A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Exploring the Efficacy, Safety, and Tolerability of Natalizumab (BG00002) as Adjunctive Therapy in Adult Subjects With Drug-Resistant Focal Epilepsy
Phase: PHASE2
Conditions: Epilepsy, Focal Seizures, Partial Seizures
Sponsor: Biogen



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.
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I n vesti gat or’s Si g nat ure
Date
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I n vesti gat or’s Na me ( Pri nt)
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St u d y  Site ( Pri nt)