A Single-Arm, Open-Label, Phase 3 Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of Natalizumab (BG00002) Administered to Japanese Participants With Relapsing-Remitting Multiple Sclerosis Via a Subcutaneous Route of Administration
Phase: PHASE3
Conditions: Multiple Sclerosis, Relapsing-Remitting
Sponsor: Biogen

C O V E R P A G E  
 
Offi ci al Titl e : A Si n gl e -Ar m, O p e n -L a b el, P h a s e 3 St u d y t o E v al u at e t h e Effi c a c y, S af et y, 
P h ar m a c o ki n eti c s, a n d P h ar m a c o d y n a mi c s of M ulti pl e D o s e s of N at ali z u m a b 
( B G 0 0 0 0 2) A d mi ni st er e d t o J a p a n e s e P arti ci p a nt s Wit h R el a p si n g-R e mitti n g 
M ulti pl e S cl er o si s Vi a a S u b c ut a n e o u s  R o ut e of A d mi ni str ati o n  
N C T n u m b er : N C T 0 5 2 6 5 7 2 8  
D o c u m e nt D at e : 2 1 -F e b -2 0 2 2  
 

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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
1  
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  
P R O T O C O L N U M B E R:   
1 0 1 M S 3 3 0  
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  
P H A S E O F D E V E L O P M E N T:   
3  
P R O T O C O L TI T L E:  A Si n gle- Ar m, O pe n- La bel, P hase 3 St u d y t o E val uate t he Efficac y, Safet y, 
P har mac o ki netics, a n d P har mac o d y na mics of M ulti ple D oses of Nataliz u ma b ( B G 0 0 0 0 2) 
A d mi nistere d t o Ja pa nese Partici pa nts Wit h Rela psi n g- Re mitti n g M ulti ple Scler osis via a 
S u bc uta ne o us R o ute of A d mi nistrati o n  
D A T E:  
2 1  Fe br uar y 2 0 2 2  
Versi o n 3. 0  
Fi n al  
S u perse des  pre vi o us Versi o n 2. 0 date d 0 4 N o ve m ber 2 0 2 1  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2  
S P O N S O R I N F O R M A TI O N  
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  
Bi o ge n Ja pa n Lt d.  
Ni h o n bas hi 1 -c h o me 
Mits ui B uil di n g 1 4 F  
4 -1 Ni h o n bas hi 1 -c h o me 
C h u o -k u, T o k y o  
1 0 3 -0 0 2 7 Ja pa n  
F or ur ge nt me dical iss ues i n w hic h t he st u d y Me dical M o nit or s h o ul d be c o ntacte d, please refer 
t o c o ntact i nf or mati o n i n t he pr ot oc ol attac h me nt  f or c o m plete c o ntact i nf or mati o n. 
T he S p o ns or  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 a n d ot her t hir d parties; h o we ver, t he S p o ns or retai ns o verall acc o u nta bilit y f or t hese 
acti vities. 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3  
S P O N S O R SI G N A T U R E P A G E  
 
Pr ot oc ol 1 0 1 M S 3 3 0 was a p pr o ve d b y:  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
  
_ _ _ _ _ _ _ _ _ _ _ _ _ _  
, M B, B C h, B A O, M R C S, M F P M  
Date ( D D M M M Y Y Y Y ) 
  
Bi o ge n  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4  
T A B L E O F C O N T E N T S  
S P O N S O R I N F O R M A TI O N ...........................................................................................................2  
S P O N S O R SI G N A T U R E P A G E  ....................................................................................................3  
T A B L E O F C O N T E N T S  .................................................................................................................4  
LI S T O F T A B L E S  ...........................................................................................................................8  
LI S T O F FI G U R E S  .........................................................................................................................8  
1.  
K E Y S T U D Y E L E M E N T S  ..........................................................................................9  
1. 1.  
S y n o psis  ........................................................................................................................9  
1. 2.  
St u d y Desi g n Sc he matic  .............................................................................................1 5  
1. 3.  
Sc he d ule of Acti vities  .................................................................................................1 6  
2.  
LI S T O F A B B R E VI A TI O N S  .....................................................................................2 0  
3.  
I N T R O D U C TI O N ......................................................................................................2 2  
3. 1.  
St u d y Rati o nale  ...........................................................................................................2 2  
3. 1. 1.  
Rati o nale f or St u d y P o p ulati o n  ...................................................................................2 2  
3. 1. 2.  
Rati o nale f or D osi n g Re gi me n  ...................................................................................2 2  
3. 2.  
Bac k gr o u n d  .................................................................................................................2 3  
3. 2. 1.  
O ver vie w of M ulti ple Scler osis  ..................................................................................2 3  
3. 2. 2.  
C urre nt T hera pies f or M ulti ple Scler osis  ...................................................................2 3  
3. 2. 3.  
Pr ofile of Pre vi o us E x perie nce Wit h Nataliz u ma b  .....................................................2 4  
3. 3.  
Be nefit -Ris k Assess me nt  ............................................................................................2 4  
4.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S  ..............................................................2 6  
5.  
S T U D Y D E SI G N  .......................................................................................................2 9  
5. 1.  
St u d y O ver vie w  ..........................................................................................................2 9  
5. 2.  
St u d y D urati o n f or Partici pa nts  ..................................................................................2 9  
5. 3.  
St u d y St o p pi n g R ules  .................................................................................................3 0  
5. 4.  
U nsc he d ule d Visits a n d Treat me nt f or M S Rela pses  .................................................3 0  
5. 5.  
E n d of St u d y  ...............................................................................................................3 1  
6.  
S T U D Y P O P U L A TI O N  .............................................................................................3 2  
6. 1.  
I ncl usi o n Criteria ........................................................................................................3 2  
6. 2.  
E xcl usi o n Criteria  .......................................................................................................3 3  
6. 3.  
Scree ni n g, Retesti n g, a n d Scree n Fail ures  ..................................................................3 6  
6. 3. 1.  
Scree ni n g  ....................................................................................................................3 6  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
C O N FI D E N TI A L  
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Bi o ge n  M A I nc.  
5  
6. 3. 2.  
Retesti n g  .....................................................................................................................3 6  
6. 3. 3.  
Scree n Fail ures  ............................................................................................................3 8  
7.  
S T U D Y T R E A T M E N T  ..............................................................................................3 9  
7. 1.  
Re gi me n  ......................................................................................................................3 9  
7. 2.  
M o dificati o n of D ose a n d/ or Treat me nt Sc he d ule  ......................................................3 9  
7. 3.  
St u d y Treat me nt Ma na ge me nt  ....................................................................................3 9  
7. 3. 1.  
Nataliz u ma b  ................................................................................................................4 0  
7. 3. 1. 1.  
Pre parati o n  ..................................................................................................................4 0  
7. 3. 1. 2.  
St ora ge  ........................................................................................................................4 1  
7. 3. 1. 3.  
Ha n dli n g a n d Dis p osal  ................................................................................................4 1  
7. 3. 1. 4.  
Acc o u nta bilit y  .............................................................................................................4 1  
7. 4.  
Bli n di n g Pr oce d ures  ....................................................................................................4 1  
7. 5.  
Preca uti o ns  ..................................................................................................................4 1  
7. 6.  
C o m plia nce  .................................................................................................................4 2  
7. 7.  
C o nc o mita nt T hera p y a n d Pr oce d ures  ........................................................................4 2  
7. 7. 1.  
C o nc o mita nt T hera p y  .................................................................................................4 2  
7. 7. 1. 1.  
All o we d C o nc o mita nt T hera p y  ...................................................................................4 2  
7. 7. 1. 2.  
Disall o we d C o nc o mita nt T hera p y  ..............................................................................4 2  
7. 7. 2.  
C o nc o mita nt Pr oce d ures  .............................................................................................4 3  
7. 7. 2. 1.  
Disall o we d C o nc o mita nt Pr oce d ures  ..........................................................................4 3  
7. 8.  
C o nti n uati o n of Treat me nt  ..........................................................................................4 4  
8.  
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 P A R TI CI P A N T S F R O M T H E S T U D Y  ...............................................................4 5  
8. 1.  
Disc o nti n uati o n of St u d y Treat me nt  ...........................................................................4 5  
8. 2.  
L ost t o F oll o w -U p  .......................................................................................................4 5  
8. 3.  
Wit h dra wal of Partici pa nts Fr o m t he St u d y  ...............................................................4 6  
9.  
E F FI C A C Y, P H A R M A C O KI N E TI C, A N D P H A R M A C O D Y N A MI C 
A S S E S S M E N T S  .........................................................................................................4 7  
9. 1.  
Cli nical Efficac y Assess me nts  ....................................................................................4 7  
9. 2.  
P har mac o ki netic Assess me nts  ....................................................................................4 7  
9. 3.  
P har mac o d y na mic Assess me nts  .................................................................................4 8  
1 0.  
S A F E T Y A S S E S S M E N T S  ........................................................................................4 9  
1 0. 1.  
Cli nical Safet y Assess me nts  .......................................................................................4 9  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6  
1 0. 2.  
La b orat or y Safet y Assess me nts  ..................................................................................4 9  
1 0. 3.  
Pr o d uct -S pecific Safet y Assess me nts  .........................................................................5 0  
1 1.  
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  .................................................................................................5 1  
1 1. 1.  
Defi niti o ns  ..................................................................................................................5 1  
1 1. 1. 1.  
A d verse E ve nt  .............................................................................................................5 1  
1 1. 1. 2.  
Seri o us A d verse E ve nt  ................................................................................................5 1  
1 1. 1. 3.  
C o m bi nati o n Pr o d uct  ..................................................................................................5 2  
1 1. 1. 4.  
Pr o d uct C o m plai nts f or I n vesti gati o nal C o m bi nati o n Pr o d ucts  .................................5 2  
1 1. 1. 5.  
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 2  
1 1. 2.  
Safet y Classificati o ns  ..................................................................................................5 3  
1 1. 2. 1.  
I n vesti gat or Assess me nt of E ve nts .............................................................................5 3  
1 1. 2. 2.  
Relati o ns hi p of E ve nts t o St u d y Treat me nt  ................................................................5 3  
1 1. 2. 3.  
Se verit y of E ve nts  .......................................................................................................5 3  
1 1. 2. 4.  
E x pecte d ness of E ve nts  ..............................................................................................5 4  
1 1. 3.  
M o nit ori n g a n d Rec or di n g E ve nts  ..............................................................................5 4  
1 1. 3. 1.  
A d verse E ve nts  ...........................................................................................................5 4  
1 1. 3. 2.  
A d verse E ve nts of S pecial I nterest  .............................................................................5 4  
1 1. 3. 3.  
Seri o us A d verse E ve nts  ..............................................................................................5 4  
1 1. 3. 4.  
Pr o d uct C o m plai nts  ....................................................................................................5 4  
1 1. 3. 5.  
I m me diate Re p orti n g of Seri o us A d verse E ve nts .......................................................5 5  
1 1. 3. 5. 1.  
Deat hs  .........................................................................................................................5 5  
1 1. 3. 6.  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns  ....................................................5 5  
1 1. 4.  
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns  ...............................................................5 6  
1 1. 4. 1.  
Pre g na nc y  ...................................................................................................................5 6  
1 1. 4. 2.  
O ver d ose  .....................................................................................................................5 6  
1 1. 4. 3.  
Me dical E mer ge nc y  ....................................................................................................5 6  
1 1. 5.  
C o ntrace pti o n Re q uire me nts  ......................................................................................5 6  
1 1. 6.  
Safet y Res p o nsi bilities  ................................................................................................5 8  
1 1. 6. 1.  
T he I n vesti gat or  ..........................................................................................................5 8  
1 1. 6. 2.  
T he S p o ns or  ................................................................................................................5 8  
1 2.  
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  ...........6 0  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
7  
1 2. 1.  
Ge neral C o nsi derati o ns  ...............................................................................................6 0  
1 2. 2.  
A nal ysis Sets  ...............................................................................................................6 0  
1 2. 3.  
Met h o ds of A nal ysis f or Efficac y E n d p oi nts  ..............................................................6 1  
1 2. 3. 1.  
A nal ysis of t he Pri mar y E n d p oi nt  ...............................................................................6 1  
1 2. 3. 2.  
A nal ysis of t he Sec o n dar y E n d p oi nts  .........................................................................6 1  
 
6 1  
1 2. 4.  
Met h o ds of A nal ysis f or P har mac o ki netic E n d p oi nts  ................................................6 1  
1 2. 5.  
Met h o ds of A nal ysis f or P har mac o d y na mic E n d p oi nts  .............................................6 2  
1 2. 6.  
Met h o ds of A nal ysis f or Safet y E n d p oi nts  .................................................................6 2  
1 2. 6. 1.  
A d verse E ve nts  ...........................................................................................................6 2  
1 2. 6. 2.  
Cli nical La b orat or y Res ults  ........................................................................................6 3  
1 2. 6. 3.  
Vital Si g ns  ..................................................................................................................6 3  
1 2. 6. 4.  
1 2 -Lea d E C G  ..............................................................................................................6 3  
1 2. 6. 5.  
C -S S R S  .......................................................................................................................6 3  
1 2. 6. 6.  
E D S S  ...........................................................................................................................6 3  
1 2. 7.  
Met h o ds of A nal ysis f or I m m u n o ge nicit y Data a n d A nti -J C V A nti b o dies ...............6 4  
1 2. 8.  
I nteri m A nal yses .........................................................................................................6 4  
1 2. 9.  
Sa m ple Size C o nsi derati o ns  .......................................................................................6 4  
1 3.  
E T HI C A L A N D R E G U L A T O R Y R E Q UI R E M E N T S  ..............................................6 5  
1 3. 1.  
Declarati o n of Helsi n ki  ...............................................................................................6 5  
1 3. 2.  
Et hics C o m mittee  ........................................................................................................6 5  
1 3. 3.  
C ha n ges t o Fi nal Pr ot oc ol  ...........................................................................................6 6  
1 3. 4.  
I nf or me d C o nse nt .......................................................................................................6 6  
1 3. 5.  
Partici pa nt Data Pr otecti o n  .........................................................................................6 6  
1 3. 6.  
C o m pe nsati o n f or I nj ur y  .............................................................................................6 7  
1 3. 7.  
C o nflict of I nterest  ......................................................................................................6 7  
1 3. 8.  
St u d y Re p ort Si g nat or y  ...............................................................................................6 7  
1 3. 9.  
Re gistrati o n of St u d y a n d Discl os ure of St u d y Res ults  ..............................................6 7  
1 3. 1 0.  
Rete nti o n of St u d y Data  ..............................................................................................6 7  
1 4.  
K E Y R O L E S A N D S T U D Y G O V E R N A N C E C O M MI T T E E S  ...............................6 9  
1 4. 1.  
Site Staff  .....................................................................................................................6 9  
1 4. 2.  
Ve n d ors  .......................................................................................................................6 9  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
8  
1 4. 2. 1.  
C o ntract Researc h Or ga nizati o n  .................................................................................6 9  
1 4. 2. 2.  
I nteracti ve Res p o nse Tec h n ol o g y ...............................................................................6 9  
1 4. 2. 3.  
Electr o nic Data Ca pt ure  ..............................................................................................6 9  
1 4. 2. 4.  
Ce ntral La b orat ories f or La b orat or y Assess me nts  .....................................................6 9  
1 4. 2. 5.  
Ce ntral Facilit y f or Ot her Assess me nts  ......................................................................6 9  
1 4. 2. 6.  
Ce ntral Re vie w of Raters  ............................................................................................6 9  
1 4. 3.  
St u d y C o m mittees  .......................................................................................................7 0  
1 5.  
A D MI NI S T R A TI V E P R O C E D U R E S  .......................................................................7 1  
1 5. 1.  
St u d y Site I nitiati o n  ....................................................................................................7 1  
1 5. 2.  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  ......................................................................7 1  
1 5. 3.  
M o nit ori n g of t he St u d y  ..............................................................................................7 1  
1 5. 4.  
St u d y F u n di n g  .............................................................................................................7 2  
1 5. 5.  
P u blicati o ns  .................................................................................................................7 2  
1 6.  
R E F E R E N C E S  ...........................................................................................................7 3  
1 7.  
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 6  
 
LI S T O F T A B L E S  
Ta ble  1:  
Sc he d ule of Acti vities  .................................................................................................1 6  
Ta ble  2:  
Criteria t o Deter mi ne Cli nicall y Rele va nt A b n or malities i n Vital Si g ns  ...................6 3  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
St u d y 1 0 1 M S 3 3 0 Sc he matic .......................................................................................1 5  
 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
9  
1.   
K E Y S T U D Y E L E M E N T S  
1. 1.   
S y n o psis  
Pr ot oc ol Title:  
A Si n gle -Ar m, O pe n -La bel, P hase 3 St u d y t o E val uate t he 
Efficac y, Safet y, P har mac o ki netics, a n d P har mac o d y na mics of 
M ulti ple D oses of Nataliz u ma b ( B G 0 0 0 0 2) A d mi nistere d t o 
Ja pa nese Partici pa nts Wit h Rela psi n g-Re mitti n g M ulti ple 
Scler osis via a S u bc uta ne o us  R o ute of A d mi nistrati o n  
Pr ot oc ol N u m ber:   
1 0 1 M S 3 3 0  
Versi o n N u m ber:   
3. 0  
Na me of St u d y Treat me nt:  
Researc h Na me:   
B G 0 0 0 0 2  
Ge neric Na me:   
Nataliz u ma b  
Tra de Na me:    
T ysa bri  
St u d y P hase:  
3  
St u d y I n dicati o n:   
Rela psi n g -Re mitti n g M ulti ple Scler osis  
St u d y Rati o nale:   
T he S p o ns or has de vel o pe d a p har mace utical f or m ulati o n f or S C 
a d mi nistrati o n i n a P F S t hat deli vers nataliz u ma b at a d ose of 
1 5 0  m g (i n 1  m L), e na bli n g a t otal d ose of 3 0 0  m g t o be 
deli vere d b y 2  c o nsec uti ve i njecti o ns, Q 4 W. St u dies i n c o h orts of 
partici pa nts wit h M S ha ve s h o w n t hat t his pr o d uct is si milar t o 
t he I V f or m ulati o n wit h res pect t o its P K a n d P D pr ofile as well 
as its efficac y a n d safet y ( St u dies  1 0 1 M S 1 0 2 a n d 1 0 1 M S 2 0 6).  
T he S C r o ute of a d mi nistrati o n ma y pr o vi de a d diti o nal be nefits 
t o patie nts a n d p h ysicia ns c o m pare d wit h I V i nf usi o n as n ote d i n 
t he be nefit-ris k a nal ysis secti o n t hat f oll o ws.  
T his P hase 3 st u d y will e val uate t he efficac y, safet y, P K, a n d P D 
of nataliz u ma b 3 0 0  m g Q 4 W a d mi nistere d t o Ja pa nese 
partici pa nts wit h R R M S via a S C r o ute of a d mi nistrati o n.  
Rati o nale f or D ose a n d 
Sc he d ule Selecti o n:  
T he nataliz u ma b S C d ose selecte d f or t his st u d y ( 3 0 0 m g Q 4 W) 
is t he a p pr o ve d d ose re gi me n i n t he E U f or t he treat me nt of 
patie nts wit h R M S a n d has bee n selecte d as t he rec o m me n de d 
d ose i n mar keti n g a p plicati o ns t o ot her healt h a ut h orities.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
1 0  
T he res ults fr o m m o delli n g a n d si m ulati o n a nal ysis of S C a n d I V 
nataliz u ma b were c o nsiste nt wit h t he o utc o mes of t he cli nical 
st u dies 1 0 1 M S 1 0 2 a n d 1 0 1 M S 2 0 6 a n d de m o nstrate d t hat 
a d mi nisteri n g nataliz u ma b 3 0 0  m g S C Q 4 W w o ul d res ult i n a 
si milar Ctr o u g h val ue a n d P D res p o nse as a d mi nisteri n g t he 
cli nicall y a p pr o ve d 3 0 0  m g I V Q 4 W d ose . T he res ults fr o m t hese 
st u dies s u p p ort t he use of t he S C i njecti o n as a n a d diti o nal r o ute 
of a d mi nistrati o n f or nataliz u ma b at t he sa me d ose le vel as t he 
c urre nt c o m mercial pr o d uct.  
St u d y O bjecti ves a n d E n d p oi nts   
 
Pri mar y O bjecti ve  
Pri mar y E n d p oi nt  
T o e val uate t he efficac y of nataliz u ma b 
3 0 0  m g S C Q 4 W a d mi nistrati o ns u p t o 
2 4  wee ks i n Ja pa nese partici pa nts wit h 
R R M S  
C u m ulati ve n u m ber of ne w acti ve lesi o ns ( s u m of 
ga d oli ni u m -e n ha nci n g lesi o ns a n d n o ne n ha nci n g 
ne w or ne wl y e nlar gi n g T 2 h y peri nte nse lesi o ns) 
o n Wee k 2 4 ( Part 1) brai n M RI sca ns  
Sec o n dar y O bjecti ves  
Sec o n dar y E n d p oi nts  
T o e val uate ot her cli nical a n d M RI 
meas ures of efficac y of nataliz u ma b 
3 0 0  m g S C Q 4 W a d mi nistrati o ns i n 
Ja pa nese partici pa nts wit h R R M S 
•  C u m ulati ve n u m ber of ne w acti ve lesi o ns 
(s u m of ga d oli ni u m-e n ha nci n g lesi o ns a n d 
n o ne n ha nci n g  ne w or ne wl y e nlar gi n g T 2 
h y peri nte nse lesi o ns) o n Wee k 4 8 ( Part 2) 
brai n M RI sca ns  
•  Pr o p orti o n of partici pa nts wit h a n y ne w 
acti ve lesi o ns ( ga d oli ni u m -e n ha nci n g lesi o ns 
or n o ne n ha nci n g  ne w or ne wl y e nlar gi n g T 2 
h y peri nte nse lesi o ns) o n Wee k 2 4 ( Part 1) 
brai n M RI sca ns  
•  Pr o p orti o n of partici pa nts wit h a n y ne w 
acti ve lesi o ns ( ga d oli ni u m -e n ha nci n g lesi o ns 
or n o ne n ha nci n g  ne w or ne wl y e nlar gi n g T 2 
h y peri nte nse lesi o ns) o n Wee k 4 8 ( Part 2) 
brai n M RI sca ns  
•  C ha n ge fr o m baseli ne i n n u m ber of 
ga d oli ni u m -e n ha nci n g lesi o ns at Wee k 2 4 
a n d Wee k 4 8  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
1 1  
•  T he n u m ber of n o ne n ha nci n g ne w or ne wl y 
e nlar gi n g T 2 h y peri nte nse lesi o ns at Wee k 2 4 
a n d Wee k  4 8  
•  T he n u m ber of ne w T 1 h y p oi nte nse lesi o ns at 
Wee k 2 4 a n d Wee k 4 8  
•  A R R at Wee k 2 4  
•  A R R at Wee k 4 8  
•  A R R at Wee k 5 2  
•  Pr o p orti o n of rela pse -free partici pa nts at 
Wee k 2 4 a n d Wee k 5 2  
•  V A S assessi n g t he partici pa nt’s gl o bal 
i m pressi o n of t heir well-bei n g at Wee k 2 4 
a n d Wee k 4 8  
T o e val uate t he safet y, t olera bilit y, a n d 
i m m u n o ge nicit y of nataliz u ma b 3 0 0 m g 
S C Q 4 W a d mi nistrati o ns u p t o 4 8 wee ks 
i n Ja pa nese partici pa nts wit h R R M S 
•  I nci de nce of treat me nt-e mer ge nt A Es a n d 
S A Es fr o m Baseli ne t o e n d of st u d y  
•  A nti -J C V a nti b o d y stat us as meas ure d b y 
a nti-J C V a nti b o dies 
•  I nci de nce of i njecti o n site reacti o ns a n d 
i njecti o n reacti o ns 
•  I m m u n o ge nicit y as meas ure d b y i nci de nce of 
a nti-nataliz u ma b a nti b o dies  
•  C ha n ge i n E D S S sc ore fr o m Baseli ne t o 
Wee k 2 4  
•  C ha n ge i n E D S S sc ore fr o m Baseli ne t o 
Wee k 4 8  
T o e val uate t he P K a n d P D of 
nataliz u ma b 3 0 0  m g S C Q 4 W 
a d mi nistrati o ns u p t o 2 4  wee ks a n d f or a n 
a d diti o nal 2 4 wee ks i n Ja pa nese 
partici pa nts wit h R R M S  
•  Ser u m nataliz u ma b c o nce ntrati o ns ( C tr o u g h) at 
eac h visit u ntil Wee k 4 8  
•  Ser u m nataliz u ma b c o nce ntrati o n bet wee n 
Da y 6 a n d Da y  8  
•  α 4 -i nte gri n sat urati o n a n d ser u m s ol u ble 
V C A M -1 c o nce ntrati o ns at eac h visit u ntil 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
1 2  
Wee k 4 8 (e xcl u di n g Wee k 1 [ Da y 6 t o Da y 8] 
visit)  
  
St u d y Desi g n:  
T his P hase 3, si n gle -ar m, o pe n-la bel st u d y will e val uate t he 
efficac y, safet y, P K, a n d P D of nataliz u ma b S C i n Ja pa nese 
partici pa nts wit h R R M S.  
St u d y L ocati o n:  
A p pr o xi matel y 1 0 sites i n Ja pa n are pla n ne d.  
St u d y P o p ulati o n:   
T his st u d y will be c o n d ucte d i n a d ult male a n d fe male Ja pa nese 
partici pa nts wit h R R M S.  
Detaile d criteria are descri be d i n Secti o n  6 .  
N u m ber of Pla n ne d 
Partici pa nts:  
A p pr o xi matel y 2 0 partici pa nts will be e nr olle d.  
Treat me nt Gr o u ps:   
Nataliz u ma b 3 0 0  m g S C will be a d mi nistere d as a Q 4 W re gi me n 
o ver 4 8  wee ks.  
Sa m ple Size 
Deter mi nati o n:  
T he st u d y pla ns t o e nr oll a p pr o xi matel y 2 0 partici pa nts w hic h 
was base d o n feasi bilit y. A p pr o xi matel y 1 5 t hr o u g h 1 7 e val ua ble 
partici pa nts are dee me d s ufficie nt t o c haracterize t he efficac y 
pr ofile of nataliz u ma b S C.  
T he mar gi n i n St u d y 1 0 1 M S 3 3 0 s h o wi n g c o m para bilit y of t he 
nataliz u ma b S C t o I V is set at 2. 3 2, w hic h is o ne -t hir d of t he 
mea n differe nce ( 1. 5 3 a n d 8. 4 9) bet wee n t he nataliz u ma b a n d 
place b o gr o u ps i n ne w acti ve lesi o ns at Wee k  2 4 i n Ja pa nese 
nataliz u ma b I V St u d y 1 0 1 M S 2 0 3. T o de m o nstrate t he 
c o m para bilit y of nataliz u ma b S C t o I V, 1 5  e val ua ble partici pa nts 
all o w at least 8 0 % pr o ba bilit y t hat t he u p per li mit of t he 9 5 % CI 
f or mea n ne w acti ve lesi o ns at Wee k 2 4 i n nataliz u ma b S C is 
l o wer t ha n 3. 8 5 (i.e., 2. 3 2 plus 1. 5 3), ass u mi n g si milar fiel d M RI 
mac hi nes are use d f or St u dies  1 0 1 M S 2 0 3 a n d 1 0 1 M S 3 3 0 a n d t he 
tr ue mea n of ne w acti ve lesi o ns f or t he nataliz u ma b S C is 1. 5 3. 
I n a d diti o n, ass u mi n g 7 0 % of partici pa nts will ha ve M RIs usi n g 
3 T mac hi nes i n St u d y  1 0 1 M S 3 3 0, c o m pare d t o a p pr o xi matel y 
1 3 % i n St u d y  1 0 1 M S 2 0 3, a n d t he tr ue mea n of ne w acti ve 
lesi o ns is 1. 7 3, 1 7 e val ua ble partici pa nts all o w 8 0 % pr o ba bilit y 
t hat o bser vi n g t he u p per li mit of 9 5 % CI f or ne w acti ve lesi o ns at 
Wee k 2 4 i n nataliz u ma b S C is l o wer t ha n 3. 8 5  [S hila ne a n d Bea n 
2 0 1 3 ]. 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
1 3  
Visit Sc he d ule:  
Partici pa nts will ha ve u p t o 1 6 sc he d ule d visits d uri n g t he st u d y 
a n d 2 safet y f oll o w -u p p h o ne calls. All visits s h o ul d be 
perf or me d ±  3  t o 1 0 da ys fr o m t he n o mi nal visit da y. Visit da ys 
are calc ulate d wit h res pect t o Da y 1 (t he date of first d ose).  
St u d y assess me nts c o n d ucte d at eac h visit are liste d i n t he  
Sc he d ule of Acti vities (  Ta ble  1 ). 
D urati o n of St u d y 
Partici pati o n:  
St u d y d urati o n f or eac h partici pa nt will be a p pr o xi matel y 
7 6  wee ks:  
•  4 -wee k Scree ni n g Peri o d  
•  2 4 -wee k Treat me nt Peri o d i n Part 1  
•  2 4 -wee k Treat me nt Peri o d i n Part 2  
•  4 -wee k Safet y F oll o w -U p Peri o d  
•  F oll o w -u p safet y p h o ne call s 1 2 a n d 2 4 wee ks after t he 
last d ose 
Be nefit -Ris k A nal ysis:  
Wit h o ver 1 7  years of e x perie nce i n t he p ost mar keti n g setti n g, 
nataliz u ma b I V c o nti n ues t o de m o nstrate a hi g h le vel of efficac y 
wit h a well -c haracterize d safet y pr ofile a n d a si g nifica nt 
be neficial i m pact o n t he q ualit y of life i n patie nts wit h R R M S. I n 
pi v otal cli nical st u dies, nataliz u ma b I V de m o nstrate d a 
6 7 %  re d ucti o n i n A R R a n d a 4 2 % re d ucti o n i n t he ris k of 
disa bilit y pr o gressi o n o ver 2  years. Si nce t he mar keti n g of 
nataliz u ma b, p u blicati o ns fr o m m ulti ple i n de pe n de nt gr o u ps, as 
well as p u blicati o ns fr o m t he S p o ns or, ha ve f urt her de m o nstrate d 
t he cli nical effecti ve ness of nataliz u ma b w he n use d i n patie nts 
w h o ha ve M S w it h hi g h disease acti vit y des pite treat me nt wit h 
first-li ne t hera pies [Belac he w 2 0 1 1 ; M orr o w 2 0 1 0 ; Ot urai 2 0 0 9 ; 
Sa n galli 2 0 1 1 ]. 
E xte nsi ve safet y data fr o m cli nical st u dies a n d t he p ost mar keti n g 
setti n g ha ve res ulte d i n a well-c haracterize d safet y pr ofile f or 
nataliz u ma b I V. I nf usi o n a n d h y perse nsiti vit y reacti o ns a n d 
a nti-nataliz u ma b a nti b o d y pr o d ucti o n are i m p orta nt safet y 
c o ncer ns; h o we ver, t he y are ma na gea ble i n r o uti ne cli nical 
practice. Seri o us, life -t hreate ni n g, a n d s o meti mes fatal cases of 
e nce p halitis a n d me ni n gitis ca use d b y her pes si m ple x or varicella 
z oster ha ve bee n re p orte d i n M S patie nts recei vi n g nataliz u ma b. 
I n p ost mar keti n g e x perie nce, t here ha ve bee n rare re p orts of 
cli nicall y si g nifica nt li ver i nj ur y.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
1 4  
T he m ost i m p orta nt A E affecti n g nataliz u ma b be nefit -ris k 
assess me nt is t he occ urre nce of P M L. 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 a n d are 
c urre ntl y i ncl u de d i n t he pr o d uct la beli n g: t hat P M L ris k is 
i ncrease d wit h t he prese nce of a nti-J C V a nti b o dies, treat me nt 
d urati o n (es peciall y be y o n d 2  years of t hera p y), a n d pri or use of 
a n i m m u n os u p pressa nt t hera p y. T hese 3  ris k fact ors, as well as 
i nf or mati o n a b o ut a nti-J C V a nti b o d y i n de x i n a nti-J C V 
a nti b o d y-p ositi ve patie nt s wit h o ut a n y pri or i m m u n os u p pressa nt 
use, ca n be utilize d t o f urt her stratif y t he ris k of P M L a n d 
t heref ore pr o vi de a n i m p orta nt t o ol f or p h ysicia ns a n d patie nts 
w he n ma ki n g i n di vi d ual be nefit -ris k decisi o ns re gar di n g 
i nitiati o n or c o nti n uati o n of natalizu ma b t hera p y.  
T he S C r o ute of a d mi nistrati o n ma y pr o vi de a d diti o nal be nefits 
t o patie nts a n d p h ysicia ns b y offeri n g a less i n vasi ve r o ute of 
a d mi nistrati o n, l o wer c o m ple xit y, a n d re d uce d ti me re q uire d at 
eac h treat me nt visit c o m pare d wit h I V i nf usi o n [Des pia u 2 0 1 7 ; 
L o pez -Vi va nc o 2 0 1 7 ]. T here is e vi de nce fr o m ot her me dical 
c o n diti o ns a n d i n dicati o ns t hat patie nts prefer S C t o I V r o ute of 
a d mi nistrati o n base d o n c o n ve nie nce a n d data fr o m 
q ualit y -of -life meas ure me nts [Fala n ga 2 0 1 9 ; Pi v ot 2 0 1 3 ; Sa nt us 
2 0 1 9 ; S yri os 2 0 1 8 ]. T he ec o n o mic a n d c ost -sa vi n g be nefits of 
S C  vers us I V r o ute of a d mi nistrati o n i n t he h os pital setti n g ha ve 
bee n de m o nstrate d [Far olfi 2 0 1 7 ; L o pez -Vi va nc o 2 0 1 7 ; Olse n 
2 0 1 8 ].  
T he safet y pr ofile o bser ve d f or nataliz u ma b a d mi nistere d S C was 
c o nsiste nt wit h t he k n o w n safet y pr ofile of nataliz u ma b 
a d mi nistere d I V, wit h t he e xce pti o n of i njecti o n site pai n. D uri n g 
t he 2 S C cli nical st u dies ( St u dies 1 0 1 M S 1 0 2 a n d 1 0 1 M S 2 0 6), 
i njecti o n site pai n was re p orte d i n 4 % ( 3 of 7 1) of partici pa nts 
recei vi n g nataliz u ma b 3 0 0 m g S C Q 4 W a n d n o partici pa nts 
recei vi n g nataliz u ma b 3 0 0 m g I V Q 4 W re p orte d i njecti o n site 
pai n.  
T he p ote ntial ris ks relate d t o partici pati o n i n t his st u d y are 
j ustifie d b y t he a ntici pate d be nefit t o partici pa nts. 
 
 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of Bi o ge n  M A I nc.  
1 6  
1. 3.   
Sc he d ule of Acti vities  
 T a ble  1 :  
Sc he d ule of Acti vities  
 
  
P art  1: 2 4 -Wee k O pe n -L a bel Tre at me nt   
P art  2: 2 4 -Wee k O pe n -L a bel 
Tre at me nt  
S afet y  
F U  
S afet y 
F U 
P h o ne 
C all 1 
S afet y 
F U 
P h o ne 
C all 2 
U nsc he d ule d  
S C R   
B L  
W 1   
W 4   W 8  W 1 2  W 1 6  W 2 0  W 2 4  W 2 8  W 3 2  W 3 6  W 4 0  W 4 4  W 4 8  W 5 2   W 6 0   W 7 2  Ne ur ol o gic al 
W orse ni n g
3 
E T  
Visit 4 
Assess me nts  
D -2 8 
t o 
D -1  
D 1  D 6 t o 
D 8  
D 2 9  
( ± 3) 
D 5 7  
( ± 3) 
D 8 5  
( ± 3) 
D 1 1 3  
( ± 3) 
D 1 4 1  
( ± 3) 
D 1 6 9  
( ± 3) 
D 1 9 7  
( ± 3) 
D 2 2 5  
( ± 3) 
D 2 5 3  
( ± 3) 
D 2 8 1  
( ± 3) 
D 3 0 9  
( ± 3) 
D 3 3 7  
( ± 3) 
D 3 6 5  
( ± 7) 
D 4 2 1 
( ± 1 0) 
D 5 0 5  
( ± 1 0) 
I nf or me d C o nse nt   
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
I ncl usi o n/ E xcl usi o n 
Criteria  
X   
X  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
Me dical Hist or y   
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
P h ysical E xa mi nati o n 5 
X   
X  
 
X   
  
X   
  
  
X   
  
  
X   
  
  
X   
X  
 
  
X   
X  
Hei g ht  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Vital Si g ns 6  
X   
X  
 
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
 
  
X   
X  
1 2 -Lea d E C G  
X   
  
  
  
  
  
  
  
X   
  
  
  
  
  
  
X   
  
  
  
X  
F S H 7 
X   
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
E D S S/ Ne ur ol o gical 
E xa mi nati o n  
X   
X  
 
  
  
  
  
  
X   
  
  
  
  
  
X   
 
 
  
X   
X  
Partici pa nt -Assesse d 
Well -Bei n g V A S  
  
X  
 
  
  
  
  
  
X   
  
  
  
  
  
X   
 
 
  
  
X  
M RI ( brai n, wit h 
c o ntrast) 8 
X 9 
 
 
  
  
X   
  
  
X   
  
  
  
  
  
X   
 
 
  
X   
X  
C -S S R S  
X   
X   
  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
  
  
  
X  
HI V/ He patitis Scree n   
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Alc o h ol a n d Dr u g 
Scree n  
X   
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
Scree ni n g f or T B 
(I G R A) 
X   
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of Bi o ge n  M A I nc.  
1 7  
 
  
P art  1: 2 4 -Wee k O pe n -L a bel Tre at me nt   
P art  2: 2 4 -Wee k O pe n -L a bel 
Tre at me nt  
S afet y  
F U  
S afet y 
F U 
P h o ne 
C all 1 
S afet y 
F U 
P h o ne 
C all 2 
U nsc he d ule d  
S C R   
B L  
W 1   
W 4   W 8  W 1 2  W 1 6  W 2 0  W 2 4  W 2 8  W 3 2  W 3 6  W 4 0  W 4 4  W 4 8  W 5 2   W 6 0   W 7 2  Ne ur ol o gic al 
W orse ni n g
3 
E T  
Visit 4 
Assess me nts  
D -2 8 
t o 
D -1  
D 1  D 6 t o 
D 8  
D 2 9  
( ± 3) 
D 5 7  
( ± 3) 
D 8 5  
( ± 3) 
D 1 1 3  
( ± 3) 
D 1 4 1  
( ± 3) 
D 1 6 9  
( ± 3) 
D 1 9 7  
( ± 3) 
D 2 2 5  
( ± 3) 
D 2 5 3  
( ± 3) 
D 2 8 1  
( ± 3) 
D 3 0 9  
( ± 3) 
D 3 3 7  
( ± 3) 
D 3 6 5  
( ± 7) 
D 4 2 1 
( ± 1 0) 
D 5 0 5  
( ± 1 0) 
Ser u m Pre g na nc y 
Test 1 0 
X   
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
Uri ne Pre g na nc y 
Test 1 0 ,1 1 
  
X  
 
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
 
  
  
X  
He mat ol o g y  
X   
X   
  
X   
  
X   
  
  
X   
X   
  
X   
  
  
X   
X   
  
  
  
X  
Bl o o d C he mistr y   
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 pli n g f or 
P K Assess me nts 1 2 
  
X  
X 1 3 
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
 
 
  
  
X  
Bl o o d Sa m pli n g f or 
P D Assess me nts 1 2 
  
X  
 
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
 
 
  
  
X  
Bl o o d Sa m ple f or 
A nti -Nataliz u ma b 
A nti b o d y 
Assess me nts 1 2 
X   
 
 
  
  
X   
  
  
X   
  
  
X   
  
  
X   
 
 
  
X   
X  
A nti -J C V A nti b o d y  
X   
  
  
  
  
  
  
  
X   
  
  
  
  
  
X   
  
  
  
X   
X  
A nti -A Q P 4 A nti b o d y  
X 1 4 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
A nti -M O G A nti b o d y  
X 1 4  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
St u d y Treat me nt 
A d mi nistrati o n 1 5 ,1 6 
  
X  
 
X   
X   
X   
X   
X   
X  
X 1 7 
X  
X 1 7 
X   
X   
X   
 
 
  
  
 
Rela pse Assess me nt   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X   
 
A d verse E ve nt 
Rec or di n g  
 
---------------------------------------------------------------------------------------- X ---------------------------------------------------------------------------------- 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of Bi o ge n  M A I nc.  
1 8  
 
  
P art  1: 2 4 -Wee k O pe n -L a bel Tre at me nt   
P art  2: 2 4 -Wee k O pe n -L a bel 
Tre at me nt  
S afet y  
F U  
S afet y 
F U 
P h o ne 
C all 1 
S afet y 
F U 
P h o ne 
C all 2 
U nsc he d ule d  
S C R   
B L  
W 1   
W 4   W 8  W 1 2  W 1 6  W 2 0  W 2 4  W 2 8  W 3 2  W 3 6  W 4 0  W 4 4  W 4 8  W 5 2   W 6 0   W 7 2  Ne ur ol o gic al 
W orse ni n g
3 
E T  
Visit 4 
Assess me nts  
D -2 8 
t o 
D -1  
D 1  D 6 t o 
D 8  
D 2 9  
( ± 3) 
D 5 7  
( ± 3) 
D 8 5  
( ± 3) 
D 1 1 3  
( ± 3) 
D 1 4 1  
( ± 3) 
D 1 6 9  
( ± 3) 
D 1 9 7  
( ± 3) 
D 2 2 5  
( ± 3) 
D 2 5 3  
( ± 3) 
D 2 8 1  
( ± 3) 
D 3 0 9  
( ± 3) 
D 3 3 7  
( ± 3) 
D 3 6 5  
( ± 7) 
D 4 2 1 
( ± 1 0) 
D 5 0 5  
( ± 1 0) 
Seri o us A d verse 
E ve nt Re p orti n g  
-------------------------------------------------------------------------------------X -------------------------------------------------------------------------------------------------  
C o nc o mita nt T hera p y 
a n d Pr oce d ures 
Rec or di n g  
---------------------------------------------------------------------------------------------- X ---------------------------------------------------------------------------------------- 
1 Partici pa nts s h o ul d ha ve a f oll o w -u p safet y p h o ne call 1 2 wee ks after t heir last d ose of st u d y treat me nt f or A E/ S A E rec or di n g a n d c o nc o mita nt t hera p y a n d 
pr oce d ure rec or di n g.  
2 Partici pa nts s h o ul d ha ve a f oll o w -u p safet y p h o ne call 2 4 wee ks after t heir last d ose of st u d y treat me nt f or A E/ S A E rec or di n g a n d c o nc o mita nt t hera p y a n d 
pr oce d ure rec or di n g a n d t o disc uss if t here has bee n 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. 
3 Partici pa nts w h o s us pect t hat t he y are e x perie nci n g ne w or w orse ni n g ne ur ol o gical s y m pt o ms, i ncl u di n g p ossi ble rela pse, nee d t o tele p h o ne t he I n vesti gat or 
wit hi n 7 2 h o urs of t he o nset of s y m pt o ms. T he partici pa nt is t o be e val uate d b y t he ne ur ol o gist wit h i n 5 da ys of t he o nset of s y m pt o ms. Rela pses s h o ul d be 
d oc u me nte d i n t he rela pse assess me nt f or m. T he ma xi m u m n u m ber of sa m ples eli gi ble f or c ollecti o n a n d a nal ysis are 2 ( 1 f or ea c h u nsc he d ule d visit). T he 
sa m ples will be na me d N W 1 a n d N W 2. 
4 Partici pa nts are e nc o ura ge d t o u n der g o a n E T Visit u nless wit h dra wal is d ue t o deat h or wit h dra wal of c o nse nt. T he E T Visit i n s uc h partici pa nts s h o ul d occ ur 
at 4 wee ks ( ± 7 da ys) after t he last d ose of st u d y treat me nt a n d s h o ul d be f oll o we d b y safet y p h o n e calls at 1 2 wee ks ( ± 1 0 da ys) a n d 2 4 wee ks ( ± 1 0 da ys) after 
t he last d ose of st u d y treat me nt. 
5 Partici pa nt wei g ht meas ure me nt t o be i ncl u de d as part of p h ysical e xa mi nati o n.  
6 Vital si g ns c ollecte d at eac h of t he s pecifie d ti me p oi nts i ncl u de te m perat ure, s yst olic a n d diast olic bl o o d press ure, p ulse r ate, a n d res pirat or y rate. Partici pa nts 
m ust re mai n i n t he sa me b o d y p ositi o n (seate d or s u pi ne) q uietl y f or 5 mi n utes pri or t o p u lse rate a n d bl o o d press ure meas ure me nts; meas ure me nts m ust be 
perf or me d wit hi n 1 h o ur pri or t o a d mi nistrati o n of st u d y treat me nt.  
7 T o be perf or me d o nl y i n w o me n w h o ha ve ha d 5 2 c o nti n u o us wee ks 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 d ical reas o n; res ult m ust be 
>  4 0  mI U/ m L t o c o nfir m p ost me n o pa usal stat us.  
8 Caref ul e val uati o n of M RI, i ncl u di n g c o m paris o n wit h pre vi o us M RI sca ns. If, i n t he o pi ni o n of t he I n vesti gat or, a partici pa n t’s i n di vi d ualize d ris k f or P M L 
re q uires m ore fre q ue nt M RI m o nit ori n g t ha n is perf or me d as part of t his st u d y, a d diti o nal M RIs t o m o nit or f or P M L ma y be perf or me d at t he I n vesti gat or’s 
discreti o n.  
9 F or i ncl usi o n criteria assess me nt, a n M RI fr o m t he partici pa nt’s me dical rec or d wit hi n 1 2 m o nt hs of t he Scree ni n g Visit ca n b e use d. F or all e nr olle d 
partici pa nts, t he scree ni n g M RI m ust ha ve bee n perf or me d wit hi n 4 wee ks pri or t o t he Baseli ne Visit.  
1 0 T o be perf or me d o nl y i n w o me n of c hil d beari n g p ote ntial; res ults m ust be ne gati ve t o c o nti n ue partici pati o n i n st u d y.  
1 1 Sa m ples f or uri ne pre g na nc y test are t o be a nal yze d l ocall y.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S 
 
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 wit h o ut t he writte n c o nse nt of Bi o ge n  M A I nc.  
1 9  
1 2 Bl o o d sa m ple will be c ollecte d bef ore d osi n g.  
1 3 O ne bl o o d sa m ple will be c ollecte d bet wee n Da y 6 a n d Da y 8.  
1 4 If a partici pa nt was e ver teste d pre vi o usl y f or a nti-A Q P 4 a n d a nti -M O G a nti b o dies a n d t he res ults were ne gati ve, t he test d oes n ot ha ve t o be re peate d at 
Scree ni n g. If n ot teste d pre vi o usl y, t he partici pa nt will nee d t o be teste d at Scree ni n g.  
1 5 Partici pa nts s h o ul d be o bser ve d d uri n g b ot h S C i njecti o ns a n d f or 1 h o ur after f or si g ns a n d s y m pt o ms of i njecti o n site react i o ns a n d i njecti o n reacti o ns 
i ncl u di n g h y perse nsiti vit y. After t he first 6 nataliz u ma b d oses, t he 1-h o ur p ost -a d mi nistrati o n o bser vati o n ti me f or s u bse q ue nt S C i njecti o ns ma y be re d uce d or 
re m o ve d acc or di n g t o cli nical j u d ge me nt if t he partici pa nts ha ve n ot e x perie nce d a n y i njecti o n reacti o ns i ncl u di n g h y perse nsiti vit y. 
1 6 All pres pecifie d e val uati o ns m ust be perf or me d pri or t o st u d y treat me nt a d mi nistrati o n at eac h visit.  
 
 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2 0  
2.   
LI S T O F A B B R E VI A TI O N S  
3 T  
3 Tesla  
1. 5 T  
1. 5 Tesla  
A D A  
a nti-dr u g a nti b o d y  
A E  
a d verse e ve nt  
a nti-H Bc  
he patitis B c ore a nti b o d y  
a nti-H Bs  
he patitis B s urface a nti b o d y  
A Q P 4  
a q ua p ori n-4  
A R R  
a n n ualize d rela pse rate  
B L  
baseli ne  
 
 
 
CI  
c o nfi de nce i nter val  
C O VI D -1 9  
c or o na vir us disease 2 0 1 9  
C R O  
c o ntract researc h or ga nizati o n  
C S S  
Cli nical Site S u p p ort  
C -S S R S  
C ol u m bia S uici de Se verit y Rati n g Scale  
C tr o u g h 
tr o u g h c o nce ntrati o n 
C V  
c oefficie nt of variati o n  
D  
da y  
D H A  
Directi o ns f or Ha n dli n g a n d A d mi nistrati o n  
D M T  
disease -m o dif yi n g t hera p y  
E C G  
electr ocar di o gra m  
e C R F  
electr o nic case re p ort f or m  
E D S S  
E x pa n de d Disa bilit y Stat us Scale  
E T  
earl y ter mi nati o n 
E U  
E ur o pea n U ni o n  
F S H  
f ollicle-sti m ulati n g h or m o ne 
F U  
f oll o w-u p  
G C P  
G o o d Cli nical Practice  
H Bs A g  
he patitis B s urface a nti ge n  
H B V  
he patitis B vir us  
 
 
H C V  
he patitis C vir us  
HI V  
h u ma n i m m u n o deficie nc y vir us 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I F N-β  
i nterfer o n beta 
I G R A 
i nterfer o n-ga m ma release assa ys  
I R T 
i nteracti ve res p o nse tec h n ol o g y 
I V 
i ntra ve n o us(l y) 
J C V 
J o h n C u n ni n g ha m vir us ( h u ma n p ol y o ma vir us)  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2 1  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M O G  
m yeli n oli g o de n dr oc yte gl yc o pr otei n  
M RI  
ma g netic res o na nce i ma gi n g  
M S  
m ulti ple scler osis  
P D  
p har mac o d y na mic(s)  
P F S  
prefille d s yri n ge  
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  
Q 4 W  
e ver y 4 wee ks  
R M S  
rela psi n g m ulti ple scler osis 
R R M S  
rela psi n g-re mitti n g m ulti ple scler osis 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S A R S -C o V -2   
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2  
S C  
s u bc uta ne o us(l y) 
S C R  
scree ni n g 
S O C  
s yste m or ga n class 
S P M S  
sec o n dar y pr o gressi ve m ulti ple scler osis 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T B  
t u berc ul osis 
T S E  
tra ns missi ble s p o n gif or m e nce p hal o pat h y 
U L N  
u p per li mit of n or mal 
U S  
U nite d States  
V A S  
vis ual a nal o g scale  
V C A M -1  
vasc ular cell a d hesi o n m olec ule -1  
W  
wee k  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2 2  
3.   
I N T R O D U C TI O N  
Nataliz u ma b  ( T ysa bri) is a rec o m bi na nt, h u ma nize d, a nti-α 4 -i nte gri n m o n ocl o nal a nti b o d y 
c urre ntl y a p pr o ve d as a D M T f or t he treat me nt of M S. Fr o m its ori gi nal a p pr o val i n t he U S i n 
2 0 0 4 t hr o u g h 3 1  J ul y 2 0 2 0, w orl d wi de 2 1 0, 0 7 2 i n di vi d uals ha ve bee n treate d wit h nataliz u ma b, 
wit h a c u m ulati ve e x p os ure of 8 3 3, 8 7 4  pers o n -years.  Nataliz u ma b  3 0 0  m g f or I V i njecti o n was 
a p pr o ve d o n 2 4  Marc h  2 0 1 4 i n Ja pa n. As of 0 7  A u g ust 2 0 1 9, 8 6 6 Ja pa nese patie nts ha ve bee n 
treate d wit h nataliz u ma b.  
3. 1.   
St u d y R ati o n ale  
T he safet y, t olera bilit y, a n d efficac y of I V nataliz u ma b i n Ja pa nese partici pa nts wit h R R M S has 
bee n s h o w n i n a 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 ( St u d y  1 0 1 M S 2 0 3) a n d a 
l o n g-ter m e xte nsi o n st u d y ( St u d y 1 0 1 M S 2 0 4). T he fi n di n gs of t hese st u dies were c o nsiste nt wit h 
t he safet y a n d efficac y pr ofiles o bser ve d i n c o h orts of n o n-Ja pa nese partici pa nts wit h R R M S. 
Des pite t he a vaila bilit y of m ulti ple D M Ts f or patie nts wit h M S, a n u n met nee d e xists f or 
effecti ve treat me nt t hat has m ore c o n ve nie nt mea ns of a d mi nistrati o n f or t he be nefit of patie nts 
a n d   
. T he S C r o ute of a d mi nistrati o n ma y pr o vi de a d diti o nal be nefits t o patie nts a n d 
p h ysicia ns c o m pare d wit h t he I V r o ute (see a d diti o nal details i n Secti o n  3. 3 ). 
T he S p o ns or has de vel o pe d a p har mace utical f or m ulati o n f or S C a d mi nistrati o n i n a P F S t hat 
deli vers nataliz u ma b at a d ose of 1 5 0 m g (i n 1 m L), e na bli n g a t otal d ose of 3 0 0 m g t o be 
deli vere d b y 2 c o nsec uti ve i njecti o ns, Q 4 W. St u dies i n c o h orts of partici pa nts wit h M S ha ve 
s h o w n t hat t his pr o d uct is si milar t o t he I V f or m ulati o n wit h res pect t o its P K a n d P D pr ofile as 
well as its efficac y a n d safet y ( St u dies 1 0 1 M S 1 0 2 a n d 1 0 1 M S 2 0 6).  
T his P hase 3 st u d y will e val uate t he efficac y, safet y, P K, a n d P D of nataliz u ma b 3 0 0  m g Q 4 W 
a d mi nistere d t o Ja pa nese partici pa nts wit h R R M S via a S C r o ute of a d mi nistrati o n.  
3. 1. 1.   
R ati o n ale f or St u d y P o p ul ati o n  
Alt h o u g h t he c o m ple x a n d m ultifact orial pat h o ge nesis of M S is c o nsi dere d t o be ge nerall y 
si milar acr oss Ca ucasia n a n d Asia n p o p ulati o ns, t here are c urre ntl y n o safet y, t olera bilit y, or 
efficac y data of nataliz u ma b S C i n Ja pa nese M S partici pa nts. T heref ore,  a d diti o nal data are 
warra nte d i n t his p o p ulati o n. T his P hase 3 st u d y is desi g ne d t o c ollect data i n Ja pa nese 
partici pa nts wit h M S w h o are treate d wit h nataliz u ma b S C.  
3. 1. 2.   
R ati o n ale f or D osi n g Re gi me n  
T he nataliz u ma b S C d ose selecte d f or t his st u d y ( 3 0 0 m g Q 4 W) is t he a p pr o ve d d ose re gi me n i n 
t he E U f or t he treat me nt of patie nts wit h R M S a n d has bee n selecte d as t he rec o m me n de d d ose 
i n mar keti n g a p plicati o ns t o ot her healt h a ut h orities. 
T he res ults fr o m m o delli n g a n d si m ulati o n a nal ysis of S C a n d I V nataliz u ma b were c o nsiste nt 
wit h t he o utc o mes of t he cli nical st u dies 1 0 1 M S 1 0 2 a n d 1 0 1 M S 2 0 6 a n d de m o nstrate d t hat 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2 3  
a d mi nisteri n g nataliz u ma b 3 0 0  m g S C Q 4 W w o ul d res ult i n a si milar C
tr o u g h val ue a n d P D 
res p o nse as a d mi nisteri n g t he cli nicall y a p pr o ve d 3 0 0 m g I V Q 4 W d ose . T he res ults fr o m t hese 
st u dies s u p p ort t he use of t he S C i njecti o n as a n a d diti o nal r o ute of a d mi nistrati o n f or 
nataliz u ma b at t he sa me d ose le vel as t he c urre nt c o m mercial pr o d uct.  
3. 2.   
B ac k gr o u n d  
3. 2. 1.   
O ver vie w of M ulti ple Scler osis  
M S is a c hr o nic a ut oi m m u ne a n d ne ur o de ge nerati ve dis or der of t he ce ntral ner v o us s yste m t hat 
is c haracterize d b y i nfla m mati o n, de m yeli nati o n, a n d oli g o de n dr oc yte a n d ne ur o nal l oss; it m ost 
fre q ue ntl y prese nts as R R M S. It is o ne of t he m ost c o m m o n pr o gressive ne ur ol o gical diseases i n 
y o u n g a d ults w orl d wi de [C olla b orat ors 2 0 1 9 ; G B D 2 0 1 6 M ulti ple Scler osis C olla b orat ors 2 0 1 9 ]. 
T he t otal n u m ber of pe o ple li vi n g wit h M S w orl d wi de is a p pr o xi matel y 2. 8 milli o n i n di vi d uals 
[Walt o n 2 0 2 0 ]. T he pre vale nce of M S varies b y race a n d ge o gra p h y a n d is l o wer i n Asia t ha n i n 
E ur o pe a n d t he U S [Kira 2 0 0 3 ; R osati 2 0 0 1 ]. M S is a p pr o xi matel y t wice as c o m m o n i n w o me n 
as i n me n a n d pre d o mi na ntl y affects a d ults a ge d 2 0  t o 6 0 years. 
Pre vale nce esti mates of M S i n t he U S ra n ge wi del y fr o m 4 2. 8 per 1 0 0, 0 0 0 t o 1 7 6. 7 per 1 0 0, 0 0 0 
[E va ns 2 0 1 3 ]. T he a vera ge pre vale nce i n t he t otal p o p ulati o n f or E ur o pe is 9 3 per 1 0 0, 0 0 0 
[K o belt a n d Kaste n g 2 0 0 9 ] a n d ra n ges fr o m as l o w as 0. 7 7 t o 1 4. 4 per 1 0 0, 0 0 0 i n East Asia. T he 
M S pre vale nce i n Ja pa n is esti mate d t o be bet wee n 7. 7 a n d 1 4. 4 per 1 0 0, 0 0 0 [Ki n os hita 2 0 1 5 ; 
Ma k ha ni 2 0 1 4 ], w hic h is a p pr o xi matel y 1 0 % of t hat i n E ur o pe a n d t he U S [H ori uc hi a n d Kira 
2 0 0 4 ]. I nci de nce i n Ja pa n has bee n re p orte d as 0. 7 9 a n d 0. 7 8 per 1 0 0, 0 0 0 [Lai a n d Tse n g 2 0 0 9 ; 
Ma k ha ni 2 0 1 4 ]. Base d o n t he real-w orl d data fr o m t he Ja pa n Me dical Data Ce nter C o., Lt d., t he 
a ge-a dj uste d pre vale nce of M S i ncrease d fr o m 0. 0 1 5 % t o 0. 0 1 9 % bet wee n 2 0 1 1 a n d 2 0 1 5. 
[O gi n o 2 0 1 7 ].   
See t he I n vesti gat or’s Br oc h ure f or a d diti o nal i nf or mati o n o n M S pat h o p h ysi ol o g y a n d 
prese ntati o n.  
3. 2. 2.   
C urre nt T her a pies f or M ulti ple Scler osis  
T he c urre nt sta n dar d of cli nical care i n t he treat me nt of R M S e m pl o ys 2 c o m ple me ntar y 
a p pr oac hes: ( 1)  t he use of i m m u n o m o d ulat or y dr u gs t o re d uce t he fre q ue nc y a n d se verit y of 
rela pses a n d acc u m ulati o n of p h ysical disa bilit y; a n d ( 2) t he use of dr u gs t hat pr o vi de 
s y m pt o matic treat me nt as nee de d f or de pressi o n, bla d der d ysf u ncti o n, a n d wal ki n g i m pair me nt. 
Im m u n o m o d ulat or y dr u gs c urre ntl y a vaila ble f or R M S i ncl u de i nterfer o n -beta pr o d ucts 
( A v o ne x, Re bif, Betaser o n, Betafer o n, E xta via, a n d Ple gri d y), glatira mer acetate ( C o pa x o ne), 
terifl u n o mi de * ( A u ba gi o), di met h yl f u marate ( Tecfi dera), m o n o met h yl f u marate * ( Bafierta m), 
nataliz u ma b ( T ysa bri), ale mt uz u ma b * ( Le mtra da), mit o xa ntr o ne * ( N o va ntr o ne), cla dri bi ne * 
( Ma ve ncla d), dir o xi mel f u marate * ( V u merit y), s p hi n g osi ne-1 -p h os p hate rece pt or m o d ulat ors 
(fi n g oli m o d [ Gile n ya], si p o ni m o d [ Ma yze nt], oza ni m o d [ Ze p osia], a n d p o nesi m o d * [ P o n v or y]), 
a n d B-cell-de pleti n g t hera pies ( ocreliz u ma b * [ Ocre v us] or ofat u m u ma b [ Kesi m pta]).  
[ N ote: Dr u gs m arke d wit h " *" are n ot a p pr ove d f or M S tre at me nt i n J a p a n.] 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2 4  
3. 2. 3.   
Pr ofile of Pre vi o us E x perie nce Wit h N at aliz u m a b  
Nataliz u ma b I V has bee n use d e xte nsi vel y i n R R M S, 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.  
T he efficac y of nataliz u ma b I V i n partici pa nts 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 safet y 
st u dies. T hese st u dies s h o w t hat treat me nt wit h nataliz u ma b I V has a pr of o u n d i m pact o n 
disa bilit y w orse ni n g a n d rela pse rate a n d mar ke dl y atte n uates brai n M RI meas ures of 
i nfla m mati o n a n d tiss ue destr ucti o n i n partici pa nts wit h rela psi n g f or ms of M S. M ore o ver, t he 
data i n dicate t hat efficac y is realize d earl y a n d per sists t hr o u g h o ut t he Treat me nt Peri o d. 
T he safet y, t olera bilit y, a n d efficac y of nataliz u ma b I V i n Ja pa nese partici pa nts wit h R R M S has 
bee n s h o w n i n a 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 ( St u d y  1 0 1 M S 2 0 3 ) a n d a 
l o n g-ter m e xte nsi o n st u d y ( St u d y 1 0 1 M S 2 0 4 ). T he fi n di n gs of t hese st u dies were c o nsiste nt wit h 
t he safet y a n d efficac y pr ofiles o bser ve d i n c o h orts of n o n-Ja pa nese partici pa nts wit h R R M S. 
T he res ults fr o m St u dies  1 0 1 M S 1 0 2 a n d 1 0 1 M S 2 0 6 s u g gest t hat t he efficac y a n d safet y pr ofiles 
of nataliz u ma b S C is si milar t o t hat of nataliz u ma b I V.  
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. 
3. 3.   
Be nefit -Ris k Assess me nt  
Wit h o ver 1 7  years of e x perie nce i n t he p ost mar keti n g setti n g, nataliz u ma b I V c o nti n ues t o 
de m o nstrate a hi g h le vel of efficac y wit h a well -c haracterize d safet y pr ofile a n d a si g nifica nt 
be neficial i m pact o n t he q ualit y of life i n patie nts wit h R R M S. I n pi v otal cli nica l st u dies, 
nataliz u ma b I V de m o nstrate d a 6 7 %  re d ucti o n i n A R R a n d a 4 2 % re d ucti o n i n t he ris k of 
disa bilit y pr o gressi o n o ver 2  years. Si nce t he mar keti n g of nataliz u ma b, p u blicati o ns fr o m 
m ulti ple i n de pe n de nt gr o u ps, as well as p u blicati o ns fr o m t he S p o ns or, ha ve f urt her 
de m o nstrate d t he cli nical effecti ve ness of nataliz u ma b w he n use d i n patie nts w h o ha ve M S wit h 
hi g h disease acti vit y des pite treat me nt wit h first -li ne t hera pies [Belac he w 2 0 1 1 ; M orr o w 2 0 1 0 ; 
Ot urai 2 0 0 9 ; Sa n galli 2 0 1 1 ]. 
E xte nsi ve safet y data fr o m cli nical st u dies a n d t he p ost mar keti n g setti n g ha ve res ulte d i n a 
well -c haracterize d safet y pr ofile f or nataliz u ma b I V. I nf usi o n a n d h y perse nsiti vit y reacti o ns a n d 
a nti-nataliz u ma b a nti b o d y pr o d ucti o n are i m p orta nt safet y c o ncer n s; h o we ver, t he y are 
ma na gea ble i n r o uti ne cli nical practice. Seri o us, life -t hreate ni n g, a n d s o meti mes fatal cases of 
e nce p halitis a n d me ni n gitis ca use d b y her pes si m ple x or varicella z oster ha ve bee n re p orte d i n 
M S patie nts recei vi n g nataliz u ma b. I n p ost m ar keti n g e x perie nce, t here ha ve bee n rare re p orts of 
cli nicall y si g nifica nt li ver i nj ur y.  
T he m ost i m p orta nt A E affecti n g nataliz u ma b be nefit -ris k assess me nt is t he occ urre nce of P M L. 
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 a n d are c urre ntl y 
i ncl u de d i n t he pr o d uct la beli n g: t hat P M L ris k is i ncrease d wit h t he prese nce of a nti-J C V 
a nti b o dies, treat me nt d urati o n (es peciall y be y o n d 2  years of t hera p y), a n d pri or use of a n 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2 5  
i m m u n os u p pressa nt t hera p y. T hese 3 ris k fact ors, as well as i nf or mati o n a b o ut a nti-J C V 
a nti b o d y i n de x i n a nti -J C V a nti b o d y-p ositi ve patie nts wit h o ut a n y pri or i m m u n os u p pressa nt use, 
ca n be utilize d t o f urt her stratif y t he ris k of P M L a n d t heref ore pr o vi de a n i m p orta nt t o ol f or 
p h ysicia ns a n d patie nts w he n ma ki n g i n di vi d ual be nefit -ris k decisi o ns re gar di n g i nitiati o n or 
c o nti n uati o n of nataliz u ma b t hera p y.  
T he S C r o ute of a d mi nistrati o n ma y pr o vi de a d diti o nal be nefits t o patie nts a n d p h ysicia ns b y 
offeri n g a less i n vasi ve r o ute of a d mi nistrati o n, l o wer c o m ple xit y, a n d re d uce d ti me re q uire d at 
eac h treat me nt visit c o m pare d wit h I V i nf usi o n [Des pia u 2 0 1 7 ; L o pez -Vi va nc o 2 0 1 7 ]. T here is 
e vi de nce fr o m ot her me dical c o n diti o ns a n d i n dicati o ns t hat patie nts prefer S C t o I V r o ute of 
a d mi nistrati o n base d o n c o n ve nie nce a n d data fr o m q ualit y -of -life meas ure me nts [Fala n ga 2 0 1 9 ; 
Pi v ot 2 0 1 3 ; Sa nt us 2 0 1 9 ; S yri os 2 0 1 8 ]. T he ec o n o mic a n d c ost -sa vi n g be nefits of S C vers us I V 
r o ute of a d mi nistrati o n i n t he h os pital setti n g ha ve bee n de m o nstrate d [Far olfi 2 0 1 7 ; L o pez -
Vi va nc o 2 0 1 7 ; Olse n 2 0 1 8 ]. 
T he safet y pr ofile o bser ve d f or nataliz u ma b a d mi nistere d S C was c o nsiste nt wit h t he k n o w n 
safet y pr ofile of nataliz u ma b a d mi nistere d I V, wit h t he e xce pti o n of i njecti o n site pai n. D uri n g 
t he 2 S C cli nical st u dies ( St u dies 1 0 1 M S 1 0 2 a n d 1 0 1 M S 2 0 6), i njecti o n site pai n was re p orte d i n 
4 % ( 3 of 7 1) of partici pa nts recei vi n g nataliz u ma b 3 0 0 m g S C Q 4 W a n d n o partici pa nts 
recei vi n g nataliz u ma b 3 0 0 m g I V Q 4 W re p orte d i njecti o n site pai n. 
T he p ote ntial ris ks relate d t o partici pati o n i n t his st u d y are j ustifie d b y t he a ntici pate d be nefit t o 
partici pa nts.  
Detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y e x pecte d 
A Es of nataliz u ma b S C is pr o vi de d i n t he I n vesti gat or’s Br oc h ure a n d I C F. A hi g h -le vel 
s u m mar y of t h ose be nefits a n d ris ks k n o w n d uri n g st u d y desi g n is pr o vi de d he re.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2 7  
•  Pr o p orti o n of rela pse -free partici pa nts at 
Wee k  2 4 a n d Wee k 5 2  
•  V A S assessi n g t he partici pa nt’s gl o bal 
i m pressi o n of t heir well-bei n g at Wee k 2 4 a n d 
Wee k 4 8  
T o e val uate t he safet y, t olera bilit y, a n d 
i m m u n o ge nicit y of nataliz u ma b 
3 0 0  m g S C Q 4 W a d mi nistrati o ns u p t o 
4 8 wee ks i n Ja pa nese partici pa nts wit h 
R R M S  
•  I nci de nce of treat me nt-e mer ge nt A Es a n d S A Es 
fr o m Baseli ne t o e n d of st u d y 
•  A nti -J C V a nti b o d y stat us as meas ure d b y 
a nti-J C V a nti b o dies 
•  I nci de nce of i njecti o n site reacti o ns a n d 
i njecti o n reacti o ns 
•  I m m u n o ge nicit y as meas ure d b y t he i nci de nce 
of a nti -nataliz u ma b a nti b o dies  
•  C ha n ge i n E D S S sc ore fr o m Baseli ne t o 
Wee k  2 4  
•  C ha n ge i n E D S S sc ore fr o m Baseli ne t o 
Wee k  4 8  
T o e val uate t he P K a n d P D of 
nataliz u ma b 3 0 0  m g S C Q 4 W 
a d mi nistrati o ns u p t o 2 4  wee ks a n d f or 
a n a d diti o nal 2 4 wee ks i n Ja pa nese 
partici pa nts wit h R R M S  
•  Ser u m nataliz u ma b c o nce ntrati o ns ( C tr o u g h) at 
eac h visit u ntil Wee k 4 8  
•  Ser u m nataliz u ma b c o nce ntrati o n bet wee n 
Da y  6 a n d Da y  8  
•  α 4 -i nte gri n sat urati o n a n d ser u m s ol u ble 
V C A M -1 c o nce ntrati o ns at eac h visit u ntil 
Wee k  4 8 (e xcl u di n g Wee k 1 [ Da y 6 t o Da y 8] 
visit)  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2 8  
 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2 9  
5.   
S T U D Y D E SI G N  
5. 1.   
St u d y O ver vie w  
T his is a m ultice nter, o pe n -la bel, si n gle-ar m P hase 3 st u d y t o e val uate t he efficac y, safet y, 
t olera bilit y, P K, a n d P D of nataliz u ma b S C f or m ulati o n i n Ja pa nese partici pa nts wit h R R M S. 
T he st u d y will be c o n d ucte d at a p pr o xi matel y 1 0 sites i n Ja pa n. T he st u d y will ha ve 2 parts a n d 
e nr oll a p pr o xi matel y 2 0 partici pa nts, w h o will recei ve nataliz u ma b 3 0 0  m g S C Q 4 W.  
Part 1 is desi g ne d f or a peri o d of 2 4 wee ks t o i ncl u de t he efficac y, safet y, t olera bilit y, P K, a n d 
P D e val uati o n of nataliz u ma b S C f or m ulati o n.  
Part 2 is desi g ne d f or a n a d diti o nal peri o d of 2 4 wee ks t o i ncl u de efficac y a n d safet y 
assess me nts. A d diti o nall y, si milar assess me nts, i ncl u di n g safet y, P K, a n d P D, will be assesse d 
after 
 i n Part 2 t o c o nfir m t he usa bilit y of a 
 of nataliz u ma b S C.  
At t he c o m pleti o n of t heir 4 8 -wee k Treat me nt Peri o d, partici pa nts will ha ve Safet y F oll o w -U p 
Visit at Wee k 5 2 a n d will recei ve a f oll o w -u p safet y p h o ne call at Wee k  6 0 a n d Wee k  7 2 (i.e., 
1 2  a n d 2 4 wee ks after t he last d ose of st u d y treat me nt o n Wee k 4 8, res pecti vel y) bef ore 
c o m pleti n g t he st u d y.  
See Fi g ure  1  f or a sc he matic of t he st u d y desi g n. 
5. 2.   
St u d y D ur ati o n f or P artici p a nts  
T he t otal st u d y d urati o n f or eac h partici pa nt will be u p t o 7 6  wee ks:  
•  4 -wee k Scree ni n g Peri o d  
•  2 4 -wee k Treat me nt Peri o d i n Part 1  
•  2 4 -wee k Treat me nt Peri o d i n Part 2  
•  4 -wee k Safet y F oll o w -U p Peri o d  
•  F oll o w -u p safet y p h o ne call s 1 2 a n d 2 4 wee ks after t he last d ose  
Partici pa nts will ha ve u p t o 1 6 sc he d ule d visits d uri n g t he st u d y a n d 2 safet y f oll o w -u p p h o ne 
calls. All visits s h o ul d be perf or me d ±  3 t o 1 0  da ys fr o m t he n o mi nal visit da y. Visit da ys are 
calc ulate d wit h res pect t o Da y 1 (t he date of first d ose).   
T he e n d of st u d y date f or a partici pa nt ma y be t he last st u d y visit, last f oll o w -u p tele p h o ne 
c o n versati o n, or last pr ot oc ol -s pecifie d assess me nt, or if t he partici pa nt has o n g oi n g A Es t hat are 
bei n g f oll o we d, t he date ma y be t he date of A E res ol uti o n or t he date t he A E bec o mes sta ble at 
discreti o n of t he I n vesti gat or.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 0  
5. 3.   
St u d y St o p pi n g R ules  
T he S p o ns or ma y ter mi nate t his st u d y, after i nf or mi n g I n vesti gat ors, at a n y ti me. T he S p o ns or 
will n otif y I n 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.  
If occ urre nce of a n y of t he f oll o wi n g at le vels greater t ha n e x pecte d f or t he a p pr o ve d d osi n g 
re gi me n ( 3 0 0 m g nataliz u ma b I V Q W 4) is detecte d, st u d y treat me nt d osi n g will be st o p pe d: 
•  a nti-nataliz u ma b a nti b o dies  
•  h y perse nsiti vit y reacti o ns  
•  st u d y treat me nt a d mi nistrati o n reacti o ns 
•  M S disease acti vit y  
5. 4.   
U nsc he d ule d Visits a n d Tre at me nt f or M S Rel a pses  
Data c ollecte d d uri n g u nsc he d ule d visits s h o ul d be rec or de d o n e C R Fs o nl y if t he data s u p p ort 
pr ot oc ol o bjecti ves a n d/ or are re q uire d f or safet y m o nit ori n g.  
If a n M S rela pse is s us pecte d d uri n g t he st u d y, t he partici pa nts s h o ul d ret ur n t o t he st u d y site f or 
a n u nsc he d ule d visit a n d be e val uate d as s o o n as p ossi ble ( wit hi n 5  da ys after o nset of t he e ve nt) 
f or c o nfir mati o n a n d t o deter mi ne t he se verit y of t he rela pse. Rela pses will be d oc u me nte d i n t he 
rela pse assess me nt f or m. 
A n M S rela pse will be defi ne d as t he o nset of ne w or rec urre nt ne ur ol o gical s y m pt o ms lasti n g at 
least 2 4 h o urs, acc o m pa nie d b y ne w o bjecti ve a b n or malities o n a ne ur ol o gical e xa mi nati o n, a n d 
n ot e x plai ne d s olel y b y n o n -M S pr ocesses s uc h as fe ver, i nfecti o n, se vere stress, or dr u g t o xicit y 
(a da pte d fr o m [Sc h u mac her 1 9 6 5 ]). 
T he u nsc he d ule d visit f or ne ur ol o gical w orse ni n g a n d rela pse assess me nt s h o ul d n ot m o dif y or 
re place t he partici pa nts’ visit sc he d ule. If a partici pa nt’s st u d y M RI is sc he d ule d t o occ ur 
<  4  wee ks after t he last d ose of ster oi d treat me nt f or rela pse, t he M RI s h o ul d be resc he d ule d s o 
t hat it is perf or me d eit her bef ore t he ster oi d treat me nt or bet wee n 4 a n d 8 wee ks after t he last 
d ose of ster oi d treat me nt. M RI d oes n ot nee d t o be perf or me d at t h e E T Visit if t he pre vi o us M RI 
was perf or me d wit hi n t he pre vi o us 4  wee ks.  
Ne w or rec urre nt ne ur ol o gical s y m pt o ms t hat occ ur < 3 0  da ys after t he o nset of a 
pr ot oc ol -defi ne d rela pse s h o ul d be c o nsi dere d as part of t he sa me rela pse. Ne w or rec urre nt 
ne ur ol o gic s y m pt o ms t hat e v ol ve gra d uall y o ver m o nt hs s h o ul d be c o nsi dere d disa bilit y 
pr o gressi o n, n ot a n ac ute rela pse, a n d s h o ul d n ot be  treate d wit h hi g h-d ose c ortic oster oi ds. 
La b orat or y tests t o i n vesti gate p ossi ble ca uses of pse u d orela pse ca n be d o ne at t he discreti o n of 
t he I n vesti gat or. 
A n u nsc he d ule d visit f or a s us pecte d rela pse s h o ul d be rec or de d at a Ne ur ol o gical W orse ni n g 
a n d Rela pse Assess me nt Visit, wit h t he rela pse re p orte d o n t he rela pse assess me nt f or m a n d n ot 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 1  
re p orte d as a n A E. A brai n M RI s h o ul d be perf or me d bef ore treat me nt of a pr ot oc ol-defi ne d 
rela pse. Treat me nt of a pr ot oc ol-defi ne d rela pse ma y pr ocee d at t he discreti o n of t he I n vesti gat or 
acc or di n g t o l ocal sta n dar d of care a n d will n ot affect t he partici pa nt’s eli gi bilit y t o c o nti n ue i n 
t he st u d y. At t he discreti o n of t he I n vesti gat or, treat me nt ma y i ncl u de met h yl pre d nis ol o ne 
1 0 0 0  m g I V a d mi nistere d dail y f or 3 t o 5 da ys wit h or wit h o ut a n oral pre d nis o ne ta per ( u p t o 
1 5  da ys).  
5. 5.   
E n d of St u d y  
T he e n d of st u d y is last partici pa nt, last visit f or fi nal c ollecti o n of data.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 2  
6.   
S T U D Y P O P U L A TI O N  
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 Da y  1 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.  
6. 1.   
I ncl usi o n Criteri a 
1.  A bilit y of t he partici pa nt a n d/ or his/ her le gall y a ut h orize d re prese ntati ve (e. g., pare nt, 
s p o use, or le gal g uar dia n), as a p pr o priate a n d a p plica ble, 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, t o pr o vi de i nf or me d c o nse nt, a n d t o a ut h orize t he use of 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 pri vac y re g ulati o ns.  
2.  Ja pa nese me n a n d w o me n a ge d 1 8 t o 6 5 years, i ncl usi ve, at t he ti me of i nf or me d c o nse nt. 
F or partici pa nts a ge d < 2 0 years *, writte n i nf or me d c o nse nt s h o ul d be o btai ne d fr o m t he 
partici pa nt a n d his or her le gall y acce pta ble re prese ntati ve.  
* I nf or me d c o nse nt fr o m a le gall y acce pta ble re prese ntati ve is n ot ma n dat or y if t he 
partici pa nt is classifie d as a n a d ult base d o n t he latest a p plica ble l ocal la ws.  
3.  M ust ha ve ha d a dia g n osis of R R M S, as defi ne d b y t he re vise d 2 0 1 7 Mc D o nal d’s criteria 
[L u bli n 2 0 1 4 ; T h o m ps o n 2 0 1 8 ]. All ot her p ossi ble ne ur ol o gic dia g n oses m ust ha ve bee n 
reas o na bl y e xcl u de d b y mea ns of la b orat or y a n d/ or i ma gi n g st u dies, i n t he o pi ni o n of t he 
I n vesti gat or. 
4.  M ust ha ve ha d a n E D S S sc ore bet wee n 0. 0 a n d 5. 5, i ncl usi ve.  
5.  M ust ha ve e x perie nce d at least 1 me dicall y d oc u me nte d cli nical e xacer bati o n wit hi n 
1 2  m o nt hs of e nr oll me nt ( Da y  1).  
6.  M ust ha ve ha d scree ni n g M RI or d oc u me ntati o n of a n M RI wit hi n t he partici pa nt’s 
me dical rec or d wit hi n 1 2 m o nt hs of t he Scree ni n g Visit t hat re veale d 3 or m ore T 2 
h y peri nte nse lesi o ns c o nsiste nt wit h M S.  
7.  M ust be willi n g t o re mai n free fr o m c o nc o mita nt i m m u n os u p pressi ve or 
i m m u n o m o d ulat or y treat me nt (i ncl u di n g I F N-β a n d c hr o nic s yste mic c ortic oster oi ds) 
w hile recei vi n g st u d y treat me nt a n d f or at least 1 2 wee ks after t he last d ose of st u d y 
treat me nt. Treat ment wit h nataliz u ma b I V is all o we d after Wee k 5 2.  
8.  All w o me n of c hil d beari n g p ote ntial m ust practice c o ntrace pti o n as descri be d i n 
Secti o n  1 1. 5 .  
9.  Was b or n i n Ja pa n, a n d bi ol o gical pare nts a n d gra n d pare nts were of Ja pa nese ori gi n.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 3  
6. 2.   
E xcl usi o n Criteri a  
Me dical Hist or y a n d C urre nt Healt h Stat us  
1.  E vi de nce of c urre nt S A R S -C o V -2 i nfecti o n wit hi n 1 4 da ys pri or t o Scree ni n g, bet wee n 
Scree ni n g a n d Baseli ne Visit, or at Baseli ne Visit, i ncl u di n g b ut n ot li mite d t o a fe ver 
(te m perat ure > 3 7. 5° C), ne w a n d persiste nt c o u g h, breat hless ness, or l oss of taste a n d/ or 
s mell. 
N ote: If a S A R S -C o V -2 test ( p ol y merase c hai n reacti o n or ot her re g ulat or y 
a p pr o ve d met h o d) is perf or me d per t he discreti o n of t he I n vesti gat or i n 
acc or da nce wit h l ocal site practice, t he test res ult m ust be ne gati ve i n or der f or t he 
partici pa nt t o be e nr olle d i n t he st u d y.    
2.  Ha ve cl ose c o ntact wit hi n 1 4  da ys pri or t o Da y 1 wit h a S A R S -C o V -2 – p ositi ve 
i n di vi d ual. Cl ose c o ntact is defi ne d as: 
a. face-t o-face c o ntact wit h a pr o ba ble or c o nfir me d case wit hi n 1 meter a n d f or at least 
1 5 mi n utes;  
b.  direct p h ysical c o ntact wit h a pr o ba ble or c o nfir me d case;  
c. direct care f or a patie nt wit h pr o ba ble or c o nfir me d C O VI D -1 9 disease wit h o ut t he 
use of rec o m me n de d pers o nal pr otecti ve e q ui p me nt; or  
d.  ot her sit uati o ns as i n dicate d b y l ocal ris k assess me nts.  
3.  Hist or y or p ositi ve test res ult at Scree ni n g f or HI V. T he re q uire me nt f or testi n g at 
Scree ni n g ma y be o mitte d if it is n ot per mitte d b y l ocal re g ulati o ns.  
4.  Dia g n osis of pri mar y pr o gressi ve M S or sec o n dar y pr o gressi ve M S.  
5.  Dia g n osis or hist or y of ne ur o m yelitis o ptica s pectr u m dis or ders, e. g., a l o n g s pi nal lesi o n 
e xte n di n g o ver 3 or m ore verte bral b o dies was detecte d, or a hist or y of p ositi ve tests f or 
a nti-A Q P 4 or a nti -M O G a nti b o dies.  
6.  A n M S e xacer bati o n (rela pse) wit hi n 3 0 da ys pri or t o e nr oll me nt or, i n t he o pi ni o n of t he 
I n vesti gat or, t he partici pa nt n ot ha vi n g sta bilize d fr o m a pre vi o us rela pse pri or t o 
e nr oll me nt ( Da y 1).  
7.  Hist or y of he patitis C i nfecti o n or p ositi ve test res ult at Scree ni n g f or H C V a nti b o d y.  
8.  C urre nt he patitis B i nfecti o n ( defi ne d as p ositi ve f or H Bs A g a n d/ or t otal a nti -H Bc). 
Partici pa nts wit h i m m u nit y t o he patitis B fr o m pre vi o us nat ural i nfecti o n ( defi ne d as 
ne gati ve H Bs A g, p ositi ve a nti -H Bc, a n d p ositi ve a nti -H Bs) or vacci nati o n ( defi ne d as 
ne gati ve H Bs A g, ne gati ve a nti -H Bc, a n d p ositi ve a nti -H Bs) are eli gi ble t o partici pate i n 
t he st u d y.   
9.  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) 
wit hi n t he 3 0 da ys pri or t o e nr oll me nt ( Da y  1).  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 4  
1 0.  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 hi n 1 4 da ys pri or t o Scree ni n g or d uri n g t he scree ni n g peri o d ( Da y -2 8 t o 
Da y  -1). Partici pa nts wit h l ocal f u n gal i nfecti o n (e. g., ca n di diasis, ti nea) are eli gi ble t o be 
rescree ne d after s uccessf ul treat me nt of t he i nfecti o n.   
1 1.  Hist or y of h y perse nsiti vit y reacti o n t o t he e xci pie nts c o ntai ne d i n t he f or m ulati o n a n d a n y 
dia g n ostic a ge nts (i ncl u di n g ga d oli ni u m) t o be a d mi nistere d d uri n g t he st u d y.  
1 2.  Hist or y of, or o n g oi n g, mali g na nt disease, i ncl u di n g s oli d t u m ors a n d he mat ol o gic 
mali g na ncies ( wit h t he e xce pti o n of basal cell carci n o mas a n d s q ua m o us cell carci n o mas 
t hat ha ve bee n c o m pletel y e xcise d a n d c o nsi dere d c ure d at least 1 2 m o nt hs pri or t o 
Da y  -1).  
1 3.  Hist or y of, or a vaila ble a b n or mal la b orat or y res ults i n dicati ve of a n y si g nifica nt car diac, 
e n d ocri n ol o gic, he mat ol o gic, he patic, i m m u n ol o gic, meta b olic, ur ol o gic, p ul m o nar y, 
gastr oi ntesti nal, der mat ol o gic, ps yc hiatric (i ncl u di n g maj or de pressi o n), re nal, a n d/ or a n y 
ot her maj or disease or k n o w n dr u g h y perse nsiti vit y t hat, i n t he o pi ni o n of t he 
I n vesti gat or, w o ul d precl u de t he a d mi nistrati o n of a rec o m bi na nt h u ma nize d a nti b o d y 
i m m u n o m o d ulati n g a ge nt f or t he c o urse of t he st u d y. T he I n vesti gat or m ust re vie w the 
partici pa nt’s me dical fit ness f or partici pati o n a n d c o nsi der a n y disease t hat w o ul d 
precl u de treat me nt.  
1 4.  Hist or y of tra ns pla ntati o n a n d a nti -rejecti o n t hera p y. 
1 5.  Hist or y of P M L.  
1 6.  S yst olic bl o o d press ure > 1 5 0 m m H g or < 9 0 m m H g after re mai ni n g i n t he sa me b o d y 
p ositi o n (seate d or s u pi ne) f or 5 mi n utes at Scree ni n g or pri or t o a d mi nistrati o n of t he 
first d ose. If o ut of ra n ge, testi n g ma y be re peate d o nce at Scree ni n g a n d o nce pri or t o 
d osi n g. Partici pa nt m ust n ot be d ose d if t he re peate d val ue is still o ut of ra n ge.  
1 7.  Cli nicall y si g nifica nt (as deter mi ne d b y t he I n vesti gat or) 1 2 -lea d E C G a b n or malities. 
1 8.  C o nfir me d de m o nstrati o n of c orrecte d Q T i nter val, usi n g Fri dericia’s c orrecti o n met h o d, 
of >  4 5 0 ms f or males a n d > 4 6 0 ms f or fe males.  
1 9.  Hist or y of alc o h ol or s u bsta nce a b use (as deter mi ne d b y t he I n vesti gat or), a p ositi ve 
dr u g/alc o h ol test at Scree ni n g, alc o h ol use wit hi n 4 8 h o urs pri or t o e nr oll me nt ( Da y  1), or 
a n u n willi n g ness t o refrai n fr o m alc o h ol, or illicit or recreati o nal dr u gs, d uri n g t he st u d y.  
2 0.  A partici pa nt w h o is p ositi ve or u ncertai n of bei n g p ositi ve f or T B * wit hi n 3 0 da ys of 
Da y 1.  
* N ote: Partici pa nts wit h f oll o wi n g I G R A test res ults will be e xcl u de d:  
T -s p ot T B test: p ositi ve or 2 s uccessi ve b or derli ne/i n vali d test res ults  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 5  
Q ua nti F E R O N -T B G ol d Pl us test: p ositi ve or 2 s uccessi ve i n deter mi nate test res ults  
2 1.  T he partici pa nt is c o nsi dere d b y t he I n vesti gat or t o be i m m u n oc o m pr o mise d (e. g., 
l y m p h o pe nic), base d o n me dical hist or y (e. g., o p p ort u nistic i nfecti o ns), p h ysical 
e xa mi nati o n, or la b orat or y testi n g (e. g., w hite bl o o d cell).  
2 2.  T he partici pa nt is u na ble t o ha ve a brai n M RI sca n (e. g., a partici pa nt wit h a metal cli p t o 
re pair a cere bral a ne ur ys m). 
Me dicati o ns  
2 3.  Pre vi o us e x p os ure t o nataliz u ma b.  
2 4.  Pre vi o us treat me nt wit h a n y of t he f oll o wi n g: t otal l y m p h oi d irra diati o n, cla dri bi ne, 
T -cell or T-cell rece pt or vacci nati o n, he mat o p oietic ste m cell t hera p y, or ale mt uz u ma b.  
2 5.  Treat me nt wit h i m m u n os u p pressa nt me dicati o ns, e. g., azat hi o pri ne, c ycl o p h os p ha mi de, 
a n d met h otre xate wit hi n 6 m o nt hs pri or t o e nr oll me nt ( Da y  1); mit o xa ntr o ne a n d 
c ycl os p ori ne wit hi n 1 2  m o nt hs pri or t o e nr oll me nt ( Da y  1).  
2 6.  Treat me nt wit h a n y of t he f oll o wi n g me dicati o ns or pr oce d ures wit hi n 6 m o nt hs pri or t o 
e nr oll me nt ( Da y  1): I V i m m u n o gl o b uli n, plas ma p heresis, or c yta p heresis.  
2 7.  Treat me nt wit h a n y of t he f oll o wi n g me dicati o ns wit hi n 3 0 da ys pri or t o e nr oll me nt 
( Da y 1):  
a. I V c ortic oster oi d treat me nt 
b.  S yste mic c ortic oster oi d treat me nt  
c. 4 -A mi n o p yri di ne or relate d pr o d ucts  
2 8.  Treat me nt wit h s p hi n g osi ne 1 -p h os p hate rece pt or m o d ulat ors (fi n g oli m o d, si p o ni m o d, or 
oza ni m o d) wit hi n 9 0  da ys pri or t o e nr oll me nt ( Da y  1).  
2 9.  Treat me nt wit h f u marates ( F u ma der m, Tecfi dera, or V u merit y) wit hi n 4 wee ks pri or t o 
e nr oll me nt ( Da y  1).  
3 0.  B -cell-tar gete d t hera pies f or t he treat me nt of M S (e. g., ocreliz u ma b, rit u xi ma b, 
ofat u m u ma b) wit hi n 1 2 m o nt hs of Scree ni n g; greater t ha n 1 2 m o nt hs of Scree ni n g is 
per missi ble wit h e vi de nce t hat t he C D 1 9 cells ha ve ret ur ne d t o wit hi n n or mal ra n ge ( per 
l ocal la b orat or y refere nce ra n ge). 
3 1.  Treat me nt wit h i m m u n o m o d ulat or y me dicati o ns (i ncl u di n g I F N -β a n d glatira mer acetate) 
wit hi n 2  wee ks of e nr oll me nt ( Da y  1).  
3 2.  A d mi nistrati o n of a n y li ve -atte n uate d vacci ne gi ve n wit hi n 3 0  da ys pri or t o Da y  -1 or 
pla n ne d t o be gi ve n d uri n g st u d y partici pati o n.  
Ot her  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 6  
3 3.  Bl o o d d o nati o n ( 1 u nit or m ore) wit hi n 9 0 da ys pri or t o Scree ni n g, plas ma d o nati o n fr o m 
1 wee k pri or t o Scree ni n g, a n d platelet d o nati o n fr o m 6 wee ks pri or t o Scree ni n g.  
3 4.  Cli nicall y si g nifica nt a b n or mal la b orat or y test val ues, as deter mi ne d b y t he I n vesti gat or, 
d uri n g t he scree ni n g peri o d  ( Da y -2 8 t o Da y  -1).  
3 5.  A b n or mal scree ni n g li ver f u ncti o n test res ults: ala ni ne a mi n otra nsferase or as partate 
a mi n otra nsferase > 2 × U L N or bilir u bi n > 1. 5 × U L N d uri n g Scree ni n g.  
3 6.  Pla ns t o u n der g o electi ve pr oce d ures or s ur geries at a n y ti me after si g ni n g t he I C F 
t hr o u g h t he Safet y F oll o w-U p Visit.  
3 7.  Partici pa nts w h o are pre g na nt or c urre ntl y breastfee di n g a n d t h ose i nte n di n g t o bec o me 
pre g na nt d uri n g t he st u d y.  
3 8.  C urre nt e nr oll me nt or a pla n t o e nr oll i n a n y 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 p y f or i n vesti gati o nal use is a d mi nistere d 
wit hi n 6 m o nt hs pri or t o t he Baseli ne Visit.   
3 9.  I na bilit y t o c o m pl y wit h st u d y re q uire me nts. 
4 0.  Ot her u ns pecifie d reas o ns t hat, i n t he o pi ni o n of t he I n vesti gat or or t he S p o ns or, ma ke t he 
partici pa nt u ns uita ble f or e nr oll me nt.  
6. 3.   
Scree ni n g, Retesti n g, a n d Scree n F ail ures  
6. 3. 1.   
Scree ni n g  
O nce i nf or me d c o nse nt is o btai ne d, scree ni n g assess me nts ca n occ ur. At t his ti me, a u ni q ue 
i de ntificati o n n u m ber is assi g ne d t hat will be use d o n st u d y-relate d d oc u me nts pertai ni n g t o t he 
partici pa nt. A n y i de ntificati o n n u m bers t hat are assi g ne d will n ot b e re use d e ve n if t he 
partici pa nt d oes n ot recei ve treat me nt or c o nti n ue i n t he st u d y. St u d y sites are re q uire d t o 
d oc u me nt all scree ne d partici pa nts i nitiall y c o nsi dere d f or i ncl usi o n i n t he st u d y.  
6. 3. 2.   
Retesti n g  
Partici pa nts w h o fail scree ni n g criteria beca use of a n o ut -of -ra n ge res ult t hat is n ot cli nicall y 
si g nifica nt ca n be reteste d o nce at t he discreti o n of t he I n vesti gat or. Partici pa nts w h o ha ve 
cli nicall y si g nifica nt a b n or mal la b orat or y test val ues s h o ul d n o t be reteste d. T he Scree ni n g 
Peri o d ma y be e xte n de d f or eli gi ble i n di vi d uals w h o ca n n ot c o m plete t he Da y  1 Visit wit hi n 
2 8  da ys of si g ni n g t he I C F. I n di vi d uals w h o si g ne d t he I C F a n d s u bse q ue ntl y d o n ot meet 
c o nc o mita nt me dicati o n criteria ca n ha ve t heir S cree ni n g Peri o d e xte n de d t o e ns ure t he 
re q uire me nts f or c o nc o mita nt me dicati o n sta bilizati o n ha ve bee n met. 
If a partici pa nt i nitiall y fails scree ni n g d ue t o meeti n g a n y of t he f oll o wi n g e xcl usi o n criteria, t he 
partici pa nt ma y be all o we d t o rescree n 1 ti me, at t he S p o ns or’s discreti o n:  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 7  
•  E xcl usi o n n o. 1: E vi de nce of c urre nt S A R S -C o V -2 i nfecti o n wit hi n 1 4 da ys pri or t o 
Scree ni n g, bet wee n Scree ni n g a n d Baseli ne Visit, or at Baseli ne Visit, i ncl u di n g b ut 
n ot li mite d t o a fe ver (te m perat ure > 3 7. 5° C), ne w a n d persiste nt c o u g h, 
breat hless ness, or l oss of taste a n d/ or s mell ( N ote: If a S A R S -C o V -2 test [p ol y merase 
c hai n reacti o n or ot her re g ulat or y a p pr o ve d met h o d ] is perf or me d per t he discreti o n 
of t he I n vesti gat or i n acc or da nce wit h l ocal site practice, t he test res ult m ust be 
ne gati ve i n or der f or t he partici pa nt t o be e nr olle d i n t he st u d y). 
•  E xcl usi o n n o. 2: Ha ve cl ose c o ntact wit hi n 1 4  da ys pri or t o Da y 1 wit h a S A R S -C o V -
2 p ositi ve i n di vi d ual. Cl ose c o ntact is defi ne d as:  
a. face-t o-face c o ntact wit h a pr o ba ble or c o nfir me d case wit hi n 1 meter a n d f or at 
least 1 5 mi n utes;  
b.  direct p h ysical c o ntact wit h a pr o ba ble or c o nfir me d case;  
c. direct care f or a patie nt wit h pr o ba ble or c o nfir me d C O VI D -1 9 disease wit h o ut 
t he use of rec o m me n de d pers o nal pr otecti ve e q ui p me nt; or  
d.  ot her sit uati o ns as i n dicate d b y l ocal ris k assess me nts.  
•  E xcl usi o n n o. 6: A n M S e xacer bati o n (rela pse) wit hi n 3 0 da ys pri or t o e nr oll me nt or, 
i n t he o pi ni o n of t he I n vesti gat or, t he partici pa nt n ot ha vi n g sta bilize d fr o m a 
pre vi o us rela pse pri or t o e nr oll me nt ( Da y 1).  
•  E xcl usi o n n o. 9: 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) wit hi n t he 3 0 da ys pri or t o e nr oll me nt ( Da y  1).  
•  E xcl usi o n n o. 1 0: 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 hi n 1 4 da ys pri or t o Scree ni n g or d uri n g t he scree ni n g 
peri o d  ( Da y -2 8 t o Da y -1) . Partici pa nts wit h l ocal f u n gal i nfecti o n (e. g., ca n di diasis, 
ti nea) are eli gi ble t o be rescree ne d after s uccessf ul treat me nt of t he i nfecti o n. 
•  E xcl usi o n n o. 2 5: Treat me nt wit h i m m u n os u p pressa nt me dicati o ns, e. g., azat hi o pri ne, 
c ycl o p h os p ha mi de, a n d met h otre xate wit hi n 6 m o nt hs pri or t o e nr oll me nt ( Da y 1); 
mit o xa ntr o ne a n d c ycl os p ori ne wit hi n 1 2 m o nt hs pri or t o e nr oll me nt ( Da y 1).  
•  E xcl usi o n n o. 2 6: Treat me nt wit h a n y of t he f oll o wi n g me dicati o ns or pr oce d ures 
wit hi n 6 m o nt hs pri or t o e nr oll me nt ( Da y 1): I V i m m u n o gl o b uli n, plas ma p heresis, or 
c yta p heresis.  
•  E xcl usi o n n o. 2 7: Treat me nt wit h a n y of t he f oll o wi n g me dicati o ns wit hi n 3 0 da ys 
pri or t o e nr oll me nt ( Da y 1):  
a. I V c ortic oster oi d treat me nt 
b.  S yste mic c ortic oster oi d treat me nt  
c. 4 -A mi n o p yri di ne or relate d pr o d ucts  
•  E xcl usi o n n o. 2 8: Treat me nt wit h s p hi n g osi ne 1 -p h os p hate rece pt or m o d ulat ors 
(fi n g oli m o d, si p o ni m o d, or oza ni m o d) wit hi n 9 0 da ys pri or t o e nr oll me nt ( Da y 1). 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 8  
•  E xcl usi o n n o. 2 9: Treat me nt wit h f u marates ( F u ma der m, Tecfi dera, or V u merit y) 
wit hi n 4 wee ks pri or t o e nr oll me nt ( Da y 1).  
•  E xcl usi o n n o. 3 0: B -cell-tar gete d t hera pies f or t he treat me nt of M S (e. g., 
ocreliz u ma b, rit u xi ma b, ofat u m u ma b) wit hi n 1 2 m o nt hs of Scree ni n g; greater t ha n 
1 2  m o nt hs of Scree ni n g is per missi ble wit h e vi de nce t hat t he C D 1 9 cells ha ve 
ret ur ne d t o wit hi n n or mal ra n ge ( per l ocal la b orat or y refere nce ra n ge). 
•  E xcl usi o n n o. 3 1: Treat me nt wit h i m m u n o m o d ulat or y me dicati o ns (i ncl u di n g I F N -β 
a n d glatira mer acetate) wit hi n 2 wee ks of e nr oll me nt ( Da y 1).  
•  E xcl usi o n n o. 3 2: A d mi nistrati o n of a n y li ve -atte n uate d vacci ne gi ve n wit hi n 3 0 da ys 
pri or t o Da y -1 or pla n ne d t o be gi ve n d uri n g st u d y partici pati o n.  
•  E xcl usi o n n o. 3 3: Bl o o d d o nati o n ( 1 u nit or m ore) wit hi n 9 0 da ys pri or t o Scree ni n g, 
plas ma d o nati o n fr o m 1 wee k pri or t o Scree ni n g, a n d platelet d o nati o n fr o m 6 wee ks 
pri or t o Scree ni n g.  
I n a d diti o n, partici pa nts wit h a n ‘i n deter mi nate res ult’ f or H C V a nti b o d y d uri n g S cree ni n g ma y 
be all o we d t o retest a n d will be re-e val uate d o n a case -b y -case basis, after disc ussi o n wit h t he 
Me dical M o nit or a n d S p o ns or Me dical St u d y Direct or t o deter mi ne eli gi bilit y.  
U p o n rescree ni n g, a n d i n c o ns ultati o n wit h t he Me dical M o nit or a n d S p o ns or Me dical St u d y 
Direct or, t he partici pa nt s h o ul d si g n t he I C F a gai n a n d re peat t he scree ni n g assess me nts as per 
disc ussi o n wit h t he I n vesti gat or a n d st u d y tea m.  
Rescree ne d partici pa nt will recei ve a ne w scree ni n g n u m ber, w here t he traili n g al p ha n u meric 
c haracter i n t he scree ni n g n u m ber will m o ve f or war d se q ue ntiall y, e. g., fr o m X X X A t o X X X B .  
If t he partici pa nt fails scree ni n g t wice, t he y ma y n ot u n der g o f urt her scree ni n g f or t his st u d y. 
6. 3. 3.   
Scree n F ail ures  
Scree n fail ures are defi ne d as partici pa nts w h o si g n t he I C F b ut are n ot s u bse q ue ntl y d ose d . If a 
partici pa nt 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 
partici pa nt’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.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3 9  
7.   
S T U D Y T R E A T M E N T  
7. 1.   
Re gi me n  
Partici pa nts will recei ve nataliz u ma b 3 0 0 m g S C Q 4 W f or 4 8 wee ks ( 2 P F S f or S C i njecti o n 
1 5 0  m g/ m L [t otal of 3 0 0 m g/ 2 m L]).  
I njecti o ns s h o ul d be a d mi nistere d o ne after t he ot her wit h o ut si g nifica nt dela y. T he sec o n d 
i njecti o n s h o ul d be a d mi nistere d n o later t ha n 3 0 mi n utes after t he first i njecti o n. Partici pa nts 
s h o ul d be o bser ve d d uri n g b ot h S C i njecti o ns a n d f or 1 h o ur after f or si g ns a n d s y m pt o ms of 
i njecti o n site reacti o ns a n d i njecti o n reacti o ns i ncl u di n g h y perse nsiti vit y. After t he first 
6  nataliz u ma b d oses, t he 1 -h o ur p osta d mi nistrati o n o bser vati o n ti me f or s u bse q ue nt S C 
i njecti o ns ma y be re d uce d or re m o ve d acc or di n g t o cli nical j u d ge me nt if t he partici pa nts ha ve 
n ot e x perie nce d a n y i njecti o n reacti o ns i ncl u di n g h y perse nsiti vit y.  
T he sites f or S C i njecti o n s h o ul d be t he t hi g h, a b d o me n, or t he p osteri or as pect of t he u p per ar m. 
D o n ot i nject i nt o a n area of t he b o d y w here t he s ki n is irritate d, re d de ne d, br uise d, i nfecte d, or 
scarre d i n a n y wa y. W he n re m o vi n g t he s yri n ge fr o m t he i njecti o n site, let g o of t he pl u n ger 
w hile p ulli n g t he nee dle strai g ht o ut. Letti n g g o of t he pl u n ger will all o w t he nee dle g uar d t o 
e xte n d a n d c o ver t he nee dle. T he sec o n d i njecti o n s h o ul d be at least 1 i nc h ( 2. 5 c m) a wa y fr o m 
t he first i njecti o n l ocati o n. 
 
 
 
Misse d d oses s h o ul d be ta ke n as s o o n as p ossi ble. D oses s h o ul d n ot be d o u ble d t o ma ke u p f or 
misse d d oses.  
7. 2.   
M o dific ati o n of D ose a n d/ or Tre at me nt Sc he d ule  
T he d osa ge or treat me nt sc he d ule ca n n ot be m o difie d.  
7. 3.   
St u d y Tre at me nt M a n a ge me nt  
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.  
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 ali g ns wit h all ot her refere nces, 
i ncl u di n g t he 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 priatel y q ualifie d staff. St u d y 
treat me nt is t o be dis pe nse d o nl y t o partici pa nts 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 partici pa nt, it ca n be a d mi nistere d o nl y t o t hat  partici pa nt. St u d y treat me nt is f or 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 0  
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 s yri n ge f or a n ot her 
partici pa nt.  
7. 3. 1.   
N at aliz u m a b  
Nataliz u ma b f or S C i njecti o n is pr o vi de d i n a 1 m L P F S c o ntai ni n g 1 5 0  m g nataliz u ma b 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 y drate, 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, p ol ys or bate 8 0, a n d water f or i njecti o n at p H  6. 0); 2 i njecti o ns i n 
s uccessi o n are re q uire d t o a d mi nister 3 0 0 m g. 
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 I R T s yste m, a n d pri nta ble assi g n me nt 
re p orts are a vaila ble t o site staff. St u d y treat me nt s h o ul d n ot be use d after t he e x pir y or use-b y 
date.  
Nataliz u ma b is pr o d uce d usi n g fetal b o vi ne ser u m t hat was use d i n cl o ni n g bef ore master cell 
ba n k pre parati o n a n d st ora ge f or t he master cell ba n k a n d w or ki n g cell ba n k. Als o, nataliz u ma b 
is pr o d uce d usi n g b o vi ne bl o o d-deri ve d b o vi ne ser u m al b u mi n t hat was  use d i n pre parati o n f or 
t he master cell ba n k a n d w or ki n g cell ba n k. T his fetal b o vi ne ser u m meets t he criteria set f ort h 
b y a p u blic a ge nc y, t he E ur o pea n Direct orate f or t he Q ualit y of Me dici nes, f or t he pre ve nti o n of 
i nfecti o n wit h T S E a ge nts t o h u ma ns. N o ne of t hese b o vi ne materials are c o ntai ne d i n t he fi nal 
pr o d uct. T here is n o re p ort of T S E bei n g tra ns mitte d fr o m t he fi nal pr o d uct t o h u ma ns.  
H u ma n tra nsferri n is use d i n t he cell ba n k me dia use d f or t he pre parati o n of t he master cell ba n k 
a n d t he w or ki n g cell ba n k f or nataliz u ma b. T he ma n ufact uri n g pr ocess f or nataliz u ma b d oes n ot 
use t he h u ma n tra nsferri n, a n d t he fi nal pr o d uct d oes n ot c o ntai n h u ma n tra nsferri n. N ucleic aci d 
a m plificati o n test is n ot c o n d ucte d f or t he s o urce plas ma of ori gi n f or h u ma n bl o o d deri vati ves, 
b ut it is c o nfir me d t hat t he res ults of ser ol o gical testi n g f or vir uses (a nti ge n a n d/ or a nti b o d y t o 
vir uses) is perf or me d. I n  a d diti o n, t here are se veral ste ps t hat ca n re m o ve/i nacti vate vir uses 
d uri n g t he ma n ufact uri n g pr ocess of nataliz u ma b. T heref ore, t he ris k of c o nta mi nati o n wit h 
H B V, H C V, HI V -1, a n d HI V -2 is e xtre mel y l o w. T here is n o re p ort of T S E bei n g tra ns mitte d 
fr o m nataliz u ma b t o h u ma ns, alt h o u g h h u ma n tra nsferri n c o mes fr o m h u ma n bl o o d o btai ne d i n 
t he U S. T he oretical ris k assess me nt f or T S E de m o nstrate d t he safet y le vel re q uire d t o e ns ure t hat 
t he ris k of tra ns missi o n of T S E b y nataliz u ma b is e xtre mel y l o w.  
H o we ver, si nce t he ris k of T S E tra ns missi o n ca n n ot t otall y a n d t he oreticall y be de nie d, t his 
pr o d uct m ust be use d after caref ul c o nsi derati o n of t he nee d f or t he pr o d uct i n t he treat me nt of 
t he disease, a n d t his i nf or mati o n m ust be pr o vi de d t o t he patie nt pri or t o t he a d mi nistrati o n of t he 
pr o d uct.  
7. 3. 1. 1.  
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.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 1  
If t he pac ka gi n g is da ma ge d, or if t here is a n yt hi n g u n us ual a b o ut t he a p peara nce or attri b utes of 
t he s yri n ges or st u d y treat me nt, d o n ot use t he st u d y treat me nt. T he s yri n ge i n q uesti o n s h o ul d be 
sa ve d at t he st u d y site a n d t he pr o ble m i m me diatel y re p orte d t o t he S p o ns or.  
C o ntact i nf or mati o n f or re p orti n g a pr o ble m is pr o vi de d i n t he st u d y refere nce g ui de.  
7. 3. 1. 2.  
St or a ge  
St u d y treat me nt m ust be st ore d i n a sec ure l ocati o n.  
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 ucti o ns pr o vi de d i n t he D H A.  
7. 3. 1. 3.  
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 s yri n ges of nataliz u ma b as i nstr ucte d b y t he 
S p o ns or u nless a p pr o ve d f or o nsite destr ucti o n.  
If a n y 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 site 
staff m ust o btai n pri or a p pr o val fr o m t he S p o ns or, 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 d estr ucti o n, t he S p o ns or 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.  
7. 3. 1. 4.  
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, a n d acc o u nts of a n y st u d y treat me nt acci de ntall y or d eli beratel y destr o ye d or l ost.  
U nless ot her wise n otifie d, all s yri n ges 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 t he S p o ns or. A 
writte n e x pla nati o n m ust be pr o vi de d f or a n y discre pa ncies.  
7. 4.   
Bli n di n g Pr oce d ures  
N ot a p plica ble. T his is a n o pe n -la bel st u d y. 
7. 5.   
Prec a uti o ns  
Refer t o t he D H A f or details o n p ost d ose o bser vati o n re q uire me nts.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 2  
7. 6.   
C o m pli a nce  
C o m plia nce wit h treat me nt d osi n g is t o be m o nit ore d a n d rec or de d b y site staff. St u d y treat me nt 
will be a d mi nistere d b y t he site staff at all visits e xce pt Wee k 2 8 a n d Wee k 3 6 Visits.   
 
 
 
7. 7.   
C o nc o mit a nt T her a p y a n d Pr oce d ures  
7. 7. 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 a d mi nistere d bet wee n t he ti me of t he 
partici pa nt’s writte n c o nse nt a n d t he partici pa nt’s last st u d y visit.  
Partici pa nts 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) or i m m u nizati o n/ vacci nati o n. 
7. 7. 1. 1.  
All o we d C o nc o mit a nt T her a p y  
C o nc o mita nt treat me nt wit h a n y of t he f oll o wi n g is all o we d s o l o n g as t he e xcl usi o nar y criteria 
descri be d i n Secti o n  6. 2  are o bser ve d:  
•  Me dicati o ns necessar y f or t he treat me nt of A Es.  
•  Me dicati o ns use d t o treat M S s y m pt o ms s uc h as s pasticit y, bla d der i m pair me nt, pai n, 
fati g ue, or de pressi o n. 
•  S h ort c o urses of hi g h -d ose c ortic oster oi ds per l ocal sta n dar d of care i n t he treat me nt 
of pr ot oc ol -defi ne d rela pse of M S disease (see Secti o n  5. 4 ). 
•  C ortic oster oi ds t hat are a d mi nistere d b y n o ns yste mic r o utes (e. g., t o pical, i n hale d) . 
7. 7. 1. 2.  
Dis all o we d C o nc o mit a nt T her a p y  
C o nc o mita nt treat me nt wit h a n y of t he f oll o wi n g is n ot all o we d w hile recei vi n g st u d y treat me nt 
a n d f or at least 1 2 wee ks after t he last d ose of st u d y treat me nt, u nless as ot her wise descri be d i n 
t his pr ot oc ol: 
•  A n y n o nst u d y treat me nts directe d t o war d t he treat me nt of M S s uc h as c hr o nic 
i m m u n os u p pressa nt t hera p y or ot her i m m u n o m o d ulat or y treat me nts. T his i ncl u des 
b ut is n ot li mite d t o i nterfer o n, glatira mer acetate, di met h yl f u marate, dir o xi mel 
f u marate, c ycl o p h osp ha mi de, met h otre xate, 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 yc o p he n olate m ofetil, fi n g oli m o d, si p o ni m o d, oza ni m o d, 
dacliz u ma b, rit u xi ma b, ocreliz u ma b, ale mt uz u ma b, c ycl os p ori ne, ofat u m u ma b, 
4 -A mi n o p yri di ne or relate d pr o d ucts, or a n y  t hera pe utic m o n ocl o nal a nti b o d y.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 3  
•  A n y i n vesti gati o nal pr o d uct, i ncl u di n g i n vesti gati o nal s y m pt o matic t hera pies f or M S 
a n d i n vesti gati o nal t hera pies f or n o n -M S i n dicati o ns.  
•  A n y ster oi d t hera p y f or treat me nt of M S ot her t ha n f or ac ute rela pse. Use of ster oi ds 
f or ot her p ur p oses is t o be c o nsi dere d o n a case-b y -case basis a n d m ust be disc usse d 
wit h t he Me dical M o nit or. Pr ot oc ol -defi ne d treat me nts of rela pses as descri be d i n 
Sec ti o n 5. 4  are all o we d . 
•  Treat me nt wit h nataliz u ma b I V is n ot all o we d u p t o Wee k 5 2 b ut is all o we d after 
Wee k 5 2.  
•  Treat me nt wit h >  8 0 0 µ g/ da y of i n hale d becl o met has o ne di pr o pi o nate f or press urize d 
metere d d ose i n halers wit h e xtra fi ne particle h y dr ofl u or oal ka ne pr o pella nt.  
•  C O VI D -1 9 vacci ne wit hi n 7  da ys pri or or 7  da ys p osta d mi nistrati o n of st u d y 
treat me nt. 
Partici pa nts w h o recei ve a n y of t hese restricte d treat me nts will be re vie we d b y t he st u d y tea m 
a n d ma y be re q uire d t o disc o nti n ue st u d y treat me nt per ma ne ntl y a n d ma y be wit h dra w n fr o m t he 
st u d y as o utli ne d i n Secti o n 8. 1 .  
7. 7. 2.   
C o nc o mit a nt Pr oce d ures  
A c o nc o mita nt pr oce 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 p y) 
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 ti me t he partici pa nt is e nr olle d i n t he st u d y a n d t he partici pa nt’s last st u d y visit.  
7. 7. 2. 1.  
Dis all o we d C o nc o mit a nt Pr oce d ures  
Treat me nt wit h a n y of t he f oll o wi n g c o nc o mita nt pr oce d ures is n ot all o we d w hile recei vi n g 
st u d y treat me nt, u nless as ot her wise descri be d i n t his pr ot oc ol: 
•  t otal l y m p h oi d irra diati o n 
•  T -cell or T-cell rece pt or vacci nati o n  
•  plas ma p heresis  
•  c yta p heresis 
•  he mat o p oietic ste m cell t hera p y  
S u bjects w h o recei ve treat me nt wit h a n y of t hese restricte d pr oce d ures ma y be re q uire d t o 
per ma ne ntl y disc o nti n ue st u d y treat me nt a n d ma y be wit h dra w n fr o m t he st u d y as o utli ne d i n 
Secti o n  8. 1 . 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 4  
T he use of c o nc o mita nt t hera pies or pr oce d ures defi ne d a b o ve m ust be rec or de d i n t he 
partici pa nt’s e C R F, acc or di n g t o t he i nstr ucti o ns f or e C R F c o m pleti o n. A Es relate d t o t he 
a d mi nistrati o n of t hese t hera pies or pr oce d ures m ust be d oc u me nte d i n t he a p pr o pr iate e C R F. 
7. 8.   
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 S C 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 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 5  
8.   
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 P A R TI CI P A N T S F R O M T H E S T U D Y  
8. 1.   
Disc o nti n u ati o n of St u d y Tre at me nt  
A partici pa nt 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 partici pa nt 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 1. 4. 1 . 
•  T he partici pa nt de vel o ps persiste nt a nti -nataliz u ma b a nti b o dies ( 2  c o nsec uti ve 
rea di n gs). 
•  T he partici pa nt 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 he partici pa nt de vel o ps P M L or a n ot her seri o us o p p ort u nistic i nfecti o n.  
•  T he partici pa nt e x perie nces a n A E or S A E t hat necessitates per ma ne nt 
disc o nti n uati o n of st u d y treat me nt.  
•  T he partici pa nt 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 st u d y treat me nt.  
•  At t he discreti o n of t he I n vesti gat or f or me dical reas o ns.  
•  T he partici pa nt wit h dra ws c o nse nt t o c o nti n ue st u d y treat me nt.  
•  T he partici pa nt 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.  
•  At t he discreti o n of t he I n vesti gat or or S p o ns or f or n o nc o m plia nce.  
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 partici pa nt’s 
e C R F.  
Partici pa nts w h o disc o nti n ue treat me nt ma y re mai n i n t he st u d y a n d c o nti n ue pr ot oc ol -re q uire d 
tests a n d assess me nts. T h us, a partici pa nt ma y c o nti n ue st u d y visits e ver y 4 wee ks u p t o 
Wee k  5 2 a n d recei ve safet y p h o ne call s at Wee k 6 0 a n d Wee k  7 2.  
8. 2.   
L ost t o F oll o w -U p  
Partici pa nts 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.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 6  
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt 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 site m ust atte m pt t o c o ntact t he partici pa nt 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 partici pa nt 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 partici pa nt 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 partici pa nt 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 partici pa nt. T hese c o ntact 
atte m pts s h o ul d be d oc u me nte d i n t he partici pa nt’s me dical rec or d.  
•  S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, t hat partici pa nt will be c o nsi dere d 
t o ha ve wit h dra w n fr o m t he st u d y wit h a pri mar y reas o n of l ost t o f oll o w-u p.  
8. 3.   
Wit h dr a w al of P artici p a nts Fr o m t he St u d y  
Partici pa nts 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 partici pa nt wit h dra ws c o nse nt f or partici pati o n i n t he st u d y.  
•  T he partici pa nt 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 p y f or i n vesti gati o nal use is a d mi nistere d. 
•  T he partici pa nt 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 pri mar y reas o n f or t he partici pa nt’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 
partici pa nt’s e C R F.  
Partici pa nts are e nc o ura ge d t o u n der g o a n E T Visit u nless wit h dra wal is d ue t o deat h or 
wit h dra wal of c o nse nt. T he E T Visit i n s uc h partici pa nts s h o ul d occ ur at 4 wee ks ( ± 7  da ys) after 
t he last d ose of st u d y treat me nt a n d s h o ul d be f oll o we d b y safet y p h o ne calls at 1 2 wee ks 
( ± 1 0 da ys) a n d 2 4 wee ks ( ± 1 0 da ys) after t he last d ose of st u d y treat me nt.  
Partici pa nts w h o wit h dra w fr o m t he st u d y ma y be re place d at t he S p o ns or’s discreti o n.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 7  
9.   
E F FI C A C Y, P H A R M A C O KI N E TI C, A N D 
P H A R M A C O D Y N A MI C A S S E S S M E N T S  
See Secti o n  1. 3  f or t he ti mi n g of all assess me nts. 
Tests a n d e val uati o ns affecti n g t he pri mar y e n d p oi nt a n d/ or a nal yses 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, partici pa nts 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. 
9. 1.   
Cli nic al Effic ac y Assess me nts  
T he f oll o wi n g cli nical assess me nts will be perf or me d t o e val uate t he efficac y of nataliz u ma b S C:  
M RI Efficac y Assess me nts  
•  T 2 h y peri nte nse lesi o n n u m ber  
•  T 1 h y p oi nte nse lesi o n n u m ber  
•  Ga d oli ni u m -e n ha nci n g lesi o n n u m ber  
T he i ma ges will be ca pt ure d acc or di n g t o t he M RI Ac q uisiti o n a n d Pr oce d ures Ma n ual pr o vi de d 
b y t he S p o ns or.  
All M RIs s h o ul d be rea d b y t he ce ntral ra di ol o gist t o e val uate o nl y f or t he p ur p ose of perf or mi n g 
q ua ntitati ve meas ure me nts of ne w acti ve lesi o ns. N o i nci de ntal fi n di n gs will be pr o vi de d t o t he 
st u d y site I n vesti gat or b y t he ce ntral ra di ol o gist. L ocal ra di ol o gists ma y pr o vi de a n y i nci de ntal 
fi n di n gs o n t he M RI sca ns t o t he site I n vesti gat or as me dicall y nee de d. L ocall y rea d M RIs will 
n ot be use d f or e n d p oi nt a nal yses.  
Cli nical Efficac y Assess me nts  
•  Rela pses ( defi ne d as t he o nset of ne w or rec urre nt ne ur ol o gical s y m pt o ms lasti n g at 
least 2 4 h o urs, acc o m pa nie d b y ne w o bjecti ve a b n or malities o n a ne ur ol o gical 
e xa mi nati o n, a n d n ot e x plai ne d s olel y b y n o n -M S pr ocesses s uc h as fe ver, i nfecti o n, 
se vere stress, or dr u g t o xicit y; see Secti o n 5. 4  f or f urt her details) 
•  Ne ur ol o gical e xa mi nati o n  
•  V A S assessi n g t he partici pa nt’s gl o bal i m pressi o n of t heir well -bei n g  
9. 2.   
P h ar m ac o ki netic Assess me nts  
T he ser u m nataliz u ma b c o nce ntrati o ns bet wee n Da y 6 a n d Da y 8 a n d at pre d ose a d mi nistrati o n 
( Ctr o u g h) at eac h visit u ntil Wee k 4 8 will be meas ure d as t he P K assess me nts. 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 8  
9. 3.   
P h ar m ac o d y n a mic Assess me nts  
T he α 4 -i nte gri n sat urati o n a n d ser u m s ol u ble V C A M-1 c o nce ntrati o ns at pre d ose a d mi nistrati o n 
at eac h visit u ntil Wee k 4 8 will be meas ure d as t he P D assess me nts.  
 
I n a d diti o n t o tr o u g h α 4 i nte gri n sat urati o n, 
 
 
 
 
 
 
 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4 9  
1 0.   
S A F E T Y A S S E S S M E N T S  
See Secti o n  1. 3  f or t he ti mi n g of all safet y assess me nts. 
1 0. 1.   
Cli nic al S afet y Assess me nts  
T he f oll o wi n g cli nical assess me nts will be perf or me d t o e val uate t he safet y pr ofile of 
nataliz u ma b S C:  
•  A E a n d S A E rec or di n g  
•  Me dical hist or y  
•  P h ysical e xa mi nati o ns  
•  Vital 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. Partici pa nts m ust re mai n i n t he sa me b o d y p ositi o n 
(seate d or s u pi ne) q uietl y f or 5 mi n utes pri or t o p ulse rate a n d bl o o d press ure 
meas ure me nts; meas ure me nts m ust be perf or me d wit hi n 1 h o ur pri or t o 
a d mi nistrati o n of st u d y treat me nt.  
•  Wei g ht meas ure me nts  
•  1 2 -L ea d E C Gs will be c ollecte d after t he partici pa nt has bee n resti n g i n a s u pi ne 
p ositi o n f or at least 5  mi n utes.  
•  E D S S  
•  C -S S R S: t he baseli ne versi o n of C -S S R S will be use d at Scree ni n g  (recall peri o d is 
lifeti me); t he Si nce Last Visit C-S S R S versi o n will be use d t hereafter. T he C -S S R S 
will be c o n d ucte d b y a trai ne d   
, a n d a n y fi n di n gs of c o ncer n will be ha n dle d as 
a p pr o priate . 
•  C o nc o mita nt t hera p y a n d pr oce d ure rec or di n g  
1 0. 2.   
L a b or at or y S afet y Assess me nts  
Sa m ples will be a nal yze d usi n g G o o d La b orat or y Practice -vali date d assa ys.  
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 pr ofile of 
nataliz u ma b S C:  
•  He 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 bs ol ute 
ne utr o p hil c o u nt, he m o gl o bi n, he mat ocrit, mea n c or p usc ular v ol u me, mea n 
c or p usc ular he m o gl o bi n, mea n c or p usc ular he m o gl o bi n c o nce ntrati o n, a n d re d bl o o d 
cell c o u nt 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5 0  
•  Bl o o d c he mistr y: s o di u m, p otassi u m, c hl ori de, al kali ne p h os p hatase, ala ni ne 
a mi n otra nsferase, as partate a mi n otra nsferase, lactate de h y dr o ge nase, ga m ma 
gl uta m yl tra nsferase, gl uc ose, calci u m, p h os p h or us, bl o o d urea nitr o ge n, creati ni ne, 
uric aci d, bilir u bi n  (t otal a n d direct), t otal pr otei n, al b u mi n, a n d bicar b o nate 
•  Uri nal ysis: c ol or, pr otei n, bl o o d, gl uc ose, ket o nes, p H, s pecific gra vit y, a n d 
micr osc o pic e xa mi nati o n if a b n or mal.  
1 0. 3.   
Pr o d uct -S pecific S afet y Assess me nts  
T he f oll o wi n g assess me nts will be perf or me d t o deter mi ne t he safet y of nataliz u ma b S C:  
•  A nti -nataliz u ma b a nti b o dies  
•  A nti -J C V a nti b o d y i n de x 

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P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5 1  
1 1.   
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 
a n d pr o d uct c o m plai nts. If a n A E or pr o d uct c o m plai nt occ urs, t he first c o ncer n s h o ul d be f or t he 
safet y of t he partici pa nt. 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 partici pa nt a n d/ 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 na mes a n d tele p h o ne n u m bers of site staff f or re p orti n g S A Es, 
pre g na ncies, o ver d oses, a n d me dical e mer ge ncies. T hr o u g h o ut t he pr ot oc ol, t he S p o ns or is 
na me d, b ut re p orti n g ma y be d o ne t hr o u g h a C R O.  
1 1. 1.   
Defi niti o ns  
1 1. 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 patie nt or cli nical i n vesti gati o n s u bject 
( partici pa nt) 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 assess me nt s uc h as a n a b n or mal la b orat or y val ue), s y 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 assess me nt (e. g., la b orat or y val ue, vital si g n, a n d E C G) 
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 partici pa nt 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 1. 1. 2.   
Seri o us A d verse 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 partici pa nt 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.  

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P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5 2  
•  Res ults i n a c o n ge nital a n o mal y/ birt h defect.  
•  Is a me dicall y 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 
partici pa nt 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. ( E xa m ples of s uc h me dical e ve nts i ncl u de aller 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 or c o n v ulsi o ns occ urri n g at h o me t hat d o n ot re q uire 
a n i n patie nt h os pitalizati o n.)  
1 1. 1. 3.   
C o m bi n ati o n Pr o d uct  
A c o m bi nati o n pr o d uct is a pr o d uct c o m p ose d of a n y c o m bi nati o n of a dr u g a n d a de vice; a 
bi ol o gical pr o d uct a n d a de vice; a dr u g a n d a bi ol o gical pr o d uct; or a dr u g, de vice, a n d a 
bi ol o gical pr o d uct. Nataliz u ma b S C is a n i n vesti gati o nal c o m bi nati o n pr o d uct  i n Ja pa n. 
1 1. 1. 4.   
Pr o d uct C o m pl ai nts f or I n vesti g ati o n al C o m bi n ati o n Pr o d ucts  
F or i n vesti gati o nal c o m bi nati o n pr o d uct wit h a me dical de vice c o m p o ne nt, c o m plai nts i ncl u de 
b ut are n ot li mite d t o a n y i na de q uac y i n t he i de ntit y, q ualit y, d ura bilit y, relia bilit y, safet y or 
perf or ma nce of a n i n vesti gati o nal de vice, i ncl u di n g malf u ncti o n, use err ors or i na de q uac y i n 
i nf or mati o n s u p plie d b y t he S p o ns or. 
1 1. 1. 5.   
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 partici pa nt is h os pitalize d. T he st u d y site m ust d oc u me nt all 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 
partici pa nt’s c o nse nt t o be 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 partici pa nt’s c o nse nt t o be 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 partici pa nt is h os pitalize d d ue t o l ocal re q uire me nts f or a d mi nistrati o 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 1. 1. 2  is met. 

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P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5 4  
1 1. 2. 4.   
E x pecte d ness of E ve nts  
E x pecte d ness of all S A Es will be deter mi ne d b y t he S p o ns or acc or di n g t o t he nataliz u ma b 
I n vesti gat or’s Br oc h ure.  
1 1. 3.   
M o nit ori n g a n d Rec or di n g E ve nts  
1 1. 3. 1.   
A d verse E ve nts  
A n y A E e x perie nce d b y t he partici pa nt bet wee n t he ti me of first d ose of st u d y treat me nt a n d 
f oll o w-u p safet y p h o ne call is t o be rec or de d o n t he e C R F, re gar dless of t he se verit y of t he e ve nt 
or its relati o ns hi p t o st u d y treat me nt. At eac h st u d y visit, t he I n vesti gat or will assess t he 
partici pa nt f or A Es a n d will rec or d a n y ne w A Es or u p dates t o pre vi o usl y re p orte d A Es o n t he 
e C R F.  
A Es t hat are o n g oi n g w he n t he partici pa nt c o m pletes or disc o nti n ues t he st u d y will be f oll o we d 
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 will be rec or de d o n t he e C R F, as a p plica ble.  
T he e ve nts of rela pse will n ot be c ollecte d as A Es as t he y are c o nsi dere d part of t he efficac y 
e n d p oi nts.  
1 1. 3. 2.   
A d verse E ve nts of S peci al I nterest  
A n A E of s pecial i nterest is a n A E of scie ntific a n d me dical c o ncer n s pecific t o t his st u d y, f or 
w hic h o n g oi n g m o nit ori n g a n d re p orti n g are re q uire d. T he f oll o wi n g A Es will be c o nsi dere d 
A E SIs: P M L, i njecti o n site pai n, o p p ort u nistic i nfecti o ns ot her t ha n P M L, her pes i nfecti o n, 
dr u g -i n d uce d li ver i nj ur y, h y perse nsiti vit y reacti o ns, a n d mali g na ncies.  
1 1. 3. 3.   
Seri o us A d verse E ve nts  
A n y S A E e x perie nce d b y t he partici pa nt bet wee n t he ti me of t he si g ni n g of t he I C F a n d 
f oll o w-u p safet y p h o ne call 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 verit y of t he 
e ve nt or its relati o ns hi p t o st u d y treat me nt. T hereafter, t he e ve nt s h o ul d  be re p orte d t o t he 
S p o ns or 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.  
S A Es m ust be re p orte d t o t he S p o ns or wit hi n 2 4 h o urs as descri be d i n Secti o n 1 1. 3. 5 . 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.  
A n y S A E t hat is o n g oi n g w he n t he partici pa nt c o m pletes or disc o nti n ues t he st u d y will be 
f oll o we d 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.  
1 1. 3. 4.   
Pr o d uct C o m pl ai nts  
All pr o d uct c o m plai nts m ust be e ntere d i nt o Bi o ge n’s C S S p ortal acc or di n g t o t he Cli nical 
Pr o d uct C o m plai nts Trai ni n g G ui deli nes.  

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P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5 6  
1 1. 4.   
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns  
1 1. 4. 1.   
Pre g n a nc y  
P artici p a nts s h o ul d n ot bec o me pre g n a nt d uri n g t he st u d y a n d f or 6 m o nt hs after t heir l ast 
d ose of st u d y tre at me nt. If a fe male partici pa nt 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 di ately. 
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 partici pa nt fr o m first d ose of 
st u d y dr u g t o 6 m o nt hs after t he last d ose of st u d y treat me nt b y fa xi n g or e maili n g t he 
a p pr o priate f or m t o t he S p o ns or wit hi n 2 4 h o urs of t he site staff bec o mi n g  a ware of t he 
pre g na nc y. Refer t o t he St u d y Refere nce G ui de’s Official 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 site staff m ust re p ort t he o utc o me of t he pre g na nc y t o 
t he S p o ns or. 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 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 partici pa nts 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 or wit hi n 
6  m o nt hs fr o m t heir last d ose of st u d y treat me nt.  
1 1. 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 partici pa nt or ta ke n b y a partici pa nt 
t hat e xcee ds t he d ose assi g ne d t o t he partici pa nt 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 e 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 t he S p o ns or wit hi n 2 4  h o urs of t he 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 t he S p o ns or 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 t he S p o ns or. 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 e C R F. 
1 1. 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, 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 M o nit or. Refer t o c o ntact i nf or mati o n i n t he pr ot oc ol attac h me nt  f or 
c o m plete c o ntact i nf or mati o n.  
1 1. 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 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 d y a n d f or 6 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, partici pa nts 
s h o ul d n ot d o nate 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 6 m o nt hs after t heir last d ose 
of st u d y treat me nt.  

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P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5 7  
F or t he p ur p oses of t his st u d y, w o me n of c hil d beari n g p ote ntial are defi ne d as all w o me n 
p h ysi ol o gicall y ca pa ble of bec o mi n g pre g na nt, U N L E S S t he y meet o ne of t he f oll o wi n g 
c o n diti o ns:  
•  P ost me n o pa usal  
− 5 2  c o nti n u o us wee ks 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 a n d a ser u m F S H le vel >  4 0  mI U/ m L  
− 6  wee ks after s ur gical bilateral o o p h orect o m y wit h or wit h o ut h ysterect o m y  
•  P ost h ysterect 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 hl y effecti ve c o ntrace pti o n is defi ne d as 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 1, or tra ns der mal 1 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 1, or i m pla nte d1 pr o gest o ge n -o nl y 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. 
•  Barrier met h o ds of c o ntrace pti o n, if a p plica ble acc or di n g t o l ocal g ui deli nes.  
•  Bilateral t u bal occl usi o n.  
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 partici pa nt, 
ca n be c o nsi dere d a n acce 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 
absti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, p ost o v ulati o n met h o ds) a n d wit h dra wal are 
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 1. 4. 1 . 
 
1 I ntra va gi nal a n d tra ns der mal c o m bi ne d h or m o nal met h o ds of c o ntrace pti o n a n d i njecte d a n d i m pla nte d h or m o nal 
met h o ds of c o ntrace pti o n are n ot a p pr o ve d f or use i n Ja pa n. 

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P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5 8  
1 1. 6.   
S afet y Res p o nsi bilities  
1 1. 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 he 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 partici pa nts 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 t he S p o ns or wit hi n 
2 4  h o urs of t he 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 t he S p o ns or wit hi n 2 4 h o urs of t he 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 partici pa nts’ 
me dical rec or ds.  
•  P urs ue A E f oll o w -u p i nf or mati o n, if 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 e 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.  
•  Re p ort a n y pr o d uct c o m plai nts i n Bi o ge n’s C S S P ortal.  
•  Re p ort pr o d uct c o m plai nts ass ociate d wit h a de vice malf u ncti o n t hat res ult i n a n S A E 
i n Bi o ge n’s C S S p ortal wit hi n 2 4 h o urs of a ware ness. 
1 1. 6. 2.   
T he S p o ns or  
T he S p o ns or’s res p o nsi bilities i ncl u de t he f oll o wi n g:  
•  Bef ore a site ca n e nr oll a n y partici pa nts, t he Me dical M o nit or is res p o nsi ble f or 
re vie wi n g wit h 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.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5 9  
•  T he S p o ns or is t o n otif 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 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 0  
1 2.   
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 o bjecti ves of t he st u d y a n d t he e n d p oi nts t o be a nal yze d are liste d i n Secti o n  4 . 
T he pri mar y e n d p oi nt of t he st u d y will be c u m ulati ve n u m ber of ne w acti ve lesi o ns (s u m of 
ga d oli ni u m -e n ha nci n g lesi o ns a n d n o ne n ha nci n g ne w or ne wl y e nlar gi n g T 2 h y peri nte nse 
lesi o ns) o n Wee k 2 4 ( Part 1) brai n M RI sca ns. T he a nal ysis of t he pri mar y e n d p oi nt will be 
perf or me d after t he last partici pa nt c o m pletes t he Wee k 2 4 Visit. T he fi nal a nal ysis of ke y 
f u ncti o nal o utc o mes will be perf or me d after t he last partici pa nt c o m pletes t he Wee k 5 2 Visit. All 
partici pa nts will be f oll o we d u p u ntil Wee k 7 2 f or f urt h er l o n g-ter m e val uati o n of safet y. 
A s u m mar y of pri mar y a n d sec o n dar y efficac y e n d p oi nts, P K, P D, safet y e n d p oi nts, a n d 
i m m u n o ge nicit y data is pr o vi de d i n t his secti o n. A nal yses of ot her s u p p orti ve e n d p oi nts, 
i ncl u di n g a nal yses of e x p os ure-res p o nse relati o ns hi ps f or cli nical, i ma gi n g, a n d safet y o utc o me 
meas ures, will be descri be d i n t he S A P, w hic h will c o ntai n t he fi nal details o n t he statistical 
met h o ds use d i n t his st u d y. T he a nal yses pla n ne d f or t he i nteri m data base l oc k after t he last 
partici pa nt c o m pletes t he Wee k 2 4 Visit a n d f or t he fi nal data base l oc k after t he last partici pa nt 
c o m pletes t he Wee k 5 2 Visit as well as f or t he l o n g -ter m safet y data base l oc k f or a n a d de n d u m 
after t he last partici pa nt c o m pletes t he Wee k 7 2 F oll o w -U p Visit will be descri be d i n t he S A P.  
1 2. 1.   
Ge ner al C o nsi der ati o ns  
Efficac y a n d safet y e n d p oi nts will be s u m marize d usi n g descri pti ve statistics ( n u m ber of 
partici pa nts wit h data, mea n, sta n dar d de viati o n, 9 5 % CI, me dia n, mi ni m u m, a n d ma xi m u m) f or 
c o nti n u o us varia bles a n d fre q ue nc y a n d perce nta ge f or cate g orical varia bles . 
1 2. 2.   
A n al ysis Sets  
F ull a nal ysis set is defi ne d as all partici pa nts w h o recei ve at least 1 d ose of st u d y treat me nt a n d 
ha ve at least 1 p ost baseli ne efficac y assess me nt.  
T he P K a nal ysis set is defi ne d as all partici pa nts w h o recei ve at least 1 d ose of st u d y treat me nt 
a n d ha ve at least 1 meas ura ble ser u m nataliz u ma b c o nce ntrati o n.  
T he P D a nal ysis set is defi ne d as all partici pa nts w h o recei ve at least 1 d ose of st u d y treat me nt 
a n d ha ve at least 1 assess me nt f or α 4 -i nte gri n sat urati o n, ser u m s ol u ble V C A M-1 c o nce ntrati o n , 
a n d 
 
 
T he safet y a nal ysis set is defi ne d as all partici pa nts w h o recei ve at least 1  d ose of st u d y 
treat me nt.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 1  
1 2. 3.   
Met h o ds of A n al ysis f or Effic ac y E n d p oi nts  
1 2. 3. 1.   
A n al ysis of t he Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt of c u m ulati ve n u m ber of ne w acti ve lesi o ns ( ga d oli ni u m -e n ha nci n g 
lesi o ns a n d n o ne n ha nci n g ne w or ne wl y e nlar gi n g T 2 h y peri nte nse lesi o ns) at Wee k 2 4 ( Part 1) 
will be calc ulate d as t he s u m of t he ne w acti ve lesi o ns o ver t he p ost baseli ne  sca ns at Wee ks 1 2 
a n d 2 4 f or all treate d partici pa nts wit h at least 1 p ost baseli ne efficac y assess me nt e xcl u di n g 
persiste nt A D A or P M L cases. T he c u m ulati ve n u m ber will be s u m marize d usi n g descri pti ve 
statistics ( n u m ber of partici pa nts wit h data, mea n, sta n dar d de viati o n, 9 5 % CI, me dia n, 
mi ni m u m, a n d ma xi m u m) a n d will be a nal yze d usi n g ne gati ve bi n o mial distri b uti o n.  
I nterc urre nt e ve nts i ncl u de start of resc ue me dicati o n, earl y disc o nti n uati o n of treat me nt d ue t o 
safet y a n d/ or lac k of efficac y a n d/ or ot her reas o ns, start of persiste nt A D A, a n d start of P M L. 
T he pr o p ose d pri mar y a n d   
 esti ma n ds will be base d o n a h y p ot hetical strate g y a n d/ or 
t he treat me nt p olic y strate g y. 
Missi n g ga d oli ni u m -e n ha nci n g or ne w or ne wl y e nlar gi n g n o ne n ha nci n g T 2 h y peri nte nse lesi o ns 
at Wee k 1 2 or 2 4 will be i m p ute d usi n g last o bser vati o n carrie d f or war d o n -treat me nt. 
1 2. 3. 2.   
A n al ysis of t he Sec o n d ar y E n d p oi nts  
T he sec o n dar y e n d p oi nt of c u m ulati ve n u m ber of ne w acti ve lesi o ns at Wee k 4 8 ( Part 2) will be 
s u m marize d usi n g descri pti ve statistics ( n u m ber of partici pa nts wit h data, mea n, sta n dar d 
de viati o n, 9 5 % CI, me dia n, mi ni m u m, a n d ma xi m u m).  
T he c ha n ge fr o m Baseli ne i n n u m ber of ga d oli ni u m -e n ha nci n g lesi o ns at Wee k 2 4 a n d Wee k 4 8, 
t he n u m ber of n o ne n ha nci n g ne w or ne wl y e nlar gi n g T 2 h y peri nte nse lesi o ns at Wee k 2 4 a n d 
Wee k 4 8, a n d t he n u m ber of ne w T 1 h y p oi nte nse lesi o ns at Wee k 2 4 a n d Wee k 4 8  will be 
s u m marize d descri pti vel y as well. 
Ot her sec o n dar y e n d p oi nts will als o be s u m marize d, i ncl u di n g pr o p orti o n of partici pa nts wit h 
a n y ne w acti ve lesi o ns at Wee ks 2 4 a n d 4 8; A R R wit hi n t he past 1 2 m o nt hs, at Wee ks 2 4, 4 8, 
a n d 5 2; pr o p orti o n of rela pse -free partici pa nts at Wee ks 2 4 a n d 5 2; a n d V A S assessi n g t he 
partici pa nt’s gl o bal i m pressi o n of t heir well -bei n g at Wee ks 2 4 a n d 4 8.  
 
  
 
 
 
 
1 2. 4.   
Met h o ds of A n al ysis f or P h ar m ac o ki netic E n d p oi nts  
Ser u m nataliz u ma b c o nce ntrati o ns ( C tr o u g h) meas ure d Q 4 W (j ust pri or t o d ose a d mi nistrati o n) 
u ntil Wee k 4 8 a n d 1 ser u m nataliz u ma b c o nce ntrati o n meas ure d bet wee n Da y 6 a n d Da y 8 t o 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 2  
o btai n a bs or pti o n i nf or mati o n f or S C a d mi nistrati o n will be s u m marize d usi n g descri pti ve 
statistics ( n u m ber of partici pa nts wit h data, mea n, sta n dar d de viati o n, ge o metric mea n, 9 5 % CIs 
of ge o metric mea n, ge o metric C V %, me dia n, mi ni m u m, a n d ma xi m u m) at eac h  ti me p oi nt. 
All meas ure d ser u m nataliz u ma b c o nce ntrati o ns i n t his st u d y will be c o m bi ne d wit h ot her 
nataliz u ma b st u d y data, a n d t he y will be use d f or p o p ulati o n P K a nal ysis t o e val uate a bs or pti o n 
pr ofile after nataliz u ma b S C a d mi nistrati o n. T he a nal ysis pla n a n d re p or ts will be pre pare d 
se paratel y fr o m t his st u d y.  
1 2. 5.   
Met h o ds of A n al ysis f or P h ar m ac o d y n a mic E n d p oi nts  
α 4 -i nte gri n sat urati o n le vels, s ol u ble V C A M-1 ser u m c o nce ntrati o ns , a n d 
 
 
 
 T he data will be s u m marize d usi n g descri pti ve statistics ( n u m ber of 
partici pa nts wit h data, mea n, sta n dar d de viati o n, ge o metric mea n, 9 5 % CI of ge o metric mea n, 
ge o metric C V %, me dia n, mi ni m u m, a n d ma xi m u m) at eac h ti me p oi nt.  
1 2. 6.   
Met h o ds of A n al ysis f or S afet y E n d p oi nts  
1 2. 6. 1.   
A d verse E ve nts  
A Es will be c o de d usi n g t he Me d D R A .  
Treat me nt -e mer ge nt A Es will be s u m marize d a n d prese nte d. A treat me nt‑e mer ge nt A E is 
defi ne d as a n y A E t hat has a n o nset date a n d ti me t hat is o n or after t he date a n d ti me of t he first 
d ose of st u d y treat me nt, or t hat has w orse ne d after t he date a n d ti me o f t he first d ose of st u d y 
treat me nt t hr o u g h 8 4 da ys after t he last d ose of st u d y treat me nt.   
All A Es will be classifie d usi n g t he Me d D R A. T he i nci de nce of A Es will be s u m marize d as 
f oll o ws: 
•  b y Me d D R A preferre d ter m  
•  b y pri mar y S O C  
•  b y pri mar y S O C a n d Me d D R A preferre d ter m  
•  b y se verit y  
•  b y relati o ns hi p t o st u d y treat me nt  
T he i nci de nce of S A Es a n d A Es lea di n g t o earl y ter mi nati o n, as well as h y perse nsiti vit y 
reacti o ns, i njecti o n site reacti o ns, i njecti o n reacti o ns, i nfecti o ns, a n d mali g na ncies will als o be 
s u m marize d. 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 3  
1 2. 6. 2.   
Cli nic al L a b or at or y Res ults  
Cli nical la b orat or y e val uati o ns i ncl u de he mat ol o g y, bl o o d c he mistr y, a n d uri nal ysis. La b orat or y 
e val uati o ns will be e val uate d t o deter mi ne t he i nci de nce of a b n or malities t hat e mer ge d uri n g t he 
st u d y. La b orat or y a b n or malities will be s u m marize d i n s hift ta bles. 
1 2. 6. 3.   
Vit al Si g ns  
Vital si g ns will be e xa mi ne d t o deter mi ne t he i nci de nce of cli nicall y rele va nt a b n or malities. T he 
defi niti o ns of t hese a b n or malities are pr o vi de d i n Ta ble  2 . 
T a ble  2 :  
Criteri a t o Deter mi ne Cli nic all y Rele v a nt A b n or m alities i n Vit al Si g ns  
Vit al Si g n  
Criteri a f or A b n or m alities  
Te m perat ure  
>  3 8 °C a n d a n i ncrease fr o m pre d osi n g of at least 1 °C  
P ulse rate  
>  1 2 0 beats per mi n ute a n d a n i ncrease fr o m pre d osi n g of m ore t ha n 
2 0  beats per mi n ute, or  
<  5 0 beats per mi n ute a n d a decrease fr o m pre d osi n g of m ore t ha n 
2 0  beats per mi n ute  
S yst olic Bl o o d Press ure  
>  1 8 0 m m H g a n d a n i ncrease fr o m pre d osi n g of m ore t ha n 4 0  m m H g, 
or  
<  9 0 m m H g a n d a decrease fr o m pre d osi n g of m ore t ha n 3 0 m m H g  
Diast olic Bl o o d Press ure  
>  1 0 5 m m H g a n d a n i ncrease fr o m pre d osi n g of m ore t ha n 3 0  m m H g, 
or  
<  5 0 m m H g a n d a decrease fr o m pre d osi n g of m ore t ha n 2 0  m m H g  
F or eac h vital si g n, t he n u m ber of partici pa nts e val uate d a n d t he n u m ber a n d perce nta ge of 
partici pa nts wit h t he defi ne d a b n or malit y at a n y ti me p ost baseli ne will be prese nte d.  
1 2. 6. 4.   
1 2 -Le a d E C G  
A listi n g of partici pa nts wit h a b n or mal stat us will be prese nte d. C ha n ges fr o m baseli ne will be 
s u m marize d usi n g s hift ta bles. 
1 2. 6. 5.   
C -S S R S  
I nci de nce of p ote ntiall y cli nicall y si g nifica nt criteria at a n y p ost baseli ne visit  a n d s hifts fr o m 
baseli ne  i n C -S S R S will be s u m marize d usi n g c o u nts a n d perce nta ges.  
1 2. 6. 6.   
E D S S  
C ha n ge i n E D S S sc ore fr o m Baseli ne t o Wee k 2 4 a n d Wee k 4 8 will be s u m marize d descri pti vel y 
( n u m ber of partici pa nts, 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). 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 4  
1 2. 7.   
Met h o ds of A n al ysis f or I m m u n o ge nicit y D at a a n d A nti -J C V 
A nti b o d ies 
I m m u n o ge nicit y is meas ure d b y t he prese nce of a nti-nataliz u ma b a nti b o dies. T he i nci de nce of 
a nti-nataliz u ma b a nti b o dies a n d a nti -J C V a nti b o dies will be s u m marize d descri pti vel y. 
1 2. 8.   
I nteri m A n al yses 
A n i nteri m a nal ysis, base d o n t he pri mar y e n d p oi nt of c u m ulati ve n u m ber of ne w acti ve lesi o ns, 
will be perf or me d at Wee k 2 4. T he i nteri m efficac y data will be s u m marize d descri pti vel y a n d 
a nal yze d usi n g ne gati ve bi n o mial distri b uti o n. 
 
 
 T he i nteri m safet y data will als o be s u m marize d. 
1 2. 9.   
S a m ple Size C o nsi der ati o ns  
T he st u d y pla ns t o e nr oll a p pr o xi matel y 2 0 partici pa nts w hic h was base d o n feasi bilit y. 
A p pr o xi matel y 1 5  t hr o u g h 1 7 e val ua ble partici pa nts are dee me d s ufficie nt t o c haracterize t he 
efficac y pr ofile of nataliz u ma b S C.  
T he mar gi n i n St u d y 1 0 1 M S 3 3 0 s h o wi n g c o m para bilit y of t he nataliz u ma b S C t o I V is set at 
2. 3 2, w hic h is o ne -t hir d of t he mea n differe nce ( 1. 5 3 a n d 8. 4 9) bet wee n t he nataliz u ma b a n d 
place b o gr o u ps i n ne w acti ve lesi o ns at Wee k  2 4 i n Ja pa nese nataliz u ma b I V st u d y 1 0 1 M S 2 0 3. 
T o de m o nstrate t he c o m para bilit y of nataliz u ma b S C t o I V, 1 5  e val ua ble partici pa nts all o w at 
least 8 0 % pr o ba bilit y t hat t he u p per li mit of t he 9 5 % CI f or mea n ne w acti ve lesi o ns at Wee k 2 4 
i n nataliz u ma b S C is l o wer t ha n 3. 8 5 (i.e., 2. 3 2 plus 1. 5 3), ass u mi n g si milar fiel d M RI mac hi nes 
are use d f or St u dies  1 0 1 M S 2 0 3 a n d 1 0 1 M S 3 3 0 a n d t he tr ue mea n of ne w acti ve lesi o ns f or t he 
nataliz u ma b S C is 1. 5 3. I n a d diti o n, ass u mi n g 7 0 % of partici pa nts will ha ve M RIs usi n g 3 T 
mac hi nes i n St u d y  1 0 1 M S 3 3 0, c o m pare d t o a p pr o xi matel y 1 3 % i n St u d y  1 0 1 M S 2 0 3, a n d t he 
tr ue mea n of ne w acti ve lesi o ns is 1. 7 3, 1 7 e val ua ble partici pa nts all o w 8 0 % pr o ba bilit y t hat 
o bser vi n g t he u p per li mit of 9 5 % CI f or ne w acti ve lesi o ns at Wee k 2 4 i n nataliz u ma b S C is 
l o wer t ha n 3. 8 5 [S hila ne a n d Bea n 2 0 1 3 ]. 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 5  
1 3.   
E T HI C A L A N D R E G U L A T O R Y R E Q UI R E M E N T S  
T he S p o ns or, a n y c o ntracte d t hir d part y, 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 C H a n d 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 ors are res p o nsi ble f or de m o nstrati n g ti mel y o versi g ht of all cli nical trial data fr o m 
t heir site, i ncl u di n g data e xter nal t o t he electr o nic data ca pt ure s yste m, s uc h as la b orat or y a n d 
i ma gi n g data. I n vesti gat ors m ust a p pr o ve all t heir data on c o m plete d e C R Fs b y si g ni n g 
electr o nicall y, at t he partici pa nt, visit, or case b o o k le vel, at a n y ti me pri or t o a n i nteri m l oc k or 
data base l oc k, as well as bef ore a n y s u bse q ue nt re -l oc k. T he electr o nic data ca pt ure s yste m d oes 
n ot pr o hi bit I n vesti gat or a p pr o val or si g ni n g i n a n y wa y.  
T he I n vesti gat or 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 grit y of t he tas ks perf or me d a n d an y data ge nerate d.  
1 3. 1.   
Decl ar ati o n of Helsi n ki  
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 3. 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 C F, a n d ot her re q uire d 
st u d y d oc u me nts pri or t o starti n g t he st u d y. T he S p o ns or will s u b mit d oc u me nts o n be half of t he 
st u d y sites.  
If t he I n vesti gat or ma kes a n y c ha n ges t o t he I C F, t he S p o ns or m ust a p pr o ve t he c ha n ges bef ore 
t he I C F 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 
t he S p o ns or. 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 t he S p o ns or.  
It is t he res p o nsi bilit y of t he I n 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.  
T he S p o ns or 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 na l 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 uall y. 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 6  
At t he c o m pleti o n or ter mi nati o n of t he st u d y, w here re q uire d, 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 t he S p o ns or.  
1 3. 3.   
C h a n ges t o Fi n al 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 partici pa nt 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 d y 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 
la w, s uc h m o dificati o ns m ust als o be a p pr o ve d b y 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, t he S p o ns or 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 partici pa nt. 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 I C F ma y re q uire si milar m o dificati o ns (see 
Secti o n  1 3. 4 ). 
1 3. 4.   
I nf or me d C o nse nt 
Pri or t o perf or mi n g a n y st 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, 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.  
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 partici pa nt m ust be e x plai ne d t o t he partici pa nt a n d/ or 
t he partici pa nt’s le gall y a ut h orize d re prese ntati ve. T he partici pa nt a n d/ or t he partici pa nt’s le gall y 
a ut h orize d re prese ntati ve 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.  
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 partici pa nt a n d/ or t he partici pa nt’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 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 partici pa nt’s me dical rec or d.  
W he n a d diti o nal i nf or mati o n t hat ma y affect partici pa nts’ willi n g ness t o c o nti n ue i n t he st u d y 
bec o mes a vaila ble, t he I n vesti gat ors will be n otifie d i n a ti mel y ma n ner, acc or di n g t o all l ocal 
a n d a p plica ble la w. A n u p date d I C F ma y be re q uire d.  
1 3. 5.   
P artici p a nt 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 a p plica ble nati o nal a n d l ocal pri vac y re g ulati o ns 
(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). 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 7  
D uri n g t he st u d y, partici pa nts’ race a n d et h nicit y will be c ollecte d ( u nless t he c ollecti o n is n ot 
per mitte d b y a p plica ble la w or n ot a p pr o ve d b y t he g o ver ni n g et hics c o m mittee). T hese data will 
be use d i n t he a nal ysis of t he safet y a n d/ or P K pr ofile of t h e st u d y treat me nt. Beca use it is n ot 
al wa ys 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, t his 
i nf or mati o n will be of val ue i n t he a nal ysis of efficac y a n d safet y data.  
St u d y re p orts will be use d f or researc h p ur p oses o nl y. T he partici pa nt will n ot be i de ntifie d b y 
na me i n e C R Fs, st u d y -relate d f or ms, st u d y re p orts, or a n y relate d p u blicati o ns. T he S p o ns or, 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 t his st u d y. E ver y eff ort will be ma de t o kee p t he partici pa nt’s pers o nal me dical 
data c o nfi de ntial.  
1 3. 6.   
C o m pe ns ati o n f or I nj ur y  
T he S p o ns or 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 3. 7.   
C o nflict of I nterest  
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 t he 
S p o ns or) wit h t he partici pa nt bef ore t he partici pa nt ma kes a decisi o n t o partici pate i n t he st u d y.  
1 3. 8.   
St u d y Re p ort Si g n at or y  
T he S p o ns or 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 mite 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 I n 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 partici pa nt e nr oll me nt; or b y ot her fact ors 
deter mi ne d t o be rele va nt b y t he S p o ns or. 
1 3. 9.   
Re gistr ati o n of St u d y a n d Discl os ure of St u d y Res ults  
T he S p o ns or will re gister t he st u d y a n d p ost st 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.  
T he S p o ns or als o will n otif y, w he n re q uire d, t he re g ulat or y a ut h orities a n d et hics c o m mittees 
a b o ut t he c o m pleti o n or ter mi nati o n of t his st u d y a n d se n d a c o p y of t he st u d y s y n o psis i n 
acc or da nce wit h necessar y ti meli nes.  
1 3. 1 0.  
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 or st u d y rec or ds will meet t he strictest sta n dar d a p plica ble t o t hat 
site, as dictate d b y 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 In vesti gat or m ust n otif y t he 
S p o ns or i n writi n g a n d recei ve writte n a ut h orizati o n fr o m t he S p o ns or t o destr o y st u d y rec or ds. 
I n a d diti o n, t he I n vesti gat or m ust n otif y t he S p o ns or of a n y c ha n ges i n t he arc hi val arra n ge me nts 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 8  
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 n vesti gat or lea ves t he site. 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6 9  
1 4.   
K E Y R O L E S A N D S T U D Y G O V E R N A N C E C O M MI T T E E S  
1 4. 1.   
Site St aff  
T he I n vesti gat or of t he site will desi g nate t he a p pr o priate site pers o n nel a n d t heir r ole i n t he 
st u d y. 
1 4. 2.   
Ve n d ors  
T he S p o ns or will e ns ure o versi g ht of a n y 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 4. 2. 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 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, ma na ge me nt of S A E re p orts, m o nit ori n g, a n d data ma na ge me nt.  
1 4. 2. 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 partici pa nts are scree ne d or e nr olle d, t he I R 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 4. 2. 3.   
Electr o nic D at a C a pt ure  
Partici pa nt 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 e C R Fs b y a We b -base d 
electr o nic data ca pt ure t o ol c o nfi g ure d b y  t he S p o ns or a n d h oste d b y t he electr o nic data ca pt ure 
ve n d or.  
1 4. 2. 4.   
Ce ntr al L a b or at ories f or L a b or at or y Assess me nts  
A ce ntral la b orat or y has bee n selecte d b y t he S p o ns or t o a nal yze t he he mat ol o g y, bl o o d 
c he mistr y, a nti b o d y , a n d uri ne sa m ples c ollecte d f or t his st u d y. P K a n d P D sa m ples will be 
a nal yze d at a la b orat or y selecte d b y t he S p o ns or . 
N o d u plicate sa m ples will be ta ke n; h o we ver, ali q u ots of t he ori gi nal sa m ples will be st ore d as 
bac k -u p i n case t he ori gi nal sa m ple s are l ost or n ot e val ua ble. 
1 4. 2. 5.   
Ce ntr al F acilit y f or Ot her Assess me nts  
A ce ntral facilit y has bee n selecte d b y t he S p o ns or t o rea d a n d i nter pret all M RI sca ns f or t his 
st u d y. 
1 4. 2. 6.   
Ce ntr al Re vie w of R aters  
T he S p o ns or has selecte d a rater ma na ge me nt gr o u p t o esta blis h rater q ualificati o ns, pr o vi de 
st u d y-s pecific trai ni n g a b o ut t he rater pr ocess, a n d pr o vi de o versi g ht. As part of t he o versi g ht 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
7 0  
pr ocess, t he rater ma na ge me nt gr o u p will i nc or p orate a ce ntral re vie w of t he raters t o e ns ure t hat 
data are c o nsiste ntl y rate d acr oss sites.  
1 4. 3.   
St u d y C o m mittees  
N ot a p plica ble.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
7 1  
1 5.   
A D MI NI S T R A TI V E P R O C E D U R E S  
1 5. 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 partici pa nts pri or t o t he S p o ns or c o m pleti n g a st u d y 
i nitiati o n visit. T his i nitiati o n visit wit h t he I n vesti gat or a n d ot her site staff, as a p pr o priate, will 
i ncl u de a detaile d re vie w of t he pr ot oc ol, st u d y pr oce d ures, a n d st u d y res p o nsi bilities.  
1 5. 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 ple me 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. T he I n vesti gat or is res p o nsi ble f or e n d orsi n g 
all e C R F data pri or t o a n y i nteri m or fi nal data base l oc k.  
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 t he S p o ns or  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 s o urce data) as re q ueste d.  
1 5. 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 b y pr o vi di n g direct access t o s o urce data 
a n d t o t he partici pa nts’ 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 Me dical 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 wil l pr o vi de t he m o nit ori n g strate g y, 
wit h e m p hasis o n partici pa nt safet y, data i nte grit y, a n d critical data a n d pr ocesses.  
D uri n g t hese visits, e 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 t he S p o ns or i n a ti mel y fas hi o n t o allo 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 partici pa nt 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, a n 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 i n vesti gati o nal site a n d its facilities. 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
7 2  
1 5. 4.   
St u d y F u n di n g  
T he S p o ns or is  res p o nsi ble f or setti n g u p t he f u n di n g f or 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, I n vesti gat or, a n d S p o ns or  
or ga ni zati o n. 
1 5. 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 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
7 3  
1 6.   
R E F E R E N C E S  
Belac he w S, P ha n -Ba R, Bart h ol o mé E, et al. Nataliz u ma b i n d uces a ra pi d i m pr o ve me nt of 
disa bilit y stat us a n d a m b ulati o n after fail ure of pre vi o us t hera p y i n rela psi n g -re mitti n g m ulti ple 
scler osis. E ur J Ne ur ol. 2 0 1 1; 1 8( 2): 2 4 0-2 4 5.  
C olla b orat ors G N. Gl o bal, re gi o nal, a n d nati o nal b ur de n of ne ur ol o gical dis or ders, 1 9 9 0 -2 0 1 6: a 
s yste matic a nal ysis f or t he Gl o bal B ur de n of Disease St u d y 2 0 1 6. La ncet Ne ur ol. 
2 0 1 9; 1 8( 5): 4 5 9 -4 8 0. E p u b 2 0 1 9/ 0 3/ 1 4.  
Des pia u F, Za gala Y, Del or d J P, et al. [ O bser vati o nal st u d y of o ut patie nt u nit d urati o n of sta y 
de pe n di n g o n t he r o ute of a d mi nistrati o n (i ntra ve n o us vs s u bc uta ne o us) f or a tar gete d t hera p y]. 
B ull Ca ncer. 2 0 1 7; 1 0 4( 1 0): 8 6 9 -8 7 4. E p u b 2 0 1 7/ 1 0/ 1 3.  
E va ns C, Bela n d S G, K ula ga S, et al. I nci de nce a n d pre vale nce of m ulti ple scler osis i n t he 
A mericas: a s yste matic re vie w. Ne ur oe pi de mi ol o g y. 2 0 1 3; 4 0( 3): 1 9 5 -2 1 0.  
Fala n ga M, Ca nz o na A, Mazz o ni D. Prefere nce f or S u bc uta ne o us I njecti o n or I ntra ve n o us 
I nf usi o n of Bi ol o gical T hera p y A m o n g Italia n Patie nts Wit h S L E. J Patie nt E x p. 2 0 1 9; 6( 1): 4 1-
4 5. E p u b 2 0 1 8/ 0 4/ 2 6.  
Far olfi A, Sili m ba ni P, Galle gati D, et al. Res o urce utilizati o n a n d c ost sa vi n g a nal ysis of 
s u bc uta ne o us vers us i ntra ve n o us trast uz u ma b i n earl y breast ca ncer patie nts. O nc otar get. 
2 0 1 7; 8( 4 6): 8 1 3 4 3 -8 1 3 4 9. E p u b 2 0 1 7/ 0 6/ 1 6.  
G B D 2 0 1 6 M ulti ple Scler osis C olla b orat ors. Gl o bal, re gi o nal, a n d nati o nal b ur de n of m ulti ple 
scler osis 1 9 9 0-2 0 1 6: a s yste matic a nal ysis f or t he Gl o bal B ur de n of Disease St u d y 2 0 1 6. La ncet 
Ne ur ol. 2 0 1 9; 1 8( 3): 2 6 9 -2 8 5. E p u b 2 0 1 9/ 0 1/ 2 1.  
H ori uc hi I, Kira J. M ulti ple scler osis. I n: Ta m ura A, Mats uta ni M, S hi miz u T, e dit ors. E vi de nce -
base d basic g ui deli nes f or treat me nt of cere br os pi nal diseases. T o k y o: Me dical Vie w; 2 0 0 4. p 
2 7 6 -9.  
Ki n os hita M, O bata K, Ta na ka M. Latit u de has m ore si g nifica nt i m pact o n pre vale nce of 
m ulti ple scler osis t ha n ultra vi olet le vel or s u ns hi ne d urati o n i n Ja pa nese p o p ulati o n. Ne ur ol Sci. 
2 0 1 5.  
Kira J. M ulti ple scler osis i n t he Ja pa nese p o p ulati o n. La ncet Ne ur ol. 2 0 0 3; 2( 2): 1 1 7 -2 7.  
K o belt G, Kaste n g F. Access t o i n n o vati ve treat me nts i n m ulti ple scler osis i n E ur o pe. A re p ort 
pre pare d f or t he E ur o pea n Fe derati o n of P har mace utical I n d ustr y Ass ociati o ns ( E F PI A). 2 0 0 9.  
Lai C H, Tse n g H F. P o p ulati o n -base d e pi de mi ol o gical st u d y of ne ur ol o gical diseases i n Tai wa n: 
I. Cre utzfel dt-Ja k o b disease a n d m ulti ple scler osis. Ne ur oe pi de mi ol o g y. 2 0 0 9; 3 3( 3): 2 4 7-5 3. 
E p u b 2 0 0 9/ 0 7/ 2 7.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
7 4  
L o pez -Vi va nc o G, Sal va d or J, Diez R, et al. C ost mi ni mizati o n a nal ysis of treat me nt wit h 
i ntra ve n o us or s u bc uta ne o us trast uz u ma b i n patie nts wit h H E R 2-p ositi ve breast ca ncer i n S pai n. 
Cli n Tra nsl O nc ol. 2 0 1 7; 1 9( 1 2): 1 4 5 4 -1 4 6 1. E p u b 2 0 1 7/ 0 6/ 0 2.  
L u bli n F D, Rei n g ol d S C, C o he n J A, et al. Defi ni n g t he cli nical c o urse of m ulti ple scler osis: t he 
2 0 1 3 re visi o ns. Ne ur ol o g y. 2 0 1 4; 8 3( 3): 2 7 8 -8 6.  
Ma k ha ni N, M orr o w S A, Fis k J, et al. M S i nci de nce a n d pre vale nce i n Africa, Asia, A ustralia 
a n d Ne w Zeala n d: A s yste matic re vie w. M ult Scler Relat Dis or d. 2 0 1 4; 3( 1): 4 8 -6 0.  
M orr o w S A, O' C o n n or P W, P ol ma n C H, et al. E val uati o n of t he s y m b ol di git m o dalities test 
( S D M T) a n d M S ne ur o ps yc h ol o gical scree ni n g q uesti o n naire ( M S N Q) i n nataliz u ma b-treate d 
M S patie nts o ver 4 8 wee ks. M ult Scler. 2 0 1 0; 1 6( 1 1): 1 3 8 5 -9 2.  
O gi n o M, O ka m ot o S, O hta H, et al. Pre vale nce, Treat me nts a n d Me dical C ost of M ulti ple 
Scler osis i n Ja pa n Base d o n A nal ysis of a Healt h I ns ura nce Clai ms Data base. Cli n E x p 
Ne ur oi m m u n ol. 2 0 1 7; 8( 4): 3 1 8 -3 2 6. E p u b 2 0 1 7/ 0 9/ 0 4.  
Olse n J, Je nse n K F, Olese n D S, et al. C osts of s u bc uta ne o us a n d i ntra ve n o us a d mi nistrati o n of 
trast uz u ma b f or patie nts wit h H E R 2-p ositi ve breast ca ncer. J C o m p Eff Res. 2 0 1 8; 7( 5): 4 1 1 -4 1 9. 
E p u b 2 0 1 7/ 1 2/ 0 4.  
Ot urai A B, K oc h -He nri kse n N, Peterse n T, et al. Efficac y of nataliz u ma b i n m ulti ple scler osis 
patie nts wit h hi g h disease acti vit y: a Da nis h nati o n wi de st u d y. E ur J Ne ur ol. 2 0 0 9; 1 6( 3): 4 2 0 -3.  
Pi v ot X, Gli g or o v J, M üller V, et al. Prefere nce f or s u bc uta ne o us or i ntra ve n o us a d mi nistrati o n 
of trast uz u ma b i n patie nts wit h H E R 2 -p ositi ve earl y breast ca ncer ( Pref Her): a n o pe n -la bel 
ra n d o mise d st u d y. La ncet O nc ol. 2 0 1 3; 1 4( 1 0): 9 6 2-7 0. E p u b 2 0 1 3/ 0 8/ 1 9.  
R osati G. T he pre vale nce of m ulti ple scler osis i n t he w orl d: a n u p date. Ne ur ol Sci. 
2 0 0 1; 2 2( 2): 1 1 7 -3 9.  
Sa n galli F, M oi ola L, B ucell o S, et al. Efficac y a n d t olera bilit y of nataliz u ma b i n rela psi n g –
re mitti n g m ulti ple scler osis patie nts: a p ost-mar keti n g o bser vati o nal st u d y. Ne ur ol Sci. 
2 0 1 1; 3 1( 0): 2 9 9 -3 0 2.  
Sa nt us P, Ferra n d o M, Baiar di ni I, et al. Patie nts beliefs o n i ntra ve n o us a n d s u bc uta ne o us r o utes 
of a d mi nistrati o n of bi ol o gics f or se vere ast h ma treat me nt: A cr oss -secti o nal o bser vati o nal 
s ur ve y st u d y. W orl d Aller g y Or ga n J. 2 0 1 9; 1 2( 4): 1 0 0 0 3 0. E p u b 2 0 1 9/0 4/ 2 8.  
Sc h u mac her G, Bee be G, Ki bler R, et al. Pr o ble ms of e x peri me ntal trials of t hera p y i n m ulti ple 
scler osis: Re p ort b y t he Pa nel o n t he E val uati o n of E x peri me ntal Trials of T hera p y i n M ulti ple 
Scler osis. A n n N Y Aca d Sci. 1 9 6 5; 1 2 2( 1): 5 5 2 -5 6 8.  
S hila ne D, Bea n D. Gr o wt h Esti mat ors a n d C o nfi de nce I nter vals f or t he Mea n of Ne gati ve 
Bi n o mial Ra n d o m Varia bles wit h U n k n o w n Dis persi o n. J o ur nal of Pr o ba bilit y a n d Statistics. 
2 0 1 3; 2 0 1 3: 1 -9.  

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
7 5  
S yri os J, Pa p pa E, V ola ka kis N, et al. Real -W orl d Data o n Healt h -Relate d Q ualit y of Life 
Assess me nt i n Patie nts Wit h Breast Ca ncer Recei vi n g S u bc uta ne o us Trast uz u ma b. Breast 
Ca ncer ( A uc kl). 2 0 1 8; 1 2: 1 1 7 8 2 2 3 4 1 8 7 5 8 0 3 1. E p u b 2 0 1 8/ 0 2/ 2 0.  
T h o m ps o n AJ, Ba n well B L, Bar k h of F, et al. Dia g n osis of m ulti ple scler osis: 2 0 1 7 re visi o ns of 
t he Mc D o nal d criteria. La ncet Ne ur ol. 2 0 1 8; 1 7( 2): 1 6 2-1 7 3. E p u b 2 0 1 7/ 1 2/ 2 1.  
Walt o n C, Ki n g R, Rec ht ma n L, et al. Risi n g pre vale nce of m ulti ple scler osis w orl d wi de: 
I nsi g hts fr o m t he Atlas of M S, t hir d e diti o n. M ult Scler. 2 0 2 0; 2 6( 1 4): 1 8 1 6-1 8 2 1. E p u b 
2 0 2 0/ 1 1/ 1 1.  
 

Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
7 6  
1 7.   
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 Si n gle-Ar m, O pe n -La bel, P hase 3 St u d y t o E val uate t he 
Efficac y, Safet y, P har mac o ki netics, a n d P har mac o d y na mics of M ulti ple D oses of Nataliz u ma b 
( B G 0 0 0 0 2) A d mi nistere d t o Ja pa nese Partici pa nts Wit h Rela psi n g-Re mitti n g M ulti ple Scler osis 
via a S u bc uta ne o us R o ute of A d mi nistrati o n,” a n d a gree t o c o n d uct t he st u d y acc or di n g t o t he 
pr ot oc ol a n d t he a p plica ble I C H g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m all w h o assist me 
i n t he c o n d uct of t his st u d y of t heir res p o nsi bilities a n d o bli gati o ns. 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
I n vesti gat or’s Si g nat ure  
  
  
  
Date  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
I n vesti gat or’s Na me ( Pri nt) 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
St u d y Site ( Pri nt)  
 
 
 

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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
1  
 
 
 
 
 
 
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  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
A M E N D M E N T S U M M A R Y  
Bi o ge n Pr ot oc ol 1 0 1 M S 3 3 0  
A Si n gle -Ar m, O pe n -La bel, P hase 3 St u d y t o E val uate t he Efficac y, Safet y, P har mac o ki netics, 
a n d P har mac o d y na mics of M ulti ple D oses of Nataliz u ma b ( B G 0 0 0 0 2) A d mi nistere d t o Ja pa nese 
Partici pa nts Wit h Rela psi n g -Re mitti n g M ulti ple Scler osis via a S u bc uta ne o us R o ute of 
A d mi nistrati o n  
Versi o n 3. 0  
Date: 2 1  Fe br uar y 2 0 2 2  
Versi o n 3. 0 of t he pr ot oc ol has bee n pre pare d f or t his a me n d me nt, w hic h s u perse des Versi o n 2. 0.  
 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2  
P RI M A R Y R E A S O N F O R A M E N D M E N T  
T he pri mar y reas o n f or t his a me n d me nt t o Pr ot oc ol 1 0 1 M S 3 3 0  was t o i ncl u de a safet y p h o ne call 
at Wee k  6 0.  
Ne w te xt is s h o w n i n b ol d t y pe; delete d te xt is s h o w n wit h a stri ket hr o u g h. 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
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 wit h o ut t he writte n c o nse nt of Bi o ge n  M A I nc.  
3  
Secti o n 1. 3, Sc he d ule of Acti vities  
N o w re a ds:  
 
  
Part  1: 2 4 -Wee k O pe n -La bel Treat me nt   
Part  2: 2 4 -Wee k O pe n -La bel Treat me nt  Safet y  
F U  
S afet y 
F U 
P h o ne 
C all 1 
Safet y F U 
P h o ne 
Call 1 2 
U nsc he d ule d  
S C R   
B L  
W 1   W 4  
W 8  W 1 2  W 1 6  W 2 0  W 2 4  W 2 8  W 3 2  W 3 6  W 4 0  W 4 4  W 4 8  W 5 2   W 6 0   
W 7 2  
Ne ur ol o gical 
W orse ni n g  
E T  
Visit  
Assess me nts  
D -2 8 
t o 
D -1  
D 1  D 6 t o 
D 8  
D 2 9  
( ± 3) 
D 5 7  
( ± 3) 
D 8 5  
( ± 3) 
D 1 1 3  
( ± 3) 
D 1 4 1  
( ± 3) 
D 1 6 9  
( ± 3) 
D 1 9 7  
( ± 3) 
D 2 2 5  
( ± 3) 
D 2 5 3  
( ± 3) 
D 2 8 1  
( ± 3) 
D 3 0 9  
( ± 3) 
D 3 3 7  
( ± 3) 
D 3 6 5  
( ± 7) 
D 4 2 1 
( ± 1 0) 
D 5 0 5  
( ± 1 0) 
A d verse E ve nt 
Rec or di n g  
 
--------------------------------------------------------------------------------------X -------------------------------------------------------------------------------------  
Seri o us A d verse 
E ve nt Re p orti n g  
-------------------------------------------------------------------------------------X ---------------------------------------------------------------------------------------------------  
C o nc o mita nt T hera p y 
a n d Pr oce d ures 
Rec or di n g  
-------------------------------------------------------------------------------------X ---------------------------------------------------------------------------------------------------  
1 P artici p a nts s h o ul d h a ve a f oll o w -u p s afet y p h o ne c all 1 2 wee ks after t heir l ast d ose of st u d y tre at me nt f or A E/ S A E rec or di n g a n d c o nc o mit a nt 
t her a p y a n d pr oce d ure rec or di n g. 
1 2 Partici pa nts s h o ul d ha ve a f oll o w -u p safet y p h o ne call 2 4 wee ks after t heir last d ose of st u d y treat me nt f or A E/ S A E rec or di n g a n d c o nc o mit a nt t her a p y  a n d 
pr oce d ure rec or di n g  a n d  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.  
R ati o n ale:  Treat me nt -e mer ge nt A E  is defi ne d as ha vi n g a n o nset date o n or after t he first ra n d o mize d i njecti o n date a n d u p t o 8 4  da ys 
after t he last i njecti o n date. C o nsi deri n g t his,  a safet y F U p h o ne call was a d de d at Wee k 6 0 t o assess safet y 1 2 wee ks (i.e., 8 4  da ys) 
after t he last d ose of st u d y treat me nt. 
T his c ha n ge als o affects Secti o n 1. 1, S y n o psis, Secti o n 1. 2, St u d y Desi g n Sc he matic, Secti o n 5. 1, St u d y O ver vie w, a n d Secti o n  5. 2, 
St u d y D urati o n f or Partici pa nts.  
 
 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4  
S U M M A R Y O F M A J O R C H A N G E S T O T H E P R O T O C O L  
C ha n ges t o t he pr ot oc ol are prese nte d c hr o n ol o gicall y. Ne w te xt is s h o w n i n b ol d t y pe; delete d 
te xt is s h o w n wit h a stri ket hr o u g h. 
S p o ns or I nf or mati o n  
C h a n ge:  C ha n ges were ma de t o t he S p o ns or i nf or mati o n t o re m o ve Bi o ge n M A I nc. N o w re a ds:
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  
Bi o ge n Ja pa n Lt d.  
Ni h o n bas hi 1 -c h o me 
Mits ui B uil di n g 1 4 F  
4 -1 Ni h o n bas hi 1 -c h o me 
C h u o -k u, T o k y o  
1 0 3 -0 0 2 7 Ja pa n  
 
F or ur ge nt me dical iss ues i n w hic h t he st u d y Me dical M o nit or s h o ul d be c o ntacte d, please refer 
t o c o ntact i nf or mati o n i n t he pr ot oc ol attac h me nt  f or c o m plete c o ntact i nf or mati o n. 
Bi o ge n  T he S p o ns or  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 a n d ot her t hir d parties; h o we ver, Bi o ge n  t he S p o ns or retai ns o verall 
acc o u nta bilit y f or t hese acti vities.  
R ati o n ale:  Bi o ge n M A I nc.  is n ot  t he S p o ns or of t he cli nical trial i n Ja pa n.  
T his c ha n ge als o affects Secti o n 1 4. 2, Ve n d ors; Secti o n 1 4. 2. 3, Electr o nic Data Ca pt ure; a n d 
Secti o n 1 5. 4, St u d y F u n di n g.  
Secti o n 6. 1, I ncl usi o n Criteria  
C h a n ge:  I ncl usi o n criteri o n 2, re gar di n g i nf or me d c o nse nt, was u p date d.  
N o w re a ds:  
2.   
Ja pa nese me n a n d w o me n a ge d 1 8 t o 6 5 years, i ncl usi ve, at t he ti me of i nf or me d c o nse nt. 
F or partici pa nts a ge d < 2 0 years * , writte n i nf or me d c o nse nt s h o ul d be o btai ne d fr o m t he 
partici pa nt a n d his or her le gall y acce pta ble re prese ntati ve.  
*I nf or me d c o nse nt fr o m a le g all y acce pt a ble re prese nt ati ve is n ot m a n d at or y if t he 
p artici p a nt is cl assifie d as a n a d ult b ase d o n t he l atest a p plic a ble l oc al l a ws.  
R ati o n ale:  T his i ncl usi o n criteri o n was u p date d t o clarif y t hat it is n ot ma n dat or y t o o btai n 
i nf or me d c o nse nt fr o m a le gall y acce pta ble re prese ntati ve if a partici pa nt was c o nsi dere d a n 
a d ult per t he latest a p plica ble l ocal la ws. 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5  
Secti o n 6. 2, E xcl usi o n Criteria  
C h a n ge: E xcl usi o n criteri o n 2 0, re gar di n g T B testi n g, was u p date d.  
N o w re a ds:  
2 0.   
A p ositi ve dia g n ostic T B test res ult wit hi n 3 0  da ys of Da y 1, defi ne d as a p ositi ve I G R A 
test res ult or 2 s uccessi ve i n deter mi nate I G R A test res ults 
A p artici p a nt w h o is p ositi ve or u ncert ai n of bei n g p ositi ve f or T B * wit hi n 3 0  d a ys of 
D a y  1.  
* N ote: P artici p a nt wit h f oll o wi n g I G R A test res ults will be e xcl u de d:  
T -s p ot T B test: p ositi ve  or 2 s uccessi ve b or derli ne/i n v ali d test res ults  
Q u a nti F E R O N -T B G ol d Pl us test: p ositi ve or 2 s uccessi ve i n deter mi n ate test res ults  
R ati o n ale: T his e xcl usi o n criteri o n was u p date d t o clarif y t hat a partici pa nt wit h 2 s uccessi ve 
b or derli ne/i n vali d test res ults base d o n a T -s p ot T B test or 2 s uccessi ve i n deter mi nate test res ults 
base d o n a Q ua nti F E R O N -T B G ol d Pl us test will be e xcl u de d beca use s uc h res ults i n dicate 
u ncertai nt y of bei n g p ositi ve f or T B.  
Secti o n 6. 3. 2, Retesti n g  
C h a n ge: T his secti o n was u p date d t o i ncl u de rescree ni n g details.  
N o w re a ds:  
Partici pa nts w h o fail scree ni n g criteria beca use of a n o ut -of -ra n ge res ult t hat is n ot cli nicall y 
si g nifica nt ca n be reteste d o nce at t he discreti o n of t he I n vesti gat or. P artici p a nts w h o h a ve 
cli nic all y si g nific a nt a b n or m al l a b or at or y test v al ues s h o ul d n ot be reteste d.  T he Scree ni n g 
Peri o d ma y be e xte n de d f or eli gi ble i n di vi d uals w h o ca n n ot c o m plete t he Da y 1 Visit wit hi n 
2 8  da ys of si g ni n g t he I C F. I n di vi d uals w h o si g ne d t he I C F a n d s u bse q ue ntl y d o n ot meet 
c o nc o mita nt me dicati o n criteria ca n ha ve t heir Scree ni n g Peri o d e xte n de d t o e ns ure t he 
re q uire me nts f or c o nc o mita nt me dicati o n sta bilizati o n ha ve bee n met. 
Partici pa nts w h o ha ve cli nicall y si g nifica nt a b n or mal la b orat or y test val ues s h o ul d n ot be 
reteste d. 
If a p artici p a nt i niti all y f ails scree ni n g d ue t o meeti n g a n y of t he f oll o wi n g e xcl usi o n 
criteri a, t he p artici p a nt m a y be all o we d t o rescree n 1 ti me, at t he S p o ns or’s discreti o n:  
•  E xcl usi o n n o. 1: E vi de nce of c urre nt S A R S -C o V -2 i nfecti o n wit hi n 1 4 d a ys pri or 
t o Scree ni n g, bet wee n Scree ni n g a n d B aseli ne Visit, or at B aseli ne Visit, 
i ncl u di n g b ut n ot li mite d t o a fe ver (te m per at ure > 3 7. 5° C), ne w a n d persiste nt 
c o u g h, bre at hless ness, or l oss of t aste a n d/ or s mell ( N ote: If a S A R S -C o V -2 test 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
C O N FI D E N TI A L  
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[p ol y mer ase c h ai n re acti o n or ot her re g ul at or y a p pr o ve d met h o d ] is perf or me d 
per t he discreti o n of t he I n vesti g at or i n acc or d a nce wit h l oc al site pr actice, t he 
test res ult m ust be ne g ati ve i n or der f or t he p artici p a nt t o be e nr olle d i n t he 
st u d y) 
•  E xcl usi o n n o. 2: H a ve cl ose c o nt act wit hi n 1 4  d a ys pri or t o D a y 1 wit h a 
S A R S -C o V -2 p ositi ve i n di vi d u al. Cl ose c o nt act is defi ne d as:  
a.  f ace-t o-f ace c o nt act wit h a pr o b a ble or c o nfir me d c ase wit hi n 1 meter a n d f or 
at le ast 1 5 mi n utes;  
b.  direct p h ysic al c o nt act wit h a pr o b a ble or c o nfir me d c ase;  
c. direct c are f or a p atie nt wit h pr o b a ble or c o nfir me d C O VI D -1 9 dise ase 
wit h o ut t he use of rec o m me n de d pers o n al pr otecti ve e q ui p me nt; or  
d.  ot her sit u ati o ns as i n dic ate d b y l oc al ris k assess me nts.  
•  E xcl usi o n n o. 6: A n M S e x acer b ati o n (rel a pse) wit hi n 3 0  d a ys pri or t o 
e nr oll me nt or, i n t he o pi ni o n of t he I n vesti g at or, t he p artici p a nt n ot h a vi n g 
st a bilize d fr o m a pre vi o us rel a pse pri or t o e nr oll me nt ( D a y 1). 
•  E xcl usi o n n o. 9: Cli nic all y si g nific a nt i nfecti o us ill ness (e. g., cell ulitis, a bscess, 
p ne u m o ni a, se ptice mi a) wit hi n t he 3 0  d a ys pri or t o e nr oll me nt ( D a y 1).  
•  E xcl usi o n n o. 1 0: S y m pt o ms of b acteri al, f u n g al, or vir al i nfecti o n (i ncl u di n g 
u p per res pir at or y tr act i nfecti o n) wit hi n 1 4  d a ys pri or t o Scree ni n g or d uri n g 
t he scree ni n g peri o d ( D a y -2 8 t o D a y -1) . P artici p a nts wit h l oc al f u n g al i nfecti o n 
(e. g., c a n di di asis, ti ne a) are eli gi ble t o be rescree ne d after s uccessf ul tre at me nt of 
t he i nfecti o n. 
•  E xcl usi o n n o. 2 5: Tre at me nt wit h i m m u n os u p press a nt me dic ati o ns, e. g., 
az at hi o pri ne, c ycl o p h os p h a mi de, a n d met h otre x ate wit hi n 6 m o nt hs pri or t o 
e nr oll me nt ( D a y 1); mit o x a ntr o ne a n d c ycl os p ori ne wit hi n 1 2 m o nt hs pri or t o 
e nr oll me nt ( D a y 1).  
•  E xcl usi o n n o. 2 6: Tre at me nt wit h a n y of t he f oll o wi n g me dic ati o ns or pr oce d ures 
wit hi n 6 m o nt hs pri or t o e nr oll me nt ( D a y 1): I V i m m u n o gl o b uli n, 
pl as m a p heresis, or c yt a p heresis.  
•  E xcl usi o n n o. 2 7: Tre at me nt wit h a n y of t he f oll o wi n g me dic ati o ns wit hi n 
3 0  d a ys pri or t o e nr oll me nt ( D a y 1):  
a.  I V c ortic oster oi d tre at me nt 
b.  S yste mic c ortic oster oi d tre at me nt  
c. 4 -A mi n o p yri di ne or rel ate d pr o d ucts  

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
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•  E xcl usi o n n o. 2 8: Tre at me nt wit h s p hi n g osi ne 1 -p h os p h ate rece pt or m o d ul at ors 
(fi n g oli m o d, si p o ni m o d, or oz a ni m o d) wit hi n 9 0 d a ys pri or t o e nr oll me nt 
( D a y 1).  
•  E xcl usi o n n o. 2 9: Tre at me nt wit h f u m ar ates ( F u m a der m, Tecfi der a, or 
V u merit y) wit hi n 4 wee ks pri or t o e nr oll me nt ( D a y 1).  
•  E xcl usi o n n o. 3 0: B -cell-t ar gete d t her a pies f or t he tre at me nt of M S (e. g., 
ocreliz u m a b, rit u xi m a b, of at u m u m a b) wit hi n 1 2 m o nt hs of Scree ni n g; gre ater 
t h a n 1 2 m o nt hs of Scree ni n g is per missi ble wit h e vi de nce t h at t he C D 1 9 cells 
h a ve ret ur ne d t o wit hi n n or m al r a n ge ( per l oc al l a b or at or y refere nce r a n ge).  
•  E xcl usi o n n o. 3 1: Tre at me nt wit h i m m u n o m o d ul at or y me dic ati o ns (i ncl u di n g 
I F N-β a n d gl atir a mer acet ate) wit hi n 2 wee ks of e nr oll me nt ( D a y 1).  
•  E xcl usi o n n o. 3 2: A d mi nistr ati o n of a n y li ve -atte n u ate d v acci ne gi ve n wit hi n 
3 0  d a ys pri or t o D a y -1 or pl a n ne d t o be gi ve n d uri n g st u d y p artici p ati o n.  
•  E xcl usi o n n o. 3 3: Bl o o d d o n ati o n ( 1 u nit or m ore) wit hi n 9 0 d a ys pri or t o 
Scree ni n g, pl as m a d o n ati o n fr o m 1 wee k pri or t o Scree ni n g, a n d pl atelet 
d o n ati o n fr o m 6 wee ks pri or t o Scree ni n g.  
I n a d diti o n, p artici p a nts wit h a n ‘i n deter mi n ate res ult’ f or H C V a nti b o d y d uri n g 
Scree ni n g m a y be all o we d t o retest a n d will be re -e v al u ate d o n a c ase -b y -c ase b asis, after 
disc ussi o n wit h t he Me dic al M o nit or a n d S p o ns or Me dic al St u d y Direct or t o deter mi ne 
eli gi bilit y . 
U p o n rescree ni n g, a n d i n c o ns ult ati o n wit h t he Me dic al M o nit or a n d S p o ns or Me dic al 
St u d y Direct or, t he p artici p a nt s h o ul d si g n t he I C F a g ai n a n d re pe at t he scree ni n g 
assess me nts as per disc ussi o n wit h t he I n vesti g at or a n d st u d y te a m. 
Rescree ne d p artici p a nt will recei ve a ne w scree ni n g n u m ber, w here t he tr aili n g 
al p h a n u meric c h ar acter i n t he scree ni n g n u m ber will m o ve f or w ar d se q ue nti all y, e. g., fr o m 
X X X A t o X X X B .  
If t he p artici p a nt f ails scree ni n g t wice, t he y m a y n ot u n der g o f urt her scree ni n g f or t his 
st u d y. 
R ati o n ale:  
Rescree ni n g: Rescree ni n g details were a d de d t o all o w rescree ni n g if t he partici pa nt di d n ot meet 
s pecific ti me-b o u n d e xcl usi o n criteria.  
Case -b y -case retesti n g all o w i n g f or H C V a nti b o d y tests of ‘i n deter mi nate res ult’: D A A f or 
he patitis C i nfecti o n are a vaila ble i n Ja pa n. As per t he Ja pa n S ociet y of He pat ol o g y g ui deli nes 
f or t he ma na ge me nt of he patitis C vir us i nfecti o n: 2 0 1 9 u p date, D A A are rec o m me n de d f or 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
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i nitial a nti viral t hera p y i n h e patitis C i nfecti o n u n der certai n c o n diti o ns. T hese me dicati o ns ha ve 
hi g h c ure rates. If partici pa nts ha ve bee n treate d f or H C V i nfecti o n wit h ot her dr u gs pri or t o a 
first-ti me D A A, it d oes n ot r ule o ut t he p ossi bilit y of pre-e xisti n g li ver da ma ge vers us 
partici pa nts w h o were treate d f or H C V i nfecti o n f or t he first ti me wit h D A A ver y earl y i n t heir 
disease traject or y. It w o ul d be ris k y t o all o w pre vi o usl y treate d partici pa nts (treate d pri or t o 
D A A) t o e nr oll i n t he st u d y beca use t here ha ve bee n rare re p orts of cli nicall y si g nifica nt li ver 
i nj ur y, i ncl u di n g cases t hat rec urre d u p o n rec halle n ge wit h T ysa bri (n ote: s o me cases occ urre d i n 
patie nts wit h pre -e xisti n g li ver disease or i n t he prese nce of ot her dr u gs t hat ha ve bee n ass ociate d 
wit h he patic i nj ur y). He nce, a n i n deter mi nate res ult o n t he H C V a nti b o d y test will be e val uate d 
o n a case -b y -case basis b ut will e xcl u de ‘ pre vi o usl y treate d’ partici pa nts (e. g., partici pa nts 
treate d wit h I F N pri or t o treat me nt wit h D A A) a n d partici pa nts wit h cirr h osis/c hr o nic li ver 
da ma ge , e ve n if t here is n o e vi de nce of c urre nt h e patitis C i nfecti o n.  
Secti o n 1 1. 3. 2, A d verse E ve nts of S pecial I nterest   
C h a n ge: List of A E SI s was u p date d.   
N o w re a ds: A n A E of s pecial i nterest is a n A E of scie ntific a n d me dical c o ncer n s pecific t o t his 
st u d y, f or w hic h o n g oi n g m o nit ori n g a n d re p orti n g are re q uire d. T he f oll o wi n g A Es will be 
c o nsi dere d A E SIs: P M L, i njecti o n site pai n, o p p ort u nistic i nfecti o ns ot her t ha n P M L, her pes 
i nfecti o n, dr u g-i n d uce d li ver i nj ur y, h y perse nsiti vit y reacti o ns, a n d mali g na ncies. 
R ati o n ale: Her pes i nfecti o n was a d de d t o t he list of A E SIs beca use it is a n i m p orta nt i de ntifie d 
ris k f or T ysa bri. 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
C O N FI D E N TI A L  
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S U M M A R Y O F MI N O R C H A N G E S T O T H E P R O T O C O L  
T he f oll o wi n g mi n or c ha n ges were ma de t o t he pr ot oc ol, as a p pr o priate:  
•  T he versi o n n u m ber a n d date were u p date d t hr o u g h o ut t he pr ot oc ol.  
•  T y p o gra p hical err ors a n d f or matti n g were c orrecte d.  
•  I n Secti o n 1. 3, Sc he d ule of Acti vities, t he f o ot n ote gi ve n t o ‘ Wee k 7 2 S afet y F U 
P h o ne C all’ was u p date d wit h  t he a d diti o n of A E/ S A E rec or di n g a n d c o nc o mita nt 
t hera p y a n d pr oce d ure rec or di n g acc or di n g t o ot her secti o ns of t he pr ot oc ol. 
•  I n Secti o n 1. 3, Sc he d ule of Acti vities, t he f o ot n ote gi ve n t o ‘ St u d y Treat me nt 
A d mi nistrati o n’ was ela b orate d as ‘ After t he first 6 nataliz u ma b d oses, t he 1 -h o ur 
p osta d mi nistrati o n o bser vati o n ti me f or s u bse q ue nt S C i njecti o ns ma y be re d uce d or 
re m o ve d acc or di n g t o cli nical j u d ge me nt if t he partici pa nts ha ve n ot e x perie nce d a n y 
i njecti o n reacti o ns i ncl u di n g h y perse nsiti vit y’ f or better clarit y. T his c ha n ge als o 
affects Secti o n 7. 1, Re gi me n.  
•  
 
 
 
 
 
 
 
 T his c ha n ge als o affects Secti o n 9. 3, 
P har mac o d y na mic Assess me nts a n d Secti o n 1 2. 2, A nal ysis Sets . 
•  I n Secti o n 6. 2, E xcl usi o n Criteri o n 1 0 (re gar di n g bacterial, f u n gal, or viral i nfecti o n), 
t he p hrase “ bet wee n Scree ni n g a n d Da y -1” was c ha n ge d t o “ d uri n g t he scree ni n g 
peri o d ( Da y -2 8 t o Da y -1)” f or a clearer u n dersta n di n g.  
•  I n Secti o n 6. 2, E xcl usi o n Criteri o n 3 2 (re gar di n g li ve-atte n uate d vacci ne), t he p hrase 
“li ve or atte n uate d i m m u nizati o n or vacci nati o n” was c ha n ge d t o “li ve -atte n uate d 
vacci ne” f or better clarit y.  
•  I n Secti o n 6. 2, E xcl usi o n Criteri o n 3 4 (re gar di n g cli nicall y si g nifica nt a b n or mal 
la b orat or y test val ues), t he p hrase “at Scree ni n g or Da y -1” was c ha n ge d t o “ d uri n g 
t he scree ni n g peri o d ( Da y -2 8 t o Da y -1)” f or a clearer u n dersta n di n g.  
•  I n Secti o n 7. 3. 1, Nataliz u ma b, t he list of e xci pie nts was u p date d t o me nti o n salts of 
s o di u m p h os p hate (i.e., m o n o basic m o n o h y drate a n d di basic he pta h y drate) a n d water 
f or i njecti o n. 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
C O N FI D E N TI A L  
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Bi o ge n  M A I nc.  
1 0  
•  I n Secti o n 8. 1, Disc o nti n uati o n of St u d y Treat me nt, a se nte nce was a d de d  t o clarif y 
t hat a partici pa nt w h o disc o nti n ues treat me nt ma y c o nti n ue f or st u d y visits e ver y 
4  wee ks u p t o Wee k  5 2 a n d recei ve safet y p h o ne calls at Wee k 6 0 a n d Wee k  7 2.  
•  I n Secti o n 8. 3, Wit h dra wal of Partici pa nts Fr o m t he St u d y, a se nte nce was a d de d t o 
clarif y t hat partici pa nts are e nc o ura ge d t o u n der g o a n E T Visit u nless wit h dra wal is 
d ue t o deat h or wit h dra wal of c o nse nt. T he E T Visit i n s uc h partici pa nts s h o ul d occ ur 
at 4 wee ks ( ± 7 da ys) after t he last d ose of st u d y treat me nt a n d s h o ul d be f oll o we d b y 
safet y p h o ne calls at 1 2 wee ks ( ± 1 0 da ys) a n d 2 4 wee ks ( ± 1 0 da ys) after t he last d ose 
of st u d y treat me nt.  T his c ha n ge als o affects Secti o n 1. 3, Sc he d ule of Acti vities . 
•  I n Secti o n 1 2. 4, Met h o ds of A nal ysis f or P har mac o ki netic E n d p oi nts, a n d 
Secti o n  1 2. 5, Met h o ds of A nal ysis f or P har mac o d y na mic E n d p oi nts, 9 5 % C V of 
ge o metric mea n was c ha n ge d t o ge o metric C V %.  
•  I n Secti o n 1 2. 5, Met h o ds of A nal ysis f or P har mac o d y na mic E n d p oi nts , te xt was 
u p date d as  ‘α 4 -i nte gri n sat urati o n le vels, s ol u ble V C A M-1 ser u m c o nce ntrati o ns, a n d 
 
 
  
•  I n Secti o n 1 2. 7, Met h o ds of A nal ysis f or I m m u n o ge nicit y Data, t he p hrase ‘ A nti -J C V 
A nti b o d ies’ was a d de d t o t he title f or better clarit y beca use im m u n o ge nicit y data 
( A D A) a n d anti -J C V a nti b o d y data are differe nt.  
•  Secti o n  1 4 . 2. 4, Ce ntral La b orat ories f or La b orat or y Assess me nts , was u p date d f or 
si m plificati o n a n d t o clarify t hat  a ce ntral la b orat or y has bee n selecte d b y t he S p o ns or 
t o a nal yze t he he mat ol o g y, bl o o d c he mistr y, a nti b o d y , a n d uri ne sa m ples c ollecte d f or 
t his st u d y. P K a n d P D sa m ples will be a nal yze d at a la b orat or y selecte d b y t he 
S p o ns or . 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 3. 0  
 
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Bi o ge n  M A I nc.  
1 1  
LI S T O F A B B R E VI A TI O N S  
A D A  
a nti-dr u g a nti b o d y  
A E  
a d verse e ve nt  
A E SI  
ad verse eve nt of special interest  
 
 
 
C O VI D -1 9   
c or o na vir us disease 2 0 1 9  
C V  
c oefficie nt of variati o n  
D A A  
direct -acti n g a nti virals  
E T  
earl y ter mi nati o n  
F U  
f oll o w-u p  
H C V  
he patitis C vir us  
I C F 
i nf or me d c o nse nt f or m 
I F N 
i nterfer o n  
I G R A 
i nterfer o n-ga m ma release assa ys  
I V 
i ntra ve n o us(l y) 
J C V 
J o h n C u n ni n g ha m vir us ( h u ma n p ol y o ma vir us) 
M S  
m ulti ple scler osis  
P M L  
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  
S A E  
seri o us a d verse e ve nt 
S A R S -C o V -2   
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2 
S C  
s u bc uta ne o us(l y) 
T B  
t u berc ul osis 
 

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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  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
A M E N D M E N T S U M M A R Y  
Bi o ge n Pr ot oc ol 1 0 1 M S 3 3 0  
A Si n gle -Ar m, O pe n -La bel, P hase 3 St u d y t o E val uate t he Efficac y, Safet y, P har mac o ki netics, 
a n d P har mac o d y na mics of M ulti ple D oses of Nataliz u ma b ( B G 0 0 0 0 2) A d mi nistere d t o Ja pa nese 
Partici pa nts Wit h Rela psi n g -Re mitti n g M ulti ple Scler osis via a S u bc uta ne o us  R o ute of 
A d mi nistrati o n  
Versi o n 2. 0  
Date: 0 4  N o ve m ber  2 0 2 1  
Versi o n 2. 0 of t he pr ot oc ol has bee n pre pare d f or t his a me n d me nt, w hic h s u perse des Versi o n 1. 0.  
 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 2. 0  
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
  
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P RI M A R Y R E A S O N F O R A M E N D M E N T  
T he pri mar y reas o n f or t his a me n d me nt t o Pr ot oc ol 1 0 1 M S 3 3 0 is t o a d d la n g ua ge t o t he rele va nt 
secti o n of t he pr ot oc ol, i n res p o nse t o a P M D A q uer y, t o clarif y t hat w hile  all of t he ra w 
materials use d d o n ot c o nf or m t o t he sta n dar ds f or bi ol o gical i n gre die nts, t he t he oretical ris k t o 
partici pa nts f or c o nta mi nati o n or T S E tra ns missi o n is e xtre mel y l o w.  

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 2. 0  
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3  
S U M M A R Y O F M A J O R C H A N G E S T O T H E P R O T O C O L  
C ha n ges t o t he pr ot oc ol are prese nte d per pr ot oc ol secti o n. Ne w te xt is s h o w n i n b ol d t y pe; 
delete d te xt is s h o w n wit h a stri ket hr o u g h. 
Secti o n 7. 3. 1, Nataliz u ma b  
C h a n ge:  A d diti o n of te xt t o t he rele va nt secti o n of t he pr ot oc ol , i n res p o nse t o a P M D A q uer y, 
t o clarif y t hat w hile  all of t he ra w materials use d d o n ot c o nf or m t o t he sta n dar ds f or bi ol o gical 
i n gre die nts, t he t he oretical ris k t o partici pa nts f or c o nta mi nati o n or T S E tra ns missi o n b y t he ra w 
materials is e xtre mel y l o w. 
N o w re a ds:  
…  
N at aliz u m a b is pr o d uce d usi n g fet al b o vi ne ser u m t h at w as use d i n cl o ni n g bef ore m aster 
cell b a n k pre p ar ati o n a n d st or a ge f or t he m aster cell b a n k a n d w or ki n g cell b a n k. Als o, 
n at aliz u m a b is pr o d uce d usi n g b o vi ne bl o o d -deri ve d b o vi ne ser u m al b u mi n t h at w as  use d 
i n pre p ar ati o n f or t he m aster cell b a n k a n d w or ki n g cell b a n k. T his fet al b o vi ne ser u m 
meets t he criteri a set f ort h b y a p u blic a ge nc y, t he E ur o pe a n Direct or ate f or t he Q u alit y of 
Me dici nes, f or t he pre ve nti o n of i nfecti o n wit h T S E  a ge nts t o h u m a ns. N o ne of t hese b o vi ne 
m ateri als are c o nt ai ne d i n t he fi n al pr o d uct. T here is n o re p ort of T S E bei n g tr a ns mitte d 
fr o m t he fi n al pr o d uct t o h u m a ns. 
H u m a n tr a nsferri n is use d i n t he cell b a n k me di a use d f or t he pre p ar ati o n of t he m aster 
cell b a n k a n d t he w or ki n g cell b a n k f or n at aliz u m a b. T he m a n uf act uri n g pr ocess f or 
n at aliz u m a b d oes n ot use t he h u m a n tr a nsferri n , a n d t he fi n al pr o d uct d oes n ot c o nt ai n 
h u m a n tr a nsferri n. N ucleic aci d a m plific ati o n test is n ot c o n d ucte d f or t he s o urce pl as m a 
of ori gi n f or h u m a n bl o o d deri v ati ves, b ut it is c o nfir me d t h at t he res ults of ser ol o gic al 
testi n g f or vir uses ( a nti ge n a n d/ or a nti b o d y t o vir uses) is perf or me d. I n  a d diti o n, t here are 
se ver al ste ps t h at c a n re m o ve/i n acti v ate vir uses d uri n g t he m a n uf act uri n g pr ocess of 
n at aliz u m a b. T heref ore, t he ris k of c o nt a mi n ati o n wit h H B V, H C V, HI V -1, a n d HI V -2 is 
e xtre mel y l o w. T here is n o re p ort of T S E bei n g tr a ns mitte d fr o m n at aliz u m a b t o h u m a ns, 
alt h o u g h h u m a n tr a nsferri n c o mes fr o m h u m a n bl o o d o bt ai ne d i n t he U S. T he oretic al ris k 
assess me nt f or T S E de m o nstr ate d t he s afet y le vel re q uire d t o e ns ure t h at t he ris k of 
tr a ns missi o n of T S E b y n at aliz u m a b is e xtre mel y l o w.  
H o we ver, si nce t he ris k of T S E tr a ns missi o n c a n n ot t ot all y a n d t he oretic all y be de nie d, t his 
pr o d uct m ust be use d after c aref ul c o nsi der ati o n of t he nee d f or t he pr o d uct i n t he 
tre at me nt of t he dise ase, a n d t his i nf or m ati o n m ust be pr o vi de d t o t he p atie nt pri or t o t he 
a d mi nistr ati o n of t he pr o d uct.  
R ati o n ale:  T he te xt was a d de d i n res p o nse t o a P M D A q uer y , to clarif y w hile all of t he ra w 
materials use d d o n ot c o nf or m t o t he sta n dar ds f or bi ol o gical i n gre die nts, t he t he oretical ris k t o 
partici pa nts f or c o nta mi nati o n or T S E tra ns missi o n b y t he ra w materials is e xtre mel y l o w. 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 2. 0  
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4  
S U M M A R Y O F MI N O R C H A N G E S T O T H E P R O T O C O L  
T he f oll o wi n g mi n or c ha n ges were ma de t o t he pr ot oc ol, as a p pr o priate:  
•  T he versi o n n u m ber a n d date were u p date d t hr o u g h o ut t he pr ot oc ol.  
•  Secti o n 2, List of A b bre viati o ns, was u p date d.  
 

A me n d me nt S u m mar y f or Pr ot oc ol 1 0 1 M S 3 3 0, Versi o n 2. 0  
P hase 3 St u d y t o E val uate Efficac y, Safet y, P K, a n d P D of S C Nataliz u ma b i n Ja pa nese Partici pa nts Wit h R R M S  
  
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 wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5  
LI S T O F A B B R E VI A TI O N S  
H B V  
he patitis B vir us  
H C V  
he patitis C vir us  
H I V 
h u ma n i m m u n o deficie nc y vir us  
P M D A  
P har mace uticals a n d Me dical De vices A ge nc y  
T S E  
tra ns missi ble s p o n gif or m e nce p hal o pat h y 
U S  
U nite d States