori gi nal res ults are l ost or da ma ge d.  I n t hese cases, s u bjects will be as ke d t o ret ur n t o t he st u d y 
site t o ha ve t he e val uati o ns re peate d.
1 4. 1. 
Cli nic al S afet y Assess me nts
T he f oll o wi n g cli nical ass ess me nts will be perf or me d t o e val uate t he safet y of t he st u d y 
treat me nt:

M e dical hist or y: s h o ul d i ncl u de a n assess me nt of pri or s u bsta nce a b use.

P h y sical e xa mi nati o ns a n d ne ur ol o gical assess me nts, i ncl u di n g hei g ht a n d wei g ht 
meas ure me nts.

V ital si g n meas ure me nts:  te m perat ure, p ulse rate, s yst olic a n d diast olic bl o o d 
press ure, a n d res pirat or y  rate.

e C-S S R S / C-S S R S :  T he U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A) 
rec o m me n ds pr os pecti ve assess me nt of s uici dal i deati o n a n d be ha vi or i n all cli nical 
st u dies of A E Ds [F D A 2 0 1 2 ].  T he C-S S R S is a pr os pecti ve assess me nt t o ol t o 
e val uate s uici dal i deati o n a n d be ha vi or de vel o pe d b y Dr. Kell y P os ner a n d c ollea g ues 
fr o m C ol u m bia U ni versit y, t he U ni versit y of Pe n ns yl va nia a n d t he U ni versit y of 
Pitts b ur g h [P os ner 2 0 1 1 ].  It has bee n i de ntifie d b y t he F D A as a n acce pta ble 
pr os pecti ve s uici dal i deati o n a n d be ha vi or assess me nt i nstr u me nt [F D A 2 0 1 2 ].  T his 
st u d y will e m pl o y t he electr o nic, c o m p uter-a ut o mate d, patie nt-re p orte d versi o n of t he 
scale, t he e C-S S R S.  H o we ver, if t he e P R O e C -S S R S ca n n ot be c o m plete d , f or 
e xa m ple, d ue t o s y ste m mai nte na nce, u na vaila bilit y of de vice at a n y visit, or if t he 
s u bject is u na ble t o i n de pe n de ntl y c o m plete t he e C -S S R S (e. g., d ue t o c o g niti ve 
li mitati o n), t he site ma y a d mi nister a pa per C-S S R S versi o n of t he assess me nt. At t he 
discreti o n of t he I n vesti gat or, if t he e C- S S R S ca n n ot be c o m plete d d ue t o patie nt 
li mitati o n, t he pa per C-S S R S s h o ul d be a d mi nister e d t hr o u g h o ut t he st u d y f or 
c o nsiste nc y.  T he s u bject will c o m plete t he “ baseli ne/scree ni n g” versi o n of t he scale 
at t he Scree ni n g Visit ( Wee k -6) a n d t he “si nce last visit” versi o n at all s u bse q ue nt 
visits.  S u bjects wit h a p ositi ve re p ort o n t he e C -S S R S / C-S S R S at t he Scree ni n g Visit 
( Wee k -6) or Wee k
0 will be e xcl u de d fr o m t he st u d y .  A p ositi ve re p ort is defi ne d as 
a “ yes” res p o nse o n i deati o n ite ms 4 a n d/ or 5, or a “ yes” res p o nse t o a n y be ha vi or 
ite m (e xce pt n o n-s uici dal self-i nj ur y).  All res p o nses at eac h assess me nt s h o ul d be 
re vie we d f or b ot h p ositi ve a n d ne gati ve re p orts; t he In vesti gat or s h o ul d deter mi ne t he 
a p pr o priate le vel of care f or t he s u bject f or a n y “ yes” res p o nse e ve n if it d oes n ot 
c o nstit ute a p ositi ve re p ort.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4 7

C o nc o mita nt t hera p y a n d pr o ce d ure rec or di n g.

A E a n d S A E rec or di n g: Seiz ures ( wit h t he e xce pti o n of stat us e pile ptic us or a 
cli nicall y si g nifica nt i ncrease i n seiz ure fre q ue nc y or i nte nsit y or e mer ge nce of a ne w 
seiz ure t ype res ulti n g i n disc o nti n uati o n of st u d y  treat me nt, w hic h s h o ul d be re p orte d 
as a n S A E ) will n ot be c ollecte d as A Es as t he y  are c o nsi dere d part of t he pri mar y 
efficac y e n d p oi nt; h o we ver, t he y s h o ul d be rec or de d i n t he seiz ure diar y.
1 4. 2. 
L a b or at or y S afet y Assess me nts
Sa m ples will be a nal y ze d usi n g G o o d La b orat or y Practice-vali date d assa y s.
T he f oll o wi n g la b orat or y assess me nts will be perf or me d t o e val uate t he safet y of t he st u d y 
treat me nt:

H e mat ol o g y:  c o m plete bl o o d c o u nt wit h differe ntial a n d platelet c o u nt, a n d A N C .  
N ote:  W hite bl o o d cell ( W B C) [ ot her t ha n A N C] data will be re vie we d b y a n 
I n de pe n de nt Safety M o nit or (I S M) [see Secti o n 1 9. 2. 4 ].

B l o o d c he mistr y:  t otal pr otei n, al b u mi n, creati ni ne, bl o o d urea nitr o ge n, uric aci d, 
bilir u bi n (t otal a n d direct), al kali ne p h os p hatase, A L T, A S T, ga m ma -gl uta m yl 
tra nsferase, gluc ose, calci u m, p h os p h or us, bicar b o nate, c hl ori de, s o di u m, a n d 
p otassi u m .

S er ol o g y: he patitis B a n d C ser ol o gies.

U ri nal ysis:  di pstic k f or bl o o d, pr otei n, a n d gl uc ose ( micr osc o pic e xa mi nati o n, if 
a b n or mal).

Ser u m a n d uri ne pre g na nc y  tests:  re q uire d o nly f or w o me n of c hil d beari n g p ote ntial 
(f or defi niti o n, see Secti o n 1 5. 5 ).  T he uri ne pre g na nc y  testi n g will be perf or me d 
l ocall y pri or t o ra n d o mizati o n.
1 4. 3. 
N at aliz u m a b -S pecific S afet y Assess me nts
A nti-J C V a nti b o dies are bei n g c ollecte d i n all st u dies of nataliz u ma b.  Assess me nt of a nti -J C V 
a nti b o d y stat us i ncl u di n g i n de x val ues will be perf or me d t o u n dersta n d t he ser o p ositi vit y  t o J C V 
i n t his p o p ulati o n of dr u g-resista nt f ocal e pile psy.  Testi n g will be perf or me d at t he Scree ni n g 
Visit ( Wee k - 6), as well as at W ee k 2 4 (t he be gi n ni n g of t he o pe n -la bel p hase), a n d at Wee k 4 8 .  
Res ults of t he testi n g will be pr o vi de d t o t he I n vesti gat or a n d ma y  be pr o vi de d t o t he s u bject 
u p o n re q uest.
A Es a n d S A Es will be rec or de d d uri n g t he st u d y as descri be d i n Secti o n 1 5. 2 .  I n ad diti o n, t he 
re p orti n g of P M L or ne ur ol o gical sy m pt o ms i n dicati ve of P M L  m ust als o c o nti n ue fr o m t he E n d 
of St u d y  Visit ( Wee k 6 0) t hr o u g h t he F oll o w-U p Safet y  P h o ne Call ( 2 4 wee ks after t he last d ose 
of st u d y  treat me nt).  Ne ur ol o gical s ym pt o ms t hat ma y  be i n dicati ve of P M L i ncl u de be ha vi oral 


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4 8
or c o g niti ve c ha n ges as well as f ocal s y m pt o ms i ncl u di n g a p hasia, vis ual fiel d deficits, 
he mi paresis, a n d ata xia.  P M L  ca n be ass ociate d wit h seiz ures a n d t heref ore c o nsi dere d i n 
s u bjects wit h a cli nicall y si g nifica nt increase i n seiz ure fre q ue nc y  or i nte nsit y or wit h e mer ge nce 
of a ne w seiz ure t y pe.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
4 9
1 5. 
S A F E T Y D E FI NI TI O N S, R E C O R DI N G, R E P O R TI N G , A N D 
R E S P O N SI BI LI TI E S
T hr o u g h o ut t he c o urse of t he st u d y , e ver y eff ort m ust be ma de t o re mai n alert t o p ossi ble A Es.  
If a n A E occ urs, t he first c o ncer n s h o ul d be f or t he safety of t he s u bject.  If necessar y, 
a p pr o priate me dical i nter ve nti o n s h o ul d be pr o vi de d.
At t he si g ni n g of t he I C F, eac h s u bject or his/ her le gall y a ut h orize d re prese ntati ve a n d/ or mai n 
care gi ver m ust be gi ve n t he n a mes a n d tele p h o ne n u m bers of st u d y  site staff f or re p orti n g A Es 
a n d me dical e mer ge ncies.
1 5. 1. 
Defi niti o ns
1 5. 1. 1. 
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct a n d t hat d oes n ot necessaril y ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), sy m pt o m, or disease te m p orall y ass ociate d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici nal (i n vesti gati o nal) 
pr o d uct.
Deter mi nati o n of w het her a n a b n or mal la b orat or y val ue a n d/ or vital si g n res ult meets t he 
defi niti o n of a n A E will be ma de b y t he I n vesti gat or.  A b n or mal res ults are n ot c o nsi dere d A Es 
u nless o ne or m ore of t he f oll o wi n g criteria are met:

T he res ult meets t he criteria f or a n S A E

T he res ult re q uires t he s u bject t o recei ve s pecific c orrecti ve t hera p y

T he res ult is c o nsi dere d b y t he I n vesti gat or t o be cli nicall y  si g nifica nt
1 5. 1. 2. 
Seri o us A d ve rse E ve nt
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

I n t he vie w of t he I n vesti gat or, places t he s u bject at i m me diate ris k of deat h (a 
life-t hreate ni n g e ve nt); h o we ver, t his d oes n ot i ncl u de a n e ve nt t hat, ha d it occ urre d 
i n a m ore se vere f or m, mi g ht ha ve ca use d deat h

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5 0

Res ults i n a c o n ge nital a n o mal y / birt h defect

Is a me dically i m p orta nt e ve nt
A me dicall y i m p orta nt e ve nt is a n A E t hat, i n t he o pi ni o n of t he I n vesti gat or, ma y  je o par dize t he 
s u bject or ma y re q uire i nter ve nti o n t o pre ve 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.  ( A n e xa m ple of s uc h a me dical e ve nts i ncl u des a ller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge nc y r o o m.)
1 5. 1. 3. 
Presc he d ule d or Electi ve Pr oce d ures or R o uti nel y Sc he d ule d Tre at me nts
A presc he d ule d or electi ve pr oce d ure or a r o uti nel y  sc he d ule d treat me nt will n ot be c o nsi dere d 
a n S A E, e ve n if t he s u bject is h os pitalize d.  T he st u d y  site m ust d oc u me nt all of t he f oll o wi n g:

T he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt was 
sc he d ule d ( or was o n a waiti n g list t o be sc he d ule d) pri or t o o btai ni n g t he s u bject’s 
c o nse nt t o partici pate i n t he st u d y.

T he c o n diti o n re q uiri n g t he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d 
treat me nt was prese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he 
I n vesti gat or bet wee n t he s u bject’s c o nse nt t o partici pate i n t he st u d y a n d t he ti me of 
t he pr oce d ure or treat me nt.

T he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s ole 
reas o n f or t he i nter ve nti o n or h os pital a d missi o n.

If a s u bject is h os pitalize d d ue t o l ocal re q uire me nts f or a d mi nistratio n of t he 
st u d y treat me nt, t he h os pitalizati o n s h o ul d n ot be c o nsi dere d a n S A E u nless o ne 
of t he re q uire me nts i n Secti o n 1 5. 1. 2 is met.
1 5. 2. 
S afet y Cl assific ati o ns
1 5. 2. 1.  
I n vesti g at or Assess me nt of E ve nts
All e ve nts m ust be assesse d t o deter mi ne t he f oll o wi n g:

If t he e ve nt meets t he criteria f or a n S A E as defi ne d i n Secti o n 1 5. 1. 2 .

T he relati o ns hi p of t he e ve nt t o st u d y  treat me nt as defi ne d i n Secti o n 1 5. 2. 2 .

T he se verit y of t he e ve nt as defi ne d i n Secti o n 1 5. 2. 3 .
1 5. 2. 2.   
Rel ati o ns hi p of E ve nts t o St u d y Tre at me nt
T he f oll o wi n g defi niti o ns s h o ul d be c o nsi dere d w he n e val uati n g t he relati o ns hi p of A Es a n d 
S A Es t o t he st u d y  treat me nt:




Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5 2
A Es t hat are o n g oi n g w he n t he s u bject c o m pletes or disc o nti n ues t he st u d y  will be f oll o we d u p 
b y  t he I n vesti gat or u ntil t he e ve nt has res ol ve d, sta bilize d, or ret ur ne d t o baseli ne stat us.  A E 
o utc o me s h o ul d be rec or de d o n t he C R F, as a p plica ble.
Seiz ures ( wit h t he e xce pti o n of stat us e pile ptic us or a cli nicall y si g nifica nt i ncrease i n seiz ure 
fre q ue nc y or i nte nsity o r e mer ge nce of a ne w seiz ure t ype res ulti n g i n disc o nti n uati o n of st u d y  
treat me nt, w hic h s h o ul d be re p orte d as a n S A E), will n ot be c ollecte d as A Es as t he y are 
c o nsi dere d part of t he pri mar y efficac y e n d p oi nt; h o we ver, t he y s h o ul d be rec or de d i n t he seiz ure 
diar y .
1 5. 3. 2. 
Seri o us A d verse E ve nts
A n y  S A E e x perie nce d b y t he s u bject bet wee n t he ti me of t he si g ni n g of t he I C F a n d t he E n d of 
St u d y  Visit or Foll o w -u p Visit f or E T S u bjects is t o be rec or de d o n a n S A E f or m, re gar dless of 
t he se verity of t he e ve nt or its re lati o ns hi p t o st u d y treat me nt.  S A Es m ust be re p orte d t o Bi o ge n 
or desi g nee wit hi n 2 4 h o urs as descri be d i n Secti o n 1 5. 3. 3 .  F oll o w-u p i nf or mati o n re gar di n g a n 
S A E als o m ust be re p orte d wit hi n 2 4 h o urs.  
S u bjects will be f oll o we d u p f or all S A Es u ntil t he E n d of St u d y  Visit or Foll o w - u p Visit f or E T 
S u bjects ( 1 6 wee ks after t he last d ose of st u d y treat me nt).  T hereafter, S A Es s h o ul d be re p orte d 
o nl y  if t he I n vesti gat or c o nsi ders t he S A E t o be relate d t o st u d y treat me nt.  A n y  S A E t hat is 
o n g oi n g w he n t he s u bject c o m pletes or disc o nti n ues t he st u d y  s h o ul d be f oll o we d u p b y t he 
I n vesti gat or u ntil t he e ve nt has res ol ve d, sta bilize d, or ret ur ne d t o baseli ne stat us. S A E o utc o me 
s h o ul d be rec or de d o n t he C R F, as a p plica ble.
I n a d diti o n, s u bjects s h o ul d be c o ntacted b y  p h o ne 2 4 wee ks after t he last d ose of st u d y 
treat me nt t o disc uss t he de vel o p me nt of a ny ne w ne ur ol o gical s y m pt o ms i n dicati ve of P M L  
(e. g., ne w or s u d de n c ha n ge i n t hi n ki n g, visi o n, bala nce, or stre n gt h persisti n g o ver se veral 
da y s), as P M L has bee n rep orte d u p t o 6 m o nt hs after t he e n d of treat me nt. At t he ti me of t he 
p h o ne call, a n y ot her n o n -P M L  b ut o n g oi n g S A Es ( or A Es) s h o ul d be f oll o we d- u p a n d u p date d 
o n t he C R F as well . 
Seiz ures t hat re q uire h os pitalizati o n, wit h t he e xce pti o n of stat us e pile pti c us, are n ot c o nsi dere d 
S A Es as t he y are c o nsi dere d part of t he pri mar y  efficac y e n d p oi nt; h o we ver, t he y s h o ul d be 
rec or de d i n t he seiz ure diar y.  A cli nicall y si g nifica nt i ncrease i n seiz ure fre q ue nc y  or i nte nsity 
or e mer ge nce of a ne w seiz ure t y pe res ult i n g i n disc o nti n uati o n of st u d y treat me nt w o ul d als o be 
c o nsi dere d as a n S A E. Of n ote, P M L  ca n be ass ociate d wit h seiz ures a n d t heref ore als o 
c o nsi dere d i n s u bjects wit h a cli nicall y si g nifica nt i ncrease i n seiz ure fre q ue nc y or i nte nsit y or 
wit h e mer ge nce of a ne w seiz ure t y pe ( Secti o n 1 4. 3 ).
1 5. 3. 3.  
I m me di ate Re p orti n g of Seri o us A d verse E ve nts
I n or der t o a d here t o all a p plica ble la ws a n d re g ulati o ns f or re p orti n g a n S A E, t he st u d y site m ust 
f or mall y n otif y Bi o ge n or desi g nee wit hi n 2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he 
S A E.  I t is t he I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t he S A E re p orti n g i nf or mati o n a n d 
pr oce d ures are use d a n d f oll o we d a p pr o priatel y .




Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5 4
T he I n vesti gat or m ust re p ort a pre g na nc y  occ urri n g i n a fe male s u bject b y fa xi n g or e maili n g t he 
a p pr o priate f or m t o Bi o ge n or desi g nee wit hi n 2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of 
t he pre g na nc y.  Refer to t he St u d y  C o ntact List f or c o m plete c o ntact i nf or mati o n.  T he 
I n vesti gat or or st u dy site staff m ust re p ort t he o utc o me of t he pre g na nc y t o Bi o ge n or desi g nee.  
A pre g na nc y  is n ot c o nsi dere d a n A E a n d s h o ul d n ot be rec or de d o n t he A E C R F.
C o n ge nital a b n or malities a n d birt h defects i n t he offs pri n g of male or fe male s u bjects s h o ul d be 
re p orte d as a n S A E if c o nce pti o n occ urre d d uri n g t he st u d y treat me nt peri o d.
1 5. 4. 2. 
O ver d ose
A n o ver d ose is a n y d ose of st u d y  treat me nt a d mi nistere d t o a s u bject or ta ke n b y a s u bject t hat 
e xcee ds t he d ose assi g ne d t o t he s u bject acc or di n g t o t he pr ot oc ol.  O ver d oses are n ot c o nsi dere d 
A Es a n d s h o ul d n ot be rec or de d as a n A E o n t he C R F; h o we ver, all o ver d oses m ust be rec or de d 
o n a n O ver d ose f or m a n d fa xe d or e maile d t o Bi o ge n or desi g nee wit hi n 2 4 h o urs of t he st u d y 
site bec o mi n g a ware of t he o ver d ose.  A n o ver d ose m ust be re p orte d t o Bi o ge n or desi g nee e ve n 
if t he o ver d ose d oes n ot res ult i n a n A E.  If a n o ver d ose res ults i n a n A E, t he A E m ust be 
rec or de d.  If a n o ver d ose res ults i n a n S A E, b ot h t he S A E a n d O ver d ose f or ms m ust be 
c o m plete d a n d fa xe d or e maile d t o Bi o ge n or desi g nee.  All st u d y  treat me nt-relate d d osi n g 
i nf or mati o n m ust be rec or de d o n t he d osi n g C R F.
1 5. 4. 3. 
Me dic al E mer ge nc y
I n a me dical e mer ge nc y re q uiri n g i m me diate atte nti o n, st u d y site staff will a p pl y a p pr o priate 
me dical i nter ve nti o n, acc or di n g t o c urre nt sta n dar ds of care.  T he I n vesti gat or ( or desi g nee) 
s h o ul d c o ntact t he st u d y’s Me dical Direct or.  Refer t o t he St u d y C o ntact List f or c o m plete 
c o ntact i nf or mati o n.
1 5. 4. 3. 1. 
U n bli n di n g f or Me dic al E mer ge nc y
I n a me dical e mer ge nc y w he n k n o wle d ge of t he s u bject’s treat me nt assi g n me nt ma y i nfl ue nce 
t he s u bject’s cli nical care, t he In vesti gat or ma y  access t he s u bject’s treat me nt assi g n me nt b y 
I R T.  T he I n vesti gat or m ust d oc u me nt t he reas o ns f or u n bli n di n g i n t he s u bject’s s o urce 
d oc u me nts.  T he I n vesti gat or is str o n gl y a d vise d n ot t o di v ul ge t he s u bject’s treat me nt 
assi g n me nt t o a n y i n di vi d ual n ot directl y  i n v ol ve d i n ma na gi n g t he me dical e mer ge nc y, or t o 
pers o n nel i n v ol ve d wit h t he a nal ys is a n d c o n d uct of t he st u d y.  T he I n vesti gat or ca n c o ntact 
Bi o ge n or desi g nee t o disc uss s uc h sit uati o ns.
1 5. 5. 
C o ntr ace pti o n Re q uire me nts
All w o me n of c hil d beari n g p ote ntial a n d all me n m ust e ns ure t hat hi g hl y effecti ve c o ntrace pti o n 
is use d d uri n g t he st u dy a n d f or at least 3 m o nt hs after t heir last d ose of st u d y  treat me nt.  I n 
a d diti o n, s u bjects s h o ul d n ot d o nate s per m or e g gs f or t he d urati o n of t he st u d y  a n d f or at least 
3 m o nt hs after t heir last d ose of st u d y treat me nt.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5 5
F or t he p ur p oses of t his st u d y , w o me n w h o d o n ot meet o ne of t he f oll o wi n g criteria are 
c o nsi dere d t o be p h ys i ol o gicall y ca pa ble of bec o mi n g pre g na nt a n d are, t heref ore, defi ne d as 
w o me n of c hil d beari n g p ote ntial:

P ost me n o pa usal
o
1 2 c o nti n u o us m o nt hs of nat ural (s p o nta ne o us) a me n orr hea wit h o ut a n alter nati ve 
me dical ca use
o
6 wee ks after s ur gical bilateral o o p h orect o m y wit h or wit h o ut h y sterect o m y

P ost h y sterect o m y

Fe male s ur gical sterilizati o n (e. g., bilateral t u bal li gati o n)  
F or t he p ur p oses of t he st u d y , hi g hly effecti ve c o ntrace pti o n is defi ne d as c o ntrace pti o n t hat 
ac hie ves a fail ure rate of less t ha n 1 % w he n use d c o nsiste ntl y a n d c orrectl y a n d i ncl u de s t he use 
of 1 of t he f oll o wi n g : 
F or fe males:

Esta blis he d use of oral, i ntra va gi nal, or tra ns der mal c o m bi ne d (estr o ge n a n d 
pr o gest o ge n c o ntai ni n g) h or m o nal met h o ds of c o ntrace pti o n ass ociate d wit h t he 
i n hi biti o n of o v ulati o n.

Esta blis he d use of oral, i njecte d, or i m pla nte d pr o gest o ge n - o nly h or m o nal met h o ds of 
c o ntrace pti o n ass ociate d wit h t he i n hi biti o n of o v ulati o n.

Place me nt of a n i ntra uteri n e de vice or i ntra uteri ne h or m o ne -releasi n g sys te m.

Bilateral t u bal occl usi o n.

Se x wit h a male w h o has u n der g o ne s ur gical sterilizati o n ( wit h t he a p pr o priate 
p ost vasect o m y  d oc u me ntati o n of t he a bse nce of s per m i n t he ejac ulate).
N ote:  Fe male s u bjects usi n g c o nc o mita nt e nz yme -i n d uci n g A E Ds s h o ul d be a d vise d t hat hi g hl y 
effecti ve c o ntrace pti o n w o ul d be li mite d t o:

Esta blis he d use of i njecte d pr o gest o ge n - o nly h or m o nal met h o ds of c o ntrace pti o n 
ass ociate d wit h t he i n hi biti o n of o v ulati o n.

Place me nt of a n i ntra uteri ne de vice or i ntra uteri ne h or m o ne -releasi n g s yste m.

Bilateral t u bal occl usi o n.

Se x wit h a male w h o has u n der g o ne s ur gical sterilizati o n ( wit h t he a p pr o priate 
p ost vasect o m y  d oc u me ntati o n of t he a bse nce of s per m i n t he ejac ulate).


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5 6
F or males:

Vasect o m y wit h ne gati ve se me n a nal ys is at f oll o w- u p.

Se x wit h a w o ma n w h o uses t he met h o ds descri be d f or fe males if s he is of 
c hil d beari n g p ote ntial.
Tr ue a bsti ne nce, w he n t his is c o nsiste nt wit h t he preferre d a n d us ual lifest yle of t he s u bject, ca n 
be c o nsi dere d a n ac ce pta ble met h o d of c o ntrace pti o n base d o n t he e val uati o n of t he I n vesti gat or 
w h o s h o ul d als o ta ke i nt o c o nsi derati o n t he d urati o n of t he cli nical st u d y.  Peri o dic a bsti ne nce 
(e. g., cale n dar, o v ulati o n, s ym pt ot her mal, p ost o v ulati o n met h o ds) a n d wit h dra wal a re n ot 
c o nsi dere d acce pta ble met h o ds of c o ntrace pti o n.
Pre g na nc y  re p orti n g is descri be d i n Secti o n 1 5. 4. 1 .
1 5. 6. 
S afet y Res p o nsi bilities
1 5. 6. 1.  
T he I n vesti g at or
T he I n vesti gat or’s res p o nsi bilities i ncl u de t he f oll o wi n g:

M o nit or a n d rec or d all A Es, i ncl u di n g S A Es, o n t h e C R F re gar dless of t he se verit y or 
relati o ns hi p t o st u d y treat me nt.

Deter mi ne t he seri o us ness, relati o ns hi p, a n d se verit y  of eac h e ve nt.

Deter mi ne t he o nset a n d res ol uti o n dates of eac h e ve nt.

M o nit or a n d rec or d all pre g na ncies i n fe male s u bjects a n d f oll o w u p o n t he o utc o me 
of all pre g na ncies.

C o m plete a n S A E f or m f or eac h S A E a n d fa x or e mail it t o Bi o ge n or desi g nee wit hi n 
2 4 h o urs of t he st u d y  site staff bec o mi n g a ware of t he e ve nt.

P urs ue S A E f oll o w- u p i nf or mati o n acti vel y a n d persiste ntl y.  F oll o w - u p i nf or mati o n 
m ust be re p orte d t o Bi o ge n or desi g nee wit hi n 2 4 h o urs of t he st u d y site staff 
bec o mi n g a ware of ne w i nf or mati o n.

E ns ure all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he s u bjects’ 
me dical rec or ds.

P urs ue A E f oll o w -u p i nf or mati o n, i f p ossi ble, u ntil t he e ve nt has res ol ve d or bec o me 
sta ble.  Rec or d A E f oll o w- u p i nf or mati o n, i ncl u di n g res ol uti o n, o n t he C R F, as 
a p plica ble.

Re p ort S A Es t o l ocal et hics c o m mittees, as re q uire d b y  l ocal la w.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5 7
1 5. 6. 2. 
Bi o ge n 
Bi o ge n’s res p o nsi bilities i ncl u de t he f o ll o wi n g:

Bef ore a st u d y site ca n e nr oll a n y s u bjects, t he Cli nical M onit or is res p o nsi ble f or 
re vie wi n g wit h st u d y site staff t he defi niti o ns of A E a n d S A E, as well as t he 
i nstr ucti o ns f or m o nit ori n g, rec or di n g, a n d re p orti n g A Es a n d S A Es.

Bi o ge n is t o n ot if y all a p pr o priate re g ulat or y a ut h orities, ce ntral et hics c o m mittees, 
a n d I n vesti gat ors of S A Es, as re q uire d b y l ocal la w, wit hi n re q uire d ti me fra mes.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5 8
1 6. 
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F
S A M P L E SI Z E
T he st u d y  o bjecti ves a n d t he e n d p oi nts of t he place b o-c o ntr olle d p hase are descri be d i n 
Secti o n 6 .  T his secti o n descri bes t he a nal ys es of t he place b o -c o ntr olle d p hase e n d p oi nts; details 
of t he e n d p oi nts a n d t he met h o d of a nal ys is f or t he o pe n-la bel p hase will be descri be d i n t he 
S A P.
1 6. 1. 
Effic ac y
1 6. 1. 1. 
A n al ysis P o p ul ati o n
T he efficac y  e n d p oi nts will be a nal yze d f or t he i nte nt -t o-treat (I T T) p o p ulati o n at t he e n d of 
place b o -c o ntr olle d p hase of t he st u d y.  T he I T T p o p ulati o n will i ncl u de all ra n d o mize d s u bjects 
w h o recei ve at least 1 d ose of d o u ble -bli n d treat me nt.  S u bjects will be a nal y ze d i n t he gr o u ps t o 
w hic h t he y  were ra n d o mize d.
1 6. 1. 2. 
Ge ner al Met h o ds of A n al ysis
U nless ot her wise s pecifie d, c o nti n u o us varia bles will be s u m marize d usi n g s u m mar y  statistics 
( mea n, sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m) b y treat me nt gr o u p, a n d 
cate g orical varia bles will be prese nte d usi n g fre q ue nc y  distri b uti o ns b y ti me p oi nt a n d treat me nt 
gr o u p.  P oi nt esti mates a n d 9 5 % c o nfi de nce i nter vals ( CI s) will be pr o vi de d w here a p plica ble.
F or t he assess me nt of seiz ure fre q ue nc y , t he seiz ure fre q ue nc y ( n u m ber of seiz ures per 2 8 da y s) 
at eac h visit will be calc ulate d base d o n t he s u m of t he seiz ures re p orte d i n t he s u bject seiz ure 
diar y  a n d t he n u m ber of da ys wit h n o n missi n g seiz ure fre q ue nc y data i n t he s u bject seiz ure diar y 
after t he pre vi o us visit.  If a n i nf usi o n is misse d, t he seiz ure fre q ue nc y  will be calc ulate d base d 
o n t he tar get visit date.  Baseli ne seiz ure fre q ue nc y  ( n u m ber of seiz ure per 2 8 da y s) will be 
calc ulate d base d o n t he s u bject seiz ure diar y  data d uri n g t he pr os pecti ve baseli ne peri o d, as 
f oll o ws:
Baseli ne seiz ure fre q ue nc y  = 
F or ot her assess me nts, B aseli ne will be defi ne d as t he cl osest n o n missi n g val ue pri or t o t he first 
i nf usi o n of st u d y treat me nt.
1 6. 1. 2. 1. 
A n al ysis of t he Pri m ar y E n d p oi nt
T he pri mar y  efficac y e n dp oi nt of c ha n ge fr o m baseli ne of l o g- tra nsf or me d seiz ure fre q ue nc y 
( n u m ber of seiz ures per 2 8 da ys) o ver Wee ks 8 t o 2 4 of treat me nt will be s u m marize d usi n g 
descri pti ve statistics b y  treat me nt gr o u ps a n d visits.  A mi xe d m o del f or re peate d meas ures 
( M M R M) will be use d t o a nal yz e t he c ha n ge fr o m Baseli ne of l o g -tra nsf or me d seiz ure fre q ue nc y 


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
5 9
( n u m ber of seiz ures per 2 8 da y s).  Treat me nt, visit, treat me nt-b y -visit i nteracti o n, 
l o g-tra nsf or me d baseli ne seiz ure fre q ue nc y ( n u m ber of seiz ures per 2 8 da y s), a n d stratificati o n 
fact ors, s uc h as hi g h seiz ure fre q ue nc y cate g or y a n d e pile ps y ty pes, will be i ncl u de d i n t he 
M M R M as fi xe d effects.  T he a vera ge effect o ver Wee ks
8 t o 2 4 of eac h treat me nt gr o u p, as well 
as t he treat me nt differe nce, will be dis pla y e d wit h a 9 5 % CI  a n d p-val ue.
Seiz ure data will be ce ns ore d after t he pr ot oc ol -s pecifie d m o dificati o n of A E Ds.  Se nsiti vit y 
a nal ys es will be perf or me d base d o n all t he seiz ure diar y  data, i ncl u di n g t he data after t he 
pr ot oc ol -s pecifie d m o dificati o n of A E Ds.
Se nsiti vit y a nal yses will be perf or me d t o e val uate t he i m pact of missi n g data.  M ulti ple 
i m p utati o ns will be use d t o ha n dle t he missi n g data, a n d t he details will be s pecifie d i n t he S A P.
1 6. 1. 2. 2. 
A n al ysis of t he Sec o n d ar y E n d p oi nts
1 6. 1. 2. 2. 1. Pr o p orti o n of Res p o n ders
A res p o n der is def i ne d as s u bject wit h a ≥5 0 % re d ucti o n fr o m Baseli ne i n seiz ure fre q ue nc y 
( n u m ber of seiz ures per 2 8 da y s) d uri n g Wee ks 8 t o 2 4 of treat me nt.  T his a nal y sis i ncl u des all 
ra n d o mize d s u bjects i n I T T p o p ulati o n w h o has at least 1 p ost baseli ne seiz ure assess me nt after 
Wee k
8.  S u bjects w h o wit h dra w fr o m treat me nt or re q uire pr ot oc ol- s pecifie d m o dificati o ns of 
A E Ds pri or t o Wee k 2 4 (c o m pleti o n of t he place b o -c o ntr olle d p hase) will be c o nsi dere d as 
n o nres p o n ders i n t he res p o n der a nal ys is.  T he pr o p orti o n of res p o nders will be a nal yz e d usi n g a 
l o gistic re gressi o n m o del, wit h effects f or treat me nt a n d stratificati o n varia bles ( w here p ossi ble) 
as fact ors (fi xe d c o variates), a n d l o g- tra nsf or me d baseli ne seiz ure fre q ue nc y ( n u m ber of seiz ures 
per 2 8 d a y s) as a c o nti n u o us c o variate ( meas ure d o ver t he pr os pecti ve baseli ne peri o d).  T he 
o d ds rati o fr o m t he l o gistic re gressi o n m o del will be dis pla y e d wit h 9 5 % CI a n d p- val ue.
Se nsiti vit y  a nal yses will be perf or me d t o e val uate t he pr o p orti o n of res p o n ders wit h a 
≥7 5 % re d ucti o n fr o m B aseli ne.
1 6. 1. 2. 2. 2. Pr o p orti o n of S u bjects Free Fr o m Seiz ures
T he pr o p orti o n of s u bjects free fr o m seiz ures d uri n g Wee ks 8 t o 2 4 of treat me nt will be a nal yz e d 
usi n g a l o gistic re gressi o n m o del, wit h effects f or treat me nt a n d stratificati o n varia bles ( w here 
p oss i ble) as fact ors (fi xe d c o variates), a n d l o g- tra nsf or me d baseli ne seiz ure fre q ue nc y ( n u m ber 
of seiz ures per 2 8 d a y s) as a c o nti n u o us c o variate ( meas ure d o ver t he pr os pecti ve baseli ne 
peri o d).  T he o d ds rati o fr o m t he l o gistic re gressi o n m o del will be dis pl a ye d wit h 9 5 % CI a n d 
p -val ue.
All s u bjects i n t he I T T p o p ulati o n w h o ha ve at least 1 p ost baseli ne seiz ure assess me nt after 
Wee k
8 will be i ncl u de d i n t his a nal y sis.  S u bjects w h o wit h dra w fr o m treat me nt, re q uire 
pr ot oc ol -s pecifie d m o dificati o n of A E Ds pri or t o Wee k 2 4 (c o m pleti o n of t he place b o -c o ntr olle d 
p hase), or ha ve a n y missi n g diar y  data d uri n g Wee ks 8 t o 2 4 of treat me nt will be c o nsi dere d as 
n ot free fr o m seiz ures i n t his a nal y sis.






Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6 2
1 6. 5. 2. 3. 
Vit al Si g ns
T he a nal ys is of vital si g ns will f oc us o n t he i nci de nce of cli nicall y rele va nt a b n or malities b y 
treat me nt gr ou p.
1 6. 5. 2. 4. 
e C-S S R S / C-S S R S
S u m mar y  statistics of t he e C-S S R S / C-S S R S at eac h visit will be prese nte d b y treat me nt gr o u p 
usi n g o bser ve d data.
1 6. 6. 
I m m u n o ge nicit y ( A nti- Nat aliz u m a b A nti b o dies)
A nti- nataliz u ma b a nti b o dies i n ser u m will be c ollecte d at ti me p oi nts o utli ne d i n t he sc he d ule of 
acti vities (Ta ble 1 ) a n d a nal yze d at t he e n d of t he st u d y.  Res ults i ncl u di n g perce nta ge of 
s u bjects w h o de vel o p a nti b o dies will be s u m marize d b y treat me nt gr o u p at eac h sc he d ule d 
ti me p oi nt. 
1 6. 7. 
I nteri m A n al yses
O ne i nteri m a nal ys is is pla n ne d t o assess f utilit y a n d sa m ple size re-esti mati o n after 
a p pr o xi matel y 5 0 % of t he e nr olle d s u bjects ha ve c o m plete d at least 1 6 wee ks of t he 2 4 - wee k 
place b o -c o ntr olle d p hase.  T he i nteri m a nal ys is will be base d o n t he c ha n ge (i n nat ural 
l o garit h mic scale) fr o m Baseli ne i n seiz ure fre q ue nc y, sta n dar dize d o ver 2 8 da y s, fr o m t he 
s u bjects w h o ha ve c o m plete d treat me nt or ter mi nate d early.  I nteri m a nal ys es will i ncl u de t he 
f oll o wi n g:

F utilit y  criteria will be base d o n t he pre dicti ve pr o ba bilit y of de m o nstrati n g 
pres pecifie d treat me nt differe nces at st u d y  c o m pleti o n gi ve n t he i nteri m o bser vati o ns.  
T he details of t he f utilit y  criteria will be f ully s pec ifie d i n t he S A P.

Sa m ple size re -esti mati o n ma y be perf or me d at t he ti me of t he i nteri m a nal ysis base d 
o n t he pri nci ple of t he pr o misi n g z o ne a p pr oac h [Me hta a n d P oc oc k 2 0 1 1 ].  T he 
details of sa m ple size re -esti mati o n a n d t he r ule of sa m ple size i ncrease will be 
s pecifie d i n t he S A P.  Sa m ple size ma y  be i ncrease d t o a ma xi m u m of 1 0 0 s u bjects i n 
t otal. 
Neit her t he f utilit y  a nalysis n or t he sa m ple size re -esti mati o n is e x pecte d t o i ncrease t he ty pe I 
err or rate; n o m ulti plicit y a dj ust me nt will be ma de t o t he pri mar y  a nalys is.
I n or der t o mai ntai n t he treat me nt bli n d, a n i n de pe n de nt gr o u p n ot i n v ol ve d i n st u d y c o n d uct, 
i ncl u di n g t he D S M C, will perf or m t he i nteri m a nal yses.  Details f or data tra nsfer will be 
i ncl u de d i n t he u n bli n di n g pla n f or t he st u d y.
1 6. 8. 
S a m ple Size C o nsi der ati o ns
T we nt y -ni ne s u bjects per treat me nt ar m will pr o vi de 8 0 % p o wer t o detect a treat me nt differe nce 
of - 0. 3 7 5 bet wee n nataliz u ma b a n d place b o i n t he nat ural l o g-tra nsf or me d seiz ure fre q ue nc y,


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6 3
sta n dar dize d o ver 2 8 da ys , at a 2-si de d si g nifica nce le vel of 0. 0 5 0, ass u mi n g a c o m m o n sta n dar d 
de viati o n of t he l o g -tra nsf or me d fre q ue nc y of 0. 5.  F or e xa m ple, if t he place b o gr o u p has a 2 0 % 
re d ucti o n fr o m Baseli ne i n seiz ure fre q ue nc y a n d t he acti ve gr o u p has a 4 5 % re d ucti o n fr o m 
B aseline i n seiz ure fre q ue nc y , t he sa m ple size w o ul d pr o vi de 8 0 % p o wer t o detect t his 
differe nce.  T o acc o u nt f or a disc o nti n uati o n rate u p t o 1 5 %, a t otal of a p pr o xi matel y 7 0 s u bjects 
will be ra n d o mize d.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6 4
1 7. 
E T HI C A L R E Q UI R E M E N T S
Bi o ge n, t he C R O, a n d t he I n vesti gat or m ust c o m pl y wit h all i nstr ucti o ns, re g ulati o ns, a n d 
a gree me nts i n t his pr ot oc ol a n d a p plica ble I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) a n d 
G o o d Cli nical Practice ( G C P) g ui deli nes a n d c o n d uct t he st u d y  acc or di n g t o l ocal re g ulati o ns.
T he I n vesti gat o r ma y dele gate res p o nsi bilities f or st u d y-relate d tas ks w here a p pr o priate t o 
i n di vi d uals s ufficie ntl y q ualifie d b y e d ucati o n, trai ni n g, a n d e x perie nce, i n acc or da nce wit h 
a p plica ble I C H a n d G C P g ui deli nes.  T he I n vesti gat or s h o ul d mai ntai n a list of t he a p pr o priatel y  
q ualifie d pers o ns t o w h o m si g nifica nt st u d y-relate d d uties ha ve bee n dele gate d.  T he I n vesti gat or 
is res p o nsi ble f or s u per visi n g t h ose i n di vi d uals a n d f or i m ple me nti n g pr oce d ures t o e ns ure t he 
i nte grity of t he tas ks perf or me d a n d a n y data ge ner ate d.
1 7. 1. 
Decl ar ati o n of Helsi n k i
T his st u d y  will be perf or me d i n ali g n me nt wit h t he et hical pri nci ples o utli ne d i n t he Declarati o n 
of Helsi n ki.
1 7. 2. 
Et hics C o m mittee
T he I n vesti gat or m ust o btai n et hics c o m mittee a p pr o val of t he pr ot oc ol, I CF, a n d ot her re q uire d 
stu d y  d oc u me nts pri or t o starti n g t he st u dy.
If t he I n vesti gat or ma kes a n y c ha n ges t o t he IC F, Bi o ge n m ust a p pr o ve t he c ha n ges bef ore t he 
I CF is s u b mitte d t o t he et hics c o m mittee.  A c o p y of t he a p pr o ve d I C F m ust be pr o vi de d t o 
Bi o ge n.  After a p pr o val, t he I C F m ust n ot be altere d wit h o ut t he a gree me nt of t he rele va nt et hics 
c o m mittee a n d Bi o ge n.
It is t he res p o nsi bilit y of t he In vesti gat ors t o e ns ure t hat all as pects of i nstit uti o nal re vie w are 
c o n d ucte d i n acc or da nce wit h c urre nt a p plica ble re g ulati o ns.
Bi o g e n m ust recei ve a letter d oc u me nti n g et hics c o m mittee a p pr o val, w hic h s pecificall y 
i de ntifies t he pr ot oc ol, pr ot oc ol n u m ber, a n d I C F, pri or t o t he i nitiati o n of t he st u d y.  Pr ot oc ol 
a me n d me nts will be s u bject t o t he sa me re q uire me nts as t he ori gi nal pr ot oc ol.
A pr o gress re p ort m ust be s u b mitte d t o t he et hics c o m mittee at re q uire d i nter vals a n d n ot less 
t ha n a n n ually.
At t he c o m pleti o n or ter mi nati o n of t he st u d y , t he st u d y site m ust s u b mit a cl ose-o ut letter t o t he 
et hics c o m mittee a n d Bi o ge n.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6 5
1 7. 3. 
S u bject I nf or m ati o n a n d C o nse nt
Pri or t o perf or mi n g a n y s t u d y-relate d acti vities u n der t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d 
assess me nts, writte n i nf or me d c o nse nt wit h t he a p pr o ve d I C F m ust be o btai ne d fr o m t he s u bject 
or s u bject’s le gall y a ut h orize d re prese ntat i ve (e. g., pare nt or le gal g uar dia n), as a p plica ble, i n 
acc or da nce wit h l ocal practice a n d re g ulati o ns.  
T he bac k gr o u n d of t he pr o p ose d st u d y , t he pr oce d ures, t he be nefits a n d ris ks of t he st u d y, a n d 
t hat st u d y partici pati o n is v ol u ntar y f or t he s u bject must be e x plai ne d t o t he s u bject ( or t he 
s u bject’s le gally a ut h orize d re prese ntati ve).  T he s u bject m ust be gi ve n s ufficie nt ti me t o 
c o nsi der w het her t o partici pate i n t he st u d y .
S u bjects will be i nf or me d t hat t heir race a n d et h nicit y  will be c ollecte d a n d will be use d d uri n g 
a nal ys is of st u d y res ults.
A c o p y of t he si g ne d a n d date d I C F m ust be gi ve n t o t he s u bject or t he s u bject’s le gall y 
a ut h orize d re prese ntati ve.  T he ori gi nal si g ne d a n d date d I C F will be retai ne d wit h t he st u d y  
rec or ds.  L ocal re g ulati o ns m ust be c o m plie d wit h i n res pect t o t he fi nal dis p ositi o n of t he 
ori gi nal ( wet si g nat ure) a n d c o pies of t he si g ne d a n d date d I C Fs.
C o nfir mati o n of i nf or me d c o nse nt m ust als o be d oc u me nte d i n t he s u bject’s me dical rec or d.
1 7. 4. 
S u bject D at a Pr otecti o n
Pri or t o a n y testi n g u n der t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d assess me nts, ca n di dates 
m ust als o pr o vi de all a ut h orizati o ns re q uire d b y l ocal la w (e. g., Pr otecte d Healt h I nf or mati o n 
a ut h orizati o n i n N ort h A merica).
D uri n g t he st u d y , s u bjects’ race a n d et h nicity will be c ollecte d.  T hese data ma y be use d i n t he 
a nal ys is of t he safet y a n d/ or P K pr ofile of t he st u d y treat me nt.  It is u n k n o w n w het her t he effects 
of t he st u d y  treat me nt are i nfl ue nce d b y race or et h nicit y.
St u d y  re p orts will be use d f or researc h p ur p oses o nl y .  T he s u bject will n ot be i de ntifie d b y na me 
i n C R Fs, st u d y-relate d f or ms, st u d y re p orts, or a ny relate d p u blicati o ns.  Bi o ge n, its part ners a n d 
desi g nees, et hics c o m mittees, a n d vari o us g o ver n me nt healt h a ge ncies ma y  i ns pect t he rec or ds of 
this st u d y .  E ver y eff ort will be ma de t o kee p t he s u bject’s pers o nal me dical data c o nfi de ntial.
1 7. 5. 
C o m pe ns ati o n f or I nj ur y
Bi o ge n mai ntai ns a p pr o priate i ns ura nce c o vera ge f or cli nical st u dies a n d will f oll o w a p plica ble 
l ocal c o m pe nsati o n la ws.
1 7. 6. 
C o nflict of I nt erest
T he I n vesti gat ors s h o ul d a d dress a n y p ote ntial c o nflicts of i nterest (e. g., fi na ncial i nterest i n 
Bi o ge n or t he C R O ) wit h t he s u bject bef ore t he s u bject ma kes a decisi o n t o partici pate i n t he 
st u d y.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6 6
1 7. 7. 
Re gistr ati o n of St u d y a n d Discl os ure of St u d y Res ul ts
Bi o ge n w ill re gister t he st u d y a n d p ostst u d y res ults re gar dless of o utc o me o n a p u blicl y 
accessi ble we bsite i n acc or da nce wit h t he a p plica ble la ws a n d re g ulati o ns.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6 7
1 8. 
A D MI NI S T R A TI V E P R O C E D U R E S
1 8. 1. 
St u d y Site I niti ati o n
T he I n vesti gat or m ust n ot scree n a n y s u bj ects pri or t o c o m pleti o n of a st u d y i nitiati o n visit, 
c o n d ucte d b y Bi o ge n or t he C R O.  T his i nitiati o n visit will i ncl u de a detaile d re vie w of t he 
pr ot oc ol a n d st u d y  pr oce d ures.
1 8. 2. 
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce
Q ualit y  c o ntr ol pr oce d ures will be i m pleme nte d at eac h sta ge of data ha n dli n g t o e ns ure t hat all 
data are relia ble a n d ha ve bee n pr ocesse d c orrectl y.  Data a n o malies will be c o m m u nicate d t o t he 
sites f or clarificati o n a n d res ol uti o n, as a p pr o priate. 
D uri n g a n d/ or after c o m pleti o n of t he st u d y , q ualit y  ass ura nce officers na me d b y Bi o ge n or t he 
re g ulat or y a ut h orities ma y wis h t o perf or m o nsite a u dits or i ns pecti o ns.  T he I n vesti gat or will be 
e x pecte d t o c o o perate wit h a n y  a u dit or i ns pecti o n a n d t o pr o vi de assista nce a n d d oc u me ntati o n 
(i ncl u di n g so urce data) as re q ueste d.
1 8. 3. 
M o nit ori n g of t he St u d y
T he I n vesti gat or m ust per mit st u d y -relate d m o nit ori n g by pr o vi di n g direct access t o s o urce data 
a n d t o t he s u bjects’ me dical hist ories.  S o urce data m ust be attri b uta ble, le gi ble, 
c o nte m p ora ne o us, ori gi nal, acc urate, a n d c o m plete.  C ha n ges t o s o urce data m ust be tracea ble, 
n ot o bsc ure t he ori gi nal e ntr y , a n d be e x plai ne d if necessar y (e. g., wit h a n a u dit trail).  T he 
I n vesti gat or s h o ul d mai ntai n a rec or d of t he l ocati o n(s) of esse ntial d oc u me nts.
T he Cli nica l M o nit or will visit t he st u d y site at re g ular i nter vals d uri n g t he st u d y a n d after t he 
st u d y has c o m plete d, as a p pr o priate.  A cli nical site m o nit ori n g pla n will detail w h o perf or ms t he 
m o nit ori n g, h o w ofte n, a n d t he e xte nt of re vie w.  It als o will pr o vi d e t he m o nit ori n g strate g y, 
wit h e m p hasis o n s u bject safet y, data i nte grit y, a n d critical data a n d pr ocesses.
D uri n g t hese visits, C R Fs, s u p p orti n g d oc u me ntati o n, a n d esse ntial d oc u me ntati o n relate d t o t he 
st u d y will be re vie we d a n d a n y discre pa ncies or o missi o ns will be res ol ve d.  D oc u me ntati o n of 
res ults will be pr o vi de d t o Bi o ge n or desi g nee i n a ti mel y fas hi o n t o all o w f oll o w-u p a n d 
verificati o n of c o m plia nce wit h t he m o nit ori n g pla n.  Re m ote e val uati o n of data (ce ntralize d 
m o nit ori n g) ma y  als o be c o n d ucte d a n d re p orte d as defi ne d i n t he m o nit ori n g pla n.
M o nit ori n g visits m ust be c o n d ucte d acc or di n g t o t he a p plica ble I C H a n d G C P g ui deli nes t o 
e ns ure t he pr otecti o n of s u bject ri g hts a n d well -bei n g, pr ot oc ol a d here nce, q ualit y  of data 
(acc urate, c o m plete, an d verifia ble), st u d y treat me nt acc o u nta bilit y, c o m plia nce wit h re g ulat or y 
re q uire me nts, a n d c o nti n ue d a de q uac y of t he st u d y site a n d its facilities.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6 8
1 8. 4. 
St u d y F u n di n g
Bi o ge n is t he S p o ns or of t he st u d y  a n d is f u n di n g t he st u d y.  All fi na ncial details are pr o vi de d i n 
t he se parate c o ntracts bet wee n t he i nstit uti o n, In vesti gat or, a n d Bi o ge n.
1 8. 5. 
P u blic ati o ns
Details are i ncl u de d i n t he cli nical trial a gree me nt f or t his st u d y .


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6 9
1 9. 
F U R T H E R R E Q UI R E M E N T S A N D G E N E R A L I N F O R M A T I O N
1 9. 1. 
E xter n al C o ntr act Or g a niz ati o ns
Bi o ge n will e n s ure o versi g ht of a ny st u d y-relate d d uties a n d f u ncti o ns carrie d o ut o n its be half 
a n d will s pecif y i n writi n g all d uties a n d f u ncti o ns t hat are tra nsferre d.
1 9. 1. 1. 
C o ntr act Rese arc h Or g a niz ati o n 
A C R O will be res p o nsi ble f or all a d mi nistrati ve as pects of t he st u d y  i ncl u di n g b ut n ot li mite d t o 
st u d y i nitiati o n, m o nit ori n g, ma na ge me nt of A Es a n d S A E re p orts, a n d data ma na ge me nt.  
Bef ore s u bjects are scree ne d at eac h st u d y  site, t he C R O will re vie w st u d y res p o nsi bilities wit h 
t he In vesti gat ors a n d ot her st u d y  site staff, as a p pr o priate.
1 9. 1. 2.  
I nter acti ve Res p o nse Tec h n ol o g y
I R T will be use d i n t his st u d y.  Bef ore s u bjects are scree ne d or e nr olle d, t he IR T ve n d or will 
pr o vi de eac h st u d y  site wit h t he necessar y trai ni n g, a user ma n ual, a n d access ri g hts t o t he 
s yste m.
1 9. 1. 3. 
Elect r o nic D at a C a pt ure
S u bject i nf or mati o n will be ca pt ure d a n d ma na ge d b y  st u d y sites o n electr o nic C R Fs b y a 
We b -base d electr o nic data ca pt ure t o ol de vel o pe d b y  t he C R O a n d c o nfi g ure d b y t he electr o nic 
data ca pt ure ve n d or.
T he e C O A will be e ntere d b y  t he s u bject or care gi ver o n a de vice de vel o pe d a n d s u p p orte d b y  
t he e C O A ve n d or. S t u d y site staff will m o nit or data via a sec ure We b p ortal de vel o pe d a n d 
s u p p orte d b y t he e C O A ve n d or.
1 9. 1. 4. 
Ce ntr al L a b or at ories f or L a b or at or y Assess me nts
Ce ntral la b orat ories ha ve bee n selecte d by Bi o ge n t o a nal y ze all he mat ol o g y, bl o o d c he mistr y, 
uri nal y sis, ser u m pre g na nc y, he patitis B a n d C, a nti -nataliz u ma b a nti b o d y, a nti- J C V a nti b o d y, 
P K,   
 
 sam ples c ollecte d f or t his st u d y .
1 9. 2. 
St u d y C o m mittees
1 9. 2. 1. 
A d vis or y C o m mit tee
A n a d vis or y  c o m mittee will be f or me d t o pr o vi de scie ntific a n d me dical directi o n f or t he st u dy 
a n d t o o versee t he a d mi nistrati ve pr o gress of t he st u d y .  T he a d vis or y c o m mittee will meet 
peri o dicall y as nee de d t o m o nit or s u bject accr ual a n d t o m o nit or c o m plia nce wit h t he pr ot oc ol at 
i n di vi d ual st u d y sites.  T he a d vis or y c o m mittee will be bli n de d t o s u bject treat me nt assi g n me nts.  


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
7 0
Me m bers of t he a d vis or y c o m mittee will i ncl u de t he Me dical Direct or, Cli nical O perati o ns Lea d, 
a n d Pr oject Statisticia n fr o m Bi o ge n (a n d/ or t heir desi g nees), a n d select I n vesti gat ors.  Bi o ge n 
will desi g nate 1 of t he partici pati n g I n vesti gat ors t o be t he c hair pers o n of t he a d vis or y  
c o m mittee.
1 9. 2. 2. 
I n de pe n de nt E pile ps y Re vie w C o m mittee
A n I E R C will be f or me d t o o versee s u bject selecti o n a n d m o dificati o n of A E Ds.  T he re vie w 
c o m mittee will c o nsist of b oar d -certifie d p h ys icia ns wit h e x pertise i n e pile ps y.  S pecifically, 
me m bers of t he re vie w c o m mittee will carr y o ut t he f oll o wi n g : 

C o nfir m t he dia g n osis of dr u g -resista nt f ocal e pile ps y i n eac h s u bject (I ncl usi o n 
Criteri o n 6).

A dj u dicate t he prese nce or a bse nce of a str uct ural eti ol o g y  f or f ocal e pile ps y 
(I ncl usi o n Criteri o n 6).

A p pr o ve a n y c ha n ge i n A E Ds after Wee k 1 2 of t he place b o -c o ntr olle d p hase t hr o u g h 
t he E n d of St u d y Visit ( Wee k 6 0) or F oll o w -u p Visit f or E T S u bjects ( 1 6 wee ks after 
t he last d ose of st u d y treat me nt) f or lac k of i m pr o ve me nt or o n g oi n g seiz ures.
1 9. 2. 3. 
Dr u g S afet y M o nit ori n g C o m mittee
A n i n de pe n de nt D S M C will be f or me d t o re vie w data re g ularl y t o assess safet y a n d ris k -be nefit 
a n d rec o m me n d a p pr o priate m o dificati o n t o t he st u d y  or ter mi nati o n of t he st u d y.  T he D S M C 
will recei ve re p orts of, f or e xa m ple, all S U S A Rs, A Es, a n d ke y  la b orat or y tests a n d will meet 
t hr o u g h o ut t he st u dy at re g ular ti me p oi nts, as descri be d i n t he D S M C c harter.  Alt h o u g h seiz ures 
will n ot be re p orte d as A Es, t he c o m mittee will als o ha ve o versi g ht of t hese data as seiz ure 
fre q ue nc y is t he pri mar y e n d p oi nt.
1 9. 2. 4. 
I n de pe n de nt S afet y M o nit or 
T he I S M is a n i n di vi d ual b oar d -certifie d p h ys icia n w h o is neit her a n e m pl o yee of Bi o ge n n or a 
partici pati n g I n vesti gat or.  T he IS M will re g ularl y assess W B C data ( ot her t ha n A N C) i n or der t o 
m o nit or s u bject safet y.  T he I S M will i nf or m t he I n vesti gat or of a ny cli nicall y si g nifica nt 
fi n di n gs o n a s pecific s u bject t hr o u g h t he M e dical M o nit or wit h o ut discl osi n g a n y p ote ntial 
treat me nt assi g n me nt i nf or mati o n.  T he IS M ma y  re q uest a ny a d diti o nal i nf or mati o n o n 
i n di vi d ual s u bjects t o c o nfir m safet y of a n i n di vi d ual s u bject.  T he I S M will als o i nf or m t he 
D S M C of a n y  safety c o ncer ns arisi n g fr o m t he re vie w of W B C data.
1 9. 3. 
C h a n ges t o Fi n al St u d y Pr ot oc ol
All pr ot oc ol a me n d me nts m ust be s u b mitte d t o t he et hics c o m mittee a n d re g ulat or y  a ut h orities if 
re q uire d b y l ocal la w.  Pr ot oc ol m o dificati o ns t hat affect s u bject safet y, t he sc o pe of t he 
i n vesti gati o n, or t he scie ntific q ualit y of t he st u dy m ust be a p pr o ve d b y t he et hics c o m mittee 
bef ore i m ple me ntati o n of s uc h m o dificati o ns t o t he c o n d uct of t he st u d y.  If re q uire d b y l ocal 


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
7 1
la w, s uc h m o dificati o ns m ust als o be a p pr o ve d by t he a p pr o priate re g ulat or y a ge nc y  pri or t o 
i m ple me ntati o n.
H o we ver, Bi o ge n ma y , at a n y ti me, a me n d t his pr ot oc ol t o eli mi nate a n a p pare nt i m me diate 
hazar d t o a s u bject.  I n t his case , t he a p pr o priate re g ulat or y a ut h orities will be n otifie d 
s u bse q ue nt t o t he m o dificati o n.
I n t he e ve nt of a pr ot oc ol m o dificati o n, t he IC F ma y  re q uire si milar m o dificati o ns (see 
Secti o n 1 7 ).
1 9. 4. 
Et hics C o m mittee N otific ati o n of St u d y C o m pleti o n or Ter mi n ati o n
W here re q uire d, t he re g ulat or y  a ut h orities a n d et hics c o m mittees m ust be n otifie d of c o m pleti o n 
or ter mi nati o n of t his st u d y  a n d se nt a c o py of t he st u d y  sy n o psis i n acc or da nce wit h necessar y  
ti meli nes.
1 9. 5. 
Rete nti o n of St u d y D at a
T he mi ni m u m rete nti o n ti me f o r st u d y rec or ds will meet t he strictest sta n dar d a p plica ble t o t hat 
st u d y site, as dictate d by a n y i nstit uti o nal re q uire me nts or l ocal, nati o nal, or re gi o nal la ws or 
re g ulati o ns.  Pri or t o pr ocee di n g wit h destr ucti o n of rec or ds, t he I n vesti gat or m ust n otify Bi o ge n 
i n writi n g a n d recei ve writte n a ut h orizati o n fr o m Bi o ge n t o destr oy st u d y rec or ds.  I n a d diti o n, 
t he In vesti gat or m ust n otif y  Bi o ge n of a n y c ha n ges i n t he arc hi val arra n ge me nts i ncl u di n g b ut 
n ot li mite d t o arc hi val at a n offsite facilit y  or tra nsfer of o w ners hi p if t he I nvesti gat or lea ves t he 
st u d y site.
1 9. 6. 
St u d y Re p ort Si g n at or y
Bi o ge n will desi g nate o ne of t he partici pati n g I n vesti gat ors as a si g nat or y f or t he st u d y re p ort.  
T his deter mi nati o n will be ma de b y se veral fact ors, i ncl u di n g b ut n ot li mit e d t o, t he 
I n vesti gat or's e x perie nce a n d re p utati o n i n t he st u die d i n dicati o n; t he In vesti gat or's c o ntri b uti o n 
t o t he st u d y i n ter ms of desi g n, ma na ge me nt, a n d/ or s u bject e nr oll me nt; or b y ot her fact ors 
deter mi ne d t o be rele va nt b y  Bi o gen.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
7 2
2 0. 
R E F E R E N C E S
Br o w ne T R, H ol mes G L. E pile ps y : Defi niti o ns a n d Bac k gr o u n d. Ha n d b o o k of E pile ps y. U nite d 
States: L i p pi nc ott Willia ms & Wil ki ns; 2 0 0 4. p 1 a n d 8.
E n gel J, Pe dle y  T A, Aicar di J, et al. O ver vie w: A ntie pile ptic Dr u gs. E pile ps y: A C o m pre he nsi ve 
T e xt b o o k. 2 n d E diti o n e d. U nite d States: L i p pi nc ott
Willia ms & Wil ki ns; 2 0 0 7. p 1 4 3 1- 2.
Fa be ne P F, Na varr o M ora G, Marti nell o M, et al. A r ole f or le u k oc y te-e n d ot helial a d hesi o n 
mec ha nis ms i n e pile ps y . Nat Me d. 2 0 0 8; 1 4( 1 2): 1 3 7 7-8 3. E p u b 2 0 0 8/ 1 1/ 2 3.
F D A, U. S . De part me nt of Healt h a n d H u ma n Ser vices, Ce nter f or Dr u g E val uati o n a n d Researc h 
( C D E R). G ui da nce f or I n d ustr y - S uici dal I deati o n a n d - Be ha vi or: Pr os pecti ve Assess me nt of 
Occ urre nce i n Cli nical Trials. htt ps:// w w w.f da. g o v/ d o w nl oa ds/ dr u gs/ g ui da nces/ uc m 2 2 5 1 3 0. p df .
Fiest K M, Sa ur o K M, Wie be S, et al. Pre vale nce a n d i nci de nce of e pile ps y:  A s yste matic re vie w 
a n d meta-a nal ys is of i nter nati o nal st u dies. Ne ur ol o g y. 2 0 1 7; 8 8( 3): 2 9 6-3 0 3. E p u b 2 0 1 6/ 1 2/ 1 6.
Fis her R S, va n E m de B oas W, Bl u me W, et al. E pile ptic seiz ures a n d e pile ps y : defi niti o ns 
pr o p ose d b y t he I nter nati o nal Lea g ue A gai nst E pile ps y (I L A E) a n d t he I nter nati o nal B urea u f or 
E pile ps y  (IB E). E pile psia. 2 0 0 5; 4 6( 4): 4 7 0 - 2.
K wa n P, Arz i ma n o gl o u A, Ber g A T, et al. Defi niti o n of dr u g resista nt e pile ps y: c o nse ns us 
pr o p osal b y  t he a d h oc Tas k F orce of t he I L A E C o m missi o n o n T hera pe utic Strate gies. 
E pile psia. 2 0 1 0; 5 1( 6): 1 0 6 9 -7 7. E p u b 2 0 0 9/ 1 1/ 0 3.
L u o J, Wa n g W, Xi Z, et al. C o nce ntrati o n of s ol u ble a d hesi o n m olec ules i n cere br os pi nal fl ui d 
a n d ser u m of e pile ps y patie nts. J M ol Ne ur osci. 2 0 1 4; 5 4( 4): 7 6 7 -7 3. E p u b 2 0 1 4/ 0 7/ 0 8.
Marc hi N, Gra nata T, G h os h C, et al. Bl o o d- brai n barrier d ys f u ncti o n a n d e pile ps y: 
pat h o p h y si ol o gic r ole a n d t hera pe utic a ppr oac hes. E pile psia. 2 0 1 2; 5 3( 1 1): 1 8 7 7 -8 6. E p u b 
2 0 1 2/ 0 8/ 2 0.
Me hta C R, P oc oc k SJ. A da pti ve i ncrease i n sa m ple size w he n i nteri m res ults are pr o misi n g: a 
practical g ui de wit h e xa m ples. Statistics i n me dici ne. 2 0 1 1; 3 0( 2 8): 3 2 6 7 -8 4. E p u b 2 0 1 0/ 1 1/ 3 0.
P os ner K, Br o w n G K, Sta nle y  B, et al. T he C ol u m bia-S uici de Se verit y Rati n g Scale: i nitial 
vali dit y  a n d i nter nal c o nsiste nc y fi n di n gs fr o m t hree m ultisite st u dies wit h a d olesce nts a n d 
a d ults. A m J Ps yc hiatr y. 2 0 1 1; 1 6 8( 1 2): 1 2 6 6- 7 7.
Ra vizza T, Ga gliar di B, N oé F, et al. I n nate a n d a da pti ve i m m u nit y d uri n g e pile pt o ge nesis a n d 
s p o nta ne o us seiz ures: e vi de nce fr o m e x peri me ntal m o dels a n d h u ma n te m p oral l o be e pile ps y. 
Ne ur o bi ol Dis. 2 0 0 8; 2 9( 1): 1 4 2 -6 0. E p u b 2 0 0 7/ 0 8/ 3 1.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
7 3
Sc heffer I E, Ber k o vic S, Ca p o villa G, et al. I L A E classific ati o n of t he e pile psies: P ositi o n pa per 
of t he I L A E C o m missi o n f or Classificati o n a n d Ter mi n ol o g y . E pile psia. 2 0 1 7; 5 8( 4): 5 1 2- 5 2 1. 
E p u b 2 0 1 7/ 0 3/ 0 8.
S ot gi u S, M urri g hile M R, C o nsta nti n G. Treat me nt of refract or y  e pile ps y wit h nataliz u ma b i n a 
patie nt wit h m u lti ple scler osis. Case re p ort. B M C Ne ur ol. 2 0 1 0; 1 0: 8 4. E p u b 2 0 1 0/ 0 9/ 2 3.
va n Vliet E A, da C osta Ara új o S, Re de ker S, et al. Bl o o d -brai n barrier lea ka ge ma y  lea d t o 
pr o gressi o n of te m p oral l o be e pile ps y. Brai n. 2 0 0 7; 1 3 0( Pt 2): 5 2 1 -3 4. E p u b 2 0 0 6/ 1 1/ 2 2.
Vezza ni A, Gra nata T. Brai n i nfla m mati o n i n e pile ps y: e x peri me ntal a n d cli nical e vi de nce. 
E pile psia. 2 0 0 5; 4 6( 1 1): 1 7 2 4 - 4 3.


Pr ot oc ol 1 0 1 E P 2 0 1
Versi o n 2
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of Nataliz u ma b i n F ocal E pile ps y
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
7 4
2 1. 
SI G N E D A G R E E M E N T O F T H E S T U D Y P R O T O C O L
I ha ve rea d t he f ore g oi n g pr ot oc ol, “ A Ra n d o mize d, D o u ble-Bli n d, Place b o -C o ntr olle d, P hase 2 
St u d y  Ex pl ori n g t he Efficac y , Safety, a n d T olera bilit y  of Nataliz u ma b ( B G 0 0 0 0 2) as A dj u ncti ve 
T hera p y i n A d ult S u bjects Wit h Dr u g- Resista nt F ocal E pile ps y” a n d a gree t o c o n d uct t he st u d y 
acc or di n g t o t he pr ot oc ol a n d t he a p plica ble I C H g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m 
all w h o assist me i n t he c o n d uct of t his st u d y  of t heir res p o nsi bilities a n d o bli gati o ns.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Si g nat ure
Date
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Na me ( Pri nt)
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
St u d y  Site ( Pri nt)

SAP_001.pdf: 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al  v 2. 0  
1  
 
St atistic al A n al ysis Pl a n
Versi o n N o.:  2. 0  
 St u d y Title: A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d, P hase  2 St u d y E x pl ori n g t he Efficac y, 
Safet y, a n d T olera bilit y of Nataliz u ma b ( B G 0 0 0 0 2) as A dj u ncti ve T hera p y i n A d ult S u bjects Wit h 
Dr u g -Resista nt F ocal E pile ps y  
Na me of St u d y Treat me nt : Nataliz u ma b  
Pr ot oc ol N o.: 1 0 1 E P 2 0 1 /N C T 0 3 2 8 3 3 7 1
St u d y P hase: P hase II  
C o nfi de nti al I nf or m ati o n  
T he i nf or m ati o n c o nt ai ne d i n t his St atistic al A n alysis Pl a n ( S A P) is c o nfi de nti al a n d m ay n ot be 
re pr o d uce d or ot her wise disse mi n ate d wit h o ut t he a p pr ov al of Bi o ge n, I nc.   






 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
4  
T A B L E O F C O N T E N T S  
 
Vers o n hist or y  ......................................................................................................................................... 3  
Ta ble of c o nt e nts  ..................................................................................................................................... 4  
List of A b bre viati o ns  .............................................................................................................................. 6  
1  
I ntr o d ucti o n .................................................................................................................................. 8  
2  
St u d y O ver vie w  ............................................................................................................................ 8  
2. 1  
St u d y O bjecti ves a n d E n d p oi nts  ........................................................................................ 8  
2. 1. 1  
Pri mar y Efficac y O bjecti ve  ................................................................................................ 8  
2. 1. 2  
Pri mar y Efficac y E n d p oi nt  ................................................................................................ 8  
2. 1. 3  
Sec o n dar y Efficac y O bjecti ves  .......................................................................................... 8  
2. 1. 4  
Sec o n dar y Efficac y E n d p oi nts  ........................................................................................... 8  
2. 1. 5  
E x pl orat or y Efficac y O bjecti ves  ........................................................................................ 8  
2. 1. 6  
E x pl orat or y Efficac y E n d p oi nts  ......................................................................................... 9  
2. 1. 7  
P K O bjecti ve  ...................................................................................................................... 9  
2. 1. 8  
P K E n d p oi n ts ..................................................................................................................... 9  
2. 1. 9  
Safet y O bjecti ves  ............................................................................................................... 9  
2. 2  
St u d y Desi g n  .................................................................................................................... 1 0  
2. 3  
St u d y D urati o n  f or S u bjects ............................................................................................. 1 1  
2. 4  
E n d of St u d y  .................................................................................................................... 1 1  
2. 5  
Sa m ple Size C o nsi derati o ns  ............................................................................................. 1 2  
3  
Defi niti o ns  .................................................................................................................................. 1 2  
3. 1  
Dates a n d P oi nts of Refere nce  ......................................................................................... 1 2  
3. 2  
Treat me nt Gr o u p  .............................................................................................................. 1 3  
3. 3  
Ke y Deri ve d Varia bles  ..................................................................................................... 1 4  
3. 3. 1  
Calc ulati o n of Sta n dar dize d Seiz ure Fre q ue nc y  .............................................................. 1 4  
3. 3. 2  
Defi niti o n of Res p o n der  ................................................................................................... 1 5  
3. 3. 3  
Defi niti o n of Free fr o m Seiz ure  ....................................................................................... 1 5  
3. 3. 4  
Defi niti o n of N u m ber of Seiz ure -free Da ys ..................................................................... 1 5  
3. 3. 5  
St u d y Treat me nt C o m plia nce  .......................................................................................... 1 5  
3. 4  
Stratificati o n Fact ors a n d S u b gr o u p Varia bles  ................................................................ 1 5  
3. 4. 1  
Stratificati o n Fact ors  ........................................................................................................ 1 5  
3. 4. 2  
S u b gr o u p Varia bles  .......................................................................................................... 1 6  
3. 5  
A nal ysis P o p ulati o ns  ........................................................................................................ 1 6  
4  
List of Pla n ne d St u d y A nal yses  .................................................................................................. 1 8  
4. 1  
I nteri m A nal ysis ............................................................................................................... 1 8  
4. 2  
Pri mar y A nal ysis  .............................................................................................................. 1 8  
4. 3  
Fi nal A nal ysis  .................................................................................................................. 1 8  
5  
Statistical Met h o ds f or Pla n ne d A nal ys es  .................................................................................. 1 8  
5. 1  
Ge neral Pri nci ples  ............................................................................................................ 1 8  
5. 2  
Missi n g Data Ha n dli n g C o n ve nti o ns  ............................................................................... 1 8  
5. 3  
S u bject acc o u nta bilit y  ...................................................................................................... 1 9  
5. 4  
De m o gra p hic a n d Baseli ne Disease C haracteristics  ........................................................ 1 9  
5. 5  
Pr ot oc ol De viati o ns  .......................................................................................................... 2 0  
5. 6  
E xte nt of E x p os ure  ........................................................................................................... 2 0  
5. 7  
N o n -A E D C o nc o mita nt Me dicati o n/ T hera p y  .................................................................. 2 0  
5. 8  
C o nc o mita nt A nti -E pile ptic Dr u gs  .................................................................................. 2 1  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
5  
5. 9  
Diar y Seiz ure C o m plia nce  ............................................................................................... 2 1  
5. 1 0  
Pri mar y E n d p oi nt  ............................................................................................................. 2 2  
5. 1 0. 1  
Ge neral A nal ysis Met h o ds f or Efficac y E n d p oi nts  ......................................................... 2 2  
5. 1 0. 2  
Pri mar y E n d p oi nt  ............................................................................................................. 2 2  
5. 1 0. 3  
Sec o n dar y E n d p oi nts  ....................................................................................................... 2 4  
5. 1 0. 4  
E x pl orat or y Efficac y E n d p oi nts d uri n g place b o -c o ntr olle d p hase  .................................. 2 5  
5. 1 0. 5  
Efficac y A nal yses d uri n g O pe n -La bel P hase  .................................................................. 2 6  
5. 1 1  
Safet y E n d p oi nts  .............................................................................................................. 2 7  
5. 1 1. 1  
A d verse E ve nts  ................................................................................................................ 2 7  
5. 1 1. 2  
Cli nical La b orat or y Res ults  ............................................................................................. 2 9  
5. 1 1. 3  
A nti -J o h n-C u n ni n g ha m -vir us (J C V) A nti b o dies  ............................................................. 3 0  
5. 1 1. 4  
Vital Si g ns  ........................................................................................................................ 3 0  
5. 1 1. 5  
e C-S S R S/ C -S S R S  ............................................................................................................ 3 1  
 
 3 1  
 
 3 1  
 
 ........................................................................ 3 2  
5. 1 5  
I m m u n o ge nicit y ( A nti-Nataliz u ma b A nti b o dies)  ............................................................ 3 2  
6  
C ha n ges fr o m Pr ot oc ol S pecifie d A nal yses  ............................................................................... 3 3  
7  
S u m mar y of C ha n ges fr o m t he Pre vi o us Versi o n of t he S A P  ................................................... 3 3  
8  
Refere n ces  .................................................................................................................................. 3 4  
A P P E N DI X A  ....................................................................................................................................... 3 5  
 
 
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
6  
LI S T O F A B B R E VI A TI O N S  
A D A  
A nti dr u g a nti b o d y  
A E  
a d verse e ve nt  
A E D  
a ntie pile ptic dr u g  
A L T  
ala ni ne a mi n otra nsferas e  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A N C O V A  
A nal ysis of c o varia nce  
A S T  
as partate a mi n otra nsferas e  
A U C ta u 
area u n d er t he s er u m c o nce ntrati o n -ti me c ur ve f or a d osi n g i nter val 
B MI  
B o d y mass i n de x  
CI  
c o nfi de nce i nter val  
C ma x  
ma xi m u m ser u m c o nce ntrati o n  
C N S  
ce ntral ner v o us s yste m  
eC R F  
electr o nic C as e re p ort f or m 
C -S S R S  
C ol u m bia -S uici de Se verit y Rati n g Scale  
C V  
C oefficie nt of variati o n  
D N A  
de o x yri b o n ucleic aci d  
D S M C  
data safet y m o nit ori n g c o m mittee  
e C-S S R S  
electr o nic C ol u m bia -S uici de Se verit y Rati n g Scal e  
E T  
Earl y Ter mi nati o n  
 
 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E R C 
i n de pe n de nt e pile ps y re vie w c o m mittee 
I T T 
i nte nt-t o-treat 
I V 
I ntra ve n o us(l y) 
I X R S 
I nteracti ve Res p o nse Tec h n ol o g y 
J C V 
J o h n C u n ni n g ha m vir us 
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
M M R M  
mi xe d m o del f or re peate d meas ures  
M RI  
ma g netic res o n a nce i ma gi n g  
M S  
m ulti ple scler osis  
P D  
p har mac o d y na mic(s)  
P K  
p har mac o ki netic(s)  
P M L  
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  
P P  
Per -pr ot oc ol  
Q 4 W  
E ver y 4 wee ks  
 
 
R E M L  
Restricte d ma xi m u m li keli h o o d  
R N A  
ri b o n ucleic aci d 
R N S  
Res p o nsi ve  ne ur osti m ulati o n  
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
 
 
 
 
U S  
U nite d States  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
7  
U S U BJI D  
U ni q ue s u bject i de ntifier  
V N S  
Va g us ner ve sti m ulati o n  
W B C  
w hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n  
 
 
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
8  
 
1  
I ntr o d ucti o n 
T he p ur p ose of t his S A P is t o pr o vi de details of t he statistical a nal yses as o utli ne d i n t he st u d y pr ot oc ol. 
T his S A P is writte n base d o n t he f oll o wi n g d oc u me ntati o n i n c o nsi derati o n of I C H g ui da nce : 
D oc u me nt  
Date  
Versi o n  
Pr ot oc ol  
3 0 Ma y 2 0 1 8  
2. 0  
e C R F 
2 4 Ja n 2 0 1 9  
3. 0  
2  
St u d y O ver vie w  
2. 1  
St u d y  O bjecti ves a n d E n d p oi nts  
2. 1. 1  Pri m ar y Effic ac y O bjecti ve  
T he pri mar y o bj ecti ve of t he st u d y is t o deter mi ne if a dj u ncti ve treat me nt wit h nataliz u ma b 3 0 0 m g I V 
i nf usi o n Q 4 W re d u ces t h e fre q u e nc y of seiz ures i n a d ult s u bjects wit h dr u g-resista nt f ocal e pile ps y. 
2. 1. 2  Pri m ar y Effic ac y E n d p oi nt  
T he pri mar y effi cac y e n d p oi nt is c ha n ge fr o m baseli ne i n l o g-tra nsf or me d seiz ure fre q ue nc y ( n u m ber 
of seiz ures p er 2 8  d a ys) d uri n g Wee ks  8 t o 2 4 of treat me nt.  
2. 1. 3  Sec o n d ar y Effic ac y O bject i ves  
T he sec o n dar y o bjecti ves of t his st u d y are desi g ne d t o assess t he effects of nataliz u ma b vers us place b o 
i n dr u g-resista nt f ocal e pile ps y o n a d diti o nal meas ures of seiz ure fre q ue nc y. 
2. 1. 4  Sec o n d ar y Effic ac y E n d p oi nts  
T he sec o n d ar y e n d p oi nts are as f oll o ws:  
•  Pr o p orti o n of res p o n ders defi ne d as s u bjects wit h a ≥5 0 % re d ucti o n fr o m bas eli ne i n seiz ure 
fre q ue n c y ( n u m ber of sei z ures per 2 8 da ys) d uri n g Wee ks  8 t o 2 4 of treat m e nt.  
•  Pr o p orti o n of s u bjects free fr o m seiz ures d uri n g Wee ks  8 t o 2 4 of treat me nt.  
•  Perce nta g e of seiz ure -free da ys gai ne d, sta n dar dize d o ver 2 8 da ys, d uri n g Wee ks  8 t o 2 4 of 
treat me nt c o m pare d wit h baseli ne . 
•  Pr o p orti o n of s u bjects wit h i na de q uate treat me nt res p o nse d uri n g Wee ks  8 t o 2 4, defi ne d as 
eit her of t he f oll o wi n g:  
− M o dificati o n of A E Ds af ter Wee k 1 2 of t he place b o -c o ntr olle d p hase d ue t o lac k of 
i m pr o ve me nt or o n g oi n g seiz ures. 
− Disc o nti n uati o n of st u d y treat me nt after t he 8 -wee k acti ve r u n -i n peri o d d ue t o lac k of 
efficac y.  
2. 1. 5  E x pl or at or y Effic ac y O bjecti ves  
 
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
9  
2. 1. 6  E x pl or at or y Effic ac y E n d p oi nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. 1. 7  P K O bjecti ve  
P K o bjecti ve of t his st u d y is t o e val uate t he P K of nataliz u ma b i n s u bjects wit h f ocal e pile ps y.  
2. 1. 8  P K E n d p oi nts  
T he P K e n d p oi nts are as f oll o ws:  
•  C ma x  at stea d y state.  
•  A U C ta u at stea d y state.  
2. 1. 9  S afet y O bjecti ves  
Safe t y o bjecti ves of t his st u d y are t o assess t he safet y a n d t olera bilit y of nataliz u ma b i n s u bjects wit h 
dr u g -resista nt f ocal e pile ps y.  Safet y a n d t olera bilit y assess me nts i ncl u de A Es/ S A Es data, cli nical 
la b orat or y dat a, a n d el ectr o nic e C-S S R S/ C -S S R S.  
 
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
1 0  
2. 2  
St u d y Desi g n  
T his is a 6 -m o nt h ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o assess t he efficac y, safet y, 
a n d t olera bilit y of natali z u ma b as a dj u ncti ve t hera p y i n t he treat me nt of a d ult s u bjects wit h dr u g -
resista nt f ocal e pile ps y. 
All s u bjects will c o m plete a 6 -wee k pr os pecti ve baseli ne peri o d wit h o ut st u d y treat me nt t o esta blis h a 
baseli ne seiz ure fre q u e nc y.  After c o m pleti n g scree ni n g assess me nts a n d f ulfilli n g t he criteria f or st u d y 
e ntr y, eli gi ble s u bjects will be ra n d o ml y assi g ne d t o 1 of 2 treat me n t gr o u ps i n a 1: 1 rati o, a n d eac h 
s u bject will recei ve 1 d ose of st u d y treat me nt at Wee k 0 wit h d osi n g Q 4 W  f or 2 4 wee ks, acc or di n g t o 
1 of t he f oll o wi n g 2 re gi me ns: 3 0 0 m g I V nataliz u ma b i nf use d o ver 1  h o ur or place b o I V. T he 
ra n d o mizati o n will be str atifie d, as m u c h as p ossi ble, base d o n t he prese nce or a bse nce of str uct ural 
eti ol o g y f or f ocal e pile ps y a n d ba s e d o n t h e prese nce or a bs e nce of a hi g h s eiz ure fre q ue nc y 
( ≥2 4 seiz ures) d uri n g t he 6-wee k pr os pecti ve bas eli ne peri o d. Str uct ural eti ol o g y f or f ocal e pile ps y is 
defi ne d as a b n or malities visi ble o n str uct ural ne ur oi ma gi n g w here t he electr ocli nical assess m e nt 
t o get her wit h t he i ma gi n g fi n di n gs lea d t o a reas o na ble i nfere nce t hat t he i ma gi n g a b n or malit y is t he 
li kel y ca use of t he s u bject’s seiz ures [Sc heffer 2 0 1 7 ]; t his assess me nt will be a dj u dicate d b y a n I E R C. 
T here will be n o d ose titrati o n of nataliz u ma b.  T he i nitial 8  wee ks of t h e place b o -c o ntr olle d p hase will 
c o nstit ute a n acti ve r u n -i n peri o d per mitti n g nataliz u ma b t o ac hie ve a p pr o xi matel y 7 5 % of stea d y state 
i n s u bjects wit h o ut a nti-nataliz u ma b a nti b o dies, base d o n pri or st u dies i n M S.  
At t he e n d of t h e place b o -c o ntr olle d p hase, s u bjects will c o nti n ue i nt o a 2 4 -wee k , o pe n -l a bel safet y 
a n d efficac y p hase i n w hic h all s u bjects will recei v e nataliz u ma b 3 0 0  m g I V i nf usi o n Q 4 W  f or 
2 4  wee ks.  
A p ost -treat me nt f oll o w-u p visit a n d a F oll o w -U p Safet y P h o ne Call will occ ur 1 6  wee ks a n d 2 4  wee ks, 
res pecti vel y, after t he l ast d ose of st u d y treat me nt. 
A p pr o xi matel y 7 0  s u bjects are e x pecte d t o be e nr olle d, ra n d o mize d, a n d d ose d ( ~ 3 5  s u bjects i n eac h 
treat me nt gr o u p) at a p pr o xi matel y 4 4 sites i n t he U S. T he st u d y will ai m t o i ncl u de a p pr o xi matel y 
2 8  s u bjects with a str uct ural eti ol o g y f or f ocal e pile ps y a n d a p pr o xi matel y 2 8  s u bjects wit h a hi g h 
seiz ure fre q u e nc y, w hic h are n ot m ut uall y e xcl usi ve.  
See Fi g ure  1  for a sc he m atic of t he st u d y desi g n.  
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
1 1  
Fi g ur e  1 :   
St u d y D e si g n S c h e m ati c  
 
2. 3  
St u d y D ur ati o n f or S u bjects  
T he t otal d urati o n of st u d y partici pati o n will be u p t o a p pr o xi matel y 7 4  wee ks f or s u bjects c o m pleti n g 
t he place b o -c o ntr olle d, o pe n -la bel, a n d f oll o w-u p p hases.  T his c o m prises: a 6-wee k pr os pecti ve 
baseli ne peri o d ; a 2 4-wee k d o u ble -bli n d place b o -c o ntr olle d p hase c o nsisti n g of a n 8 -wee k acti ve r u n -i n 
peri o d a n d a 1 6 -wee k effi cac y p eri o d ; a 2 4-wee k o pe n -la bel p has e; a 1 2-wee k p ost -treat me nt f oll o w-u p 
peri o d ; a n d a F oll o w-U p Safet y P h o ne Call ( 2 4  wee ks after t he last d ose of st u d y treat me nt).  
T he e n d of st u d y date f or a s u bject ma y be t he last st u d y visit, last pr ot oc ol -s pecifie d ass ess me nt, or 
date of A E res ol uti o n if t he s u bject has o n g oi n g A Es re q uiri n g f oll o w-u p . 
2. 4  
E n d of St u d y  
T he e n d of st u d y is last s u bject, last p h o ne call f or fi nal c ollecti o n of data.  T he e n d of t he 
place b o -c o ntr olle d p has e will be after t he ass ess me nts are ta ke n at Wee k  2 4, bef ore st u d y trea t me nt 
a d mi nistrati o n f or t he o p e n -la bel p hase. 
 
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al  v 2. 0  
 
1 2  
2. 5  
S a m ple Size C o nsi der ati o ns  
T we nt y -ni ne s u bj ects p er treat me nt ar m will pr o vi de 8 0 % p o wer t o detect a treat me nt differe nce 
of -0. 3 7 5 bet w ee n n ataliz u ma b a n d place b o i n t he nat ural l o g -tra nsf or me d seiz ure fre q ue nc y, 
sta n dar dize d o ver 2 8 d a ys, at a 2 -si de d si g nifica nce l e vel of 0. 0 5 0, ass u mi n g a c o m m o n sta n dar d 
de viati o n of t he l o g -tra nsf or me d fre q ue nc y of 0. 5. F or e xa m ple, if t he place b o gr o u p has a 2 0 % 
re d ucti o n fr o m baseli ne i n seiz ure fre q ue nc y a n d t he acti ve gr o u p has a 4 5 % re d ucti o n fr o m baseli ne i n 
seiz ure fre q ue n c y, t he s a m ple size w o ul d pr o vi de 8 0 % p o wer t o detect t his differe nce. A t otal of 
a p pr o xi matel y 7 0  s u bjects will be ra n d o mize d to all o w f or a disc o nti n uati o n rate u p t o 1 5 %. 
3  
Defi niti o ns  
3. 1  
D ates a n d P oi nts of Refere nce  
I n ge n eral, data t hat are s u m marize d b y visit; E T  v isits or u nsc he d ule d visits will be assi g ne d t o a n 
a p pr o priate s c he d ule d visit b y usi n g t he wi n d o wi n g sc he me s h o w n i n Ta ble 2 . If t he dat e of t he E T  visi t 
falls bet wee n t he l o wer b o u n d a n d u p per b o u n d dates f or an  a nal ysis visit, it will be assi g ne d t o t hat 
visit.  H o we ver, if a pri or visit is ma p pe d t o t he sa me a nal ysis visit, t he n t he E T  visit will be re ma p pe d 
t o t he ne xt a nal ysis visit. T he visit wi n d o w ma p pi n g will n ot be a p plie d t o t he e n d of st u d y visit Wee k 
6 0  or F oll o w -u p visit f or E T s u bjects . 
T he date of t he first i nf usi o n will be t he refere nce p oi nt ( Da y 1). Rela ti ve da ys after Day 1 are calc ulate d 
as (ass ess me nt date - Da y 1 date) + 1. Rel ati ve da ys pri or t o Da y 1 are calc ulate d as (assess me nt dat e - 
Da y 1 date) . T he da y pri or t o Da y 1 is Da y -1.  
T a bl e 2 : Vi sit Wi n d o w M a p pi n g  
P h a s e - St u d y Vi sit  
A n al y si s 
Vi sit    
T ar g et D a y  
Vi sit Wi n d o w  
Vit al si g n s, 
l a b or at or y 
a s s e s s m e nt ,  
e C -S S R S/ C -S S R S  
S cr e e ni n g  - 
S cr e e ni n g  
W e e k -6    
-4 2  
≤ -1  
≤ -1  
P C P - B a s eli n e    
B a s eli n e    
≤1  
≤1  
≤1  
P C P - Vi sit 2    
W e e k 4  
2 8  
2 -4 1  
-- 
P C P  - Vi sit 3    
W e e k 8  
5 6  
4 2 -6 9  
-- 
P C P - Vi sit 4    
W e e k 1 2    
8 4  
7 0 -9 7  
2 -9 7  
P C P - Vi sit 5    
W e e k 1 6    
1 1 2    
9 8 -1 2 5  
-- 
P C P - Vi sit 6    
W e e k 2 0    
1 4 0    
1 2 6 -1 5 3  
-- 
P C P - Vi sit 7    
W e e k 2 4    
1 6 8    
1 5 4 -1 8 1  
9 8 -1 8 1  
O L P - Vi sit 8    
W e e k 2 8    
1 9 6    
1 8 2 -2 0 9  
-- 
O L P - Vi sit 9    
W e e k 3 2    
2 2 4    
2 1 0 -2 3 7  
-- 
O L P - Vi sit 1 0    
W e e k 3 6    
2 5 2    
2 3 8 -2 6 5    
1 8 2 -2 6 5  
O L P - Vi sit 1 1    
W e e k 4 0    
2 8 0    
2 6 6 -2 9 3  
-- 
O L P - Vi sit 1 2    
W e e k 4 4    
3 0 8    
2 9 4 -3 2 1  
-- 
O L P - Vi sit 1 3    
W e e k 4 8    
3 3 6    
3 2 2 -3 4 9    
2 6 6 -3 4 9  
A b br e vi ati o n s: P C P = P l a c e b o-C o ntr oll e d P h a s e ; O L P = O p e n-L a b el P h a s e  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
1 3  
If m ore t ha n o ne o bs er vati o n is wit hi n t he sa me wi n d o w, data cl osest t o t he tar get re g ular l y sc he d ule d 
visit will be use d i n t he s u m mar y statistics a n d a nal yses.  If m ore t ha n o ne o bser vati o n falls i n t he sa me 
dista nce fr o m t h e tar g et re g ular l y sc h e d ule d visit da y, t he last o bser vati o n will be use d i n t he s u m m ar y 
statistics a n d a nal yses.  
T he seiz ure calc ulati o n wi n d o w f or a visit will start o n  t he date of pre vi o us visit a n d e n d o n t he date 
i m me diatel y bef ore t he c urre nt visit  date.  If a n i nf usi o n is misse d, t he seiz ure fre q ue nc y will be 
calc ulate d b ase d o n t he pr ojecte d visit date (i.e., 2 8 da ys fr o m t he date of pre vi o us visit). If t h e s u bject 
wit h dre w fr o m t he st u d y pre mat urel y, t he seiz ure fre q ue nc y after t he last i nf usi o n will be calc ulate d 
fr o m last i nf usi o n u ntil t he date of t he E T visit or 2 8 da ys after last i nf usi o n, w hic he ver is earlier. T he 
calc ulate d fre q u e nc y will be assi g ne d t o t he ne xt sc he d ule d visit ha d  E T n ot occ urre d . I n t he p ost-
treat me nt peri o d, t he n u m ber of seiz ures will be c o u nte d f or e ver y 2 8 da ys a n d t he calc ulate d seiz ure 
fre q ue n c y will be assi g ne d t o wee ks i n a 4-wee k i nter val.  
St u d y Peri o ds  
Baseli ne peri o d is d efi ne d  as t he p eri o d fr o m scree ni n g visit t o t he da y pri or t o first i nf usi o n of st u d y 
treat me nt (i.e., place b o a n d nataliz u ma b ).  
T he e n d -of -treat me nt da y is defi ne d as 27  da ys after last i nf usi o n i n t h e st u d y or  t he da y  pri or t o  E T 
visit , w hic he ver is earlier. Treat me nt peri o d  is defi ne d as t he peri o d fr o m first d osi n g date t o t he e n d-
of -treat me nt da y, i ncl usi ve. Wit hi n treat me nt peri o d, place b o -c o ntr olle d p hase is defi ne d as t he peri o d 
fr o m first i nf usi o n i n t he st u d y u ntil  pri or t o i nf usi o n at t he Wee k 2 4  visit , w hile o pe n -la bel p hase is 
defi ne d as t he peri o d fr o m i nf usi o n at t he Wee k 2 4 visit t o t he e n d-of -treat me nt da y.  
P ost -treat me nt peri o d  is d efi ne d as t he peri o d fr o m 2 8 da ys after  last i nf usi o n date  or E T v isit, w hic he ver 
is earlier, t o e n d-of -st u d y visit ( Wee k 6 0 v isit f or c o m pleters a n d F oll o w -u p  v isit f or earl y wit h dra wal  
s u bjects).  
B aseli ne defi niti o n  
•  St u d y baseli ne: T he baseli ne assess me nts i n ge neral will be defi ne d as t he cl osest n o n -missi n g 
val ue pri or t o/ o n t he d at e of t h e first i nf usi o n of st u d y treat me nt e xce pt f or t hat of  t he s eiz ure 
data. St u d y b aseli ne f or seiz ure data will be deri ve d usi n g t he sta n dar dize d calc ulati o n  f or 
baseli ne peri o d sei z ure di ar y data, as descri be d i n Secti o n 3. 3 . 1.  
•  O pe n -la bel p h ase b aseli n e: O pe n -la bel p has e baseli ne i n ge neral e xce pt f or t hat of t he  seiz ure 
data is defi ne d as t he cl osest n o n-missi n g val ue pri or t o/ o n t he date of t he first i nf usi o n of 
nataliz u ma b i n t he st u d y. O pe n-la bel p has e baseli ne f or seiz ure fre q ue nc y is defi ne d as t he 2 8-
da y sta n dar dize d seiz ure fre q ue nc y assi g ne d t o t h e visit of t he first n ataliz u ma b i nf usi o n i n t he 
st u d y. 
3. 2  
 Tre at me nt Gr o u p  
U nless ot her wise s pecifie d, data will be s u m marize d usi n g t he f oll o wi n g la bels f or treat me nt gr o u p i n 
t he place b o -c o ntr olle d p h ase a nal ysis, i n t he or der prese nte d:  
•  Place b o  
•  Nataliz u ma b 3 0 0 m g ,  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
1 4  
a n d usi n g t he f oll o wi n g la bels f or treat me nt gr o u p i n t he o pe n -la bel p hase a nal ysis, i n t he or der 
prese nte d:  
•  Place b o t o Nataliz u ma b 3 0 0 m g  
•  Nataliz u ma b 3 0 0 m g t o Nataliz u ma b 3 0 0 m g  
T he ra n d o mize d treat me nt will be base d o n I X R S ra n d o mizati o n c o de. T he act ua l recei ve d treat me nt i n 
t he place b o-c o ntr olle d p hase will be nataliz u ma b  if t he s u bject recei v e a n y d ose of nataliz u ma b ; 
ot her wise, t he act ual treat me nt will be place b o.  T he act ual recei v e d treat me nt i n t he o pe n-la bel p hase 
will be n ataliz u ma b t o n ataliz u ma b if t he s u bject recei ve a n y d os e of nataliz u ma b  i n t he place b o-
c o ntr olle d p hase; ot her wise, t he act ual treat me nt will be place b o t o nataliz u ma b . 
3. 3  
Ke y Deri ve d V a ri a bles   
3. 3. 1  C alc ul ati o n of S t a n d ar dize d S eiz ure F re q ue nc y  
B ot h s o urces of seiz ure diar y data (electr o nic a n d pa per) will be p o ole d t o get her f or t he efficac y 
a nal ysis. T he p o ole d d ata will be referre d t o as seiz ure di ar y dat a i n t he a nal ysis.  Seiz ures i ncl u de d i n 
efficac y a nal yses are f ocal a ware seiz ures ( pre vi o usl y ter me d “si m ple partial seiz ures ”) wit h m ot or 
si g ns, f ocal i m paire d a ware ness seiz ures ( pre vi o usl y ter me d “c o m ple x partial seiz ures”), a n d f ocal t o 
bilateral t o nic -cl o nic sei z ures ( pre vi o usl y ter m e d “ partial o nset wit h sec o n dar y ge neralizati o n”). F ocal 
a ware seiz ures wit h o ut m ot or si g ns will n ot be i ncl u de d i n t he calc ulati o n of seiz ure fre q ue nc y.  
F or t he assess me nt of s eiz ure fre q ue n c y, t he sta n dar dize d s eiz ure fre q ue nc y ( n u m ber of seiz ures per 
2 8  da ys) at eac h visit will be calc ulate d base d o n t he s u m of t he seiz ures re p orte d i n t he s u b ject seiz ure 
diar y a n d t he n u m ber of d a ys wit h n o n -missi n g seiz ure fre q ue nc y data i n t he seiz ure calc ulati o n wi n d o w  
f or t he c orres p o n di n g visit ( defi ne d i n Secti o n 3. 1 ). A re p ort of u n k n o w n seiz ure occ urre nce  will be 
c o nsi dere d as a missi n g seiz ure diar y data b ut i n c o m plia nce t o seiz ure re p orti n g.  
Seiz ure fre q ue nc y ( n u m b er of seiz ures per 2 8  da ys) will be calc ulate d base d o n b ot h s o urces of s u bject 
seiz ure diar y data (electr o nic a n d pa per) i n t he sei z ure calc ulati o n wi n d o w , as f oll o ws: 
St a n d ar di z e d  S ei z ur e  Fr e q u e nc y =
N u m b e r  of  s ei z u r e s
N u m b e r  of  d a y s  wit h  n o n −mi s si n g  s ei z u r e  di a r y × 2 8   
St u d y tea m will m o nit or t he n u m ber of visits wit h zer o c o u nts i n t he sta n dar dize d seiz ure fre q ue nc y 
( n u m ber of s eiz ures o ver 2 8 da ys). If m ore t h a n fi ve perce nt of t he visits d uri n g t he place b o-c o ntr olle d 
p hase ha v e zer os i n t he st a n dar dize d seiz ure fre q ue nc y acr oss all t he s u bjects i n t he I T T p o p ulati o n, t he 
f oll o wi n g f or m ula will be use d t o perf or m t he nat ural l o g-tra nsf or mati o n, y =l n( x + 0. 2), w here x is t he 
sta n dar dize d seiz ure fre q ue nc y. T he fi nal a nal ysis res ults will be bac k calc ulate d b y a dj usti n g f or 0. 2 
i ncre me nt. T he me dia n  sta n dar dize d seiz ure fre q ue nc y will be calc ulate d as ex p (me a n of l o g 
sta n dar dize d s eiz ure fre q ue nc y) -0. 2 . 
If n o m ore t ha n 5 % of t he visits d uri n g t he place b o -c o ntr olle d p hase are o bser ve d wit h zer os i n t he 
sta n dar dize d seiz ure fre q ue nc y acr oss all t he s u bj ects i n t he I T T p o p ulati o n, y =l n( x + 0. 2) will o nl y be 
use d f or t he visits wit h ze r o seiz ure fre q ue ncy . T he fi nal a nal ysis res ults will n ot be a dj uste d f or t he 
s mall i ncre me nt of 0. 2 . T his met h o d o nl y a p plies t o t he l o g tra nsf or me d a nal ysis a n d will n ot be 
e m pl o ye d f or t he res p o n der a nal ysis.  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
1 5  
T o mai ntai n t he hi g h c o m plia nce rate f or se iz ure data p ost baseli ne , if 1 5 % of diar y data or m ore  are 
missi n g bet wee n t w o i nf usi o ns (i.e., t he diar y  c o m plia nce  < 8 5 %) , t he seiz ure fre q ue nc y at t he f oll o wi n g 
visit will be assi g ne d t o missi n g. If a visit d oes n’t ta ke place, pr ojecte d visit date ( defi n e d as 2 8 da ys 
fr o m t he date of pre vi o us visit) will be use d t o cal c ulate t he sei z ure fre q ue nc y. Als o, s eiz ure data will 
n ot be use d after m o dificati o n of A E Ds as rec or de d o n t he eC R F pa ge of A nti -E pile ptic Treat me nt 
C o m plia nce.  
Se nsiti vit y a nal yses  (details i n Secti o n 5. 1 0. 2 ) will be perf or me d t o i ncl u de all t he o bser ve d seiz ure 
data.   
3. 3. 2  Defi niti o n of Res p o n der  
A res p o n der is defi ne d as  a s u bject wit h a ≥5 0 % re d ucti o n fr o m st u d y b aseli ne i n seiz ure fre q ue nc y 
( n u m ber of sei z ures p er 2 8 da ys) d uri n g Wee ks  8 t o 2 4 of treat me nt.  T he o verall seiz ure fre q ue nc y per 
2 8 da ys d uri n g W ee ks 8 t o 2 4 will be calc ulate d si milar l y as descri be d i n S ecti o n 3. 3 .1 . A n y s u bjects 
w h o ha ve recei v e d m o dificati o n of A E D s d uri n g t he place b o -c o ntr olle d p hase  will be c o nsi dere d as 
n o n -res p o n der. M o dificati o n of A E D s will be deter mi ne d base d  o n  w hat is re p orte d o n t he eC R F  pa ge 
of  A nti -E pile ptic Treat me nt C o m plia nce. F ocal a ware s eiz ures wit h o ut m ot or si g ns will n ot be 
i ncl u de d i n t he calc ulati o n of seiz ure fre q ue nc y. 
3. 3. 3  Defi niti o n of Free fr o m Seiz ure  
A s eiz ure -free s u bject is defi ne d as a s u bject w h o has n o ( zer o) seiz ures (calc ulati o n of seiz ure fre q ue nc y 
descri be d i n Secti o n 3. 3. 1 ) d uri n g Wee ks  8 t o 2 4 of treat me nt. U nless ot her wise s pecifie d, i f s u bjects 
ha ve missi n g seiz ure diar y data, t he y will n ot be c o nsi dere d as seiz ure free.  
3. 3. 4  Defi niti o n of N u m ber of Seiz ure -free D a ys 
T he n u m ber of sei z ure -free da ys will be calc ulate d base d o n t he n u m ber of s eiz ure -free da ys a m o n g t he 
da ys wit h n o n -missi n g seiz ure diar y  d ata i n t he s eiz ure cal c ulati o n wi n d o w f or a visit . T he n u m b er of 
seiz ure-free da ys per  2 8  da ys will be calc ulate d as : (n u m ber of seiz ure -free da ys / n u m ber of da ys wit h 
n o n -missi n g seiz ure dair y) × 2 8 da ys.  
3. 3. 5  St u d y  Tre at me nt  C o m pli a nce  
T he st u d y treat me nt c o m plia nce i n t he place b o-c o ntr olle d p hase  is defi ne d as t he perce nt a ge of st u d y 
treat me nt i nf usi o ns recei ve d o ver t he n u m ber of i nf usi o ns t hat t he s u bject is e x pecte d t o ha ve recei ve d 
u p t o t he e n d of t he place b o -c o ntr olle d  p hase.  T he defi niti o n of s t u d y treat me nt c o m plia nce i n t he o pe n-
la bel p hase is t he sa me. 
3. 4  
Str atific ati o n F act ors a n d S u b gr o u p V ari a bles  
3. 4. 1  Str atific ati o n F act ors  
T he stratificati o n fact ors use d i n t he I X R S ra n d o mizati o n are liste d as f oll o ws : 
•  S eiz ure fre q ue n c y cat e g or y  d uri n g t he 6 -wee k pr os pecti ve baseli ne peri o d:  
o  ≥2 4 seiz ures  
o  < 2 4 seiz ures  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
1 6  
•  Str uct ural eti ol o g y cate g or y  f or f ocal e pile ps y:  
o  Prese nce of str uct ural eti ol o g y   
o  A bse nce of str uct ural eti ol o g y  
3. 4. 2  S u b gr o u p V ari a bles  
T he f oll o wi n g varia bles  will be use d f or s u b gr o u p a nal yses : 
•  S tr uct ural eti ol o g y cate g or y f or f ocal e pile ps y (prese nce, a bse nce)  
T he I E R C assess me nt of str uct ural eti ol o g y will be use d as t he tr ue prese nce of str uct ural 
eti ol o g y. 
•  S eiz ure fre q ue n c y  cat e g or y ( hi g h: ≥2 4; l o w: < 2 4 seiz ures) 
Base d o n seiz ure diar y data i n t he baseli ne peri o d, t he o bser ve d seiz ure fre q ue nc y will be 
sta n dar dize d t o 4 2 da ys t o acc o u nt f or t he 6-wee k baseli ne peri o d. T he 4 2 -da y sta n dar dize d 
seiz ure fre q u e nc y will be cate g orize d b y ≥2 4 or < 2 4 seiz ures as t he o bs er ve d hi g h or l o w seiz ure 
fre q ue n c y cate g or y. 
•  D urati o n of e pile ps y  (i n years) fr o m dia g n os is t o ra n d o mizati o n date (< 1 0  a n d ≥1 0 years)  
T he year of e pile ps y dia g n osis will be use d t o calc ulate t he d urati o n of e pile ps y , as (year of 
ra n d o mizati o n date - year of e pile ps y dia g n osis) .  
T he s u b gr o u p v aria bl es  will be deter mi ne d b y t h e I E R C-a dj u dicate d or o bser ve d baseli ne data i nstea d 
of ra n d o mizati o n stratificati o n fact ors.  
3. 5  
A n al ysis P o p ul ati o n s  
T he a nal ysis will i ncl u de t he I T T, P P , Safet y, P K , a n d P D p o p ulati o n s. 
 I T T P o p ul ati o n 
T he I T T p o p ulati o n is d efi ne d as all s u bjects w h o we re ra n d o mize d a n d recei v e d a n y  d ose of st u d y 
treat me nt. S u bjects will b e a nal yze d i n t he treat me nt gr o u p t o w hic h t he y were ra n d o mize d. All effi cac y 
e n d p oi nts will be e val uat e d base d o n t he I T T p o p ulati o n  acc or di n g t o t he ra n d o mize d treat me nt .  
All s u bjects w h o recei ve d a n y  d os e of st u d y treat me nt d uri n g t he o pe n -la bel p hase will be i ncl u de d i n 
t he I T T p o p ulati o n f or t he o pe n-la bel p hase. T he data d uri n g t he o pe n -la bel p hase will be s u m marize d 
b y t he act ual treat me nts r ecei ve d i n t he st u d y.   
P P P o p ul ati o n  
T he P P  p o p ulati o n w ill i ncl u de t he s u bs et of t h e I T T p o p ulati o n w h o ha ve c o m plete d t he place b o -
c o ntr olle d p hase (as rec or de d o n t he e C R F pa ge ‘ E n d of Treat me nt [ Place b o-C o ntr olle d P hase]’ ), ha ve 
o verall diar y c o m plia nce greater t ha n 9 0 % d uri n g t he place b o -c o ntr olle d p hase , an d ha ve n o si g nifica nt 
pr ot oc ol de viati o ns t hat w o ul d be e x pecte d t o affect efficac y assess me nts. S u bjects will be a nal yze d 
base d o n act ual treat me nt recei ve d f or t he P P p o p ulati o n.  T he P P p o p ulati o n will be  use d f or a nal ysis 
of p ri mar y e n d p oi nt a n d selecte d sec o n dar y effi cac y e n d p oi nts.  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
1 7  
T he list of si g nifica nt pr ot oc ol de viati o ns f or e xcl usi o n fr o m t he P P  p o p ulati o n i ncl u des, b ut is n ot 
li mite d t o: 
•  S u bjects w h o misse d at least 1 i nf usi o n d uri n g t he place b o -c o ntr olle d p has e . 
•  S u bjects  w h o  e x p erie nce d < 6  sei z ures d uri n g t he baseli ne peri o d  or were  s eiz ure free f or m ore 
t ha n 2 1 c o nsec uti ve da ys d uri n g t he baseli ne peri o d  a n d were ra n d o mize d i n t he st u d y . F ocal  
a ware seiz ures wit h o ut m ot or si g ns will n ot be i ncl u de d  i n t he seiz ure c o u nt. 
•  S u bjects w h o misse d m ore t ha n 6 da ys of seiz ure diar y data d uri n g t he bas eli ne peri o d  a n d were 
ra n d o mize d i n t he st u d y. 
•  S u bjects w h o m o difie d A E Ds d uri n g t he baseli ne peri o d.  
•  S u bjects w h o were acci de ntall y u n bli n de d.  
T he vali dit y of s u bject  i ncl usi o n i n t he P P p o p ulati o n will be re vie we d a n d a p pr o ve d pri or t o t he 
data base l oc k.  
S afet y P o p ul ati o n  
T he Safet y p o p ulati o n, c o m pris i n g all s u bjects w h o were ra n d o mize d a n d recei ve d a n y d ose of st u d y 
treat me nt, will be use d f or t he a n al ysis of safet y data. S u bjects will be a nal yze d base d o n act u al 
treat me nt recei ve d f or t h e safet y p o p ulati o n. 
All s u bjects w h o recei ve d a n y d os e of st u d y tr eat me nt d uri n g t he o pe n -la bel p hase will be i ncl u de d i n 
t he safet y p o p ulati o n f or t he o pe n-la bel p h ase.  
P K  P o p ul ati o n  
T he P K p o p ulati o n is defi ne d as all s u bjects w h o recei ve d  a n y d ose of st u d y treat ment  a n d had  at least 
1  meas ura ble c o nce ntrati o n of nata liz u ma b i n ser u m.   
T he P K p o p ulati o n f or t h e o pe n -la bel p hase is defi ne d as all s u bjects w h o recei v ed  a n y d ose of st u d y  
treat me nt d uri n g t he o pe n -la bel p hase a n d had  at least 1 meas ura ble c o nce ntrati o n of nataliz u ma b i n 
ser u m.  
S u bjects will be a nal yze d base d o n act u al treat me nt recei ve d f or t he P K p o p ulati o n.  
P D P o p ul ati o n  
T he P D p o p ulati o n is defi ne d as all s u bjects w h o recei ve d a n y d ose of st u d y treat me nt a n d ha d  at least 
1  p ost baseli ne meas ure me nt of t he para meter bei n g a nal yze d f or P D.   
T he P D p o p ulati o n f or t h e o pe n -la bel p hase is defi ne d as all s u bjects w h o recei v ed  a n y d ose of  st u d y 
treat me nt a n d had  at least 1 p ost baseli ne meas ure me nt of t he P D para m eters.    
S u bjects will be a nal yze d base d o n act u al treat me nt recei ve d f or t he P D p o p ulati o n.  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
1 8  
4  
List of Pl a n ne d St u d y A n al yses  
4. 1  
I nteri m A n al ysis 
A pla n ne d i nteri m a nal ysis wit h o pti o nal sa m ple size re -esti mati o n  is descri be d i n Secti o n 1 6. 7 of t he 
pr ot oc ol. H o we v er, bas e d o n act ual st u d y recr uit me nt, t his p ote ntial a nal ysis w o ul d ha ve occ ur re d 
o nl y a p pr o xi matel y 6 m o nt hs pri or t o t he e n d of t h e st u d y a n d after all s u bjects w o ul d ha ve bee n 
e x pecte d t o b e  e nr olle d. T heref or e, Bi o ge n i n c oll a b orati o n wit h t he st u d y a d vis or y c o m mittee a n d 
dr u g -safet y m o nit ori n g c o m mittee deci de d t hat a f or mal i nteri m a nal ysis wit h sa m ple size re -
esti mati o n wa s n ot warra nte d. N o st o p pi n g decisi o n will be ma de base d o n t he effi cac y data  bef ore 
2 4  wee ks of treat me nt.  
4. 2  
Pri m ar y A n al ysis  
T he pri mar y  dat a base l o c k a n d rea d o ut will occ ur at t he e n d of t he place b o -c o ntr olle d p hase after all 
st u d y s u bjects ha ve h a d t he o p p ort u nit y t o c o m plet e t he W ee k  2 4 visit . T he pri mar y a nal ysis will  i ncl u de 
t he efficac y a n d safet y of nataliz u ma b as a dj u ncti ve t hera p y i n a d ult s u bjects wit h dr u g-resista nt f ocal 
e pile ps y d uri n g t he place b o -c o ntr olle d p hase.  
4. 3  
Fi n al A n al ysis  
T he fi nal data base l oc k will occ ur after all s u bjects ha ve c o m pleted  t he e ntire st u d y. T he a nal ysis will 
be perf or me d t o a ssess t he d ura bilit y of treat me nt res p o nse , q ualit y of life, m o o d, a n d t he safet y of 
nataliz u ma b d uri n g t he o pe n -la bel p hase.  
5  
St atistic al Met h o ds f or Pl a n ne d A n al yses  
5. 1  
Ge ner al Pri nci ples  
F or c o nti n u o us e n d p oi nts, t h e s u m mar y statistics will ge nerall y i ncl u de n u m ber of s u bjects wit h data  
( n), mea n, sta n dar d d e viati o n, me dia n, q uartiles, a n d ra n ge. F or cat e g orical e n d p oi nts, t he s u m mar y 
statistics will ge nerall y i ncl u de t he n u m ber of s u bjects i n t he c orres p o n di n g a nal ysis p o p ulati o n, a n d 
t he n u m ber a n d perce nta ge of s u bjects i n eac h cat e g or y. T he statistical s oft ware, S A S ®  versi o n 9. 4 or 
a b o ve, will be use d f or all s u m maries a n d statistical a nal yses.  
5. 2  
Missi n g D at a H a n dli n g C o n ve nti o ns  
N o i m p utati o n 
will 
be 
perf or me d f or 
c o m pletel y 
missi n g 
dates 
of 
A E s, c o nc o mita nt 
me dicati o ns /t hera pies, a n d me dical hist or y e ve nts . T he f oll o wi n g r ule s will be use d t o i m p ute t he partial 
start dates  of A E s a n d c o nc o mita nt me dicati o ns/t hera pies : 
•  If o nl y t he da y is missi n g  a n d m o nt h a n d year are prese nt,  
o  If m o nt h a n d year  are t he sa me as t he first d ose date  of st u d y treat me nt, t he n assi g n t o 
t he da y of t he first d ose date of st u d y treat me nt; 
o  If m o nt h a n d year are n ot t he sa me as t he m o nt h a n d year of t he first d ose date of st u d y 
treat me nt, t he n assi g n t o t he first da y of t he m o nt h. 
•  If o nl y t he year is prese nt a nd m o nt h a n d da y are missi n g, 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
1 9  
o  If year is t he sa me as t he year of t he first d ose date of st u d y treat me nt, t he n assi g n t o t he 
m o nt h a n d da y of  t he first d ose date of st u d y treat me nt; 
o  If year is n ot t he sa me as t he year of t he first d ose date of st u d y treat me nt, t he n assi g n 
t o Ja nuar y  1 st. 
T he partial e n d dates  will be i m p ute d as f oll o ws:  
•  If o nl y da y is missi n g a n d m o nt h a n d year are prese nt, t he n assi g n t o t he last da y of t he m o nt h; 
•  If o nl y year is prese nt a n d m o nt h a n d da y are missi n g, t he n assi g n t o Dece m ber 3 1 st. 
F or me dical hist or y e ve nts wit h partial o nset dates, t he f oll o wi n g r ules will be a p plie d: 
•  If year a n d m o nt h are prese nt, a n d da y is missi n g, i m p ute t he da y as t he 1 5t h of t he m o nt h; 
•  If year is pres e nt, a n d m o nt h a n d da y are missi n g, i m p ute t he m o nt h a n d da y as J u ne 3 0 t h of t he 
year.  
5. 3  
S u bject A cc o u nt a bilit y  
T he n u m ber (a n d %) of s u bjects will be prese nt e d  as f oll o ws : t h ose ra n d o mize d; t h ose d ose d ; t h ose 
i ncl u de d i n eac h of t he a nal ysis p o p ulati o ns; t h ose c o m plet i n g t he treat me nt i n t he place b o -c o ntr oll e d 
p hase ; t h ose w h o disc o nti n ue d  t he treat me nt i n t he place b o-c o ntr olle d p hase,  al o n g wit h reas o ns f or  
disc o nti n uati o n ; t h ose e nteri n g t he o pe n-la bel p hase; t h ose c o m pleti n g t he treat me nt i n t he o pe n-la bel 
p hase ; t h ose w h o disc o nti n ue d  t he treat me nt i n t he o pe n-la bel p hase, al o n g wit h reas o ns f or 
disc o nti n u ati o n; a n d t h ose wit h dr a wi n g fr o m t he st u d y wit h t he reas o n f or wit h dra wal.  
Listi n gs of t h ose s u bjects w h o disc o nti n ue d treat m e nt d uri n g  t he place b o -c o ntr olle d p hase or t he o pe n -
la bel p hase a n d/ or wit h dre w fr o m t he st u d y, al o n g wit h t he reas o ns f or disc o nti n uati o n/ wit h dra wal, will 
be prese nt e d.  
5. 4  
De m o gr a p hic a n d B aseli ne D ise ase C h a r acteristics  
De m o gra p hic a n d st u d y b aseli ne dat a ( de m o gra p h y, me dical hist or y, epile ps y hist or y, seiz ure hist or y, 
n u m ber of pri or a n d c o nc o mita nt e pile ps y dr u g a n d n o n -dr u g t hera pies) will be s u m marize d  f or t h e I T T 
p o p ulati o n o nl y .  
De m o gra p h y i n cl u des a g e, a ge gr o u p ( ≤3 0, 3 1 t o 4 5, 4 6 t o 6 0, ≥6 1  years ol d), se x, race, st u d y baseli ne 
hei g ht, st u d y baseli ne wei g ht a n d st u d y baseli ne B MI . Ra n d o mizati o n stratificati o n fact ors t o be 
s u m marize d i ncl u de: str uct ural eti ol o g y f or f ocal e pile ps y ( prese nce, a bse nce); cate g or y of seiz ure 
fre q ue n c y (≥2 4 seiz ures , < 2 4 seiz ures) d uri n g t he 6-wee k pr os pecti ve bas eli ne peri o d use d i n I X R S ; 
a n d t he o bser ve d/a dj u dicate d val ues of t he t w o fact ors .  
Me dical hist or y will be c o de d  usi n g t he latest versi o n of  Me d D R A (versi o n 2 2. 1  or later if u p date d)  a n d 
t he n u m ber (a n d %) of s u bjects wit h eac h hist or y will be prese nte d  usi n g t he preferre d ter m .  
E pile ps y  hist or y i ncl u des a ge at epile ps y dia g n osis, prese nce or a bs e nce of f ocal e pile ps y, prese nce or 
a bse nce of m ultif ocal e pile ps y, a n d m ost li kel y epile ps y eti ol o g y. Rele va nt  res ults of ne ur oi ma gi n g , 
ne ur o p h ysi ol o g y , a n d n e ur o ps yc h ol o g y fi n di n gs will be prese nte d i n t he listi n gs.  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 0  
Seiz ure hist or y i n cl u d es the d urati o n of seiz ure t y pes si nce o nset, calc ulate d as (ra n d o mizati o n date - 
first seiz ure o nset dat e)/ 3 6 5. 2 5, a n d t he esti mate d fre q ue nc y i n t he last year, w hic h will be s u m marize d 
b y t y pe of seiz ure  a n d treat me nt gr o u p . T he partial o nset date will f oll o w t he i m p utati o n r ules f or 
me dical hist or y e ve nts descri be d i n Secti o n 5. 2 . 
E pile ps y treat me nt h ist or y will be ta b ulate d b y treat me nt gr o u ps. T he n u m ber (a n d %) of s u bjects ta ki n g 
p re vi o us epile ps y treat me nt as well as pri or or o n g oi n g n o n -dr u g t hera pies f or e pile ps y ( V N S, R N S, 
e pile ps y s ur ger y , a n d ket o ge nic diet) will be s u m marize d. A listi n g of E pile ps y treat me nt hist or y f or all 
s u bjects will be prese nte d. 
F or mal statistical a nal yses will n ot be d o ne t o test f or h o m o ge neit y bet wee n treat me nt gr o u ps. If t here 
are a p pare nt heter o ge neities bet wee n t he gr o u ps i n a n y of t h e s u bject c haracteristics t hat are of cli nical 
i m p orta nce or c o ul d affect t he treat me nt o utco me, t he i m pact of t he i m bala nces will be i n vesti gate d, 
a n d a dj ust me nts ma de i n t he efficac y a n d safet y a nal yses  if a p pr o priate. 
5. 5  
Pr ot oc ol D e vi ati o ns  
T he maj or /critical p r ot oc ol de viati o ns will be s u m marize d f or t he I T T p o p ulati o n. A listi n g of 
maj or/critic al pr ot oc ol de viati o ns will be prese nte d.  
5. 6  
E xte nt of E x p os ure  
S u bjects will recei ve st u d y treat me nt Q 4 W i n t he treat me nt peri o d.  
St u d y treat me nt c o m plia nce ( defi ne d i n Secti o n 3. 3. 5 ) will be s u m marize d f or t he Safet y  p o p ulati o n b y 
treat me nt gr o u ps i n t he pl ace b o -c o ntr olle d p has e. T he n u m ber of  i nterr u pte d i nf usi o ns a n d t otal v ol u me 
a d mi nistere d will als o be s u m marize d b y treat me nt gr o u p i n t he place b o -c o ntr olle d p hase.  
St u d y treat me nt c o m plia nce, i nterr u pte d i nf usi o ns, a n d t otal v ol u me a d mi nistere d  i n t he o pe n-la bel 
p hase will be s u m marize d i n t he sa me ma n ner as  i n t he place b o -c o ntr olle d p hase.  
5. 7  
N o n -A E D C o nc o mit a nt M e dic ati on /T her a p y  
All n o n -A E D  c o nc o mita nt me dicati o ns will be c o de d usi n g t he W H O me dicati o n dicti o nar y ( W H O D D 
G L O B A L versi o n B 3 M arc h 2 0 1 9, or later if u p date d ). All c o nc o mita nt n o n-dr u g t hera pies will be  
c o de d usi n g M e d D R A  (versi o n 2 2. 1  or later if u p date d ). A c o nc o mita nt t hera p y i n t he pl ace b o-
c o ntr olle d p hase will be  defi ne d as a n y t hera p y t hat was ta ke n o n or after t he da y of t he first d ose of 
st u d y treat me nt i n t he place b o-c o ntr olle d p hase.  A c o nc o mita nt t hera p y i n t he o pe n -la bel p has e will be 
defi ne d as a n y t hera p y t h at was ta ke n o n or after t he da y of t he first d ose of st u d y treat me nt i n t he o pe n-
la bel p hase. 
F or t he place b o -c o ntr olle d p hase, t his i ncl u des t hera pies t hat start pri or t o t he i nitiati o n of t he first d os e 
of st u d y treatme nt  if t heir use c o nti n ues o n  or after t he date of t he first d ose of st u d y treat me nt i n t he 
place b o -c o ntr olle d p hase . F or t he o p e n -la bel p has e, t his i ncl u des t hera pies start pri or t o t he i nitiati o n of 
t he first d ose of st u d y treat me nt if t heir use c o nti n ues o n or after t he dat e of t he first d ose of st u d y 
treat me nt i n t he o pe n-la bel p hase. I n or der t o defi ne c o nc o mita nt f or t hera pi es wit h c o m pletel y missi n g 
start or st o p dates, t he f oll o wi n g a d diti o nal criteria will be use d: 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 1  
•  If b ot h t he start a n d st o p dates of a t h era p y  are c o m plet el y missi n g, t hat t hera p y will be  
c o nsi dere d c o nc o mita nt i n  b ot h  t he place b o-c o ntr olle d p hase  a n d t he o pe n -la bel p hase.  
•  If t he start date of a t hera p y is c o m pletel y missi n g a n d t he st o p date of t hat t hera p y falls  o n or 
after t he date of t he first d ose of st u d y treat me nt i n t he place b o-c o ntr olle d p hase, t hat t hera p y 
will be c o nsi dere d c o nc o mita nt i n t he place b o -c o ntr olle d p hase.   
•  If t he start date of a t hera p y is c o m pletel y missi n g a n d t he st o p date of t hat t hera p y falls o n or 
after t he d ate of t h e first d ose i n t he o pe n -la bel p hase, t hat t hera p y will be c o nsi dere d 
c o nc o mita nt i n b ot h t he place b o -c o ntr olle d p hase a n d t he o pe n -la bel p h ase. 
•  If t he st o p d ate of a t hera p y is c o m pletel y missi n g a n d t he start date of t hat t hera p y falls bef ore 
t he date of t he first d ose i n t he o pe n-la bel p hase, t h at t hera p y will be c o nsi dere d c o nc o mita nt i n 
b ot h t he place b o -c o ntr olle d p hase a n d t h e o pe n -l a bel p hase. 
F or a t h era p y wit h a parti al start or st o p date , t h e i m p utati o n will be perf or me d as descri be d i n Secti o n 
5. 2  a n d t he i m p ute d dates will be use d t o deter mi ne w het her t h e t hera p y is c o nc o mita nt. 
T he n u m ber ( %) of s u bjects ta ki n g n o n -A E D c o nc o mita nt me dicati o ns a n d n o n -dr u g t her a pies will be 
s u m marize d f or t h e I T T p o p ulati o n b y treat me nt gr o u ps i n t he place b o -c o ntr olle d p hase a n d t he o pe n -
la bel p hase se p arat el y.  
5. 8  
C o nc o mit a nt A nti -E pile ptic Dr u gs  
T he n u m ber (a n d %) of s u bjects ta ki n g co nc o mita nt A E Ds  at ra n d o mizati o n will be s u m marize d  f or t he 
I T T p o p ul ati o n.  
Be nz o diaze pi n e s (i ncl u di n g L oraze pa m, Cl o naze pa m, Cl o baza m, Diaze pa m, Al praz ola m, Mi daz ol a m, 
C hl or diaze p o xi de)  t hat are use d as resc ue me dicati o n f or occasi o nal s eiz ure e xacer bati o n will  be 
i de ntifie d fr o m sei z ure di ar y s o urces ( b ot h electr o nic a n d pa per ). T he n u m ber (a n d %) of s u bjects ta ki n g 
a n y res c ue me dicati o n will be s u m marize d f or  t he baseli ne peri o d a n d place b o -c o ntr olle d p hase  i n t he 
I T T p o p ulati o n. T he n u m ber of d a ys a b e nz o diaze pi n e is ta ke n as resc ue me dicati o n  per 2 8 da ys d uri n g 
t he baseli ne peri o d a n d  place b o -c o ntr olle d p has e will be s u m marize d descri pti vel y  b y treat me nt gr o u p . 
T he n u m ber (a n d %) of s u bjects w h o ha d a n A E D m o dificati o n will be ta b ulate d b y treat me nt gr o u p 
a n d treat me nt peri o d  bas e d o n t he st u d y visit (i.e., 6 -wee k pr os pecti ve bas eli ne peri o d, 8 -wee k acti ve 
r u n-i n peri o d, 1 6-wee k efficac y p eri o d , t he o verall place b o-c o ntr olle d p hase ). The reas o n a n d detai ls of 
A E D m o dificati o n s will be prese nte d i n a listi n g.  M o dificati o ns of A E Ds d uri n g t he o pe n -la bel p hase 
will be ta b ulate d a n d liste d se paratel y.  
5. 9  
D i ar y S eiz ure C o m pli a nce  
C o m plia nce of re p orti n g seiz ure data via e lectr o ni c s o urce a n d t he c o m plia nce of o verall seiz ure diar y 
data  (i ncl u di n g b ot h  electr o nic a n d pa per s o urces) i n t he place b o -c o ntr olle d p hase will be s u m marize d 
b y visit a n d o verall f or eac h treat me nt gr o u p  i n t he I T T p o p ulati o n. T he c o m plia nce of diar y data at 
eac h vis it is defi ne d b y t he n u m ber of da ys wit h n o n-missi n g diar y e ntr y , i ncl u di n g t he d oc u me ntati o n 
of seiz ures , t he c o nfir mati o n of n o sei z ure o n t he da y, a n d re p ort of ‘u n k n o w n ’ seiz ure occ urre nce , 
di vi de d b y t he n u m ber of st u d y da ys bet wee n t w o visits.  T he electr o nic diar y seiz ure c o m plia nce a n d 
t he o verall diar y c o m plia nce of eac h s u bject will be liste d  b y visit.  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 2  
C o m plia nce of re p orti n g seiz ure d ata via electr o ni c diar y a n d t he c o m plia nce of o verall diar y dat a will 
als o be s u m marize d f or t he o pe n -la bel p hase.  
5. 1 0  Pri m ar y E n d p oi nt  
5. 1 0. 1  Ge ner al A n al ysis Met h o ds f or Effic ac y E n d p oi nts  
T he f oll o wi n g  statistical met h o ds will be use d t o a nal yze t he efficac y e n d p oi nts  i n t he place b o-
c o ntr olle d p hase : 
•  T he pri mar y met h o d f or a nal yzi n g  t he c o nti n u o us efficac y e n d p oi nts assesse d at ≥1 visit  
p ost baseli ne will use a n  M M R M  u n der t he missi n g at ra n d o m fra me w or k base d o n t he R E M L 
met h o d  f or esti mati o n. All p ost baseli ne visits d uri n g t he place b o -c o ntr olle d p hase will be use d 
i n t he M M R M. F or c ha n ge fr o m baseli ne  of a n e n d p oi nt, a n M M R M will i ncl u de t he f oll o wi n g: 
treat me nt; visit ; treat me nt-b y -visit i nteracti o n ; I X R S ra n d o mizati o n strata of seiz ure fre q ue nc y 
cate g or y  (hi g h: ≥2 4 , l o w: < 2 4  seiz ures d uri n g bas eli ne peri o d); I X R S ra n d o mizati o n strata of 
str uct ural eti ol o g y ( pres e nce, a bse nce); a n d bas eli ne val ue  of t he e n d p oi nt  o n a nal ysis  as fi xe d -
effect c o v ariates. A n u nstr uct ure d varia nce -c o varia nce matri x will be use d i n t he m o del. If t here 
is a c o n ver ge nce pr o ble m f or t he u nstr uct ure d c o varia nce matri x, a p pr o priate c o varia nce matri x 
str uct ures, s uc h as c o m p o u n d s y m metr y a n d a ut o-re gressi ve ( 1), will be e x pl ore d, a n d t he o ne 
wit h t he least A k ai ke inf or mati o n criteria will be e m pl o ye d i n t he pri mar y a nal ysis. De n o mi nat or 
de gr ees of free d o m f or t he F -test f or fi xe d effects will be esti mate d usi n g Ke n war d-R o ger 
a p pr o xi mati o n.   
•  A N C O V A m o dels will be use d as t he pri mar y met h o d t o a nal y ze t he c o nti n u o us e n d p oi nts wit h 
1 p ost baseli ne assess me nt (f or e xa m ple,   
 ), i ncl u di n g treat me nt, I X R S ra n d o mizati o n 
stratificati o n fact ors of seiz ure fre q ue nc y cat e g or y a n d str uct ural eti ol o g y , a n d baseli ne val ue as 
fi xe d effects. 
•  L o gistic re gressi o ns will be use d as t h e sta n dar d met h o d f or bi nar y effi cac y e n d p oi nts, wit h 
c o variates i ncl u di n g treat me nt, I X R S ra n d o mizati o n stratificati o n fact ors of seiz ure fre q ue nc y 
cate g or y a n d str u ct ural eti ol o g y, a n d l o g-tra nsf or me d st u d y baseli ne seiz ure fre q ue nc y per 
2 8  da ys .  
5. 1 0. 2  Pri m ar y E n d p oi nt  
T he pri mar y efficac y e n d p oi nt of c ha n ge fr o m  st u d y baseli ne of l o g -tra nsf or me d seiz ure fre q ue nc y 
( n u m ber of seiz ures per 2 8 da ys), as defi ne d i n Secti o n 3. 3. 1 , will be s u m marize d usi n g descri pti ve 
statistics b y treat me nt gr o u p a n d visit (i ncl u di n g 2 8-da y sta n dar dize d s eiz ure fre q ue nc y d uri n g Wee ks  8 
t o 2 4). T he pri mar y met h o d f or a nal yzi n g t he c ha n ge fr o m st u d y baseli ne of l o g -tra nsf or me d seiz ure 
fre q ue n c y is t he M M R M m o del as d escri be d i n S ecti o n 5. 1 0. 1 . T he a vera ge effect o ver Wee ks  8 t o 2 4 
of eac h treat me nt gr o u p, as well as t he treat me nt differe nce, will be dis pla ye d wit h a  9 5 % CI a n d p -
val ue.  T he effect of eac h treat me nt gr o u p, as well as t he treat me nt differe nce will be s u m marize d b y 
visit. T he res ults after t he bac k tra nsf or m will be dis pla ye d.  
I n a d diti o n, t he seiz ure fre q ue nc y per 2 8 da ys at t he ori gi nal scale will be s u m marize d descri pti vel y b y 
treat me nt gr o u p a n d visit (i ncl u di n g 2 8-da y sta n dar dize d seiz ure fre q ue nc y d uri n g Wee ks 8 t o 2 4) . T he  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 3  
least s q uare m ea n of  c h a n ge fr o m b aseli ne i n  l o g-tra nsf or me d seiz ure fre q ue nc y o btai ne d fr o m t he 
M M R M m o del a n d t he ass ociate d 9 5 % CI  will be pl otte d se paratel y b y visit a n d treat me nt gr o u ps.   
F oll o wi n g se nsiti vit y a nal yses will be perf or me d : 
•  T he sa me a nal ysis as t he pri mar y a nal ysis i n t he I T T p o p ulati o n i ncl u di n g o bser ve d seiz ure 
fre q ue n c y at all visits re g ar dless w het h er c o m plia nce is ≥8 5 % or n ot. 
•  T he sa me a nal ysis as t he pri mar y a nal ysis will be re peate d f or t he P P p o p ulati o n as a se nsiti vit y 
a nal ysis. 
•  T he sa me a nal ysis as t he pri mar y a nal ysis i n t he I T T p o p ulati o n usi n g stratificati o n fact ors bas e d 
o n o bser ve d  or a dj u dicate d data  i nstea d of t he o nes  us e d i n I X R S f or ra n d o mizati o n 
stratificati o n.  
•  M ulti ple i m p utati o n of missi n g dail y seiz ure occ urre nce will als o be perf or me d . T he A N C O V A 
m o del will be use d i n a nal yzi n g t he c ha n ge fr o m st u d y baseli ne of l o g -tra nsf or me d sei z ure 
fre q ue n c y ( n u m ber of sei z ures per 2 8 da ys) o ver Wee ks 8 t o 2 4 of treat me nt a n d t he i m p utati o ns 
will be perf or me d o n t he dail y seiz ure data . Seiz ure fre q ue nc y o ver Wee ks  8 t o 2 4 will be 
calc ulate d base d o n t h e i m p ute d dail y seiz ure data . M ulti ple i m p utati o ns  will be perf or me d  usi n g 
P R O C MI i n S A S. F ull y c o n diti o nal s pecificati o n  l o gistic re gressi o n met h o d will be use d t o 
i m p ute t he missi n g p ost baseli ne dail y s eiz ure data d uri n g t he place b o -c o ntr olle d p hase . T he 
treat me nt varia ble will be c o de d s o t hat t h e nataliz u ma b  gr o u p is t h e first i n t he s ort or der . W he n  
t he m ulti ple i m p utati o n  pr oce d ure is perf or me d b y treat me nt , t he i m p utati o n will be d o ne o n t h e 
nataliz u ma b  s u bjects first. 
Pri or t o t he P R O C MI ste p t he dataset will be s orte d b y desce n di n g treat me nt c o de a n d t he n 
asce n di n g U S U BJI D. T he i m p utati o n will i ncl u de  t he treat me nt, t he l o g-tra nsf or me d st u d y 
baseli ne seiz ure fre q ue n c y ( n u m ber of s eiz ures per 2 8  da ys), a n d stratificati o n fact ors  as well as 
all a vaila ble p ost baseli ne seiz ure diar y data d uri n g t he place b o -c o ntr olle d p hase  a n d t he st u d y 
da y fr o m t h e date of ra n d o mizati o n i n t he m o del. A set of 1 0 0 c o m plet e i m p ute d data sets will 
be ge nerate d wit h 1 0 b ur n -i n iterati o ns a n d t he relati ve effi cie nc y para meter will be c hec ke d.  
T he f oll o wi n g pse u d o S A S c o de a n d s ee d 1 7 4 8 4 6 3 will b e use d t o perf or m t h e m ulti ple 
i m p utati o n.  
pr oc mi data = i n _ dat a see d = x ni m p ute = 1 0 0  o ut =i m p _ data;  
class   < treat me nt>  <str atificati o n fact o rs > < dail y diar y fre q ue nc y > ; 
var  <treat me nt > <str atificati o n fact ors >  < l o g base>  <st u d y da y  of diar y >  < dail y diar y 
fre q ue n c y >; 
fcs N BI T E R = 1 0 l o gistic(< dail y s eiz ure fre q ue nc y > = <treat me nt > <stratificati o n 
fact ors > <l o g base > <st u d y da y of diar y > ); 
r u n; 
T he a v era g e effect o ver Wee ks  8 t o 2 4 of eac h treat me nt gr o u p, t he treat me nt differe nce  as well 
as p -val ue  fr o m t he pri m ar y a nal ysis m o del will be o btai ne d usi n g P R O C MI A N A L Y Z E. T he 
res ults after t he b ac k tra nsf or m will be dis pla ye d. 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 4  
S u b gr o u p a nal ysis (as defi ne d i n  Secti o n 3. 4. 2 ) will be perf or me d f or t he pri mar y e n d p oi nt usi n g t he 
M M R M  as descri be d i n Secti o n 5. 1 0. 1 . 
5. 1 0. 3  Sec o n d ar y E n d p oi nts  
Pr o p orti o n of Res p o n ders  
A res p o n der is as defi ne d i n S ecti o n 3. 3 . 2. T his a nal ysis i ncl u des all ra n d o mize d s u bjects i n t he I T T 
p o p ulati o n w h o ha ve  at least 1 p ost baseli ne seiz ure assess me nt after Wee k  8.  S u bjects w h o wit h dra w 
fr o m treat me nt or re q uire 
m o dificati o ns of 
A E Ds pri or t o  
Wee k 2 4 (c o m pleti o n of t he 
place b o -c o ntr olle d p hase) or deat h relate d t o epile ps y will be c o nsi dere d as n o n -res p o n d ers i n t h e 
res p o n der a n al ysis. T he pr o p orti o n of res p o n ders will be a nal yze d usi n g a l o gistic re gressi o n m o del, as 
descri be d i n Secti o n 5. 1 0. 1 . T he o d ds rati o fr o m t he l o gistic re gressi o n m o del will be dis pla ye d wit h 
9 5 % CI a n d p -val u e  a n d t he res p o n der rate will be s u m marize d b y treat me nt gr o u ps.  
Se nsiti vit y a nal yses will be perf or me d t o e val uate t he pr o p orti o n of res p o n ders wit h ≥2 5 % re d ucti o n 
a n d ≥7 5 %  re d u cti o n fr o m st u d y baseli ne .  
T hese  a n al yses will be re peate d f or t he P P p o p ulati o n.  
Pr o p orti o n of S u bjects Free fr o m Seiz ures  
T he pr o p orti o n of s u bjects free fr o m seiz ures d uri n g Wee ks 8 t o 2 4 of treat me nt will be s u m marize d 
descri pti vel y  wit h pr o p orti o n a n d 9 5 % e xact bi n o mial CI b y treat me nt gr o u p  f or t he I T T p o p ulati o n 
w h o ha ve at least 1  p ost baseli ne seiz ure assess m e nt after W ee k 8 . T he differe nce of t he pr o p orti o n 
bet wee n nat aliz u ma b  a n d place b o gr o u p a n d t he 9 5 % Mietti ne n -N ur mi ne n CI  of t he differe n ce will be 
prese nt e d.  S u bjects w h o wit h dr ew fr o m treat me nt, re q uire d  m o dificati o n of A E Ds pri or t o Wee k  2 4 
(c o m pleti o n of t h e place b o-c o ntr olle d p hase), or ha d  a n y missi n g diar y data  d uri n g Wee ks 8 t o 2 4 of 
treat me nt will n ot be c o nsi dere d as free fr o m seiz ures i n t his a nal ysis.  
A se nsiti vit y a nal ysis will be perf or me d bas e d o n t he re p orte d s eiz ure data  ass u mi n g t hat n o seiz ure 
occ urs w he n t h e diar y is missi n g. If t he s u bject ha d n o s eiz ure re p orte d bet wee n W ee k 8 visit a n d 
W ee k 2 4 visit a n d di d n’t disc o nti n ue t he st u d y d ue t o lac k of efficac y, t he s u bject will be c o nsi dere d 
seiz ure free.  
T hese  a n al yses will be re peate d f or t he P P p o p ulati o n.   
Perce nt a ge of Seiz ure -Free D a ys G ai ne d, St a n d ar dize d O ver 2 8  D a ys, D uri n g Wee ks  8 t o 2 4 of 
Tre at me nt C o m p are d w it h St u d y B aseli ne  
A n M M R M , as d escri be d i n Secti o n 5. 1 0. 1 , will be use d t o a nal yze t he c ha n ge fr o m  st u d y baseli ne of 
l o g-tra nsf or me d s eiz ure-free d a ys per 2 8 da ys (defi ne d i n Secti o n 3. 3. 1 ). T he a vera ge effect o ver 
Wee ks  8 t o 2 4 of eac h treat me nt gr o u p  a n d t he effect b y visit , as well as t he treat me nt differe nce, will 
be dis pla ye d wit h a 9 5 % CI a n d p -val ue.  
T hese  a n al yses will be re peate d f or t he P P p o p ulati o n.   
Pr o p orti o n of S u bjects w it h I n a de q u ate Tre at me nt Res p o nse D uri n g Wee ks  8 t o  2 4  
T he pr o p orti o n of s u bjects wit h pr ot oc ol -defi ne d i na de q uate treat me nt res p o nse after W ee k 8 visit a n d 
pri or t o Wee k 2 4 visit will be a nal yze d usi n g a l o gistic re gressi o n m o del , as descri be d i n Secti o n 5. 1 0. 1 . 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 5  
If t here are fe wer t h a n 5 e ve nts, t he I X R S ra n d o mi zati o n stratificati o n fact ors will be dr o p pe d o ut of t he 
l o gistic m o del. P r ot oc ol-defi ne d i na de q uate treat me nt res p o nse i ncl u des s u bjects w h o wit h dra w fr o m 
treat me nt d ue t o lac k of efficac y , re q uire m o dificati o ns of A E Ds pri or t o Wee k 2 4 (c o m pleti o n of t he 
place b o -c o ntr olle d p hase) , or die  i n a ma n ner relate d t o E pile ps y. T he o d ds rati o fr o m t he l o gistic 
re gressi o n will be dis pla y e d wit h 9 5 % CI a n d p-val ue.  T he pr o p orti o n of s u bjects wit h pr ot oc ol -defi ne d 
i na de q uate treat me nt res p o nse will be ta b ulate d b y treat me nt gr o u ps a n d visit.  
Ti me t o i na de q uate treat me nt res p o nse will be a nal yze d usi n g t he C o x pr o p orti o nal hazar ds m o d el. 
I n d e pe n de nt varia bles t o be i ncl u de d i n t he m o del are treat me nt a n d I X R S ra n d o mizati o n stratificati o n 
fact ors. Ka pla n-M eier C ur ve b y treat me nt gr o u ps will als o be prese nt e d. Ti me t o i na de q uate treat m e nt 
res p o nse is d efi ne d as t h e ti me fr o m t he first i nf usi o n of st u d y treat me nt t o t he first re p orte d dat e of 
pr ot oc ol -defi ne d i n a de q u ate treat me nt res p o nse .  
S u bjects w h o d o n ot ha ve a pr ot oc ol -defi ne d i na de q uate treat me nt res p o nse d uri n g t he place b o -
c o ntr olle d p hase  will be ce ns ore d. T he ce ns or date is t he ti me of t he last st u d y c o ntact  (last 
sc he d ule d/ u nsc he d ul e d visit) d uri n g t he place b o -c o ntr olle d p hase .  
T hese  a n al yses will be re peate d f or t he P P p o p ulati o n.   
5. 1 0. 4  E x pl or at or y Effic ac y E n d p oi nts D uri n g t he Pl ace b o-c o ntr olle d P h ase  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 6  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
5. 1 0. 5  Effic ac y A n al yses  d uri n g O pe n -L a bel P h ase  
T he f or m al a nal ysis of o pe n -la bel p h ase data will be perf or me d at t he fi nal a nal ysis at t he e n d of st u d y. 
S u m mar y statistics will be prese nt e d f or seiz ure fre q ue nc y data b y visit  (i ncl u di n g 2 8 -da y sta n dar dize d 
seiz ure fre q uen c y d uri n g Wee ks 3 2  t o 4 8 ) a n d treat me nt gr o u p d uri n g t he o pe n -la bel p has e as descri be d 
bel o w : 
•  C ha n ge fr o m  st u d y baseli ne  i n l o g-tra nsf or me d s eiz ure fre q ue nc y 
•  P erce nt c ha n ge fr o m st u d y baseli ne i n seiz ure fre q ue nc y at ori gi nal scale  
•  C ha n ge fr o m o pe n -la bel baseli ne i n l o g-tra nsf or me d seiz ure fre q ue nc y  
•  P erce nt c ha n ge fr o m o pe n -la bel baseli ne i n l o g-tra nsf or me d sei z ure fre q ue nc y 
T he d ura bilit y  of treat m e nt res p o nse t o nataliz u ma b  i n t he o pe n -l a bel p hase will be assesse d b y t he 
pr o p orti o n of s u bjects  w h o c o nti n ue t o res p o n d t o nataliz u ma b  i n t he o pe n-la bel p hase a m o ng t he 
res p o n ders i n t he place b o-c o ntr olle d p hase  ( defi ne d i n Secti o n 3. 3 . 2). A  res p o n der i n t he o pe n -la bel 
p hase is defi ne d  as a s u bj ect wit h a ≥5 0 % re d ucti o n fr o m st u d y baseli ne i n seiz ure fre q ue nc y ( n u m ber 
of seiz ures per 2 8  da ys) d uri n g Wee ks  3 2  t o 4 8  of treat me nt . Se nsit i vit y a nal yses will be perf or me d t o 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 7  
e val uate t he d ura bilit y of treat me nt res p o nse b y defi ni n g  res p o n ders as 1) s u bjects wit h ≥2 5 % re d ucti o n 
a n d 2)  s u bjects wit h ≥7 5 %  re d ucti o n fr o m st u d y baseli ne, f or b ot h t he place b o -c o ntr olle d p hase a n d 
o pe n -la bel p hase. 
 
 
 
  
 
 
 
 
  
 
 
 
 
5. 1 1  S afet y  E n d p oi nts  
N o f or mal st atistical testi n g will be perf or me d o n t he safet y data. Safet y assess me nt will be prese nt e d 
se parat el y f or t he pl ace b o-c o ntr olle d p has e a n d t he o pe n -la bel p hase base d o n the date of s a m ple 
c ollecti o n. T he bas eli ne use d i n safet y ass ess me nts f or place b o -c o ntr olle d p hase a n d o pe n -la bel p hase 
will pri maril y be  t he st u d y baseli ne a n d o pe n -l a bel p hase baseli ne, res pecti vel y, u nless ot her wise 
s pecifie d. T he safet y assess me nts f or t he o pe n -la bel p hase will n ot be perf or me d i n t he pri mar y rea d o ut, 
b ut  will be perf or me d  i n t he fi nal a nal ysis at t he e n d of st u d y.   
5. 1 1. 1  A d verse E ve nts  
A Es  will be prese nt e d se paratel y f or t h e place b o -c ontr olle d p has e a n d t he o pe n -la bel p has e bas e d o n 
t he start date of t he e ve nt. A Es will be c o de d usi n g t he Me d D R A (versi o n 2 2. 1  or later if u p dat e d ). 
Treat me nt -e mer ge nt A Es are defi ne d as t he e ve nts ha vi n g o nset o n/after t he date of t he first i nf usi o n i n 
eac h p h ase, or a si g n, s y m pt o m, or dia g n osis t hat w orse ns si nce t he e ve nt was pre vi o usl y re p orte d. If a 
s u bject is n ot e nr olle d i nt o t he o pe n-la bel p hase of t he st u d y or ne ver recei ves o pe n-la bel i nf usi o n of 
nataliz u ma b d uri n g t he o pe n -la bel p has e, all treatme nt -e mer ge nt A Es  will be c o nsi dere d as occ urri n g 
d uri n g t he place b o -c o ntr olle d p hase of t he st u d y.  
I n or der t o defi ne treat m e nt-e mer g e nt A Es i n eac h p hase wit h c o m pletel y missi n g start or st o p dates , 
t he f oll o wi n g a d diti o nal criteria will be use d: 
•  If b ot h t he start a n d st o p dates f or a partic ular e ve nt are c o m pletel y missi n g, t he n t hat e ve nt is 
c o nsi dere d treat me nt e m er ge nt.  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 8  
•  If t he start d ate f or a partic ular e v e nt is c o m pletel y missi n g a n d t he st o p date occ urs  after t he start 
date/ti me of t he st u d y first d ose, t he n t hat e ve nt is c o nsi dere d treat me nt e mer ge nt.  
I n or der t o defi ne t he st u d y peri o d f or A Es  wit h c o m pletel y missi n g start or st o p dates, t he f oll o wi n g 
a d diti o nal criteria will be use d:  
•  If b ot h t he start a n d st o p dates f or a partic ular e ve nt are c o m pletel y missi n g, t he n t hat e ve nt is 
c o nsi dere d as a n e v e nt i n t he place b o -c o ntr olle d p hase.  
•  If t he start d ate f or a partic ular e v e nt is c o m pletel y missi n g a n d t he st o p date occ urs  after t he start 
date of t he st u d y first d ose, t he n t hat e ve nt is c o nsi dere d as a n e ve nt i n t he place b o -c o ntr olle d p hase.  
•  If t he st o p d ate f or a partic ular e ve nt is c o m plet el y missi n g a n d t he start da te occ urs  o n/ after t he start 
date of t he first d ose i n t he place b o -c o ntr olle d p hase a n d bef ore t he date of t he first i nf usi o n i n t he 
o pe n -la bel p hase, t he n t h at e ve nt is c o nsi dere d as a n e ve nt i n t he place b o-c o ntr olle d p hase.  
•  If t he st o p d ate f or a partic ular e ve nt is c o m plet el y missi n g a n d t he start date occ urs  o n/ after t he start 
date of t he first d ose i n t he o pe n -la bel p has e, t he n t hat e ve nt is c o nsi dere d as a n e ve nt i n t he o pe n-
la bel p hase. 
F or A E s wit h a partial start date, t he i m p utati o n r ule will be perf or me d as descri be d i n Secti o n 5. 2  a n d 
t he i m p ute d date s will be use d  t o deter mi ne w het her t he e ve nt is treat me nt-e mer ge nt a n d t he st u d y 
peri o d t o w hic h it bel o n gs. If treat me nt-e mer ge n ce a n d st u d y peri o d ca n n ot be deter mi ne d , t he e ve nt 
will be ass u me d t o be a treat me nt -e mer ge nt d uri n g t he place b o -c o ntr olle d p hase.  
A  s u m mar y of t he i nci de nce of treat me nt -e m er ge nt A Es will be pr o vi de d  b y treat me nt  gr o u p o verall , 
b y  se verit y, b y  rel ati o ns hi p t o st u d y treat me nt, b y seri o usness , a n d b y  treat m e nt disc o nti n uati o n or st u d y 
wit h dra wal.  
T he i nci de nce of treat me nt -e mer g e nt A Es will als o be ta b ulate d o verall a n d b y treat me nt gr o u p, 
se verit y, a n d relati o ns hi p t o st u d y treat me nt. T he ta b ular s u m maries  will i ncl u de i nci de nce b y s yst e m 
or ga n class a n d b y preferre d ter m. A Es a n d S A Es res ulti n g i n st u d y wit h dra wal will be s u m marize d b y 
treat me nt gr o u p. 
Treat me nt -e mer ge nt  A Es will be s u m marize d se paratel y b y treat me nt gr o u p  a n d o verall  as f oll o ws:  
•  B y preferre d ter m  
•  B y pri mar y s yste m or ga n class  
•  B y pri mar y s yste m or ga n class a n d preferre d ter m  
•  B y se verit y, pri mar y s yste m or ga n class a n d preferre d ter m  
•  B y relati o ns hi p t o st u d y treat me nt, pri mar y s yste m or ga n class , a n d preferre d ter m  
•  B y pri mar y s yste m or ga n class a n d preferre d ter m f or seri o us a d verse e ve nts . 
A listi n g of t he f oll o wi n g will be prese nte d:  
•  S eri o us a d verse e ve nts  
•  A Es lea di n g t o disc o nti n uati o n of st u d y treat me nt  
•  A Es lea di n g t o wit h dra wal fr o m st u d y  


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
2 9  
•  D eat hs  
T he i nci de nce of treat me nt-e mer ge nt a d verse e ve nts occ urri n g i n at least 5 % i n a n y treat me nt gr o u p 
will be prese nte d b y preferre d t er m , a n d b y s yste m or ga n class a n d preferre d ter m .  
F or t he a n al ysis of i nci de nce b y se v erit y, t he occ urre nce of t he A E wit h t he great est se ve rit y will be 
use d, a n d a s u bject will be c o u nte d o nl y o nce a n d o nl y i n t he  e ve nt cate g or y of t he ma xi m u m  se verit y. 
F or t he a n al ysis of i nci d e nce b y relati o ns hi p t o st u d y treat me nt, t he occ urre nce of t he A E wit h t he 
str o n gest relati o ns hi p t o st u d y treat me nt will be use d a n d a s u bj ect will be c o u nte d o nl y o nce a n d o nl y 
i n t he cate g or y of t he str o n gest relati o ns hi p t o st u d y treat me nt f or eac h e ve nt. 
I n a d diti o n, A Es of s peci al i nterest will be i d e ntifie d b y a pre -s p ecifie d list of c o de d ter ms. F or eac h A E 
of s pecial i nterest, t he n u m ber (a n d %)  of s u bjects wit h sai d e ve nt will be s u m marize d b y preferre d 
ter m. T he A Es of s pecial i nterest ma y i ncl u de b ut are n ot li mite d t o t he f oll o wi n g:  
•  P M L  
•  I nf usi o n site reacti o ns 
•  O p p ort u nistic i nfecti o ns  
•  Dr u g -i n d uce d li ver i nj ur y 
•  H y perse nsiti vit y reacti o ns  
5. 1 1. 2  Cli nic al L a b or at or y Res ults  
T he f oll o wi n g la b orat or y assess me nts will be perf or me d t o e val uate t h e safet y of t he st u d y treat me nt:  
•  He mat ol o g y:  c o m plete bl o o d c o u nt wit h differe nti al a n d platelet c o u nt, a n d A N C  
•  Bl o o d c he mistr y:  t otal pr otei n, al b u mi n, creati ni n e, bl o o d urea nitr o ge n, uric aci d, bilir u bi n 
(t otal a n d direct), al kali n e p h os p hatase, A L T, A S T, ga m ma-gl uta m yl tra nsferas e, gl uc ose, 
calci u m, p h os p h or us, bicar b o nate, c hl ori de, s o di u m, a n d p otassi u m  
•  Ser ol o g y: he patitis B a n d C ser ol o gies  
•  Uri nal ysis:  di pstic k f or bl o o d, pr otei n, a n d gl uc ose ( micr osc o pic e xa mi nati o n, if a b n or mal)  
•  Ser u m a n d uri ne pre g na n c y tests  
T he la b orat or y dat a will f oc us o n a nal ys is of data fr o m baseli ne t o p ost baseli ne. I n t he place b o -
c o ntr oll e d p hase, la b orat or y data will be s u m marize d usi n g s hift ta bles w here a p pr o priate.  S u bj ect 
he mat ol o g y a n d bl o o d c he mistr y val ues will be fla g ge d as “l o w”, “ n or mal”, or “ hi g h” relati ve t o t he 
n or mal ra n ges of t he ce ntral la b orat or y or as “ u n k n o w n” if n o res ult is a vaila ble.   
I n t he place b o-c o ntr olle d p hase, s hifts fr o m baseli ne t o hi g h/l o w stat us f or he mat ol o g y a n d bl o o d 
c he mistr y para meters will be pres e nte d. I n eac h s u m mar y, t he de n o mi nat or f or t he perce nta ge is t he 
n u m ber of s u bjects at ris k f or t he s hift . T he n u m ber at ris k f or s hift t o l o w is t he n u m ber of s u bjects 
w h ose baseli ne val ue was n ot l o w a n d w h o ha d at least o ne p ost baseli ne val ue. T he n u m ber at ris k f or 
s hift t o hi g h is t he n u m b er of s u bjects w h ose bas eli ne val ue was n ot hi g h a n d w h o ha d at le ast o ne 
p ost baseli ne val ue. S u bjects will be c o u nte d o nl y o nce f or eac h para meter a n d eac h t y pe of s hift 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
3 0  
re gar dless of h o w ma n y p ost d osi n g assess me nts ha d t hat t y pe of s hift. S u bjects wit h s hift t o l o w or hi g h 
will be liste d b y la b orat or y para m eter a n d s hi ft t y pe. 
S u m mar y statistics f or act ual val ues a n d c ha n ges fr o m baseli ne d uri n g t he place b o -c o ntr olle d p hase 
will als o be s u m marize d b y treat me nt gr o u ps a n d o verall b y visit.  
La b orat or y data  will als o be liste d f or eac h s u bject.  
A s u m mar y of t he n u m ber a n d perce nta ges of s u bjects meeti n g t he la b orat or y a b n or malit y crit eria 
d uri n g t he place b o -c o ntr olle d p hase liste d bel o w will be pr o vi de d:  
•    
A L T > 3 x  U L N  
•    
A L T > 5 x  U L N  
•    
A S T > 3 x  U L N  
•    
A S T > 5 x  U L N  
•    
A S T or A L T > 3 x  U L N  
•    
A S T or A L T > 5 x  U L N  
•    
T otal Bilir u bi n > 2 x  U L N  
•    
A L P > 1. 5 x  U L N  
•    
A S T or A L T > 3 x U L N a n d T otal Bilir u bi n > 2 x U L N  
T hese a n al yses will be re peate d f or t he o pe n -l a bel p hase.  
5. 1 1. 3  A nti -J o h n  C u n ni n g h a m  V ir us A nti b o dies  
Ser u m a nti -J C V a nti b o d y res ults, i ncl u di n g i n de x val ues, will be s u m marize d b y treat me nt gr o u p a n d 
o verall b y visits f or t he place b o -c o ntr olle d p has e a n d t he o pe n -la bel p hase. Ser u m a nti-J C V a nti b o d y 
res ults, i ncl u di n g i n de x val ues, will als o be liste d f or  eac h s u bj ect.  
5. 1 1. 4  Vit al Si g ns  
T he a nal ysis of vital si g ns will f oc us o n t he i nci de nce of cli nicall y rele va nt a b n or malities.  
F or t h e place b o -c o ntr olle d p hase, t he n u m ber of s u bjects e val u ate d a n d t he n u m ber a n d perce nta ge of 
s u bjects wit h cli nicall y rele va nt p ost bas eli ne a b n or malities will be prese nte d b y treat me nt gr o u p. T he 
criteria f or cli nicall y rele va nt p ost baseli ne a b n or malities are s h o w n i n t h e f oll o wi n g ta ble.  S u m mar y 
statistics f or act ual val ues a n d c ha n ge fr o m baseli ne will als o be prese nt e d.  
T he sa me a n al ysis will be perf or me d f or t h e o pe n -la bel p hase. 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
3 1  
T a ble 3 : Criteri a  t o Deter mi ne Cli nic all y Rele v a nt A b n or m alities i n Vit al Si g ns 
Vit al Si g n  
Criteri a f or A b n or m alities  
Te m perat ure  
> 3 8° C a n d a n i ncrease fr o m pre d ose of at least 1° C  
Heart rate  
> 1 2 0 beat per mi n ute a n d a n i ncreas e fr o m pre d ose of m ore t ha n 
2 0  beats per mi n ute.  
< 5 0 beats per mi n ute a n d a decrease fr o m pre d ose of m ore t ha n 
2 0  beats per mi n ute.  
S yst olic Bl o o d Press ure  > 1 8 0 m m H g a n d a n i ncrease fr o m pre d ose of m ore t ha n 4 0 m m H g.  
< 9 0 m m H g a n d a decreas e fr o m pre d os e of m ore t ha n 3 0  m m H g.  
Diast olic    
Bl o o d 
Press ure  
> 1 0 5  m m H g a n d a n i ncrease fr o m pre d ose of m ore t ha n 3 0  m m H g.  
< 5 0  m m H g a n d a decreas e fr o m pre d os e of m ore t ha n 2 0  m m H g.  
Res pirat or y rate    
≥2 0 breat hs per mi n ute wit h a pre d ose rate of < 2 0 breat hs per mi n ute  
≤1 0 breat hs per mi n ute wit h a pre d ose rate of > 1 0 breat hs per mi n ute  
5. 1 1. 5  e C-S S R S/ C -S S R S  
S u m mar y statistics f or t he e C-S S R S/ C -S S R S at eac h visit will be prese nte d b y treat me nt gr o u p a n d 
st u d y peri o d usi n g o bser ve d data.  T he baseli ne val ue will be base d o n t h e cl osest n o n -missi n g  rece nc y 
sc ore pri or t o first d ose of st u d y dr u g . 
T he n u m ber of s u bjects e val uate d a n d t he n u m ber a n d perce nta ge of s u bjects wit h a n y p ositi ve re p ort 
at p ost baseli ne visits will be prese nte d b y treat m e nt gr o u p. A p ositi ve re p ort is defi ne d as a “yes ” 
res p o nse o n i deati o n ite ms 4 a n d/ or 5, or a “yes ” res p onse t o a n y be ha vi or ite m (e xce pt n o n -s uici dal 
self-i nj ur y). e C-S S R S/ C -S S R S assess me nts will als o be pres e nte d i n se parat e s hift ta bles (t he s hift fr o m 
baseli ne t o t he ma xi m u m p ost baseli ne val ue) f or t h e place b o -c o ntr olle d p has e a n d t he o pe n -la bel p has e.  
eC -S S R S / C-S S R S assess me nt res ults f or eac h s u bject at eac h visit will be liste d b y treat me nt gr o u p 
usi n g o bser ve d data.  B ot h lifeti me a n d rece nc y s c ores d uri n g t he bas eli ne peri o d will be liste d.  
 
 
 
 
 
 
 
 
 
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
3 2  
 
 
 
5. 1 5  I m m u n o ge nicit y ( A nti-N at aliz u m a b A nti b o dies)  
A nti -nataliz u ma b a nti b o dies i n ser u m will be c ollecte d at ti me p oi nts o utli ne d i n t he sc he d ule of 
acti vities (A p pe n di x A ) a n d a nal yze d at t he pri mar y rea d o ut wit h data i n t h e place b o -c o ntr olle d p hase  
a n d at  t he e n d of t he st u d y wit h data i n t he o verall treat me nt peri o d. Res ults i ncl u di n g perce nta ge of 
s u bjects w h o de vel o p A D As will be s u m marize d b y treat me nt gr o u ps at eac h sc he d ule d ti me p oi nt.  
T he  perce nt a ge of s u bjects w h o de v el o p A D As will be deter mi ne d a n d s u m marize d b y treat me nt gr o u p 
i n t he place b o -c o ntr olle d  p hase  a n d o verall  treat me nt peri o d b y ti me p oi nt. T he o verall perce nta ge of 
s u bjects w h o are A D A p ositi ve at a n y ti me will als o be s u m marize d b y treat me nt gr o u p i n t he place b o -
c o ntr olle d p hase  a n d i n t he o verall treat me nt peri o d.  
T he a na l ysis p o p ulati o n f or i m m u n o ge nicit y will be defi ne d as all s u bjects i n t he safet y p o p ulati o n w h o 
ha ve at least 1 p ost d ose sa m ple e val uate d f or i m m u n o ge nicit y.  
•  
F or i m m u n o ge nicit y, t he baseli ne val ue is defi ne d as t he latest i m m u n o ge nicit y data c ollecte d 
at a n y ti me pri or t o t he first d ose  of st u d y treat me nt . If n o i m m u n o ge nicit y data are c ollecte d 
pri or t o t he first d ose, t he baseli ne val ue is missi n g a n d will be i m p ute d as A D A  ne gati ve f or 
i m m u n o ge nicit y a nal yses.  
•  S u bjects wit h at least o ne c o nfir me d p ost baseli ne p ositi ve A D A res ult will be c o nsi dere d A D A 
p o siti ve if t heir baseli ne res ult is ne gati ve. 
•  S u bjects f or w h o m n o ne of t he p ost baseli ne sa m pl es were p ositi ve f or A D As  will be c o nsi dere d 
ne gati ve re g ar dless of t h eir baseli ne res ult.  
•  F or s u bjects w h o are c o nfir me d p ositi ve at baseli ne a n d  ha ve at least o n e p ost baseli ne sa m ple 
wit h a ≥4 -f ol d i ncrease i n titer will be c o nsi dere d A D A p ositi ve. S u bjects w h o are p ositi ve at 
baseli ne wit h s u bse q ue nt p ost baseli ne sa m ples titers t hat are wit hi n 2 -f ol d will be c o nsi dere d 
A D A ne gati ve.  
•  I n a d diti o n, f or s u bjects w h o  are c o nsi dere d A D A  p ositi ve wit h fi nal i m m u n o ge nicit y data, t h e 
f oll o wi n g ma y be e val uat e d: 
o  Persiste nce of t he A D A  res p o nse: p ositi ve res ult detecte d at t he last p ost baseli ne 
sa m pli n g ti me p oi nt, or t w o or m ore ti me p oi nts d uri n g treat me nt w here t he first  a n d last 
p ositi ve sa m ples are se parate d b y a peri o d ≥1 1 2 da ys , irres pecti ve of a n y ne gati ve 
sa m ples i n bet wee n.  
o  Tra nsie nt A D A  res p o ns e: p ositi ve res ult detect e d at o nl y o ne p ost baseli ne sa m pli n g ti me 
p oi nt (e xcl u di n g last ti me p oi nt) or at t w o or m ore ti me p oi nts d uri n g treat me nt w here 
t he first a n d last p ositi ve sa m ples are se parate d b y a peri o d < 1 1 2 da ys, i rres pecti ve of 
a n y ne gati ve sa m ples i n bet wee n . 




 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
3 4  
 
8  
Refere nces  
Sc heffer I E, Ber k o vic S, Ca p o villa G, et al. I L A E classificati o n of t he e pile psies: P ositi o n pa per of t he 
I L A E C o m missi o n f or Classificati o n a n d Ter mi n ol o g y. E pile psia. 2 0 1 7; 5 8( 4): 5 1 2-5 2 1. E p u b 
2 0 1 7/ 0 3/ 0 8.  
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al  v 2. 0  
 
3 5  
A P P E N DI X A  
T a bl e  4 :   
S c h e d ul e of A cti viti e s f or St u d y 1 0 1 E P 2 0 1  
St u d y Visits/ Wee ks  Scree ni n g 
Visit  
Wee k  -6  
Visit  1  
B aseli ne  
Wee k  0  
Visit  2  
Wee k  4  
Visit  3  
Wee k  8  
Visit  4  
Wee k  1 2  
Visit  5  
Wee k  1 6  
Visit  6  
Wee k  2 0  
Visit  7  
Wee k  2 4 1 
Visit  8  
Wee k  2 8  
Visit  9  
Wee k  3 2  
Visit  1 0  
Wee k  3 6  
Vi sit 1 1  
Wee k  4 0  
Visit  1 2  
Wee k  4 4  
Visit  1 3  
Wee k  4 8  
or E T 
Visit 2 
E n d of 
St u d y Visit  
Wee k  6 0  
or 
F oll o w -u p 
Visit f or 
E T 
S u bjects  
( 1 6 wee ks 
after l ast 
d ose of 
st u d y 
tre at me nt3 ) 
F oll o w -u p 
S afet y  
P h o ne C all  
Wee k  6 8 
( 2 4 wee ks 
after t he 
l ast d ose of 
st u d y 
tre at me nt)4 
P h ase of St u d y    
Scree ni n g  
Pl ace b o -C o ntr olle d P h ase  
O pe n -L a bel P h ase  
P ost -Tre at me nt 
F oll o w -U p  
St u d y D a ys    
D a y  -4 2  
+ 1  d a y 5 
D a y  1  
+ 5  d a ys 5 
D a y  2 8  
± 5  d a ys  
D a y  5 6  
± 5  d a ys  
D a y  8 4  
± 5  d a ys  
D a y  1 1 2  
± 5  d a ys  
D a y  1 4 0  
± 5  d a ys  
D a y  1 6 8  
± 5  d a ys  
D a y  1 9 6  
± 5  d a ys  
D a y  2 2 4  
± 5  d a ys  
D a y  2 5 2  
± 5  d a ys  
D a y  2 8 0  
± 5  d a ys  
D a y  3 0 8  
± 5  d a ys  
D a y  3 3 6  
± 5  d a ys  
D a y  4 2 0  
± 5  d a ys  
D a y  4 7 6  
± 5  d a ys  
I nf or me d C o nse nt   
X    
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
Re vie w I ncl usi o n 
a n d E xcl usi o n 
Criteria  
X    
X    
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
De m o gra p hics a n d 
Me dical Hist or y 
I ncl u di n g Seiz ure 
a n d A ntie pile ptic 
Me dicati o n Hist or y
6 
X    
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
P h ysical a n d 
Ne ur ol o gical 
E xa mi nati o n 7 
X    
   
   
   
   
   
   
X    
   
   
   
   
   
   
X    
X    
 
Vital Si g ns 8 
X    
X    
X    
X    
X    
X    
X    
X    
   
X    
X    
X    
X    
X    
X    
X    
 
M RI brai n sca n
9   
X    
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
Pre g na nc y Test 1 0   
X    
X    
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
Ra n d o mizati o n    
   
X    
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
3 6  
St u d y Visits/ Wee ks  Scree ni n g 
Visit  
Wee k  -6  
Visit  1  
B aseli ne  
Wee k  0  
Visit  2  
Wee k  4  
Visit  3  
Wee k  8  
Visit  4  
Wee k  1 2  
Visit  5  
Wee k  1 6  
Visit  6  
Wee k  2 0  
Visit  7  
Wee k  2 4 1 
Visit  8  
Wee k  2 8  
Visit  9  
Wee k  3 2  
Visit  1 0  
Wee k  3 6  
Vi sit 1 1  
Wee k  4 0  
Visit  1 2  
Wee k  4 4  
Visit  1 3  
Wee k  4 8  
or E T 
Visit 2 
E n d of 
St u d y Visit  
Wee k  6 0  
or 
F oll o w -u p 
Visit f or 
E T 
S u bjects  
( 1 6 wee ks 
after l ast 
d ose of 
st u d y 
tre at me nt3 ) 
F oll o w -u p 
S afet y  
P h o ne C all  
Wee k  6 8 
( 2 4 wee ks 
after t he 
l ast d ose of 
st u d y 
tre at me nt)4 
P h ase of St u d y    
Scree ni n g  
Pl ace b o -C o ntr olle d P h ase  
O pe n -L a bel P h ase  
P ost -Tre at me nt 
F oll o w -U p  
St u d y D a ys    
D a y  -4 2  
+ 1  d a y 5 
D a y  1  
+ 5  d a ys 5 
D a y  2 8  
± 5  d a ys  
D a y  5 6  
± 5  d a ys  
D a y  8 4  
± 5  d a ys  
D a y  1 1 2  
± 5  d a ys  
D a y  1 4 0  
± 5  d a ys  
D a y  1 6 8  
± 5  d a ys  
D a y  1 9 6  
± 5  d a ys  
D a y  2 2 4  
± 5  d a ys  
D a y  2 5 2  
± 5  d a ys  
D a y  2 8 0  
± 5  d a ys  
D a y  3 0 8  
± 5  d a ys  
D a y  3 3 6  
± 5  d a ys  
D a y  4 2 0  
± 5  d a ys  
D a y  4 7 6  
± 5  d a ys  
St u d y Treat me nt 
A d mi nistrati o n 1 1 
   
X    
X    
X    
X    
X    
X    
   
X    
X    
X    
X    
X    
X    
   
 
 
Distri b ute Seiz ure 
Diar y 1 2 
X    
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
Re vie w Seiz ure 
Diar y 1 3 
   
X    
X    
X    
X    
X    
X    
X    
   
X    
X    
X    
X    
X    
X    
X    
 
He mat ol o g y a n d 
Bl o o d C he mistr y 1 3 , 1 4 
X    
X    
X    
X    
X    
X    
X    
X    
   
X    
X    
X    
X    
X    
X    
X    
 
Uri nal ysis  
X    
X    
X    
X    
X    
X    
X    
X    
   
   
   
X    
   
   
X    
 
 
Bl o o d Sa m ple f or 
He patitis B a n d C 
Ser ol o gies  
X    
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
Bl o o d Sa m ple f or 
A nti -Nataliz u ma b 
A nti b o dies 1 3 
   
X    
   
   
X    
   
   
X    
   
   
   
   
   
   
X    
 
 
Bl o o d Sa m ple f or 
A nti -J C V A nti b o d y 
I n de x 
X    
   
   
   
   
   
   
X    
   
   
   
   
   
   
X    
 
 
Bl o o d Sa m ple f or 
Fl o w C yt o metr y 
I ncl u di n g 
α 4  Sat urati o n 1 3 
   
X    
X    
   
X    
   
   
X    
   
   
X    
   
X    
   
X    
 
 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
3 7  
St u d y Visits/ Wee ks  Scree ni n g 
Visit  
Wee k  -6  
Visit  1  
B aseli ne  
Wee k  0  
Visit  2  
Wee k  4  
Visit  3  
Wee k  8  
Visit  4  
Wee k  1 2  
Visit  5  
Wee k  1 6  
Visit  6  
Wee k  2 0  
Visit  7  
Wee k  2 4 1 
Visit  8  
Wee k  2 8  
Visit  9  
Wee k  3 2  
Visit  1 0  
Wee k  3 6  
Vi sit 1 1  
Wee k  4 0  
Visit  1 2  
Wee k  4 4  
Visit  1 3  
Wee k  4 8  
or E T 
Visit 2 
E n d of 
St u d y Visit  
Wee k  6 0  
or 
F oll o w -u p 
Visit f or 
E T 
S u bjects  
( 1 6 wee ks 
after l ast 
d ose of 
st u d y 
tre at me nt3 ) 
F oll o w -u p 
S afet y  
P h o ne C all  
Wee k  6 8 
( 2 4 wee ks 
after t he 
l ast d ose of 
st u d y 
tre at me nt)4 
P h ase of St u d y    
Scree ni n g  
Pl ace b o -C o ntr olle d P h ase  
O pe n -L a bel P h ase  
P ost -Tre at me nt 
F oll o w -U p  
St u d y D a ys    
D a y  -4 2  
+ 1  d a y 5 
D a y  1  
+ 5  d a ys 5 
D a y  2 8  
± 5  d a ys  
D a y  5 6  
± 5  d a ys  
D a y  8 4  
± 5  d a ys  
D a y  1 1 2  
± 5  d a ys  
D a y  1 4 0  
± 5  d a ys  
D a y  1 6 8  
± 5  d a ys  
D a y  1 9 6  
± 5  d a ys  
D a y  2 2 4  
± 5  d a ys  
D a y  2 5 2  
± 5  d a ys  
D a y  2 8 0  
± 5  d a ys  
D a y  3 0 8  
± 5  d a ys  
D a y  3 3 6  
± 5  d a ys  
D a y  4 2 0  
± 5  d a ys  
D a y  4 7 6  
± 5  d a ys  
Bl o o d Sa m ples f or 
P K 1 3 
   
X 1 6   
X    
X    
X    
X  
X 1 6  
X    
   
X    
X    
X    
X  
X 1 6  
X    
 
 
e C-S S R S/ C -S S R S 1 8   
X    
X    
X    
X    
X    
X    
X    
X    
   
X    
X    
X    
X    
X    
X    
X    
 
A Es a n d S A Es 1 9    
 
X  
C o nc o mita nt 
T hera pies/ Pr oce d ures  
 
X  
 
Assess me nt of ne w 
ne ur ol o gical 
s y m pt o ms 2 0 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
X  
A b bre viati o ns: A E  =  a d verse e ve nt; C N S  =  ce ntral ner v o us s yste m; C R F  =  case re p ort f or m; C -S S R S  =  C ol u m bia S uici de Se verit y Rati n g Scale; D N A  =  de o x yri b o n ucleic aci d; e C -
S S R S  =  electr o nic C ol u m bia S uici de Se verit y Rati n g Scale; E T  =  Earl y Ter mi nati o n; I E R C =  i n de pe n de nt e pile ps y re vie w c o m mittee; J C V =  J o h n C u n ni n g ha m vir us; 


 
St atistic al A n al ysis Pl a n f or 1 0 1 E P 2 0 1  
P hase 2 Efficac y, Safet y, a n d T olera bilit y St u d y of 
Nataliz u ma b i n F ocal E pile ps y  
Fi n al v 2. 0   
 
3 8  
; M RI =  ma g netic res o na nce i ma gi n g; P K  =  p har mac o ki netics; P M L  =  pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y; 
 R N A =  ri b o n ucleic aci d; S A E =  seri o us a d verse e ve nt; 
; W B C =  w hite bl o o d cell.  
1 All st u d y assess me nts at Wee k  2 4 m ust be perf or me d pri or t o st u d y treat me nt a d mi nistrati o n as part of t he place b o -c o ntr olle d p hase.  St u d y treat me nt a d mi nistrati o n at Wee k  2 4 will 
be t he start of t he o pe n -la bel p hase. 
2 S u bjects w h o ter mi nate t he st u d y earl y s h o ul d ha ve a n Earl y Ter mi nati o n Visit 4  wee ks after t heir last d ose of st u d y treat me nt.  
3 S u bjects w h o ter mi na te t he st u d y earl y s h o ul d ha ve a F oll o w-u p Visit 1 6  wee ks after t heir last d ose of st u d y treat me nt.  
4 S u bjects w h o ter mi nate t he st u d y earl y s h o ul d ha ve a F oll o w -U p Safet y P h o ne Call 2 4  wee ks after t heir last d ose of st u d y treat me nt.  
5 Da y -4 2 is t he da y o f si g ni n g t he i nf or me d c o nse nt.  Da y 1 is t he da y of eli gi bilit y deter mi nati o n a n d ra n d o mizati o n a n d m ust be at least 4 2  da ys after i nitiati n g seiz ure diar y 
c ollecti o n.  A d diti o nal da ys of diar y e ntr y ma y be c o m plete d if re q uire d f or visit sc he d uli n g; h o we ver, eli gi bilit y criteria a p pl y t o diar y data c o m plete d i n t he 4 2 da ys i m me diatel y 
pri or t o Da y 1. T he st u d y da y wi n d o ws all o w f or c o m pleti o n of ot her st u d y acti vities, if necessar y.  
6 Me dical hist or y s h o ul d i ncl u de a n assess me nt of pri or s u bsta nce a b use.  
7 I ncl u des hei g ht a n d wei g ht meas ure me nts. Hei g ht s h o ul d o nl y be meas ure d at t he Scree ni n g Visit ( Wee k  -6).  Hei g ht a n d wei g ht meas ure me nts t hat are perf or me d as sta n dar d of care 
d o n ot nee d t o be re peate d f or t he st u d y, pr o vi de d t hat Bi o ge n has access t o t he i nf or mati o n a n d data are rec or de d i n s u bject’s C R F.  
8  Vital si g ns c ollecte d at eac h of t he s pecifie d ti me p oi nts i ncl u de te m perat ure, s yst olic a n d diast olic bl o o d press ure, p ulse rate, a n d res pirat or y rate.  Vital si g ns c ollecte d as part of t he 
s u bject’s sta n dar d of care o n t he sa me da y as a st u d y visit d o n ot nee d t o be re peate d f or t he st u d y, pr o vi de d t hat Bi o ge n has access t o t he i nf or mati o n a n d data are rec or de d i n t he 
s u bject’s C R F. Vital si g ns at Wee k  0 t hr o u g h Wee k  4 4 m ust be perf or me d pri or t o st u d y treat me nt a d mi nistrati o n.  
9  M RI sca n of t he brai n is re q uire d wit hi n 4 8  m o nt hs pri or t o scree ni n g t o assist i n t he electr ocli nical assess me nt of a str uct ural eti ol o g y f or f ocal e pile ps y.  M RI d o ne as part of t he 
s u bject’s sta n dar d of care a n d t hat falls wit hi n 4 8 m o nt hs pri or t o scree ni n g d oes n ot nee d t o be re peate d f or t he st u d y, pr o vi de d t hat Bi o ge n has access t o t he i nf or mati o n a n d data 
are rec or de d i n t he s u bject’s C R F.  If M RI is n ot perf or me d wit hi n t his ti me fra me a n d t he s u bject meets ot her i ncl usio n a n d e xcl usi o n criteria, M RI sca n of t he brai n s h o ul d be 
perf or me d d uri n g t he scree ni n g peri o d a n d res ults s h o ul d be re vie we d b y t he I E R C pri or t o Visit  1 i n or der t o a dj u dicate t he prese nce or a bse nce of a str uct ural eti ol o g y f or f ocal 
e pile ps y. 3 T M RI sca n ni n g is preferre d w here ver p ossi ble. S u bjects wit h o ut a n M RI of t he brai n wit hi n 4 8  m o nt hs pri or t o scree ni n g a n d wit h a n a bs ol ute c o ntrai n dicati o n t o M RI 
will be c o nsi dere d o n a case -b y -case basis.   
1 0 Re q uire d o nl y f or w o me n of c hil d beari n g p ote ntial.  A ser u m pre g na nc y test s h o ul d be perf or me d at t he Scree ni n g Visit ( Wee k  -6), a n d a uri ne pre g na nc y test s h o ul d be perf or me d at 
Wee k  0 pri or t o ra n d o mizati o n.  T he uri ne pre g na nc y testi n g will be perf or me d l ocall y pri or t o ra n d o mizati o n.  F oll o w -u p pre g na nc y testi n g t hr o u g h o ut t he st u d y will be d o ne at t he 
discreti o n of t he I n vesti gat or or as re q uire d b y l ocal la w.  
1 1 S u bjects m ust be o bser ve d f or 1 h o ur after c o m pleti o n of i nf usi o n.  
1 2 S u bjects ( or t heir care gi vers) m ust rec or d t heir s eiz ure t y pe a n d fre q ue nc y dail y fr o m Scree ni n g Visit ( Wee k  -6) t hr o u g h E n d of St u d y Visit ( Wee k  6 0), or f or s u bjects w h o ter mi nate 
t he st u d y earl y t hr o u g h t he F oll o w-u p Visit 1 6  wee ks after t heir last d ose of st u d y treat me nt.  S u bjects m ust bri n g t heir seiz ure diar y wit h t he m t o eac h st u d y visit.  
1 3 Bl o o d sa m ples s h o ul d be c ollecte d pri or t o st u d y treat me nt a d mi nistrati o n at Wee k  0 t hr o u g h Wee k  4 4.  T he ti me of c ollecti o n, al o n g wit h t he start a n d st o p ti mes f or t he st u d y 
treat me nt i nf usi o n, m ust be rec or de d i n t he s u bject’s s o urce data a n d o n t he s u bject’s C R F. 
1 4 W B C ( ot her t ha n a bs ol ute ne utr o p hil c o u nt) data will be re vie we d b y a n I n de pe n de nt Safet y M o nit or.  
1 6 B ot h pre d ose a n d p ost d ose bl o o d sa m ples are t o be c ollecte d f or P K at Wee k  0 , Wee k  2 0 , a n d Wee k  4 4 . T he p ost d ose sa m ple m ust be c ollecte d wit hi n 1  h o ur after c o m pleti o n of 
st u d y treat me nt i nf usi o n. T he ti me of c ollect i o n, al o n g wit h t he start a n d st o p ti mes f or t he st u d y treat me nt i nf usi o n, m ust be rec or de d i n t he s u bject’s s o urce data a n d o n t he 
s u bject’s C R F  
1 8 T he “ baseli ne/scree ni n g” e C -S S R S/ C -S S R S m ust be c o m plete d at t he Scree ni n g Visit ( Wee k  -6); at all ot her visits, t he “si nce last visit” e C -S S R S/ C -S S R S m ust be use d.  
1 9 S A E re p orti n g f or P M L or ne w ne ur ol o gical s y m pt o ms i n dicati ve of P M L (e. g., ne w or s u d de n c ha n ge i n t hi n ki n g, visi o n, bala nce, or stre n gt h persisti n g o ver se veral da ys) m ust 
c o nti n ue fr o m t he E n d of St u d y Visit ( Wee k 6 0) t hr o u g h t he F oll o w -U p Safet y P h o ne Call.  Ot her wise, after t he E n d of St u d y Visit or F oll o w -u p Visit f or E T s u bjects, S A Es s h o ul d 
be re p orte d o nl y if t he I n vesti gat or c o nsi ders t he S A E t o be relate d t o st u d y treat me nt.   
2 0 S u bjects s h o ul d be c o ntacte d b y p h o ne 2 4 wee ks after t he last d ose of st u d y treat me nt t o disc uss if t here has bee n a n y ne w de vel o p me nt of a n y ne w ne ur ol o gical s y m pt o ms.  P M L or 
ne w ne ur ol o gical s y m pt o ms i n dicati ve of P M L (e. g., ne w or s u d de n c ha n ge i n t hi n ki n g, visi o n, bala nce, or stre n gt h persisti n g o ver se veral da ys ) m ust be i m me diatel y re p orte d as a n 
S A E.