A Phase 3b, 12-month, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of BIIB019, Daclizumab, in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS) Switching From Natalizumab (SUSTAIN)
Phase: PHASE3
Conditions: Relapsing-Remitting Multiple Sclerosis (RRMS)
Sponsor: Biogen



Pr ot oc ol 2 0 5 M S 3 0 5
Ver si o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3
T A B L E O F C O N T E N T S
1.
S P O N S O R I N F O R M A TI O N .......................................................................................7
2.
LI S T O F A B B R E VI A TI O N S................................ .......................................................8
3.
S Y N O P SI S ................................ .................................................................................1 0
4.
S T U D Y S C H E M A TI C A N D S C H E D U L E O F A C TI VI TI E S ..................................1 4
4. 1.
St u d y  Desi g n...............................................................................................................1 4
4. 2.
Sc he d ule of Assess me nts ............................................................................................1 5
5.
I NT R O D U C TI O N ......................................................................................................1 9
5. 1.
Bac k gr o u n d .................................................................................................................1 9
5. 1. 1.  
O ver vie w of M ulti ple Scler osis................................ ..................................................1 9
5. 1. 2. 
C urre nt T hera pies f or M ulti ple Scler osis ................................ ...................................1 9
5. 1. 3.
Dacliz u ma b .................................................................................................................2 2
5. 1. 4. 
Pr ofile of Pre vi o us E x perie nce wit h Dacliz u ma b................................ .......................2 2
5. 2.
O verall Rati o nale ........................................................................................................2 6
5. 2. 1.
Rati o nale f or D urati o n bet wee n T hera pies .................................................................2 7
5. 2. 2.
Rati o nale f or D ose a n d Sc he d ule Selecti o n ................................................................2 8
6.
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S................................ ..............................2 9
6. 1.
O bjecti ves ...................................................................................................................2 9
6. 1. 1.
Pri mar y  O bjecti ve a n d E n d p oi nts...............................................................................2 9
6. 1. 2.
Sec o n dar y  O bjecti ves a n d E n d p oi nts .........................................................................2 9
6. 1. 3.
E x pl orat or y  O bjecti ves a n d E n d p oi nts.......................................................................2 9
7.
S T U D Y D E SI G N .......................................................................................................3 1
7. 1 .
St u d y  O ver vie w..........................................................................................................3 1
7. 2.
O verall St u d y  D urati o n a n d F oll o w-U p .....................................................................3 1
7. 3.
Earl y Ter mi nati o n of St u d y........................................................................................ 3 1
8.
S T U D Y P O P U L A T I O N.............................................................................................3 2
8. 1.
I ncl usi o n Criteria........................................................................................................ 3 2
8. 2.
E xcl usi o n Criteria .......................................................................................................3 2
9. 
S T U D Y P R O C E D U R E S................................ ............................................................3 4
9. 1.
Scree ni n g, E nr oll me nt a n d Ra n d o mizati o n ................................................................3 4
9. 2.
F oll o w -U p ...................................................................................................................3 4

Pr ot oc ol 2 0 5 M S 3 0 5
Ver si o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 4
9. 3.
Wit h dra wal of S u bjects fr o m t he St u d y ......................................................................3 4
1 0.
S T U D Y T R E A T M E N T ..............................................................................................3 5
1 0. 1.
D osi n g Re gi me n a n d A d mi nistrati o n .........................................................................3 5
1 0. 2.
Treat me nt C o m plia nce ................................................................................................3 5
1 0. 3.
Dacliz u ma b Sta bilit y  a n d St ora ge ..............................................................................3 6
1 0. 3. 1.  
Dacliz u ma b Pre parati o n................................ ..............................................................3 6
1 0. 3. 2.
Dacliz u ma b Ha n dli n g a n d Dis p osal ...........................................................................3 6
1 0. 4.
Dacliz u ma b Acc o u nta bilit y ........................................................................................3 6
1 0. 5.
Treat me nt Sc he d ule M o dificati o n ..............................................................................3 7
1 0. 5. 1. 
Ele vate d Li ver F u ncti o n Tests................................ ....................................................3 7
1 1.
D A T A C O L L E C TI O N ...............................................................................................3 8
1 1. 1.
Site Pers o n nel .............................................................................................................3 8
1 1. 2.
Assess me nts ................................................................................................................3 9
1 1. 2. 1.  
Assess me nts at Scree ni n g................................ ...........................................................3 9
1 1. 2. 2.  
Assess me nts at Baseli ne a n d F oll o w- u p................................ .....................................3 9
1 1. 3.
S pecial I nstr ucti o ns f or Tests a n d Assess me nts .........................................................4 1
1 1. 3. 1.
Rescree ni n g .................................................................................................................4 1
1 1. 3. 2.
Li ver F u ncti o n Test Ass ess me nts Pri or t o Dacliz u ma b D osi n g................................. 4 1
1 1. 3. 3.
M RI  Sca ns ..................................................................................................................4 2
1 1. 3. 4.
Ot her Assess me nts ......................................................................................................4 2
1 2. 
S A F E T Y D E FI NI TI O N S, R E C O R DI N G, R E P O R TI N G , A N D 
R E S P O N SI BI LI T I ES................................ .................................................................4 3
1 2. 1.  
Defi niti o ns................................ ..................................................................................4 3
1 2. 1. 1.
A d verse E ve nt .............................................................................................................4 3
1 2. 1. 2.
Seri o us A d verse E ve nt ................................................................................................4 3
1 2. 1. 3. 
Presc he d ule d or Electi ve Pr o ce d ures or R o uti nel y Sc he d ule d Treat me nts................4 4
1 2. 2.
Safet y  Classificati o ns..................................................................................................4 4
1 2. 2. 1.
I n vesti gat or Assess me nt of E ve nts .............................................................................4 4
1 2. 2. 2. 
Relati o ns hi p of E ve nts t o St u d y  Treat me nt................................................................4 4
1 2. 2. 3.
Se verit y  of E ve nts.......................................................................................................4 5
1 2. 2. 4.
E x pecte d ness of E ve nts ..............................................................................................4 5
1 2. 3.
M o nit ori n g a n d Rec or di n g E ve nts ..............................................................................4 5

Pr ot oc ol 2 0 5 M S 3 0 5
Ver si o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 5
1 2. 3. 1.
A d verse E ve nts ...........................................................................................................4 5
1 2. 3. 2.
Seri o us A d verse E ve nts ..............................................................................................4 6
1 2. 3. 3. 
I m me diate Re p orti n g of Seri o us A d verse E ve nts................................ .......................4 6
1 2. 3. 4.
Deat hs .........................................................................................................................4 6
1 2. 3. 5. 
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns................................ ....................4 6
1 2. 4.
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns ...............................................................4 7
1 2. 4. 1.
Re p orti n g Pre g na nc y ..................................................................................................4 7
1 2. 4. 2.
O ver d ose .....................................................................................................................4 7
1 2. 4. 3.
Me dical E mer ge nc y ....................................................................................................4 7
1 2. 5.
I n vesti gat or Res p o nsi bilities.......................................................................................4 7
1 2. 6. 
Bi o ge n Res p o nsi bilities................................ ..............................................................4 8
1 3.
S T A TI S TI C A L C O N SI D E R A TI O N S .......................................................................4 9
1 3. 1.
Sa m ple Size J ustificati o n ............................................................................................4 9
1 3. 2.
A nal y sis P o p ulati o n ....................................................................................................4 9
1 3. 3.
Met h o ds of A nal ys is...................................................................................................4 9
1 3. 4.
Pri mar y  E n d p oi nt A nalys is.........................................................................................4 9
1 3. 4. 1.
Efficac y  A nalys is........................................................................................................4 9
1 3. 5.
Sec o n dar y  E n d p oi nts A nal ysis ...................................................................................5 0
1 3. 5. 1.
Efficac y  A nalys is........................................................................................................5 0
1 3. 5. 2.
Safet y ..........................................................................................................................5 1
1 3. 6.
E x pl orat or y  A nalys is ..................................................................................................5 2
1 3. 7.
I nteri m A nalys is..........................................................................................................5 4
1 4.
E T HI C A L  R E Q UI R E M E N T S ...................................................................................5 5
1 4. 1.
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee ...........................................................5 5
1 4. 2.
S u bject I nf or mati o n a n d C o nse nt ...............................................................................5 5
1 4. 3.
S u bject Data Pr otecti o n ..............................................................................................5 6
1 4. 4.
C o m pe nsati o n f or I nj ur y.............................................................................................5 6
1 4. 5.
C o nflict of I nterest ......................................................................................................5 6
1 4. 6.
Re gistrati o n of St u d y a n d Discl os ure of St u d y Res ults ..............................................5 6
1 5.
A D MI NI S T R A TI V E P R O C E D U R E S .......................................................................5 7
1 5. 1.
St u d y  Site I nitiati o n....................................................................................................5 7
1 5. 2.
Q ualit y  Ass ura nce.......................................................................................................5 7

Pr ot oc ol 2 0 5 M S 3 0 5
Ver si o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 6
1 5. 3.
M o nit ori n g of t he St u d y................................ ..............................................................5 7
1 5. 4.
St u d y  F u n di n g.............................................................................................................5 7
1 5. 5.
P u blicati o ns ................................................................................................................. 5 7
1 6.
F U R T H E R R E Q UI R E M E N T S A N D G E N E R A L I N F O R M A T I O N........................5 8
1 6. 1.
E xter nal C o ntract Or ga nizati o ns .................................................................................5 8
1 6. 1. 1.
C o ntract Researc h Or ga nizati o n .................................................................................5 8
1 6. 1. 2.
Electr o nic Data Ca pt ure ..............................................................................................5 8
1 6. 1. 3.
Ce ntral La b orat ories f or La b orat or y  Assess me nts .....................................................5 8
1 6. 1. 4.
Ce ntral Facilit y  f or M RI Assess me nts........................................................................5 8
1 6. 2.
A d vis or y C o m mittee ...................................................................................................5 8
1 6. 3.
Data Safet y M o nit ori n g B oar d ....................................................................................5 9
1 6. 4.
C ha n ges t o Fi nal St u d y  Pr ot oc ol ................................................................................5 9
1 6. 5. 
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee N otificati o n of St u d y  
C o m pleti o n or Ter mi nati o n........................................................................................ 5 9
1 6. 6.
Rete nti o n of St u d y  Data..............................................................................................5 9
1 7.
R E F E R E N C E S ...........................................................................................................6 0
1 8.
I NV E S TI G A T O R S SI G N E D A G R E E M E N T O F S T U D Y P R O T O C O L .................6 6
LI S T O F T A B L E S
Ta ble 1:
St u d y  Sc he d ule of Assess me nts..................................................................................1 6
Ta ble 2:
Criteria t o Deter mi ne Cli nicall y  Rele va nt A b n ormalities i n Vital Si g ns ...................5 2
LI S T O F FI G U R E S
Fi g ure 1:
St u d y  Desi g n...............................................................................................................1 4

Pr ot oc ol 2 0 5 M S 3 0 5
Ver si o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 8
2.
LI S T O F A B B R E VI A TI O N S
A E
ad verse eve nt
A L T
ala ni ne t ra nsa mi nase
A R R
an n ualize d rela pse rate
A S T
as partate tra nsa mi nase
B P M
b eats per m i n ute
C B C
co m plete b l o o d c o u nt
C D 2 5
α s u b u nit of i nterl u ki n- 2
C D 1 2 2
β s u b u nit of i nterl u ki n- 2
C D 1 3 2
γ s u b u nit of i nterl u ki n- 2
CI
co nfi de nce inter val
CI S
cli nicall y is olate d sy n dr o me
C N S
ce ntral n er v o us sys te m
C R F
case re p ort f or m
C R O
c o ntract researc h o r ga nizati o n
D M F
Di met h y l F u marate
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 y i n g thera p y
D S M B
D ata S afet y M o nit ori n g B oar d
E C
et hics co m mittee
E D C
electr o nic data c a pt ure
E D S S
E x pa n de d Disa bilit y  Stat us Scale
E M A
E ur o pea n Me dici nes A ge nc y
G A
glatira mer a cetate
G d
g a d oli ni u m
G d +
ga d oli ni u m e n ha nce d
H Bc A b
he patitis B c ore a nti b o d y
H Bs A g
he patitis B s urface a nti ge n
H C V A b
he patitis C vir us a nti b o d y
HI V
h u ma n i m m u n o defici e nc y vir us
I CF
inf or me d co nse nt for m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I F N- β
interfer o n β
I L- 2
interle u ki n 2
I L- 2 R
interle u ki n 2 rece pt or
I M
intra m usc ular
I S
im m u n os u p pressa nt
I RB
I nstit uti o nal Re vie w B oar k
I T T
inte nt -t o-treat
I V
intra ve n o us
J C V
J o h n C u n ni n g ha m Vir us

Pr ot oc ol 2 0 5 M S 3 0 5
Ver si o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 9
L F T
li ver f u ncti o n tests
M RI
m a g netic res o na nce ima gi n g
M S
M ulti ple Scler osis
M S F C
M ulti ple Scler osis F u ncti o nal C o m p osite
N E D A
n o evi de nce of d isease acti vit y
N K
nat ural k iller T cells
P D
p har mac o d y n a mic
P HI
p r otecte d h ealt h inf or mati o n
P M L
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y
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 B R
safet y a n d b e nefit-ris k
S A E
seri o us a d verse eve nt
S A P
statistical anal y sis p la n
S C
su bc uta ne o us
S D M T
S y m b ol Di git M o dalities Test
S G O T
ser u m gl uta mic o xal oacetic tra nsa mi nase  
S G P T
ser u m gl uta mic pyr u vate t ra nsa mi nase
S U S A R
sus pecte d u ne x pecte d seri o us ad verse reacti o ns
U L N
u p per li mit n or mal
U S
U nite d States

Pr ot oc ol 2 0 5 M S 3 0 5
Ver si o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 1 0
3.
S Y N O P SI S
Trac ki n g n u m ber:
2 0 5 M S 3 0 5
Pr ot oc ol Title:
A P hase 3 b, 1 2 - mo nt h, O pe n -la bel, M ultice nter St u d y t o 
E val uate t he Efficac y  a n d Safet y of BII B 0 1 9, Dacliz u ma b, i n 
S u bjects wit h Rela psi n g -Re mitti n g M ulti ple Scler osis ( R R M S) 
S witc hi n g fr o m Nataliz u ma b ( S U S T AI N)
Versi o n N u m ber:
1. 0
Na me of St u d y Treat me nt:
Dacliz u ma b ( h i g h yi el d f or m ulati o n) 
St u d y  In dicati o n:
Rela psi n g- Re mitti n g M ulti ple Scler osis ( R R M S)
P hase of De vel o p me nt:
3 b
Rati o nale f or t he St u d y :
T he p ur p ose of t his st u d y is t o e val uate t he efficac y a n d safet y 
of dacliz u ma b ( hi g h yi el d f or m ulati o n) i n s u bjects s witc hi n g 
fr o m nataliz u ma b d ue t o safety c o ncer ns.  T here is a nee d f or 
clearer e vi de nce -base d g ui deli nes o n alter nati ve t hera p y a n d 
ma na ge me nt of s u bjects d uri n g a n d p ost -tra nsiti o n fr o m 
nataliz u ma b.  Wit h a well -esta blis he d safet y a n d efficac y 
pr ofile, dacliz u ma b ca n be c o nsi dere d a g o o d t hera pe utic 
o pti o n f or R R M S s u bjects treate d wit h nataliz u ma b, w h o 
deci de t o c ha n ge t hera p y.
St u d y  O bjecti ves a n d 
E n d p oi nts:
Pri m ar y O bjecti ve 
T he pri mar y  o bjecti ve of t he st u d y is t o e val uate t he effects of 
treat me nt wit h dacliz u ma b o n pr o p orti o n of s u bjects rela pse-
free at 6 mo nt hs, i n R R M S s u bjects w h o s witc he d fr o m 
treat me nt wit h nataliz u ma b t o dacliz u ma b d ue t o safety 
c o ncer ns.
Pri m ar y E n d p oi nt
T he pri mar y  e n d p oi nt i n relati o n t o t his o bjecti ve is t he 
pr o p orti o n of s u bjects rela pse-free at M o nt h 6, i n R R M S 
s u bjects treate d wit h dacliz u ma b w h o s witc he d fr o m treat me nt 
wit h nataliz u ma b.

P r ot oc ol 2 0 5 M S 3 0 5
    Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
Pa ge 1 6
T a bl e 1:
St u d y Sc he d ule of Assess me nts
St u d y Peri o d
Scree ni n g
St u d y F oll o w -u p
Visit N u m ber
1
2
3
4
5
6
7
8
9
1 0
Title
E nr oll me nt 
( Da y - [ 2 8 + 3] 
t o -1)
Baseli ne
( Da y 0)
M o nt h 1
( ± 4 da ys)
M o nt h 3
( ± 4 da ys)
M o nt h 4
( ± 4 da ys)
M o nt h 6
( ± 4 da ys)
M o nt h 9
( ± 4 da ys)
M o nt h 1 2
( ± 4 da ys)
M o nt h 1 5
Safet y   
f oll o w-u p 1 3
( ± 1 4 da ys)
Earl y 
disc o nti n uati o n 1 4
I nf or me d co nse nt 1
X
I ncl usi o n/e xcl usi o n 
criteria
X
De m o gra p hics
X
Disease a n d 
m e dical h ist or y
X
M S t reat me nt 
h ist or y
X
M RI
2
X
X
X
X
X
Pre g na nc y testi n g 3
M o nit or a n d rec or d t hr o u g h o ut t he st u d y
Li ver f u ncti o n 
testi n g  
( A S T/ A L T) 4
X
X
X
X
X
X
X
X 5
X
C o nc o mita nt 
m e dicati o ns a n d       
n o n- dr u g t hera pies
M o nit or a n d rec or d
t hr o u g h o ut t he st u d y
X
X
X
X
X
X
X
Vital si g ns
X
X
X
X
X
X
X
X
P h y sical 
exa mi nati o n
X
X
X
X
X
X
X
X
X
X
X
X
X
M S rela pse 
assess me nt
X
X
X
X
X
X
X
X
Dacliz u ma b 
d is pe nsati o n/ 
ad mi nistrati o n 8
X
X
X
X
X
X

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 1 9
5.
I N T R O D U C TI O N
5. 1.
B ac k gr o u n d
5. 1. 1.  
O ver vie w of M ulti ple Scler osis
M ulti ple Scler osis ( M S) is a c hr o nic i nfla m mat or y d isease of t he ce ntral ner v o us s yste m ( C N S) 
affecti n g a p pr o xi matel y 4 0 0, 0 0 0 i n di vi d uals i n t he U nite d States ( U S) a n d o ver 2 milli o n pers o ns 
w orl d wi de [Ca m p bell 2 0 1 4 ; Flac he nec ker a n d St u ke 2 0 0 8 ; Ha ns o n 2 0 1 4 ].  Disease i nci de nce is 
a p pr o xi matel y 5 –6 per 1 0 0, 0 0 0 pers o ns per ye ar i n n ort her n parts of N or t h A merica a n d E ur o pe 
w here it is m ost c o m m o n, a n d it t y picall y prese nts i n i n di vi d uals a ge d 1 5 t o 4 5 y ears [G o o di n 
2 0 1 4 ].  Alt h o u g h t he eti ol o g y of M S is u ncertai n, e vi de nce s u g gests t hat it be gi ns as a n 
i nfla m mat or y i m m u ne-m e diate d dis or der c haracterize d b y  a ut oreacti ve l ym p h oc y tes [R oac h
2 0 0 4 ; Wei ner 2 0 0 4 ].  Patie nts t ypicall y first p rese nt wit h cli nicall y is olate d s yn dr o me ( CI S), a 
sta ge i n w hic h c haracteristics of i nfla m mat or y de m yeli nati o n t hat c o ul d be M S are prese nt (e. g., 
o ptic ne uritis, brai nste m s y n dr o mes, or tra ns verse m y elitis), b ut Mc D o nal d criteria of 
disse mi nati o n i n ti me ha ve yet t o be f ulfille d [L u bli n 2 0 1 4 ; Mc D o nal d 2 0 0 1 ]. A sec o n d 
ne ur ol o gic e xacer bati o n c o nsiste nt wit h de m y eli nati o n a n d se parate d b ot h i n ti me a n d l ocati o n is 
re q uire d f or a cli nicall y defi niti ve dia g n osis [P oser 1 9 8 3 ].  H o we ver, use of t he 2 0 1 0 re visi o ns t o 
t he Mc D o nal d dia g n ostic criteria all o ws f or fe wer t ha n 2 ne ur ol o gic attac ks w he n t here is 
s u p p orti ve para-cli nical e vi de nce base d o n M RI or cere br os pi nal fl ui d res ults [P ol ma n 2 0 1 1 ]. 
T he c ore M S p he n ot y pes i ncl u de rela psi n g a n d pr o gressi ve disease a n d are f urt her cate g orize d 
b y  t he f oll o wi n g clinical s u bt y pes: CI S, Rela psi n g -Re mitti n g M ulti ple Scler osis ( R R M S), 
sec o n dar y pr o gressi ve M S, a n d pri mar y pr o gressi ve M S [L u bli n 2 0 1 4 ].  A b o ut 7 0 –9 0 % of 
patie nt s wit h M S start o ut wit h R R M S, a cli nical c o urse c haracterize d b y rela pses of ne ur ol o gic 
d y sf u ncti o n, w hic h occ ur o ver ma n y years [S u mela hti 2 0 1 4 ].  S ym pt o ms of s uc h rela pses ma y  
i ncl u de l oss of visi o n or d o u ble visi o n, n u m b ness or ti n gli n g se nsati o n i n t he e xtre mities, m uscle 
wea k ness, sl urre d s peec h, diffic ult y  wit h c o or di nati o n, a n d/ or bla d der d ysf u ncti o n.  Early i n t he 
c o urse of t his p hase of t he disease, s y m pt o ms ma y s u bsi de c o m pletel y  after eac h attac k.  O ver 
ti me, t here te n ds t o be i nc o m plete rec o ver y fr o m s uc h attac ks a n d gra d ual pr o gressi ve 
deteri orati o n of ne ur ol o gic f u ncti o n.  M ost patie nts de vel o p pr o gressi ve disa bilit y , wit h or 
wit h o ut occasi o nal rela pses, mi n or re missi o ns, a n d platea us.  Wit h o ut effecti ve treat me nt, 
ap pr o xi matel y  half of all patie nts wit h M S are u na ble t o wal k wit h o ut assista nce wit hi n 1 5 years 
of t heir i nitial dia g n osis [R u n mar ker a n d A n derse n 1 9 9 3 ; Wei ns he n ker 1 9 8 9 ]. 
5. 1. 2.
C urre nt T her a pies f or M ulti ple Scler osis
Se veral c o m merciall y a vaila ble treat me nt o pti o ns e xist f or patie nts wit h rela psi n g m ulti ple 
scler osis ( R M S), i ncl u di n g i nterfer o n beta (I F N - β) pre parati o ns, glatira mer acetate ( G A), 
nataliz u ma b, ale mt uz u ma b, di met h yl f u marate ( D M F), terifl u n o mi de, a n d fi n g oli m o d [G o o di n 
2 0 0 2 ; Miller 2 0 1 2 ; Nati o nal C olla b orati n g Ce ntre f or C hr o nic C o n diti o ns 2 0 0 4 ; Per u mal a n d
K ha n 2 0 1 2 ; T ull ma n 2 0 1 3 ]. T he c h oice of t he s pecific t hera pe utic a ge nt is i n di vi d ualize d t o t he 
patie nt acc or di n g t o disease acti vit y a n d patie nt val ues a n d prefere nces.  

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 0
T he I F N - β t hera pies a n d G A ha ve well-esta blis he d safet y a n d efficac y pr ofiles, b ut ma n y 
patie nts c o nti n ue t o e x perie nce si g nifica nt M S disease acti vit y  w hile o n treat me nt. T hese 
t hera pies are als o ass ociate d wit h k n o w n si de effects, i ncl u di n g fl u-li ke sy m pt o ms f or t he I F N -β 
t hera pies a n d li p oatr o p hy a n d ot her i njecti o n site pat h ol o gies f or G A, w hic h ca n be a si g nifica nt 
b ur de n f or s o me patie nts. F urt her m ore, a vaila ble data s u g gest t hat a p pr o xi matel y  4 0 % of M S 
patie nts ma y  n ot a d here t o prescri be d i njecta ble t hera pies f or M S o ut of fear of or t he 
i nc o n ve nie nce ass ociate d wit h s uc h fre q ue nt i njecti o ns [De v o ns hire 2 0 1 1 ; K o belt 2 0 0 6a ; K o belt
2 0 0 6 b ; Trea da wa y  2 0 0 9].
Ale mt uz u ma b is a m o n ocl o nal a nti b o d y  t hat has s h o w n s u peri or efficacy t o I F N β -1a i n patie nts 
wit h R M S b ut e ntails ris ks of life-t hreate ni n g a ut oi m m u ne dis or ders, i ncl u di n g fatal 
t hr o m b oc yt o pe nia a n d ne p hr o pat hies; a d diti o nall y, a ut oi m m u ne t h yr oi d disease is c o m m o n 
d uri n g treat me nt wit h ale mt uz u ma b.
D M F, fi n g oli m o d, a n d te rifl u n o mi de are oral disease-m o dif y i n g t hera pies ( D M Ts) a p pr o ve d f or 
t he treat me nt of R M S. W hile t hese t hera pies offer a n i m pr o ve d r o ute of a d mi nistrati o n f or s o me 
patie nts, t he y  re q uire dail y a d mi nistrati o n, a n d s o me patie nts ma y n ot t olerate t he m or ma y
c o nti n ue t o e x perie nce disease acti vit y  w hile o n treat me nt. Oral t hera pies ha ve als o bee n 
ass ociate d wit h si de effects, s uc h as l y m p h o pe nia i n D M F -treate d patie nts [F o x 2 0 1 2 ; G ol d
2 0 1 2 ]; bra d y car dia, atri o ve ntric ular bl oc k, a n d mac ular e de ma i n fi n g oli m o d -treate d patie nts
[Ka wasa ki 2 0 1 0 ; K hatri 2 0 1 1 ]; a n d he pat ot o xicit y a n d ly m p h o pe nia i n terifl u n o mi de -treate d 
patie nts [C o nfa vre u x 2 0 1 2 ]. I n a d diti o n, cases of P M L ha ve bee n re p orte d i n patie nts treate d 
wit h D M F a n d wit h fi n g oli m o d [GI L E N Y A U S PI 2 0 1 6 ; Nati o nal M ulti ple Scler osis S ociet y  
2 0 1 5 ; Nie u w ka m p 2 0 1 5 ; R ose n kra nz 2 0 1 5 ; T E C FI D E R A ™ U S PI  2 0 1 4]. P M L  is a se vere 
de m y eli nati n g disease of t he C N S ca use d b y reacti vati o n of J C V, a p ol yo ma vir us t hat is 
pat h o ge nic o nl y i n h u ma ns. T hese ris ks re q uire s pecialize d m o nit ori n g b ot h pri or t o i nitiati o n 
a n d d uri n g t hera p y a n d ma y necessitate e xcl usi o n of v ul nera ble patie nts.
Nataliz u ma b is a D M T a vaila ble f or t he treat me nt of R M S t hat is k n o w n t o be hi g hl y effecti ve. 
I n t he pi v otal 2-year, place b o -c o ntr olle d, p hase 3 A F FIR M trial, nataliz u ma b was s h o w n t o 
re d uce 1 2-wee k c o nfir me d disa bilit y  pr o gressi o n b y 4 2 %, a n n ualize d rela pse rate ( A R R) b y 
6 8 %, a n d f or mati o n of M RI  lesi o ns b y 9 2 % ( ga d oli ni u m-e n ha nci n g [ G d +]) a n d 8 3 % 
( T 2-h y peri nte nse) c o m pare d t o place b o [ P ol ma n 2 0 0 6 ].
Nataliz u ma b was als o t he first R M S 
t hera py f or w hic h n o e vi de nce of disease acti vit y ( N E D A; n o rela pses, n o disa bilit y  pr o gressi o n, 
n o G d + or ne w/e nlar gi n g T 2- h y peri nte n se lesi o ns) was de m o nstrate d, wit h 3 7 % of nataliz u ma b 
patie nts i n A F FI R M ac hie vi n g N E D A o ver 2 y ears c o m pare d t o 7 % of place b o patie nts
[Ha vr d o va 2 0 0 9 ]. Fr o m a safet y pers pecti ve, t he m ost critical c o ncer n f or nataliz u ma b is a n 
i ncrease d ris k of P M L, a n d as s uc h nataliz u ma b carries a b o xe d war ni n g f or P M L a n d is 
c o ntrai n dicate d i n patie nts wit h a hist or y  of P M L a n d i n patie nts wit h i ncrease d ris k f or 
o p p ort u nis tic i nfecti o ns, i ncl u di n g i m m u n oc o m pr o mise d patie nts [T y sa bri ® Prescri bi n g 
I nf or mati o n 2 0 1 3/ S m P C ; T y sa bri ® U S PI 2 0 1 3 ]. Nataliz u ma b is als o c o ntrai n dicate d i n patie nts 
w h o ha ve ha d a h y perse nsiti vit y  reacti o n t o nataliz u ma b.
T hre e fact ors ass ociate d wit h a n i ncrease d ris k of nataliz u ma b -ass ociate d P M L ha ve bee n 
i de ntifie d: 1) t he prese nce of a nti-J C V a nti b o dies; 2) pri or e x p os ure t o a n i m m u n os u p pressa nt 
(IS; e . g., mit o xa ntr o ne, met h otre xate, azat hi o pri ne, c ycl o p h os p ha mi de, m yc o p he n olate m ofetil); 

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 1
a n d 3) nataliz u ma b treat me nt d urati o n ≥2 y ears [Bl o o m gre n 2 0 1 2 ; F o x a n d R u dic k 2 0 1 2 ;
Ka p p os 2 0 1 1 ; T y sa bri® U S PI  2 0 1 3].
I n a 2 0 1 2 re vie w of nataliz u ma b-ass ociate d P M L a n d relate d ris k fact ors, data fr o m 3 cli nical 
trials a n d a re gistr y of patie nts wit h M S were e val uate d t o esti mate t he ris k of P M L w hile o n 
nataliz u ma b treat me nt [Bl o o m gre n 2 0 1 2 ]. F or patie nts w h o were ser o ne gati ve f or a nti-J C V 
a nti b o dies, t he esti mate d ris k of nataliz u ma b -ass ociate d P M L was ≤0. 0 9 per 1 0 0 0 ( ≈1/ 1 0, 0 0 0). 
T he esti mate d ris k of nataliz u ma b -ass ociate d P M L a m o n g patie nts w h o were ser o p ositi ve f or 
a nti-J C V a nti b o dies b ut wit h o ut pri or e x p os ure t o IS treat me nt was 0. 5 6 per 1 0 0 0 ( 5. 6/ 1 0, 0 0 0) 
f or t h ose treate d wit h nataliz u ma b f or 1 t o 2 4 m o nt hs a n d 4. 6 per 1 0 0 0 ( 4 6/ 1 0, 0 0 0) f or t h ose 
treate d f or 2 5 t o 4 8 m o nt hs. T he esti mate d ris k of nataliz u ma b -ass ociate d P M L a m o n g patie nts 
w h o ha d pri or I S treat me nt was 0. 8 8 per 1 0 0 0 ( 8. 8/ 1 0, 0 0 0) f or t h ose treate d f or 1 t o 2 4 m o nt hs 
a n d 6. 1 per 1 0 0 0 ( 6 1/ 1 0, 0 0 0) f or t h ose treate d f or 2 5 t o 4 8 m o nt hs. F or patie nts w h o were 
ser o p ositi ve f or a nti-J C V a nti b o dies wit h pri or IS treat me nt, t he ris k of nataliz u ma b -ass ociate d 
P M L  was 1. 6 per 1 0 0 0 ( 1 6/ 1 0, 0 0 0) f or t h ose treate d f or 1 t o 2 4 m o nt hs a n d 1 1. 1 per 1 0 0 0 
( 1 1 1/ 1 0, 0 0 0) f or t h ose treate d f or 2 5 t o 4 8 m o nt hs.
F or nataliz u ma b -treate d patie nts w h o ha ve n o pri or IS use a n d a p ositi ve test f or a nti -J C V 
a nti b o dies, t he a nti -J C V a nti b o d y i n de x ma y  f urt her differe ntiate patie nts at hi g her a n d l o wer 
ris k of P M L. T he a nti -J C V a nti b o d y i n de x is calc ulate d usi n g a n a nti b o d y E LI S A test a n d is a 
c or ollar y t o a nti-J C V a nti b o d y titer [Lee 2 0 1 3 ; Pla vi na 2 0 1 4 ]. I n nataliz u ma b-treate d patie nts 
wit h n o pri or I S use, a nti -J C V a nti b o d y i n de x val ues ha ve bee n s h o w n t o be si g nifica ntl y hi g her 
i n patie nts wit h P M L c o m pare d t o patie nts wit h o ut P M L ( me dia n = 2. 4 vs 1. 4; P < 0. 0 0 0 1).   I n 
c o ntrast, i n de x distri b uti o n was s h o w n t o be si milar f or P M L a n d n o n -P M L patie nts wit h pri or I S 
use ( me dia n = 1. 6 f or b ot h gr o u ps; P = 0. 8 2). Rece ntl y , t he E ur o pea n Me dici nes A ge nc y  (E M A)
c on d ucte d a re vie w of t he a vaila ble data o n t he ris k of nataliz u ma b -ass ociate d P M L a n d 
pr o vi de d rec o m me n dati o ns f or i de ntif yi n g patie nts at hi g her ris k of de vel o pi n g P M L [E ur o pea n
Me dici nes A ge nc y  2 0 1 6].
T hese rec o m me n dati o ns f or hi g her ris k patie nts are as f oll o ws:

Ha ve teste d p ositi ve f or J C V , a n d

Ha ve bee n treate d wit h nataliz u ma b f or m ore t ha n 2 y ears, a n d

Eit her ha ve use d a n I S bef ore starti n g nataliz u ma b, or ha ve n ot use d a n I S a n d ha ve a 
hi g h J C V a nti b o d y i n de x ( > 1. 5).
Re vise d ma na ge me nt strate gies f or patie nts o n natali z u ma b treat me nt were als o part of t he E M A 
rec o m me n dati o ns beca use early detecti o n a n d treat me nt of P M L  w he n t he disease is 
as ym pt o matic (i. e. , still i n t he i nitial sta ges a n d s h o wi n g n o sy m pt o ms) ma y  i m pr o ve patie nts’ 
o utc o mes. All patie nts o n nataliz u ma b s h o ul d u n der g o f ull M RI sca ns at least o nce a year, b ut 
o n t he basis of ne w data, t he E M A n o w rec o m me n ds t hat f or patie nts at hi g her ris k of P M L m ore 
fre q ue nt M RI sca ns (e. g., e ver y 3 t o 6 m o nt hs) perf or me d usi n g si m plifie d pr ot oc ols (e. g., fl ui d 
atte n uate d i n versi o n rec o ver y, T 2-wei g hte d, a n d diff usi o n wei g hte d) s h o ul d be c o nsi dere d.
If 
lesi o ns s u g gesti ve of P M L are disc o vere d, t he M RI pr ot oc ol s h o ul d be e xte n de d t o i ncl u de 
‘c o ntrast-e n ha nce d T 1 - wei g hte d M RI’, a n d testi n g t he patie nt’s s pi nal fl ui d f or the prese nce of 
J CV s h o ul d be c o nsi dere d. Patie nts s h o ul d als o be m o nit ore d at re g ular i nter vals f or si g ns a n d 
s ym pt o ms of ne w ne ur ol o gical d y sf u ncti o n [E ur o pea n Me dici nes A ge nc y  2 0 1 6].

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 2
Gi ve n t hat d urati o n of nataliz u ma b treat me nt is a ris k fact or f or P M L, ma n y patie nts w h o a re 
ser o p ositi ve f or a nti-J C V a nti b o dies c h o ose t o disc o nti n ue nataliz u ma b after 2 years of 
treat me nt. A d diti o nall y , patie nts w h o were ser o ne gati ve f or a nti-J C V a nti b o dies w he n starti n g 
treat me nt ma y bec o me ser o p ositi ve, a n d, as a c o nse q ue nce, c h o ose t o disc o nti n ue nataliz u ma b 
d ue t o a n i ncrease d ris k of P M L . Beca use of t hese circ u msta nces, it is bec o mi n g i ncreasi n gl y  
i m p orta nt t o de vel o p f oll o w-o n treat me nt strate gies f or patie nts w h o disc o nti n ue nataliz u ma b
[B utz k ue ve n 2 0 1 4 ; Sa n galli 2 0 1 4 ].
5. 1. 3.
D acliz u m a b 
I nterle u ki n-2 (I L -2) is a c y t o ki ne si g nali n g m olec ule t hat re g ulates t he acti vities of l ym p h oc y tes 
res p o nsi ble f or c o nferri n g i m m u nit y. Effects of I L-2 are me diate d b y  t he I L-2 rece pt or (I L-2 R) , 
w hic h has 3 f or ms t hat differ i n affi nit y f or I L- 2, a n d i n t heir e x pressi o n patter ns.  T hree pr otei n 
c hai ns ma ke u p t he vari o us f or ms of t he rece pt or: α (al p ha or C D 2 5), β ( beta, or C D 1 2 2), a n d γ 
( ga m ma, or C D 1 3 2). C D 2 5 al o ne bi n ds t o I L -2 wit h l o w affi nit y, C D 1 2 2 a n d C D 13 2 t o get her 
f or m a c o m ple x f o u n d o n me m or y T cells a n d N K cells w hic h bi n ds t o I L-2 wit h i nter me diate 
affi nit y, a n d t he 3 c hai ns t o get her f or m a c o m ple x o n acti vate d T cells a n d re g ulat or y T cells 
w hic h bi n ds t o I L -2 wit h hi g h affi nit y [Gaffe n a n d L i u 2 0 0 4]. T he i nter me diate affi nit y I L-2 R is 
hi g hl y e x presse d b y C D 5 6 bri g ht N K T cells, a s u bset of N K cells t hat ca n directl y kill acti vate d T 
cells [P oli 2 0 0 9 ]. 
Dacliz u ma b Hi g h Yiel d Pr ocess, referre d t o as " dacliz u ma b" t hr o u g h o ut t his pr ot oc ol, is a 
h u ma nize d m o n ocl o nal a nti b o d y  t hat bi n ds t o C D 2 5 a n d bl oc ks t he hi g h affi nity I L-2 R, b ut d oes 
n ot affect i nter me diate affi nit y  I L- 2 R me diate d si g nali n g. As s uc h, t his hi g h yiel d f or m ulati o n of 
dacliz u ma b bl oc ks pr oliferati o n of pr o -i nfla m mat or y T cells a n d dri ves e x pa nsi o n of C D 5 6bri g ht
N K cells , w hic h i n t ur n ca n kill pr o-i nfla mmat or y  T cells [Biele k o va 2 0 0 6 ]. T his e x pa nsi o n is 
hi g hl y c orrelate d wit h a pr of o u n d treat me nt res p o nse of re d ucti o n i n brai n i nfla m mat or y  acti vit y 
as de m o nstrate d b y s u b sta ntial re d ucti o n i n t he n u m ber of M RI G d + lesi o ns [El ki ns 2 0 1 5 ].
H o we ver, trial data de pict t he e x perie nce of s u bjects treate d wit h dacliz u ma b w h o res p o n d 
fa v ora bly wit h l o wer le vels of e x pa nsi o n of C D 5 6 bri g ht N K cells [El ki ns 2 0 1 5 ]. 
5. 1. 4. 
Pr ofile of Pre vi o us E x perie nce wit h D acliz u m a b
T he e fficac y a n d safety of t he hi g h yi el d f or m ulati o n of dacliz u ma b f or t he treat me nt of R R M S 
has bee n e val uate d i n 2 pi v otal st u dies. I n t he first, a m ultice nter d o u ble bli n d, place b o -
c o ntr olle d P hase 2b st u d y ( S E L E C T, St u d y 2 0 5 M S 2 0 1), t he efficac y of dacliz u ma b was 
e xa mi ne d i n o ver 6 0 0 a d ults wit h R R M S [G ol d 2 0 1 3 ].  S u bjects were ra n d o mize d t o 1 of 3 
gr o u ps: ( 1) s u bc uta ne o us (S C ) place b o, ( 2) 1 5 0 m g dacliz u ma b e ver y 4 wee ks f or 5 2 wee ks , or 
( 3) 3 0 0 m g dacliz u ma b e ver y 4 wee ks f or 5 2 wee ks . O ne year res ults s h o we d t hat t he A R R was 
si g nifica ntly l o wer i n gr o u ps assi g ne d t o dacliz u ma b 1 5 0 m g a n d da cliz u ma b 3 0 0 m g t ha n 
place b o ( 0. 2 1 a n d 0. 2 3, vers us 0. 4 6 f or place b o), c orres p o n di n g t o re d ucti o ns of 5 4 % a n d 5 0 %, 
res pecti vely.  A d diti o nall y, s u bjects i n t he dacliz u ma b 1 5 0 m g a n d 3 0 0 m g gr o u ps ha d 
re d ucti o ns i n t he ris k of disa bilit y pr o gressi o n vers us place b o ( hazar d rati os 0. 4 3 a n d 0. 5 7, 
p = 0. 0 2 1 a n d p = 0. 0 9 1, res pecti vel y ) at Wee k 5 2; t he re d ucti o n f or dacliz u ma b 1 5 0 m g vers us 
place b o is statisticall y  si g nifica nt.  Dacliz u ma b re d uce d ne w lesi o n acti vit y i n all s u bjects, wit h 
l o n git u di nal a nalys is s h o wi ng t hat G d + lesi o n acti vit y  was greater i n t he 1 5 0 m g gr o u p t ha n i n 
t he 3 0 0 m g gr o u p d uri n g wee ks 4– 2 4, b ut was si milar at W ee k 5 2.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 3
Dacliz u ma b was ge nerall y  well t olerate d a m o n g s u bjects i n S E LE C T wit h a d verse e ve nts ( A Es )
occ urri n g i n a si milar pr o p orti o n of s u bjects acr oss all st u d y gr o u ps.  More s u bjects i n t he 
dacliz u ma b gr o u ps ha d c uta ne o us e ve nts (e. g., i njecti o n site irritati o n a n d ras h) t ha n i n t he 
place b o gr o u ps.  A d diti o nall y , m ore s u bjects i n t he dacliz u ma b gr o u ps ha d he patic e nz y m e 
ele vati o ns > 5 ti mes t he U L N .  F o ur mali g na ncies were detecte d d uri n g t he trial, i ncl u di n g 2 
cases of cer vical carci n o ma ( 1 i n t he place b o gr o u p a n d 1 i n t he dacliz u ma b 1 5 0 m g gr o u p), a n d 
2 cases of mela n o ma i n t he dacliz u ma b 3 0 0 m g gr o u p.  O ne s u bject gi ve n dacliz u ma b , w h o was 
rec o veri n g fr o m a seri o us ras h, die d beca use of l ocal c o m plicati o n of a ps oas a bscess. T he 
n u m ber of Tre gs c o u nts was re d uce d d uri n g treat me nt wit h dacliz u ma b , b ut t his was n ot 
ass ociate d wit h cli nical/ M RI  o utc o mes or A Es [Mil o 2 0 1 4 ; Sel maj 2 0 1 3 ].  C D 5 6 bri g ht N K cells 
i ncrease d i n s u bjects gi ve n dacliz u ma b fr o m a me dia n of 8 cells per μ L ( 0.6 % of l y m p h oc y tes) at 
baseli ne t o 4 0 cells per μ L ( 3 .6 % of l y m p h oc y tes) at t he e n d of treat me nt. I ncreases i n C D 5 6 bri g ht
N K cells were a p pare nt s h ortl y  after baseli ne ( wee k 4) i n b ot h dacliz u ma b gr o u ps vers us place b o 
( p <0 .0 0 0 1). C D 4 + a n d C D 8 + T -cell c o u nts m o destl y  decrease d b y a b o ut 7 – 1 0 % at wee k 5 2 i n 
s u bjects gi ve n dacliz u ma b , a n d t he C D 4+ / C D 8+ rati o re mai ne d c o nsta nt.  Ne utralizi n g 
a nti b o dies t o dacliz u ma b were detecte d i n 2 % of s u bjects i n t he dacliz u ma b gr o u ps at w ee k 2 4, 
b ut i n < 1 % at wee k 5 2. W hile t here were m o derate re d ucti o ns i n t he n u m ber of circ ulati n g 
C D 4 + a n d C D 8 + cells, t he res ults of t he st u d y were c o nsiste nt wit h pre vi o us fi n di n gs t hat 
s h o we d t he p ote ntial f or preser vati o n of T-cell effect or res p o nses in t he a bse nce of hi g h -affi nit y 
I L-2 si g nali n g [G ol d 2 0 1 3 ].  N o i ncrease i n i nfecti o ns associate d wit h deficits i n T -cell me diate d 
i m m u nit y were n ote d.
I n vesti gat ors c o n d ucte d a m ultice nter, d o u ble bli n d, 1-ye ar e xte nsi o n st u d y ( S E LE C TI O N , St u d y 
2 0 5 M S 2 0 2 ) s p o ns ore d b y Bi o ge n t o assess t he safet y a n d i m m u n o ge nicit y of dacliz u ma b , as 
well as t he d ura bilit y of dacliz u ma b treat me nt effect o n disease acti vit y [Gi o va n n o ni 2 0 1 4 ].  
S u bject s w h o recei ve d place b o i n S E L E C T were ra n d o ml y assi g ne d ( 1: 1) t o recei ve 1 5 0 m g or 
3 0 0 m g S C dacliz u ma b e ver y 4 wee ks f or 5 2 wee ks (treat me nt i nitiati o n gr o u p); w hile s u bjects 
w h o ha d recei ve d dacliz u ma b were ra n d o ml y assi g ne d ( 1: 1) t o c o nti n ue t heir prese nt d ose wit h 
( was h o ut a n d re-i nitiati o n gr o u p) or wit h o ut (c o nti n u ous treat me nt gr o u p) a was h o ut peri o d of 2 0 
wee ks.  I n t he c o nti n u o us treat me nt gr o u p, t he A R R was si milar i n year 1 ( S E LE C T) a n d ye ar 2 
( S E LE C TI O N). T he n u m bers of ne w G d + lesi o ns i n t his gr o u p were als o c o nsiste nt bet wee n 
ye ars 1 a n d 2. H o we ver, t he n u m ber of ne w or ne wl y  e nlar gi n g T 2 h yperi nte nse lesi o ns t hat 
f or me d d uri n g ye ar 2 was l o wer t ha n i n year 1, as was t he v ol u me of ne w T 1 h y p oi nte nse 
lesi o ns. T he pr o p orti o n of s u bjects w h o ha d c o nfir me d disa bilit y pr o gressi o n was si milar i n year 
1 a n d y ear 2 i n t his gr o u p.  I n t he treat me nt i nitiati o n gr o u p, t he A R R ( 0. 4 3 4 i n year 1, c o m pare d 
t o 0. 1 7 9 i n year 2), pr o p orti o n of s u bjects w h o rela pse d ( 0. 3 6 2 i n year 1, c o m pare d t o 0. 1 7 6 i n 
ye ar 2), a n d pr o p orti o n of s u bjects wit h c o nfir me d disa bilit y pr o gressi o n ( 1 1 % i n year 1, 
c o m pare d t o 5 % i n ye ar 2) were re d uce d si g nifica ntl y  i n year 2. Si milarl y,  t he n u m bers of ne w 
G d + lesi o ns ( 1. 4 i n year 1, c o m pare d t o 0. 2 i n year 2) a n d ne w or ne wl y e nlar gi n g T 2 lesi o ns 
( 8. 0 i n year 1, c o m pare d t o 2. 1 i n year 2) were re d uce d i n year 2. Si g nifica nt re d ucti o ns were 
als o rec or de d f or t he perce nta ge c ha n ge i n v ol u me of t otal T 2 lesi o ns a n d t he v ol u me of ne w T 1 
h y p oi nte nse lesi o ns.
I n t he was h o ut a n d re-i nitiati o n gro u p, ser u m c o nce ntrati o n of dacliz u ma b a n d n u m ber of 
C D 5 6 bri g ht N K cells ret ur ne d t o pre -treat me nt val ues d uri n g t he 2 4-wee k was h o ut peri o d. T he 
m ea n n u m ber of ne w G d + lesi o ns were si milar at baseli ne ( p o ole d 1 5 0 m g a n d 3 0 0 m g treat me nt 
gr o u ps, mea n n u m ber 1 .6 [ S D 3 .5]) a n d at t he e n d of was h o ut ( 1 .1 [ 2 .3]; fi g ure 3 B).   D uri n g t he 

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 4
was h o ut peri o d, t he A R R ( 0.4 3 7) was si milar t o t hat i n t he place b o gr o u p i n S E L E C T ( 0 . 4 3 4). 
O verall, t he A R R i n t he was h o ut a n d re-i nitiati o n gr o u p was n ot si g nifica ntl y hi g her i n ye ar 2 
t ha n i n year 1. At wee k 1 0 4, t he n u m ber of ne w G d + lesi o ns i n t his gr o u p was si milar t o t he 
n u m ber at t he e n d of year 1 , as well as t o t he n u m bers i n s u bjects i n t he c o nti n u o us a n d treat me nt 
i nitiati o n gr o u ps. A d diti o nall y , t he n u m bers of C D 5 6bri g ht N K cells at wee k 1 0 4 (dacliz u ma b 
1 5 0 m g: me dia n 4 9 . 8 cells/m m 3 [i nter q uartile ra n ge (I Q R) 3 2 .3 – 7 0. 9]; 3 0 0 m g: me dia n 4 7. 2 
[ 2 6.5 – 6 4 .5]) were si milar t o t h ose i n s u bjects w h o ha d re mai ne d o n c o nti n u o us treat me nt f or 2 
ye ars (dacliz u ma b 1 5 0 m g: me dia n 5 3 .4 cells/ m m 3 [ 3 8. 3 – 6 8.8]; 3 0 0 m g: me dia n 5 7 .7 [ 3 9 . 8 –
8 5 .7]) .  I n t otal, 6 s u bjects ( 1 %) ha d seri o us c uta ne o us e ve nts. I n t he 1 5 0 m g treat me nt i nitiati o n 
gr o u p, 1 s u bject ha d dr u g er u pti o n a n d 1 ha d ecze ma; i n t he 1 5 0 m g was h o ut a n d re -i nitiati o n 
gr o u p, 1 s u bject ha d pit yriasis r u bra pilaris; a n d i n t he 3 0 0 m g c o nt i n u o us treat me nt gr o u p, 1 
s u bject ha d dr u g er u pti o n a n d ecze ma, 1 ha d e xf oliati ve der matitis, a n d 1 ha d urticaria. O ne 
s u bject i n t he 3 0 0 m g treat me nt i nitiati o n gr o u p de vel o pe d breast ca ncer, w hic h was n ot 
c o nsi dere d t o be relate d t o treat me nt. Ele vati o n i n li ver e nz y me c o nce ntrati o ns of m ore t ha n 5 
ti mes t he U L N occ urre d i n 1 1 s u bjects ( 2 %), wit h si milar fre q ue ncies i n eac h gr o u p. Te n of 
t hese s u bjects res u me d dacliz u ma b wit h o ut rec urre nce d uri n g t he st u dy a n d o ne s u bject di d n ot 
restart me dicati o n. T he i ncreases of m ore t ha n fi ve ti mes t he U L N res ol ve d i n a me dia n ti me of 
8 4 .5 da y s (I Q R 2 9. 0 – 1 0 8.0).
O ne s u bject i n t he was h o ut a n d re-i nitiati o n gr o u p die d d ue t o a ut oi m m u ne he patitis after re-
i nitiati o n of 3 0 0 m g dacliz u ma b. Ala ni ne a mi n otra nsferase ha d i ncrease d t o  
 U/ L 
a p pr o xi matel y 8 wee ks after dacliz u ma b re-i nitiati o n a n d c o nti n ue d t o rise i n t he f oll o wi n g 3 
m o nt hs t o  
 U/ L  i n c o nj u ncti o n wit h a n i ncrease i n ser u m bilir u bi n c o nce ntrati o n t o 
t o 
ti mes greater t ha n t he U L N bef ore cli nical s y m p t o ms of li ver fail ure de vel o pe d. A c o ntri b ut or y  
r ole of dacliz u ma b c o ul d n ot be e xcl u de d.
O ver t he c o urse of t he st u d y , 7 s u bjects teste d p ositi ve f or ne utralizi n g a nti dr u g a nti b o dies.  O ne 
of t he 1 2 8 s u bjects ( 1 %) wit h a vaila ble data i n t he treat me nt i nitiati o n gr o u p teste d p ositi ve (t his 
s u bject als o teste d p ositi ve at baseli ne), 4 s u bjects ( 2 %) i n t he c o nti n u o us treat me nt gr o u p teste d 
p ositi ve, a n d 2 of t he 1 2 9 s u bjects ( 2 %) i n t he was h o ut a n d re-i nitiati o n gr o u p teste d p ositi ve.  
O verall, A Es a n d i m m u n o ge nicit y  were n ot i ncrease d i n t he sec o n d year of c o nti n u o us treat me nt 
wit h dacliz u ma b or d uri n g treat me nt was h o ut a n d re -i nitiati o n, a n d cli nical effects of treat me nt 
were s ustai ne d.
I n t he sec o n d pi v otal trial ( D E CI D E, St u d y  2 0 5 M S 3 0 1), a d o u ble bli n d, acti ve -c o ntr olle d st u d y, 
m ore t ha n 1 8 0 0 s u bjects wit h R R M S were ra n d o mize d t o recei ve eit her S C dacliz u ma b ( 1 5 0 m g 
e ver y 4 wee ks) or i ntra m usc ular (I M) I F N β-1a ( 3 0 mc g o nce a wee k) f or at least 9 6 a n d u p t o 
1 4 4 wee ks [Ka p p os 2 0 1 5c ].  S u bject s assi g ne d t o dacliz u ma b ha d a si g nifica ntl y  l o wer A R R 
c o m pare d wit h t h ose assi g ne d t o I F N β-1a ( 0. 2 2 vers us 0. 3 9), c orres p o n di n g t o a 4 5 % re d ucti o n
( p < 0. 0 0 1). W he n e val uate d at 6- m o nt h a n d y earl y i nter vals, A R R was si g nifica ntl y  l o wer f or 
s u bjects i n t he dacliz u ma b gr o u p c o m pare d t o t h ose i n t he I F N β -1a gr o u p f or all s pecifie d ti me 
peri o ds . S u bject s i n t he dacliz u ma b gr o u p als o ha d a si g nifica ntl y l o wer n u m ber of ne w or 
ne wl y  e nlar ge d brai n lesi o ns o n T 2- wei g hte d M RI ( 4. 3 vers us 9. 4) at 9 6 wee ks c o m pare d wit h 
s u bjects treate d wit h I F N β- 1a ( p < 0. 0 0 1). T he v ol u me of ne w or ne wl y e nlar ge d h y peri nte nse 
lesi o ns o n T 2-wei g hte d M RI  was si g nifica ntl y l o wer i n t he dacliz u ma b gr o u p c o m pare d t o t he 
I F N β-1a gr o u p ( 2 2 5. 7 m m 3 vers us 5 5 6. 8 m m 3) at 9 6 wee ks ( p < 0. 0 0 1). Re gar di n g G d + lesi o ns, 
s u bjects treate d wit h dacliz u ma b ha d a l o wer mea n n u m ber of lesi o ns c o m pare d t o t h ose i n t he 

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 5
I F N β-1 a gr o u p at b ot h 2 4 wee ks ( 0. 5 vers us 0. 8, p < 0. 0 0 1) a n d 9 6 wee ks ( 0. 4 vers us 1. 0, 
p < 0. 0 0 1). T he mea n n u m ber of ne w h y p oi nte nse lesi o ns o n T 1- wei g hte d M RI  was als o l o wer i n 
t he dacliz u ma b gr o u p o ver a peri o d of 9 6 wee ks c o m pare d t o t he I F N β -1 a gr o u p ( 2. 1 3 vers us 
4. 4 3, p < 0. 0 0 1). At 9 6 wee ks, t he c ha n ge s i n v ol u me of h yp oi nte nse lesi o ns o n T 1 -wei g hte d 
M RI  a n d hy p eri nte nse lesi o ns o n T 2- wei g hte d M RI  were b ot h si g nifica ntl y  greater i n s u bjects 
treate d wit h I F N β-1a c o m pare d t o s u bjects treate d wit h dacliz u ma b ( p < 0. 0 0 1). Fr o m baseli ne t o 
9 6 wee ks, s u bjects treate d wit h dacliz u ma b ha d a l o wer mea n a n n ualize d perce nta ge of brai n 
v ol u me l oss t ha n s u bjects treate d wit h I F N β- 1a (-0. 5 5 9 vers us -0. 5 8 5, p < 0. 0 0 1). 
I n s u bjects w h o ha d disa bilit y pr o gressi o n, as meas ure d by t he E x pa n de d Disa bilit y  Stat us Scale 
( E D S S), t hat was c o nfir me d at 1 2 wee ks, t he esti mate d rate of s ustai ne d disa bilit y  pr o gressi o n at 
W ee k 1 4 4 was l o wer i n t he dacliz u ma b gr o u p t ha n i n t he I F N β-1a gr o u p ( 1 6 % versus 2 0 % , 
p = 0. 1 6 ). Si milarl y , i n s u bjects wit h c o nfir me d disa bilit y pr o gressi o n at 2 4 wee ks, t he esti mate d 
rate of s ustai ne d disa bilit y pr o gressi o n at W ee k 1 4 4 was 1 3 % i n t he dacliz u ma b gr o u p a n d 1 8 % 
i n t he I F N β- 1a gr o u p ( p = 0. 0 3) . Pres pecifie d a nal y ses t o assess t he se nsiti vit y of ass u m pti o ns 
ma de a b o ut disa bilit y  pr o gressi o n at 1 2 wee ks i n ce ns ore d s u bjects s h o we d a statisticall y 
si g nifica nt be nefit of dacliz u ma b o ver I F N β- 1a. T he o utc o mes of pres pecifie d a nal ys es of 
disa bilit y  pr o gressi o n at 2 4 wee ks were als o si g nifica nt i n fa v or of dacliz u ma b , e xce pt f or w he n 
it was ass u me d t hat disa bilit y pr o gressi o n di d n ot occ ur i n a ny s u bject w h o was ce ns ore d after a 
te ntati ve disa bilit y pr o gressi o n (i.e., after d oc u me nte d w orse ni n g i n t he E D S S sc ore b ut bef ore a 
c o nfir mat or y visit). At 1 4 4 wee ks, t he perce nta ge of s u bjects w h o were free fr o m rela pse was 
hi g her at 6 7 % i n t he dacliz u ma b gr o u p, c o m pare d t o 5 1 % of s u bjects free fr o m rela pse i n t he 
I F N β- 1a gr o u p. Cli nicall y  mea ni n gf ul w orse ni n g ( defi ne d as a n i ncrease of ≥7. 5 p oi nts) i n t he 
s u bject-re p orte d p hys ical effect of M S, as assesse d wit h t he m ulti ple scler osis ( M S) i m pact scale 
( M SIS- 2 9) p h ys ical s u bscale, was o bser ve d i n 1 9 % of t he s u bjects in t he dacliz u ma b gr o u p a n d 
2 3 % of t h ose i n t he I F N β- 1a gr o u p. I n t he dacliz u ma b gr o u p, a hi g her perce nta ge of s u bjects 
s h o we d n o e vi de nce of disease acti vit y ( N E D A) o ver 9 6 wee ks ( 2 2 %) c o m pare d wit h s u bjects i n 
t he I F N β- 1a gr o u p ( 1 3 %). 
T he M S
f u ncti o nal c o m p osite ( M S F C) was use d t o meas ure a m b ulati o n, ar m f u ncti o n, a n d 
c o g niti o n i n s u bjects e nr olle d i nt o t he st u d y.  Ne gati ve c ha n ges fr o m baseli ne i n M S F C sc ore 
a n d c o m p o ne nt Z sc ores i n dicate w orse ni n g i n disa bilit y , a n d p ositi ve c ha n ges i n dicate 
i m pr o ve me nt i n disa bilit y [P ol ma n a n d R u dic k 2 0 1 0 ].  T he me dia n c ha n ge i n M F S C sc ore fr o m 
baseli ne t o wee ks 4 8 a n d 9 6 was l o wer i n t he I F N β- 1a gr o u p.  T he me dia n c ha n ge i n sc ore fr o m 
baseli ne t o wee k 4 8 was 0. 0 5 8 f or s u bjects i n t he I F N β-1a gr o u p, c o m pare d t o 0. 0 7 1 i n t he 
dacliz u ma b gr o u p ( p = 0. 0 5).  T he me dia n c ha n ge i n sc ore fr o m baseli ne t o wee k 9 6 was 0. 0 5 5 i n 
t he I F N β-1a gr o u p, c o m pare d t o 0. 0 9 1 i n t he dacliz u ma b ( p < 0. 0 0 1).  C ha n ges i n c o m p o ne nt Z-
sc ores varie d by test.  I F N β -1a treate d s u bjects s h o we d w orse ni n g o n t he 2 5-f o ot wal k test, 
w hic h meas ures a m b ulati o n, fr o m baseli ne t o wee k 9 6, w hile dacliz u ma b treate d s u bjects 
s h o we d n o c ha n ge ( p = 0. 0 0 6).  B ot h gr o u ps i m pr o ve d o n t he 9-h ole pe g test, w hic h meas ures ar m 
f u ncti o n, wit h t he me dia n c ha n ge fr o m baseli ne bei n g si g nifica ntl y greater f or t he dacliz u ma b 
gr o u p vers us t he I F N β -1a gr o u p at 4 8 wee ks ( p = 0. 0 8) a n d 9 6 wee ks ( p = 0. 0 0 2).  S u b jects i n bot h
t he dacliz u ma b a n d I F N β- 1a gr o u ps i m pr o ve d e q uall y o n t he 3-sec o n d pace d a u dit or y serial 
a d diti o n test, w hic h meas ures c o g niti o n, wit h e q ual me dia n c ha n ges i n sc ore fr o m baseli ne t o 
wee ks 4 8 a n d 9 6.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 6
I n vesti gat ors use d t he sy m b ol di git m o dali ties test ( S D M T) t o meas ure c ha n ges i n c o g niti ve 
i m pair me nt o ver ti me i n s u bjects e nr olle d i nt o t he st u d y.  Sc ores f or t he S D M T ra n ge fr o m 0 t o 
1 1 0 wit h hi g her sc ores i n dicati ve of faster c o g niti ve pr ocessi n g s pee d [Be ver 1 9 9 5 ].  Mea n 
c ha n ge i n S D M T sc ores fr o m baseli ne were si g nifica ntl y  differe nt acr oss gr o u ps at wee k 9 6
( p = 0. 0 3).  S u bject s i n t he I F N β- 1a gr o u p i ncrease d b y  a n a vera ge of 2. 9 ± 1 2. 7 p oi nts w hile 
s u bjects i n t he dacliz u ma b gr o u p i ncrease d b y a n a vera ge of 4. 1 ± 1 2. 4 p oi nts.
S eri o us a d verse e ve nts ( S A Es ) were m ore c o m m o n i n t he dacliz u ma b gr o u p c o m pare d wit h t he 
I F N β-1a gr o u p ( 1 5 % vers us 1 0 %) , i ncl u di n g rates of i nfecti o n ( 4 % vers us 2 %).  T he m ost 
fre q ue nt i nfecti o ns were uri nar y tract i nfecti o ns, re p orte d i n 8 s u bjects treate d wit h dacliz u ma b 
a n d 2 s u bject s treate d wit h I F N β-1a. T his was f oll o we d b y  p ne u m o nia, w hic h occ urre d i n 5 
s u bjects an d 2 s u bjects i n t he dacliz u ma b a n d I F N β- 1a gr o u ps, res pecti vel y. C uta ne o us A Es 
(i ncl u di n g ras h a n d ecze ma as t he m ost c o m m o n) were re p orte d i n 3 7 % of dacliz u ma b s u bjects 
a n d 1 9 % of I F N β -1a s u bjects, lea di n g t o treat me nt disc o nti n uati o n i n 5 % a n d 1 % of dacliz u ma b
a n d I F N β -1a s u bjects, res pecti vel y.
C uta ne o us S A Es occ urre d i n 2 % of s u bjects i n t he 
dacliz u ma b gr o u p a n d < 1 % of s u bjects i n t he I N F β- 1a gr o u p, i ncl u di n g der matitis a n d 
a n gi oe de ma as t he S A Es re p orte d i n m ore t ha n 1 s u bject. A hi g her perce nt a ge of s u bjects i n t he 
dacliz u ma b gr o u p were o bser ve d t o ha ve ele vati o ns i n li ver a mi n otra nsferase le vels t hat were > 5 
ti mes t he U LN ( 6 % vers us 3 % of s u bjects i n t he I F N β-1a gr o u p) [Ka p p os 2 0 1 5c ].
5. 2.
O ver all R ati o n ale
T he cli nical de vel o p me nt pr o gra m f or dacliz u ma b t o date has de m o nstrate d t hat t he t hera py is 
hi g hl y efficaci o us i n t he treat me nt of R M S, is well t olerate d, has a safet y pr ofile t hat is 
ma na gea ble wit h a p pr o priate m o nit ori n g a n d r o uti ne cli nical care, a n d offers c o n ve nie nt o nce -
m o nt hl y  self-a d mi nistere d S C i njecti o n d osi n g [Ka p p os 2 0 1 5c ; Sel maj 2 0 1 3 ]. I n t he 2 t o 3 y ear, 
c o m parat or -c o ntr olle d, p hase 3 D E CI D E trial, dacliz u ma b ( 1 5 0 m g) treat me nt res ulte d i n se veral 
statisticall y si g nifica nt effects c o m pare d t o o nce-wee kl y I M I F N β-1a i ncl u di n g re d ucti o n i n 
A R R b y  4 5 %, re d ucti o n i n 2 4-wee k c o nfir me d disa bilit y  pr o gressi o n b y 2 7 %, a n d re d ucti o n i n 
t he f or mati o n of M RI lesi o ns b y 6 5 % ( G d +), 5 4 % ( ne w/ ne wl y e nlar gi n g T 2 -h y peri nte nse), a n d 
5 2 % ( ne w T 1 -h y p oi nte nse lesi o ns) [Ka p p os 2 0 1 5a ; Ka p p os 2 0 1 5 b ]. A d diti o nal fi n di n gs fr o m 
D E CI D E i n dicate d t hat dacliz u ma b res ulte d i n cli nicall y mea ni n gf ul c o g niti ve i m pr o ve me nt (as 
assesse d b y t he S D M T) c o m pare d t o I M I F N β -1a, a n d fe wer s u bjects recei vi n g dacliz u ma b 
e x perie nce d c o g niti ve decli ne [Be ne dict 2 0 1 5 ]. 
Fr o m a safety pers pecti ve, cli nical data t o date i n dicate n o ris k of o p p ort u nistic i nfecti o ns wit h 
dacliz u ma b a n d, i m p orta ntl y, n o ris k of P M L. T he ris ks ass ociate d wit h dacliz u ma b 
(e. g., i nfecti o ns, ras h, der matitis, he patic e nz yme a b n or malities) ha ve bee n s h o w n t o be 
ma na gea ble wit h sta n dar d m o nit ori n g a n d me dical i nter ve nti o ns [ G ol d 2 0 1 3 ; Ka p p os 2 0 1 5a ;
Ka p p os 2 0 1 5c ].
Alt h o u g h e vi de nce de m o nstrates t hat nataliz u ma b is a hi g hl y effecti ve treat me nt f or R M S, a 
n u m ber of patie nts w h o are effecti vel y res p o n di n g t o t hera p y ulti matel y disc o nti n ue treat me nt 
d ue t o c o nce r ns re gar di n g t he ris k of P M L or t he occ urre nce of A Es [B utz k ue ve n 2 0 1 4 ; P ol ma n
2 0 0 6 ]. M ulti ple D M Ts h a ve bee n i n vesti gate d as p ost- nataliz u ma b treat me nt o pti o ns, i ncl u di n g 
fi n g oli m o d, D M F, I F N β, G A, a n d p ulse d ster oi ds, b ut t he res ults ha ve bee n mi xe d, wit h s o me 
patie nts e x hi biti n g M S disease acti vit y des pite alter nati ve treat me nt [Ce nt o nze 2 0 1 2 ; Cleric o
2 0 1 4 ; C o ha n 2 0 1 5 ; C o he n 2 0 1 4 ; Faiss ner 2 0 1 5 ; F o x 2 0 1 4 ; Ka p p os 2 0 1 5 b ; R ossi 2 0 1 3 ]. I n 

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 7
m ulti ple st u dies i n vesti gati n g t he efficac y  of fi n g oli m o d f oll o wi n g disc o nti n uati o n of 
nataliz u ma b, u p war ds of 2 5 % of s u bjects e x perie nce d a cli nical rela pse wit hi n t he first 6 m o nt hs 
of starti n g fi n g oli m o d [C o mi 2 0 1 5 ; C o mi 2 0 1 3 ; Ka p p os 2 0 1 5c ]. I n a retr os pecti ve, 
o bser vat i o nal st u d y i n vesti gati n g t he efficac y of D M F f oll o wi n g disc o nti n uati o n of nataliz u ma b 
( S T R A T E G Y), o verall A R R i ncrease d fr o m 0. 1 1 4 o n nataliz u ma b t o 0. 2 4 8 after 1 ye ar of D M F 
treat me nt [C o ha n 2 0 1 5 ]. T heref ore, t here re mai ns a n u n met me dical nee d f or ne w alter nati ve 
hi g h -efficac y treat me nt o pti o ns f or t he ofte n diffic ult t o treat p o p ulati o n of R M S patie nts w h o 
fi n d it necessar y t o disc o nti n ue a t hera p y t hat ot her wise ma y be effecti vely ma na gi n g t heir 
disease.
C o nsi deri n g t hat dacliz u ma b is a hi g hly efficaci o us treat me nt f or R M S wit h a ma na gea ble safet y 
pr ofile a n d n o i ncrease d ris k of P M L  t o date, it c o ul d be a c o m pelli n g o pti o n f or patie nts 
s witc hi n g off nataliz u ma b. T heref ore, t he S U S T AI N st u d y ai ms t o esta blis h w het her dacliz u ma b 
is a s uita ble D M T f or R M S patie nts disc o nti n ui n g nataliz u ma b.
5. 2. 1.  
R ati o n ale f or D ur ati o n bet wee n T her a pies
As part of t he st u d y desi g n, s u bjects m ust recei ve t heir first d ose of dacliz u ma b at 2 8 ( + 3) d a y s 
f oll o wi n g disc o nti n uati o n of nataliz u ma b. T he rati o nale f or t his re q uire me nt is t o mi ni mize t he 
was h o ut peri o d bet wee n dacliz u ma b a n d nataliz u ma b. Cli nical researc h st u dies i n patie nts 
s witc hi n g fr o m nataliz u ma b t o a n alter nati ve treat me nt o pti o n ha ve s h o w n t hat disease acti vit y 
ca n occ ur wit hi n t he first 6 m o nt hs of disc o nti n ui n g nataliz u ma b. H o we ver, i n se veral of t hese 
st u dies, t he ris k of disease rec urre nce was s h o w n t o be miti gate d wit h a s h orter was h o ut peri o d 
bet wee n treat me nts [C o ha n 2 0 1 5 ; Ka p p os 2 0 1 5c ]. In a ra n d o mize d trial e val uati n g t he effects of 
nataliz u ma b treat me nt i nterr u pti o n ( R E S T O R E), it was s h o w n t hat nataliz u ma b c o nce ntrati o ns 
reac h u n detecta ble le vels 8 wee ks after disc o nti n uati o n [Cree 2 0 1 3 ]. P har mac o dy na mic ( P D) 
st u dies wit h dacliz u ma b de m o nstrate d i ncreases i n C D 5 6 bri g ht N K cells a n d ser u m I L -2 le ve ls 
wit hi n t he first 4 wee ks of treat me nt [A mara va di 2 0 1 5 ] a n d effects o n disease acti vit y, as 
e vi de nce d b y re d ucti o ns i n G d + lesi o n acti vit y, were a p pare nt wit hi n 8 t o 1 2 wee ks ( S E L E C T; 
Bi o ge n, data o n file).
T hese data i n dicate t hat a 2 8 -d a y  ga p bet ween t he disc o nti n uati o n of 
nataliz u ma b a n d t he i nitiati o n of dacliz u ma b w o ul d ma xi mize t he P D o verla p of t hese 2 
t hera pies a n d t h us mi ni mize t he a m o u nt of ti me patie nts are n ot pr otecte d b y a hi g hly efficaci o us 
t hera py.
Wit h res pect t o t he ti me i nter val bet w ee n nataliz u ma b disc o nti n uati o n a n d dacliz u ma b i nitiati o n, 
it is als o i m p orta nt t o c o nsi der h o w t hese t hera pies are t h o u g ht t o f u ncti o n i n t he b o d y a n d t he 
p ossi bilit y  of a d diti ve i m m u n os u p pressi ve effects. Dacliz u ma b a n d nataliz u ma b i m pact t he 
pat h o p h y siol o g y  of M S i n disti nct a n d re versi ble wa ys. Dacliz u ma b is a h u ma nize d m o n ocl o nal 
a nti b o d y t hat tar gets C D 2 5 a n d re versi bl y m o d ulates I L-2 si g nali n g. T hese effects res ult i n 
1) selecti ve a nta g o nis m of pr o -i nfla m mat or y acti vate d T cell f u ncti o n a n d 2) e xpa nsi o n of 
i m m u n ore g ulat or y C D 5 6bri g ht N K cells [Biele k o va 2 0 1 3 ; Pfe n der a n d Marti n 2 0 1 4 ; Wie n dl a n d
Gr oss 2 0 1 3 ]. Nataliz u ma b is a selecti ve a d hesi o n m olec ule i n hi bit or t hat bi n ds t o t he α 4-s u b u nit 
of h u ma n i nte gri ns, disr u pti n g t heir i nteracti o n wit h li ga n ds s uc h as vasc ular cell a d hesi o n 
m olec ule - 1. T his acti o n re d uces t he a bilit y  of i m m u ne cells t o cr oss t he bl o o d-brai n barrier a n d 
e nter t he C N S [P ol ma n 2 0 0 6 ; T y sa bri® Prescri bi n g I nf or mat i o n 2 0 1 3/ S m P C]. Prese ntl y , n o 
bi ol o gical e vi de nce s u g gests a ris k of A Es res ulti n g fr o m t he a d diti ve bi ol o gical effects of t hese 
2 t hera pies; t he S U S T AI N st u d y is e x pecte d t o a d dress t his pa ucit y  of data. Ulti matel y , a 

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 8
nataliz u ma b was h o ut peri o d of 2 8 d a y s is t h o u g ht t o re prese nt a n effecti ve bala nce bet wee n 
efficac y a n d safety, a n d fi n di n gs fr o m t his st u d y  are a ntici pate d t o hel p a d dress t he i m p orta nt 
u n met me dical nee d of s uccessf ul treat me nt p ost- nataliz u ma b.
5. 2. 2.
R ati o n ale f or D ose a n d Sc he d ule Selecti o n
Si n gle -use, dis p osa ble pre -fille d pe ns, als o k n o w n as a ut oi nject ors, will be pr o vi de d t o si m plif y  
t he i njecti o n pr ocess a n d t here b y re d uce t he b ur de n of a d mi nisteri n g a l o n g-ter m t hera py s uc h as 
dacliz u ma b i n t he cli nic or at h o me.  T he d ose a n d fre q ue nc y of dacliz u ma b use d i n t his st u d y  is 
t he sa me use d i n ot her p hase 3 st u dies of dacliz u ma b ( D E CI D E, St u dy 2 0 5 M S 3 0 1; O B S E R V E, 
St u d y  2 0 5 M S 3 0 2; E X T E N D, St u d y  2 0 5 M S 3 0 3).  

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 2 9
6.
S T U D Y O B J E C TI V E S A N D E N D P OI N T S
6. 1.
O bjecti ves
6. 1. 1.
Pri m ar y O bjecti ve a n d E n d p oi nts
T he pri mar y  o bjecti ve of t he st u d y is t o e val uate t he effects of treat me nt wit h dacliz u ma b o n t he 
p r o p orti o n of s u bjects rela pse-free at 6 m o nt hs i n R R M S s u bjects, w h o s witc he d fr o m treat me nt 
wit h nataliz u ma b t o dacliz u ma b d ue t o safet y c o ncer ns.
T he pri mar y  e n d p oi nt is t he pr o p orti o n of s u bjects rela pse -free at M o nt h 6 i n R R M S s u bjects 
treate d wit h dacliz u ma b , w h o s witc he d fr o m treat me nt wit h nataliz u ma b.
See Secti o n 1 1 f or t he defi niti o n of rela pse.
6. 1. 2.
Sec o n d ar y O bjecti ve s a n d E n d p oi nts
T he sec o n dar y  o bjecti ves of t his st ud y i n t his st u d y p o p ulati o n are t o e val uate t he effects of 
dacliz u ma b o n t he f oll o wi n g:

M S rela pse acti vit y i ncl u di n g t he A R R a n d t he pr o p orti o n of s u bjects e x perie nci n g 
rela pses re q uiri n g h os pitalizati o n a n d/ or ster oi d treat me nt.

M S -relate d o utc o mes meas ure d usi n g M RI.

Safet y  a n d t olera bilit y i n s u bjects pre vi o usl y treate d wit h nataliz u ma b. 
T he sec o n dar y  e n d p oi nts t hat relate t o t hese o bjecti ve s are t he f oll o wi n g:

T he pr o p orti o n of s u bjects rela pse -free at M o nt h 1 2.

T he pr o p orti o n of s u bjects e x perie nci n g rela pse re q uiri n g h os pitalizati o n a n d/ or 
ster oi d treat me nt at M o nt h 1 2.

T he A R R at M o nt h 1 2.

T he n u m ber of ne w G d + e n ha nce d a n d T 1 h y p oi nte nse lesi o ns at M o nt h 6 a n d M o nt h 
1 2 o n M RI .

T he n u m ber of ne w or ne wl y  e nlar ge d T 2 hy p eri nte nse lesi o ns at M o nt h 6 a n d M o nt h 
1 2 o n M RI .

T he per ma ne nt disc o nti n uati o n rate of dacliz u ma b at M o nt h 1 2.

T he i nci de nce of A Es a n d S A Es i ncl u di n g cli nicall y  rele va nt s hifts i n cli nical 
la b orat or y assess me nts.
6. 1. 3.
E x pl or at or y O bjecti ve s a n d E n d p oi nts
T he e x pl orat or y  o bjecti ves of t his st u d y i n t his st u d y p o p ulati o n are t o e val uate t he effects of 
dacliz u ma b o n:

.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3 1
7.
S T U D Y D E SI G N
7. 1.
St u d y O ver vie w
T his is a m ultice nter, o pe n -la bel st u d y of dacliz u ma b m o n ot hera p y i n s u bjects wit h R R M S w h o 
were pre vi o usl y treate d w it h nataliz u ma b f or at least 1 2 m o nt hs.  A p pr o xi matel y  1 0 0 s u bjects 
will be e nr olle d fr o m a p pr o xi matel y  4 0 sites i n t he U S a n d rest of w orl d over a 1 2 -m o nt h peri o d. 
F oll o wi n g c o nse nt a n d e val uati o n of eli gi bilit y , s u bjects will disc o nti n ue nataliz u ma b a n d
c o m me nce treat me nt wit h dacliz u ma b .  S u bjects will i nitiate treat me nt wit h dacliz u ma b at 2 8
( + 3) d a y s f oll o wi n g t he last i nf usi o n of nataliz u ma b.  A detaile d descri pti o n of st u d y assess me nts 
is pr o vi de d i n Secti o n 9. 2 . 
T he assess me nt sc he matic pr o vi des a n o ver vie w of t he st u d y  assess me nt sc he d ule (Ta ble 1 ).  
Assess me nts will be perf or me d at e nr oll me nt, baseli ne, M o nt h 1, M o nt h 3,
M o nt h 4,
M o nt h 6, 
M o nt h 9 a n d M o nt h 1 2.  T he a d diti o nal safet y f oll o w-u p visit will be c o n d ucte d re m otel y. 
7. 2.
O ver all St u d y D ur at i o n a n d F oll o w-U p
T he st u d y  will c o nsist of a 2 8-d a y ( + 3 d a y s) scree ni n g peri o d f or eac h s u bject, a 1 2-m o nt h 
treat me nt peri o d, a n d a 4-m o nt h re m ote safet y  f oll o w- u p visit after t he s u bject’s last treat me nt
i njecti o n.  T he e n d of t he st u d y f or eac h s u bject will be t he last st u d y  visit or t he visit at w hic h 
t he s u bject disc o nti n ues fr o m t he st u d y ( bef ore t he 1 2-m o nt h visit).  Eac h f oll o w -u p visit will 
i ncl u de a 4-d a y  wi n d o w bef ore a n d after t he visit f or c o m pleti o n of all assess me nts.  T he f oll o w-
u p peri o d wi ll i ncl u de efficac y a n d safety f oll o wi n g treat me nt i nitiati o n of dacliz u ma b . T he e n d 
of t he st u d y  o verall will be defi ne d as t he e n d of t he 1 2- m o nt h st u d y  f oll o w-u p peri o d f or t he last 
patie nt .  T he 4-m o nt h safet y  f oll o w- u p visit will be c o n d ucte d re m otel y after t he 1 2-m o nt h st u d y  
f oll o w-u p visits ha ve bee n c o m plete d.
S u bjects ha vi n g te ntati ve disa bilit y  pr o gressi o n i de ntifie d near t he e n d of t he c ore st u d y (e. g., 
M o nt h 1 2) will atte n d a d diti o nal f oll o w- u p visits 1 2 a n d 2 4 wee ks later t o c o nfir m pr o gressi o n. 
S u bjects ma y  disc o nti n ue treat me nt at a ny ti me d uri n g t he st u d y, a n d t he y  will be f oll o we d f or 
a n a d diti o nal 4 m o nt hs t o c ollect data o n safet y, L F T , M S treat me nt, rela pses, a n d t he use of 
c o nc o mita nt me dicati o ns.
7. 3.
E arl y Ter mi n ati o n of St u d y
Bi o ge n ma y  ter mi nate t his st u d y at a ny ti me, after i nf or mi n g t he I n vesti gat or(s).  Bi o ge n will 
n otif y t he I n vesti gat ors if t he st u d y is place d o n h ol d, c o m plete d, or cl ose d.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3 2
8.
S T U D Y P O P U L A TI O N
8. 1.
I ncl usi o n Criteri a
T o be eli gi ble t o partici pate i n t his st u d y , ca n di dates must meet t he f oll o wi n g eli gi bilit y  criteria 
d uri n g t he scree ni n g peri o d ( 2 8 da y s [+ 3 d a y s] f oll o wi n g t he last d ose of nataliz u ma b):
1.
A bilit y  t o u n dersta n d t he p ur p ose a n d ris ks of t he st u d y a n d pr o vi de si g ne d a n d date d 
i nf or me d c o nse nt a n d a ut h orizati o n t o use pr otecte d healt h i nf or mati o n ( P HI) i n 
acc or da nce wit h nati o nal a n d l ocal s u bject pri vac y re g ulati o ns.
2.
A ge d 1 8 t o 5 5 ye ars ol d, i ncl usi ve, at t he ti me of i nf or me d c o nse nt.
3.
M ust ha ve d oc u me nte d dia g n osis of R R M S ( Mc D o nal d 2 0 1 0 Criteria) at scree ni n g
[P ol ma n 2 0 1 1 ].
4.
M ust ha ve bee n treate d wit h nataliz u ma b f or at least t he 1 2 m o nt hs pri or t o scree ni n g a n d
ha ve n ot misse d 2 or m ore c o nsec uti ve sc he d ule d d oses.
5.
M ust be naï ve t o dacliz u ma b a n d ot her f or ms of dacliz u ma b s uc h as Ze na pa x ® pri or t o 
e nr oll me nt.
6.
M ust ha ve a c o nfir me d E D S S sc ore of 0 t o 5. 5, i ncl usi ve, at scree ni n g.
7.
Fe male s u bjects of c hil d beari n g p ote ntial m ust practice effecti ve c o ntrace pti o n fr o m Da y  
-1 a n d be willi n g a n d a ble t o c o nti n ue c o ntrace pti o n f or d urati o n of t he st u d y .
8. 2.
E xcl usi o n Criteri a
Ca n di dates will be e xcl u de d fr o m st u d y e ntr y if a n y of t he f oll o wi n g e xcl usi o n criteria e xist 
d uri n g t he scree ni n g peri o d ( 2 8 da ys [+ 3 d a y s] f oll o wi n g t he last d ose of nataliz u ma b):
1.
I na bilit y t o c o m ply wit h st u d y re q uire me nts or, at t he discreti o n of t he I n vesti gat or, is 
dee me d u ns uita ble f or st u d y  partici pati o n.
2.
C urre nt partici pati o n i n a n ot her i n vesti ga ti o nal st u d y.
3.
Dia g n osis of pri mar y  pr o gressi ve, sec o n dar y pr o gressi ve, or pr o gressi ve rela psi n g M S (as 
defi ne d b y L u bli n a n d Rei n g ol d) [L u bli n 2 0 1 4 ].
4.
Fe males br eastfee di n g, pre g na nt, or pla n ni n g t o bec o me pre g na nt; or w o me n w h o ha ve a 
p ositi ve pre g na nc y  test res ult d uri n g scree ni n g.
5.
Hist or y  of dr u g or alc o h ol a b use (as defi ne d b y t he In vesti gat or) wit hi n 1 y ear pri or t o 
scree ni n g.
6.
Hist or y  of se vere o p p ort u nistic i nfecti o ns (i ncl u di n g P M L) or a ny cli nicall 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 , ne ur ol o gic ( ot her t ha n M S), der mat ol o gic, psyc hiatric, a n d re nal, or ot her 
maj or disease, as deter mi ne d b y t he I n vesti gat or .
7.
Disc o nti n ue d nataliz u ma b d ue t o s us pici o n of P M L.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3 3
8.
K n o w n acti ve mali g na ncies (s u bjects wit h c uta ne o us basal cell carci n o ma t hat has bee n 
c o m pletel y e xcise d pri or t o st u d y e ntr y re mai n eli gi ble).
9.
Cli nicall y  si g nifica nt la b a b n or malities reveale d b y  bl o o d tests at scree ni n g a part fr o m 
t h ose k n o w n t o be ass ociate d wit h nataliz u ma b (e. g., ly m p h oc y t osis).
1 0. Pre -e xisti n g he patic disease or he patic i m pair me nt, i ncl u di n g A L T or A S T at least 2 
ti mes t he U L N ( n or mal ra n ge f or A S T: 8 t o 4 8 u nits per liter a n d f or A L T: 7 t o 5 5 u nits 
per liter).  T h e n or mal ra n ge f or li ver e nz yme le vels ma y  var y sli g htly b y la b orat or y.
1 1. A hist or y  of a ut oi m m u ne he patitis or ot her a ut oi m m u ne c o n diti o n i n v ol vi n g t he li ver.
1 2. T he s u bject is usi n g a n ot her M S t hera p y c o nc o mita ntl y.
1 3. K n o w n hist or y  of h u ma n i m m u n o deficie nc y vir us ( HI V).
1 4. P ositi ve test res ult f or He patitis C vir us (test f or he patitis C vir us a nti b o d y  [ H C V A b]) or 
he patitis B vir us (test f or he patitis B s urface a nti ge n [ H Bs A g] a n d/ or he patitis B c ore 
a nti b o d y [ H Bc A b]).  Hist or y  of tra ns pla ntati o n or a n y a nti-rejecti o n t hera p y.
1 5. Ha ve ha d e vi de nce of disease acti vit y wit hi n t he 6 m o nt hs pri or t o scree ni n g visit defi ne d 
as t he f oll o wi n g: 

M S r ela pse, or

G d + e n ha nci n g lesi o ns, or ne w or e nlar gi n g T 2 lesi o ns o ver t he last 6 m o nt hs , or

D isease pr o gressi o n (a ny i ncrease of E D S S i n t he past 6 m o nt hs) .
1 6. T he s u bject 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 base d o n 
me dical hist or y , p h ysical e xa mi nati o n, or la b orat or y testi n g.
1 7. T he s u bject has bee n treate d wit h i m m u n os u p pressi ve or i m m u n o m o d ulati n g treat me nts 
i ncl u di n g mit o xa ntr o ne, azat hi o pri ne, met h otre xate, c y cl o p h os p ha mi de, or 
m y c o p he n olate m ofetil.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3 4
9.
S T U D Y P R O C E D U R E S
O nce t he i n vesti gati o nal site is acti vate d f or st u d y partici pati o n, s u bjects ma y be e nr olle d if t he y 
ha ve met t he i ncl usi o n criteria i n Secti o n 8. 1 a n d ha ve n ot bee n e xcl u de d base d o n t he e xcl usi o n 
criteria i n Secti o n 8. 2 .
9. 1.
Scree ni n g , E nr oll me nt a n d R a n d o miz ati o n
S u bjects m ust be c o nse nte d bef ore a n y scree ni n g tests or assess me nts are perf or me d.  At t he ti me 
of c o nse nt, t he s u bject will be e nr olle d i nt o t he st u d y .  
S u bjects will be i nitiate d o n dacliz u ma b after all scree ni n g assess me nts ha ve bee n c o m plete d a n d 
after t he I n vesti gat or has verifie d t hat t he y are eli gi ble per criteria i n Secti o ns 8. 1 a n d 8. 2 . N o 
s u bject ma y be gi n treat me nt pri or t o re gistrati o n a n d assi g n me nt of a u ni q ue s u bject 
i de ntificati o n n u m ber.  A n y s u bject i de ntificati o n n u m bers t hat are assi g ne d will n ot be re use d 
e ve n if t he s u bject d oes n ot recei ve treat me nt.  If a n eli gi ble s u bject was a p pr oac he d a n d di d n ot 
partici pate i n t he st u d y, t he reas o n f or n o n partici pati o n will be d oc u me nte d i n t he scree ni n g l o g
9. 2.
F oll o w - U p
S u bjects will be f oll o we d -u p f or 1 2 m o nt hs wit h assess me nts at M o nt hs 1, 3, 4, 6, 9, a n d 1 2.  
T here will be a 4-m o nt h sa fety visit c o n d ucte d re m otel y . T he f oll o w -u p st u d y  assess me nts are 
descri be d i n Secti o n 1 1. 2 .
S u bjects ha vi n g te ntati ve disa bilit y  pr o gressi o n i de ntifie d near t he e n d of t he c ore st u d y (e. g., 
M o nt h 1 2) will atte n d a d diti o nal f oll o w- u p visits 1 2 a n d 2 4 wee ks later t o c o nfir m pr o gressi o n. 
S u bjects w h o d o n ot recei ve a treat me nt d ose f or 2 or m ore c o nsec uti ve m o nt hs will c o nti n ue t o 
be f oll o we d f or data c ollecti o n. 
9. 3.
Wit h dr a w al of S u bject s fr o m t he St u d y
S u bjects m ust be wit h dra w n fr o m t he st u d y f or a n y o ne o f t he f oll o wi n g reas o ns:

T he s u bject wit h dra ws c o nse nt.  

T he s u bject 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 I n vesti gat or wit h dra ws t he s u bject fr o m t he st u d y  f or me dical reas o ns.
T he reas o n f or t he s u bject’s wit h dra wal fr o m t he st u d y  m ust be rec or de d i n t he s u bject’s case 
re p ort f or m ( C R F).
S u bjects w h o wit h dra w fr o m t he st u d y will n ot be re place d.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3 5
1 0.
S T U D Y T R E A T M E N T
Bi o ge n M A I nc. will pr o vi de dacliz u ma b t o sites i n t he U S.  Bi o ge n I dec Researc h Li mite d will 
pr o vi de dacliz u ma b t o sites i n all ot her c o u ntries. Dacliz u ma b m ust be a d mi nistere d o n -site 
d uri n g t he first 6 m o nt hs, a n d at t he M o nt h 9 visit. S ites ha ve t he o pti o n t o all o w s u bjects t o 
a d mi nister t he dr u g at h o me f or d oses at M o nt h 7, 8, 1 0, a n d 1 1. 
1 0. 1.
D osi n g Re gi me n a n d A d mi nistr ati o n
Refer t o a n d f oll o w t he pre vaili n g l ocal la beli n g , directi o ns f or ha n dli n g a n d a d mi nistrati o n 
( D H A) a n d I n vesti gat or Br oc h ure .
Dacliz u ma b is s u p plie d as a sterile, preser vati ve-free, c ol orless t o sli g htl y yell o w, a n d clear t o 
sli g htl y o palesce nt li q ui d.  The dr u g pr o d uct is s u p plie d i n a si n gle -use pre -fille d pe n, als o 
k n o w n as a n a ut oi nject or , i n t his st u d y.  Dacliz u ma b is s u p plie d as 1 5 0 m g of dacliz u ma b per 1. 0 
m L  a n d is a d mi nistere d S C o nce a m o nt h.
As s h o w n i n t he st u d y  sc he matic, d oses at M o nt hs 7, 8, 1 0 a n d 1 1 ca n be a d mi nistere d eit her at 
h o me or s u per vise d at t he site. T heref ore , at M o nt hs 6 a n d 9, s u bject s c h o osi n g t o self-
a d mi nister at h o me will be pr o vi de d wit h 2 kits t o ta ke h o me al o n g wit h c o ol ba gs a n d s har p 
b i ns.
S u bject s s h o ul d be trai ne d i n t he pr o per tec h ni q ue a n d st ora ge f or self-a d mi nisteri n g S C 
i njecti o n usi n g t he a ut oi nject or.  T he us ual sites f or S C i njecti o n i ncl u de t he t hi g h, a b d o me n, a n d 
bac k of t he u p per ar m.
Eac h dacliz u ma b a ut oi nject or is pr o vi de d wit h t he nee dle pre- attac he d. A ut oi nject ors c o ntai n a 
si n gle d ose o nly a n d s h o ul d be discar de d after use. O nce re m o ve d fr o m t he refri gerat or 
dacliz u ma b s h o ul d be all o we d t o war m t o r o o m te m perat ure (a b o ut 3 0 mi n utes) pri or t o 
i njecti o n.  E xter nal heat s o urces s uc h as h ot water m ust not be use d t o war m dacliz u ma b . T he 
d acliz u ma b a ut oi nject or m ust n ot be use d if t he li q ui d is cl o u d y  or c o ntai ns fl oati n g particles.  
T he li q ui d m ust be c ol orless t o sli g htl y  yell o w.
1 0. 2.
T re at me nt C o m pli a nce
C o m plia nce wit h at-h o me treat me nt d osi n g is t o be m onit ore d a n d rec or de d b y  s u bjects.
Be gi n ni n g wit h t he M o nt h 7 visit w he n at -h o me, self -a d mi nistere d treat me nt ca n be i nitiate d, 
self-re p orte d s u bject a d here nce t o treat me nt al o n g wit h M S treat me nt i nf or mati o n will be 
ca pt ure d usi n g a d osi n g diar y, f or s u bjects w h o self-a d mi nister.  T he d osi n g diar ies will be 
pr o vi de d at t he M o nt h 6 a n d M o nt h 9 visits, a n d will be re vie we d peri o dicall y  b y st u d y site staff 
a n d t he Cli nical M o nit or. T he pr o vi de d dr u g kits will be i n di vi d uall y  n u m bere d i n or der t o hel p 
wit h trac ki n g of a n y c o m plia nce differe nces bet wee n d oses a d mi nistere d at h o me a n d i n t he 
cli nic.
I n t he e ve nt t hat a d ose is misse d a n d less t ha n 2 wee ks ha ve passe d si nce t he date t he misse d 
d ose was ori gi nall y sc he d ule d , s u bjects s h o ul d be i nstr ucte d t o i nject their misse d d ose as s o o n 
as it is re me m bere d a n d re mai n o n t heir ori gi nal m o nt hl y  d osi n g sc he d ule.  If a d ose is misse d 
a n d m ore t ha n 2 wee ks ha ve passe d fr o m t he date t he misse d d ose was ori gi nall y  sc he d ule d, 

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3 6
s u bjects s h o ul d s ki p t he misse d d ose, wait t o d ose a gai n u ntil t heir ne xt sc he d ule d d ose, a n d t he n 
re mai n o n t heir ori gi nal m o nt hl y d osi n g sc he d ule.  O nl y 1 d ose s h o ul d be a d mi nistere d at a ti me.
1 0. 3.
D acliz u m a b St a bilit y a n d St or a ge
Dacliz u ma b will be s u p plie d as a s ol uti o n f or i njecti o n, i n t he a ut oi nject or.  I n a d diti o n t o t he 
acti ve i n gre die nt dacliz u ma b, t he s ol uti o n i ncl u des t he f oll o wi n g e xci pie nts: s o di u m s ucci nate 
a n h ydr o us ( 5. 9 4 m g), s ucci nic aci d ( 0. 3 5 m g), s o di u m c hl ori de ( 5. 8 4 m g), p ol y s or bate 8 0 
( 0. 3 0 m g), water f or i njecti o n, a n d 0. 1 4 m m ol s o di u m per d ose.
T he la bel i ncl u des c o n diti o ns f or st ora ge, l ot n u m ber, a n d ot her perti ne nt i nf or mati o n s uc h as 
S p o ns or a n d ca uti o n state me nt.
St u d y  treat me nt m ust be st ore d i n a sec ure l ocati o n.  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.  M ore details c o ncer ni n g t his res p o nsi bilit y are i ncl u de d i n 
Secti o n 1 0. 4 .
St u d y  treat me nt m ust o nl y be dis pe nse d b y a P har macist or a p pr o priately trai ne d staff.  St u d y 
treat me nt is t o be dis pe nse d o nl y t o s u bjects e nr olle d i n t his st u d y.  
St u d y  site staff s h o ul d refer t o t he I n vesti gat or Br oc h ure a n d/ or Pr o d uct Leaflet 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
1 0. 3. 1.
D acliz u m a b Pre p ar ati o n
T he i n di vi d ual a d mi nisteri n g dacliz u ma b s h o ul d first caref ull y re vie w i nstr ucti o ns pr o vi de d i n 
t he pre vaili n g l ocal la beli n g, D H A , a n d I nf or mati o n f or Patie nts (if s u bjects are self-
a d mi nisteri n g) or I n vesti gat or’s Br oc h ure (f or I n vesti gat ors a d mi nisteri n g treat me nt).  If kit 
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 
pe n de vice, it s h o ul d n ot be use d.  T he kit or pe n 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 Bi o ge n.
Dacliz u ma b is t o be st ore d i n c o ntr olle d refri gerati o n bet wee n 2° C t o 8° C ( 3 6° F t o 4 6° F) i n t he 
cl ose d ori gi nal cart o n t o pr otect fr o m li g ht.  If nee de d, dacliz u ma b m a y  be st ore d wit h o ut 
refri gerati o n u p t o 3 0° C ( u p t o 8 6° F) f or u p t o 3 0 da ys.  T he dacliz u ma b pe n s h o ul d n ot be 
place d bac k i nt o t he refri gerat or after war mi n g t o r o o m te m perat ure.  It s h o ul d n ot be fr oze n or 
e x p ose d t o hi g h te m perat ures.  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 a p pr o ve d pac ka ge i nsert
1 0. 3. 2.
D acliz u m a b H a n dli n g a n d Dis p os al
T he I n vesti gat or m ust destr o y  all u n use d pe ns of dacliz u ma b as i nstr ucte d b y Bi o ge n.
1 0. 4.
D acliz u m a b Acc o u nt a bilit y
Acc o u nta bilit y  f or st u d y treat me nt is t he res p o nsi bilit y of t he I n vesti gat or.  T he st u d y site m ust 
mai ntai n acc urate rec or ds de m o nstrati n g d ates a n d a m o u nt of st u d y treat me nt recei ve d, t o w h o m 
dis pe nse d (s u bject -b y -s u bject acc o u nti n g), a n d acc o u nts of a n y st u d y treat me nt acci de ntally or 
deli beratel y destr o ye d or l ost.   

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3 7
U nless ot her wise n otifie d, all t y pe of pac ka gi n g b ot h use d a n d u n use d m us t be sa ve d f or st u d y 
treat me nt acc o u nta bilit y.  S u bjects self-a d mi nisteri n g dacliz u ma b at h o me will be pr o vi de d wit h 
s har ps bi ns f or dis p osal of pac ka gi n g. S u bjects m ust bri n g s har ps bi ns wit h t he m t o cli nic visi ts 
f or acc o u nta bilit y.  At 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 
dacliz 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 or ret ur ne d t o Bi o ge n.  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.
If a ny st u d y treat me nt s u p plies are t o be destr o ye d  at the site, t he Pri nci ple I n vesti gat or(s) m ust 
o btai n pri or a p pr o val b y Bi o ge n.  T he Pri nci ple I nvesti gat or(s) m ust n otif y  Bi o ge n, i n writi n g, of 
t he met h o d, date, a n d l ocati o n of t he destr ucti o n.
1 0. 5.
Tre at me nt Sc he d ule M o dific ati o n 
S u bjects w h o e x perie nce a si g nifica nt c ha n ge i n t heir me dical stat us (e. g., ne ur ol o gical 
w orse ni n g/s us pecte d M S rela pse, p ossi ble i njecti o n -site reacti o n, i nfecti o n, c uta ne o us e ve nt, 
fe ver, a b d o mi nal pai n, persiste nt diarr hea, ja u n dice, na usea, v o miti n g, pr urit us) m ust c o ntact t he
St u d y  Ne ur ol o gist as s o o n as p ossi ble a n d n o m ore t ha n 4 8 h o urs after s y m pt o m o nset.  T he 
s u bject s h o ul d t he n be e val uate d by t he St u d y  Ne ur ol o gist wit hi n n o m ore t ha n 7 2 h o urs f or 
p h y sical a n d ne ur ol o gical assess me nts a n d f urt her treat me nt rec o m me n dati o ns if a p pr o priate. 
T hese s u bjects s h o ul d n ot a d mi nister a d diti o nal dacliz u ma b u ntil t he y  ha ve bee n e val uate d b y 
t he St u d y  Ne ur ol o gist or t heir bac k u p
1 0. 5. 1. 
Ele v ate d Li ver F u ncti o n Tests
L F T pr oce d ures are descri be d i n Secti o n 1 1. 3. 2 . Pri or t o starti n g treat me nt wit h dacliz u ma b , 
ser u m tra nsa mi nases ( A L T a n d A S T) a n d bilir u bi n le vels m ust be o btai ne d. Ser u m 
tra nsa mi nases m ust be m o nit ore d m o nt hl y d uri n g treat me nt a n d u p t o 4 m o nt hs after t he last 
st u d y d ose of dacliz u ma b (see Secti o n 4. 2, f or ti mi n g). 
St u d y  treat me nt m ust be te m p orarily s us pe n de d if a s u bject de vel o ps a n y of t he f oll o wi n g:

A L T/ S G P T, or A S T/ S G O T  > 3 * U L N .

A L T or A S T ha ve n ot e xcee de d 5 ti mes t he U L N ; dacliz u ma b ma y  be res u me d w he n 
A L T or A S T ha ve reac he d < 2 ti mes t he U L N.

A n y  ot her cli nically si g nifica n t he patic c o n diti o n i n t he o pi ni o n of t he I n vesti gat or 
i ncl u di n g ja u n dice.
N ote: F or s u bjects w h o prese nt wit h ja u n dice, a n L F T m ust be perf or me d as s o o n as p ossi ble. 
After a s us pe nsi o n, d osi n g of dacliz u ma b ma y  be res u me d w he n A L T/ S G P T a n d A S T/ S G O T are 
< 2 * U L N pr o vi de d t hat t he criteria f or per ma ne nt disc o nti n uati o n ha ve n ot bee n met.
St u d y  treat me nt m ust be per ma ne ntl y disc o nti n ue d if a s u bject de vel o ps a n y of t he f oll o wi n g:

C o nfir me d A L T or A S T of > 5 ti mes t he U L N A L T/ S G P T or A S T/ S G O T > 3 * U L N 
wit h c o nc o mit a nt ele vati o n of t otal bilir u bi n > 2 * U L N.

If a s u bject has treat me nt s us pe n de d f or a n L F T ele vati o n a n d has als o ha d a pri or 
treat me nt s us pe nsi o n f or a n L F T ele vati o n d uri n g dacliz u ma b use, dacliz u ma b m ust 
be per ma ne ntl y  disc o nti n ue d u nless a n alter nati ve ex pla nati o n f or t he L F T ele vati o n 
u nrelate d t o dacliz u ma b use is clearl y i de ntifie d b y t he I n vesti gat or.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3 8
1 1.
D A T A C O L L E C TI O N
A writte n, si g ne d I nf or me d C o nse nt F or m (I C F) a n d all a ut h orizati o ns re q uire d b y  l ocal la w 
(e. g., P HI i n N ort h A merica) m ust be o btai ne d pri or t o perf or mi n g a n y t ests or assess me nts u n der 
t his pr ot oc ol. 
1 1. 1.
Site Pers o n nel
F or eac h s u bject, t he Pri nci pal I n vesti gat or will desi g nate t he f oll o wi n g st u d y  site pers o n nel:

A pri mar y  St u d y  Ne ur ol o gist a n d bac k u p ne ur ol o gist .

A pri mar y  a n d bac k u p N urs e ( or St u d y C o or di nat or).

A pri mar y  a n d bac k u p E xa mi ni n g Tec h nicia n.

A n M RI  Tec h nicia n.

A P har macist ( or a ut h orize d desi g nee).
T he St u d y  Ne ur ol o gists ma y desi g nate a n ot her ne ur ol o gist at t he ce nter w h o meets t he sa me 
q ualificati o ns t o perf or m t he  
 assess me nts a n d ot her ne ur ol o gic assess me nt d uri n g t he trial. 
T he pri mar y  St u d y Ne ur ol o gist will be res p o nsi ble f or t he f oll o wi n g:

Ma na ge me nt of t he r o uti ne ne ur ol o gical care of t he s u bject .

Assess me nt (i ncl u di n g assi g n me nt of ca usalit y ) a n d treat me nt of A Es a n d M S 
rela pses.

O btai ni n g a n  
 sc ore.

Re vie w of selecte d he mat ol o g y  a n d all bl o o d c he mistr y res ults fr o m t he ce ntral 
la b orat or y.

Assess me nt of L F T res ults, as detaile d i n Secti o n 1 1. 3. 2.

M o nit ori n g a n d f oll o w -u p of a n y  a b n or mal he patic tests.
He mat ol o g y a n d bl o o d c he mistr y data will be se nt t o t he i n vesti gati o nal sites t o ai d i n 
ma na ge me nt of t he s u bject.
T he pri mar y  N urse or St u d y C o or di nat or will be res p o nsi ble f or t he f oll o wi n g:

Assisti n g t he St u d y  Ne ur ol o gist i n s u bject ma na ge me nt, i ncl u di n g t he treat me nt of 
A Es, t he treat me nt a n d assess me nt of disease rela pses, a n d t he rec or di n g of A Es a n d 
c o nc o mita nt me dicati o ns .

M o nit ori n g t he  
 sc ores .

C ollecti o n of bl o o d sa m ples a n d o btai ni n g vital si g ns .

St u d y  treat me nt a d mi nistrati o n/ dis pe nsati o n/acc o u nta bilit y.
T he M RI  Tec h nicia n will be res p o nsi ble f or t he f oll o wi n g:

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 3 9

Perf or mi n g a brai n M RI  sca n wit h a n d wit h o ut G d at all pr ot oc ol-re q uire d ti me p oi nts. 
St u d y -s pecific M RI sca n pr oce d ures a n d pr ot oc ols, w hic h will be pr o vi de d pri or t o 
st u d y start, m ust be f ollo we d.
T he P har macist ( or a ut h orize d desi g nee) will be res p o nsi ble f or t he f oll o wi n g:

St ora ge, distri b uti o n, a n d acc o u nta bilit y of st u d y treat me nt.
1 1. 2.
Assess me nts
1 1. 2. 1.
Assess me nts at Scree ni n g
T he f oll o wi n g varia bles will be c ollecte d d uri n g scree ni n g at t he e nr ollme nt visit :

Date of si g ne d I CF.

C o nfir mati o n of eli gi bilit y criteria .

De m o gra p hic i nf or mati o n: a ge at scree ni n g ( y ears), se x .

M S disease hist or y  (ty p e of M S, date of i nitial M S dia g n osis, rela pse hist or y ).

Rele va nt me dical hist or y a n d c o -m or bi dities i ncl u di n g: assess me nt of cli nicall y  
si g nifica nt me dical a n d s ur gical hist or y a n d c o nc o mita nt diseases, a n d k n o w n 
car di o vasc ular ris k fact ors.  Of i nterest are: s m o ki n g; alc o h ol c o ns u m pti o n; s u bject
a n d fa mil y hist or y of hi g h c h olester ol; hi g h bl o o d press ure; car diac disease; 
peri p heral arter y  disease; arr hyt h mia; cere br o vasc ular disease; dia betes mellit us; 
HI V; he patitis C vir us (test f or H C V A b) or he patitis B vir us (test f or H Bs A g a n d/ or 
H Bc A b); hist or y  of tra ns pla ntati o n or a n y a nti-rejecti o n t hera py.

Pri or u se a n d d urati o n of nataliz u ma b (e. g., start a n d st o p dates, i nitial d ose, d ose 
re d ucti o ns or escalati o ns, d osi n g fre q ue nc y).

Pri or use a n d d urati o n of ot her t hera pies f or M S (if a n y ) (e. g., start a n d st o p dates, 
i nitial d ose, d ose re d ucti o ns or escalati o ns, prescri be d d osi n g fre q ue nc y, reas o n f or 
disc o nti n uati o n , pri or use of i m m u n os u p presa nts).

Vital si g ns .

P h y sical e xa mi nati o n.
Refer t o Secti o n 4 f or t he ti mi n g of assess me nts.
1 1. 2. 2.
Assess me nts at B aseli ne a n d F oll o w -u p
1 1. 2. 2. 1.
M S Tre at me nts a n d C o nc o mit a nt Me dic ati o ns
M S treat me nts a n d c o nc o mita nt me dicati o ns will be rec or de d as f oll o ws:

Dacliz u ma b d ose a n d dates of a d mi nistrati o n o n- site.  

Dacliz u ma b self-a d mi nistere d d ose, a n d dates of a d mi nistrati o n rec or de d b y  s u bject 
i n d osi n g diar y ( be gi n ni n g at M o nt h 7, w here ap plica ble ).

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 4 2
st u d y visit a n d f or sa m ples w hic h mi g ht be c ollecte d o utsi de of t he cli nic (e. g., b y 
visiti n g n urses).  Acc o m m o dati o ns will be ma de f or L F T sa m pli n g a n d ce ntral testi n g 
f or s u bjects c h o osi n g at- h o me d osi n g at M o nt h 7, 8, 1 0 a n d 1 1. 

Res ults fr o m eit her l ocal or ce ntral L F T tests ca n be use d f or t he me dical 
ma na ge me n t of t he patie nt a n d t o deter mi ne w het her d osi n g s h o ul d c o nti n ue or be 
s us pe n de d at t he m o nt hl y d osi n g ti me p oi nt (see Secti o n 1 0 ).

I n a ny cases w here L F Ts are teste d l ocall y (e. g., at a l ocal la b orat or y), sa m ples m ust 
als o be c ollecte d f or ce ntral a nal ys is f or t he p ur p oses of t his st u d y. 

If t he s u bject is a d mi nisteri n g dacliz u ma b i njecti o ns at h o me, site pers o n nel m ust 
c o ntact t he s u bject after re vie w of pri or L F T res ults perf or me d wit hi n 2 8 ( +3 ) da ys t o 
a ut h orize t he m o nt hl y i njecti o n, or if L F T res ults warra nt, t o i nstr uct t he s u bject t o 
wit h h ol d t heir i njecti o n.

L F Ts f oll o wi n g a treat me nt s us pe nsi o n m ust be perf or me d t hr o u g h t he ce ntral 
la b orat or y u ntil t he L F T a b n or malit y has res ol ve d.  In cases w here L F Ts ca n n ot be 
perf or me d via ce ntral la b orat or y , re peat L F T res ults fr o m l ocal la b orat or y  ca n be use d 
f or c o nfir mati o n.
1 1. 3. 3.
M RI Sc a ns
M RI  sca n res ults will be assesse d b y a ce ntral rea di n g ce nter a n d will n ot be e ntere d i nt o t he 
electr o nic data ca pt ure ( E D C ) t o ol.  Please refer t o t he M RI  Ac q uisiti o n a n d Pr oce dures Ma n ual 
f or a detaile d list of res ults fr o m t he ce ntral rea di n g ce nter.
1 1. 3. 4.
Ot her Assess me nts
Vital si g ns i ncl u de s ys t olic a n d diast olic bl o o d press ure, p ulse, a n d b o dy te m perat ure, meas ure d 
pre -d ose.  T he s u bject m ust rest q uietl y  f or 5 mi n utes pri or t o b l o o d press ure a n d p ulse 
meas ure me nts.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 4 3
1 2.
S A F E T Y D E FI NI TI O N S, R E C O R DI N G, R E P O R TI N G , A N D 
R E S P O N SI BI LI TI E S
T hr o u g h o ut t he c o urse of t he st u d y , e ver y eff ort m ust be ma de t o re mai n alert t o p ossi ble A Es.   
If a n A E occ urs, t he first c o ncer n s h o ul d be f or t he safety of t he s u bject.  If necessar y, 
a p pr o priate me dical i nter ve nti o n s h o ul d be pr o vi de d. 
At t he si g ni n g of t he I C F, eac h s u bject or his/ her le gall y a ut h orize d re prese ntati ve a n d/ or mai n 
care gi ver m ust be gi ve n t he na mes a n d tele p h o ne n u m bers of st u d y  site staff f or re p orti n g A Es 
a n d me dical e mer ge ncies.
1 2. 1.
Defi niti o ns
1 2. 1. 1.
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct 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 ny u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), sy m pt o m, or disease te m p orall y ass ociate d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici na l (i n vesti gati o nal) 
pr o d uct.
Deter mi nati o n of w het her a n a b n or mal la b orat or y  val ue 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.  Alt h o u g h a b n or mal la b orat or y val ues are t y picall y  n ot c o nsi dere d 
A Es, t he f oll o wi n g c o nsi derati o ns ma y  res ult i n a n a b n or mal la b orat or y val ue bei n g c o nsi dere d 
a n A E:

A la b orat or y  test res ult t hat meets t he criteria f or as S A E.

A la b orat or y  test res ult t hat re q uires t he s u bject t o recei ve s pecific c orrecti ve t hera p y.

A la b orat or y a b n or malit y t hat t he I n vesti gat o r c o nsi ders t o be cli nically si g nifica nt .
1 2. 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 s u bject at i m me diate ris k of deat h (a 
life-t hreate ni n g e ve nt); h o we ver, t his d oes n ot i ncl u de a n e ve nt t hat, ha d it occ urre d 
i n a m ore se vere f or m, mi g ht ha ve ca use d deat h,

re q uires i npatie 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, or

res ults i n a c o n ge nital a n o mal y/ birt h defect.
A n S A E ma y  als o be a n y ot her me dically i m p orta nt e ve nt t hat, i n t he o pi ni o n of t he I n vesti gat or, 
ma y  je o par dize t he s u bject or ma y  re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes 

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 4 4
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 npatie nt h os pitalizati o n.)
1 2. 1. 3.
Presc he d ule d or Electi ve Pr oce d ures or R o uti nel y Sc he d ul e d Tre at me nts
A presc he d ule d or electi ve pr oce d ure or a r o uti nel y  sc he d ule d treat me nt will n ot be c o nsi dere d 
a n S A E, e ve n if t he s u bject is h os pitalize d; t he st u d y  site m ust d oc u me nt all of t he f oll o wi n g:

T he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt was 
sc he d ule d ( or was o n a waiti n g list t o be sc he d ule d) pri or t o o btai ni n g t he s u bject’s 
c o nse nt t o partici pate i n t he st u d y .

T he c o n diti o n re q uiri n g t he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d 
treat me nt was prese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he 
I n vesti gat or bet wee n t he s u bject’s c o nse nt t o partici pate i n t he st u d y a n d t he ti me of 
t he pr oce d ure or treat me nt.

T he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s o le 
reas o n f or t he i nter ve nti o n or h os pital a d missi o n. 

If a s u bject is h os pitalize d d ue t o l ocal re q uire me nts f or a d mi 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 1 of t he 
re q uire me nts i n Secti o n 1 2. 1. 2 is met.
1 2. 2.
S afet y Cl assific ati o ns
1 2. 2. 1. 
I n vesti g at or Assess me nt of E ve nts
All e ve nts m ust be assesse d t o deter mi ne t he f oll o wi n g:

If t he e ve nt meets t he criteria of a n S A E as defi ne d i n Secti o n 1 2. 1. 2 .

T he relati o ns hi p of t he e ve nt t o st u d y  treat me nt as defi ne d i n Secti o n 1 2. 2. 2 .

T he se verit y of t he e ve nt as defi ne d i n Secti o n 1 2. 2. 3 .
1 2. 2. 2.  
Rel ati o ns hi p of E ve nts t o St u d y Tre at me nt
T he f oll o wi n g defi niti o ns s h o ul d be c o nsi dere d w he n e val uati n g t he relati o ns hi p of A Es a n d 
S A Es t o t he st u d y  treat me nt:

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 4 7
1 2. 4.
Pr oce d ures f or H a n dli n g S peci al Sit u a ti o ns
1 2. 4. 1.
Re p orti n g Pre g n a nc y
T he I n vesti gat or s h o ul d refer t o t he a p pr o ve d l ocal la bel f or g ui da nce if fe male s u bjects bec o me 
pre g na nt or are c o nsi deri n g bec o mi n g pre g na nt d uri n g t he st u d y.
At eac h r o uti ne visit, fe male s u bjects of c hil d beari n g p ote ntial will be as ke d a b o ut t heir 
pre g na nc y  stat us a n d p ossi ble pre g na ncies/s p o nta ne o us a b orti o ns si nce t he last visit or c o ntact.  
S p o nta ne o us a b orti o ns are c o nsi dere d t o be S A Es a n d m ust be re p orte d as s uc h.
If t he part ner of a male s u bject recei vi n g dacliz u ma b bec o mes pre g na nt at a n y  ti me d uri n g t he 
st u d y, t he I n vesti gat or s h o ul d f oll o w t he pre g na nc y o utc o me a n d re p ort a n y c o n ge nital a n o maly 
or birt h defect as a n S A E t o Bi o ge n or desi g nee. 
1 2. 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 gi ve n t o a s u bject or take n b y a s u bject t hat e xcee ds 
t he d ose descri be d i n t he pr ot oc ol.  O ver d oses are n ot c o nsi dere d A Es; h o we ver, all o ver d oses 
s h o ul d be rec or de d o n a n O ver d ose F or m a n d fa xe d t o Bi o ge n S A B R or desi g nee wit hi n 2 4 
h o urs.  A n o ver d ose s h o ul d be re p orte d e ve n if it d oes n ot res ult i n a n A E.  O ver d oses d o n ot 
nee d t o be rec or de d i n t he C R F; d osi n g i nf or mati o n is rec or de d o n a C R F.
1 2. 4. 3.
Me dic al E mer ge nc y 
I n a me dical e mer ge nc y re q uiri n g i m me diate atte nti o n, st u d y site staff will a p pl y a p pr o priate 
me dical i nter ve nti o n, acc or di n g t o c urre nt sta n dar ds of care.
1 2. 5.
I n vesti g at or Res p o nsi bilities
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 (refer t o Secti o n 1 2. 1 ):

Re vie w all A Es t o deter mi ne seri o us ness a n d f ulfill me nt of c ollecti o n criteria.

M o nit or a n d rec or d all S A Es, re gar dless of t he relati o ns hi p t o dacliz u ma b .

Deter mi ne t he relati o ns hi p of eac h S A E t o dacliz u ma b .

Deter mi ne t he o nset a n d res ol uti o n dates of eac h S A E .

Rec or d all pre g na ncies .

C o m plete t he a p pr o priate f or m f or eac h S A E, pre g na nc y  a n d o ver d ose a n d fa x or 
e mail it t o Bi o ge n S A B R or desi g nee wit hi n 2 4 h o urs of t he st u d y  site staff bec o mi n g 
a ware of t he e ve nt .

P urs ue S A E f oll o w- u p i nf or mati o n acti vel y a n d persiste ntl y.  F oll o w -u p i nf or mati o n 
m ust be re p orte d t o Bi o ge n S A B R or desi g nee wit hi n 2 4 h o urs of t he st u d y  site staff 
bec o mi n g a ware of ne w i nf or mati o n.

E ns ure all S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he s u bjects’ me dical 
rec or ds.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 4 8

Re p ort S A Es t o l ocal i nstit uti o nal re vie w b oar d (I R B)/et hics c o m mittees ( E Cs), as 
re q uire d by l ocal la w.
1 2. 6.
Bi o g e n Res p o nsi bilities
Bi o ge n’s res p o nsi bilities i ncl u de t he f oll o wi n g:

Bef ore st u d y site acti vati o n a n d s u bject e nr oll me nt, t he Cli nical M o nit or or desi g nee 
is res p o nsi ble f or re vie wi n g wit h st u d y site staff t he defi niti o ns of A E a n d S A E, as 
well as t he i nst r ucti o ns f or m o nit ori n g, rec or di n g, a n d re p orti n g S A Es.

Deter mi ne t he e x pecte d ness of all S A Es.

Bi o ge n is t o n otif y  all a p pr o priate re g ulat or y a ut h orities, ce ntral E Cs, a n d 
I n vesti gat ors of S A Es, as re q uire d by l ocal la w, wit hi n re q uire d ti me fra mes.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 4 9
1 3.
S T A TI S TI C A L C O N SI D E R A TI O N S
1 3. 1.
S a m ple Size J ustific ati o n
T his st u d y  will e nr oll a p pr o xi matel y 1 0 0 s u bjects.  T he sa m ple size is esti mate d base d o n t he 
pr o p orti o n of s u bjects w h o are rela pse -free at M o nt h 6.
Ass u mi n g a dr o p - o ut rate of 1 0 %, t he e val ua ble sa m ple size will be 9 0.  A t w o-si de d 9 5 % 
c o nfi de nce i nter val ( CI) f or a si n gle pr o p orti o n of s u bjects o n dacliz u ma b 1 5 0 m g re mai ni n g free 
of rela pses at t he e n d of M o nt h 6 will e xte n d bet wee n 8. 3 % a n d 6. 7 % fr o m t he o bser ve d 
pr o p orti o n f or a n e x pecte d pr o p orti o n of 8 0 % t o 8 8 %, res pecti vel y .
1 3. 2.
A n al ysis P o p ul ati o n
T he a nal ys is p o p ulati o n is base d o n i nte nt-t o-treat (I T T), w here t he s u bjects s h o ul d recei ve at 
least 1 d ose of t he me dicati o n d uri n g f oll o w - u p.  S u bjects disc o nti n ui n g treat me nt will als o be 
i ncl u de d i n t he anal ys is. 
1 3. 3.
Met h o ds of A n al ysis
Baseli ne disease a n d de m o gra p hic c haracteristics will be s u m marize d o verall.  T he de m o gra p hic 
pr ofile (a ge, se x, a n d race/et h nicit y ), rele va nt me dical hist or y, M S disease hist or y, M S treat me nt 
pri or t o start of nataliz u ma b treat me nt, a n d c o nc o mita nt me dicati o ns a n d t hera pies use d will be 
liste d a n d s u m marize d usi n g t he a p pr o priate descri pti ve statistics f or c o nti n u o us a n d cate g orical 
varia bles.
Descri pti ve a nal ys es c orres p o n di n g t o t he s pecific researc h o bjecti ves will be perf o r me d t o 
c haracterize t he s u bjects st u die d.  C o nti n u o us varia bles will be re p orte d as mea n, sta n dar d 
de viati o n, me dia n, 2 5 t h a n d 7 5 t h perce ntile ( Q 1, Q 3), mi ni m u m a n d ma xi m u m w here a p pr o priate. 
Cate g orical varia bles will be s u m marize d as fre q ue ncies a n d per ce nta ge.  Pr o p orti o ns will be 
prese nte d wit h e xact 9 5 % CI s as f urt her s pecifie d i n t he statistical a nal ysis pla n ( S A P). 
Details o n ha n dli n g of all missi n g data, w hic h are c o m m o n i n o bser vati o nal st u dies , will be 
descri be d f ull y i n t he S A P.  T he pr o p orti o n of missi n g data will be re p orte d f or eac h meas ure d 
varia ble i n t he st u d y.  I n ge neral, missi n g data will n ot be i m p ute d a n d t he data will be a nal yz e d 
as t he y are rec or de d i n t he st u d y electr o nic case re p ort f or ms (e C R Fs).
All c o m p utati o ns a n d ge nerati o n o f ta bles, listi n gs a n d data f or fi g ures will be perf or me d usi n g 
S A S ® versi o n 9. 3 or hi g her ( S A S I nstit ute, Car y , N C, U S A). 
A nal y ses c orres p o n di n g t o t he s pecific researc h o bjecti ves of t he st u d y are descri be d i n t he 
secti o ns bel o w.
1 3. 4.
Pri m ar y E n d p oi nt A n al ys is
1 3. 4. 1.
Effic ac y A n al ysis
T he pr o p orti o n of s u bjects rela pse -free at M o nt h 6 will be esti mate d usi n g t he Ka pla n-Meier 
a p pr oac h.  T his will be calc ulate d as 1 mi n us t he pr o p orti o n of s u bjects wit h rela pses at M o nt h 6. 

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 5 0
F or t he Ka pla n - Meier a p pr oac h, t he ti me t o rela pse is t he n u m ber of da y s fr o m t he date of t he 
first d ose of dacliz u ma b t o t he date of first rela pse, or e n d of st u dy, w hic he ver c o mes first.  T he 
C o x pr o p orti o nal hazar d m o del will be use d t o esti mate t he hazar d rati o of rela pses wit hi n 
s u bject s u b gr o ups of i nterest.  T he s u b gr o u ps of i nterest will be defi ne d i n t he S A P.
T he pr o p orti o n of s u bjects rela pse -free 6 m o nt hs bef ore a n d 6 m o nt hs after s witc hi n g t o 
dacliz u ma b will be c o m pare d usi n g Mc Ne mar's Test f or s u bjects w h o ha d rela pse i nf or mati o n 
a vaila ble at t he a b o ve ti me p oi nts.
F or pri mar y  e n d p oi nts, se nsiti vit y a nalys es will be perf or me d o n t he I T T p o p ulati o n e xcl u di n g 
t h ose patie nts w h o misse d 2 or m ore c o nsec uti ve d oses wit hi n 6 m o nt hs. A d diti o nal details 
re gar di n g t he se nsiti vit y a nalys is will be descri b e d i n t he S A P. 
1 3. 5.
Sec o n d ar y E n d p oi nts A n al ysis
1 3. 5. 1.
Effic ac y A n al ysis
T he pr o p orti o n of s u bjects rela pse -free at M o nt h 1 2 will be esti mate d usi n g Ka pla n-Meier 
a p pr oac h.  T his will be calc ulate d as 1 mi n us t he pr o p orti o n of s u bjects wit h rela pses at M o nt h 
1 2.  F or t he Ka pla n Meier a p pr oac h, t he ti me t o rela pse is t he n u m ber of da ys fr o m t he date of 
t he first d ose of dacliz u ma b t o t he date of first rela pse, or e n d of st u dy, w hic he ver c o mes first.  
T he C o x pr o p orti o nal hazar d m o del will be use d t o esti mate t h e hazar d rati o of rela pses bet wee n 
s u bject s u b gr o u ps of i nterest. 
T he pr o p orti o n of s u bjects rela pse -free 1 2 m o nt hs bef ore a n d 1 2 m o nt hs after s witc hi n g t o 
dacliz u ma b will be c o m pare d usi n g Mc Ne mar's Test f or s u bject s w h o ha d rela pse i nf or mati o n 
a vaila ble at t he a b o ve ti me p oi nts (st u d y c o m pleters).
T he pr o p orti o n of s u bjects e x perie nci n g rela pse re q uiri n g h os pitalizati o n a n d/ or ster oi d treat me nt 
at M o nt h 1 2 will be esti mate d usi n g t he Ka pla n -Meier a p pr oac h.  F or t he Ka pla n -Meier 
a p pr oac h, t he ti me t o rela pse re q uiri n g h os pitalizati o n a n d/ or ster oi d treat me nt will be t he 
n u m ber of da y s fr o m t he date of t he first d ose of dacliz u ma b t o t he date of first rela pse re q uiri n g 
h os pitalizati o n a n d/ or ster oi ds treat me nt, or e n d of st u d y , w hic he ver c o mes first.  A C o x
pr o p orti o nal hazar d m o del will be use d t o esti mate t he hazar d rati o of rela pses re q uiri n g 
h os pitalizati o n a n d/ or ster oi ds treat me nt bet wee n s u bject s u b gr o u ps of i nterest. 
T he A R R wit h 9 5 % CI  at M o nt h 1 2 (calc ulate d as t he t otal n u m ber of rela pses di vi de d b y  t he 
t otal n u m ber of pers o n -years i n t he st u d y at t he e n d of M o nt h 1 2 f or eac h s u bject) will be 
esti mate d usi n g a ne gati ve bi n o mial m o del.  If t he data are u n der -dis perse d or if t he ne gati ve 
bi n o mial re gressi o n d oes n ot c o n ver ge, a P oiss o n re gressi o n m o del wit h t he sa me c o variates will 
be use d i nstea d.  Gi ve n t hat s u bjects ma y  ha ve m ore t ha n 1 rela pse i n 1 2 m o nt hs, t he n u m ber of 
rela pses will be s u m marize d b ot h as a c o nti n u o us varia ble a n d as a cate g orical varia ble. 
T he n u m ber of ne w G d + e n ha nce d a n d T 1 h y p oi nte nse lesi o ns at M o nt h 6 a n d M o nt h 1 2 a n d t he 
n u m ber of ne w or ne wl y e nlar ge d T 2 h y p eri nte nse lesi o ns at M o nt h 6 a n d M o nt h 1 2 w he n 
c o m pare d wit h baseli ne will be s u m marize d b ot h as c o nti n u o us varia bles a n d as cate g orical 
varia bles.  A ne gati ve bi n o m ial m o del a dj usti n g f or t he c orres p o n di n g baseli ne M RI lesi o n 
c o u nts will be use d t o esti mate t he a dj uste d mea n a n d lesi o n mea n rati o bet wee n s u bject 
s u b gr o u ps of i nterest.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 5 1
T he dacliz u ma b per ma ne nt disc o nti n uati o n rate at M o nt h 1 2 will be s u m marize d as t he rati o of 
n u m ber of s u bjects w h o ha d per ma ne ntl y  disc o nti n ue d dacliz u ma b pri or t o M o nt h 1 2 o ver t he 
t otal n u m ber of s u bjects w h o recei ve d at least 1 d ose of dacliz u ma b i n t he st u d y, al o n g wit h a 
9 5 % CI  f or t he pr o p orti o n.
T he n u m ber of patie nts w h o misse d 2 or m ore c o nsec uti ve d oses wit hi n 6 m o nt hs a n d wit hi n 1 2 
m o nt hs will be re p orte d.   F or sec o n dar y e n d p oi nts, se nsiti vit y a nalys es ma y be c o nsi dere d o n
t he I T T p o p ulati o n, e xcl u di n g t h ose patie nts w h o misse d 2 or m ore c o nsec uti ve d oses wit hi n 6 
m o nt hs f or e n d p oi nts e val uate d at/ u p t o 6 m o nt hs , a n d wit hi n 1 2 m o nt hs f or e n d p oi nts e val uate d 
at/ u p t o 1 2 m o nt hs.   A d diti o nal details re gar di n g se nsiti vit y  a nalys es will be descri b e d i n t he 
S A P.
1 3. 5. 2.
S afet y
1 3. 5. 2. 1.
A n al ysis P o p ul ati o n
T he safet y p o p ulati o n will be defi ne d as all s u bjects w h o recei ve d at least 1 d ose of st u d y  
treat me nt.
1 3. 5. 2. 2.
Met h o ds of A n al ysis
All A Es, S A Es, la b orat or y  a b n or malities, p h ysical e xa mi nati o n res ults, a n d vital si g ns will be 
e val uate d f or safet y.
1 3. 5. 2. 3.
A d verse E ve nts
T he i nci de nce of treat me nt -e mer ge nt A Es will be s u m marize d b y  se verit y a n d b y relati o ns hi p t o 
st u d y treat me nt.  T he s u m mar y ta bles will i ncl u de A Es b y sys te m or ga n class as well as b y 
preferre d ter m wit hi n eac h s yste m or ga n class.  A Es will be c o de d usi n g t he Me dical Dicti o nar y  
f or Re g ulat or y Acti vities.
1 3. 5. 2. 4.
L a b or at or y D at a
La b orat or y  data will be s u m marize d usi n g s hift ta bles.  S hifts fr o m baseli ne t o hi g h/l o w stat us 
f or he mat ol o g y a n d bl o o d c he mistr y para meters will be prese nte d.  I n a d diti o n, t he s hift fr o m 
baseli ne t o t he ma xi m u m p ost -baseli ne val ue a n d t he s hift fr o m baseli ne t o t he mi ni m u m p ost -
baseli ne stat us will be prese nte d f or eac h la b orat or y  test b y treat me nt gr o u p.  S u m mar y statistics 
f or act ual val ues a n d c ha n ge fr o m baseli ne will als o be prese nte d f or q ua ntitati ve la b orat or y data.
1 3. 5. 2. 5.
P h ysic al E x a mi n ati o n Res ults
A listi n g of s u bjects wit h n or mal stat us at baseli ne b ut a b n or mal stat us at a n y  ti me after t he date 
of t he first d ose will be prese nte d.
1 3. 5. 2. 6.
Vit al Si g ns
T he a nal ys is of vital si g ns will f oc us o n t he i nci de nce of cli nicall y rele va nt a b n or malities.  T he 
n u m ber of s u bjects e val uate d a n d t he n u m ber a n d perce nta ge of s u bjects wit h cli nicall y  rele va nt 
p ost - baseli ne a b n or malities (Ta ble 2 : ) will be prese nte d.  S u m mar y  statistics f or act ual val ues 
a n d c ha n ge fr o m baseli ne will als o be prese nte d. 

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 5 4
1 3. 7.
I nteri m A n al ysis
T here are n o pla n ne d i nteri m a nal ys es f or t his st u d y.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 5 5
1 4.
E T HI C A L R E Q UI R E M E N T S
Bi o ge n,  
 a n d t he I n vesti gat or m ust c o m pl y  wit h all i nstr ucti o ns, re g ulati o ns, a n d 
a gree me nts i n t his pr ot oc ol a n d a p plica ble I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) 
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 s u bject’s pri vac y ; p h ysical, 
me ntal, a n d s ocial i nte grit y ; a n d t he c o nfi de ntialit y of his or her pers o nal i nf or mati o n will be 
strictl y res pecte d i n acc or da nce wit h t he W orl d Me dical Ass ociati o n Declarati o n of Helsi n ki.
1 4. 1.
I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee
T he I n vesti gat or m ust o btai n I RB/ E C 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.  
If t he I n vesti gat or ma kes a n y c ha n ges t o t he IC F, Bi o ge n m ust a p pr o ve t he c ha n ges bef ore t he 
I CF i s s u b mitte d t o t he I R B/E C.  A c o p y of t he a p pr o ve d I C F m ust be pr o vi de d t o Bi o ge n.  After 
a p pr o val, t he I C F m ust n ot be altere d wit h o ut t he a gree me nt of t he rele va nt I RB/ E C a n d Bi o ge n.
It is t he res p o nsi bilit y of t he In vesti gat or(s) t o e ns ure t hat all as pe cts 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 g o ver n me ntal re g ulati o ns.
Bi o ge n m ust recei ve a letter d oc u me nti n g I R B/ E C a p pr o val, w hic h s pecificall y i de ntifies t he 
pr ot oc ol, trac ki n g n u m ber, a n d I C F versi o n, pri or t o t he i nitiati o n o f t he st u d y.  Pr ot oc ol 
a me n d me nts will be s u bject t o t he sa me re q uire me nts as t he ori gi nal pr ot oc ol.
A pr o gress re p ort m ust be s u b mitte d t o t he I RB/ E C at re q uire d i nter vals a n d n ot less t ha n 
a n n uall y.  D oc u me ntati o n of t he s u b missi o n m ust be pr o vi de d t o Bio ge n.
At t he c o m pleti o n or ter mi nati o n of t he st u d y , t he i n vesti gati o nal site m ust s u b mit a cl ose-o ut 
letter t o t he I RB/ E C a n d Bi o ge n
1 4. 2.
S u bject I nf or m ati o n a n d C o nse nt
Pri or t o perf or mi n g a n y s t u d y-relate d acti vities u n der t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d 
assess me nts, writte n i nf or me d c o nse nt wit h t he a p pr o ve d I C F m ust be o btai ne d fr o m t he s u bject 
or s u bject’s le gall y a ut h orize d re prese ntati ve, as a p plica ble, i n acc or da nce wit h l ocal practice a n d 
re g ulati o ns.
T he bac k gr o u n d of t he pr o p ose d st u d y , t he pr oce d ures, t he be nefits a n d ris ks of t he st u d y, a n d 
t hat st u d y partici pati o n is v ol u ntar y f or t he s u bject m ust be e x plai ne d t o t he s u bject ( or t he 
s u bject’s le gally a ut h orize d re prese ntati ve).  T he s u bject m ust be gi ve n s ufficie nt ti me t o 
c o nsi der w he t 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 s u bject or t he s u bject’s le gall y 
a ut h orize d re prese ntati ve.  C o nfir mati o n of a s u bject’s i nf or me d c o nse nt m ust als o be 
d oc u me nte d i n t he s u bject’s me dical rec or d pri o r 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.
T he si g ne d I C F will be retai ne d wit h t he st u d y rec or ds.  L ocal re g ulati o ns m ust be c o m plie d wit h 
i n res pect t o t he fi nal dis p ositi o n of t he ori gi nal ( wet si g nat ure) a n d c o pies of t he si g ne d a n d 
date d I C Fs .

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 5 6
1 4. 3.
S u bject D at a Pr otecti o n
Pri or t o a n y  testi n g u n der t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d assess me nts, ca n di dates 
m ust als o pr o vi de all a ut h orizati o ns re q uire d b y l ocal la w (e. g., P HI a ut h orizati o n i n N ort h 
A merica).
T h e s u bject will n ot be i de ntifie d b y na me i n t he C R F or i n a n y st u d y re p orts, a n d t hese re p orts 
will be use d f or researc h p ur p oses o nl y .  Bi o ge n, its part ner(s) a n d desi g nee(s), E Cs, 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 ud y .  E ver y eff ort will be ma de t o 
kee p t he s u bject’s pers o nal me dical data c o nfi de ntial.
1 4. 4.
C o m pe ns ati o n f or I nj ur y
Bi o ge n mai ntai ns a p pr o priate i ns ura nce c o vera ge f or cli nical trials a n d will f oll o w a p plica ble 
l ocal c o m pe nsati o n la ws.
1 4. 5.
C o nflict of I nterest
T h e 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 s u bject bef ore t he s u bject ma kes a decisi o n t o partici pat e i n t he st u d y.
1 4. 6.
Re gistr ati o n of St u d y a n d Discl os ure of St u d y Res ults
Bi o ge n 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 u lati o ns.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 5 7
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 s u bjects pri or t o c o m pleti o n of a st u d y i nitiati o n visit, 
c o n d ucte d b y Bi o ge n or desi g nee.  T his i nitiati o n visit will i ncl u de a detaile d re vie w of t he 
pr ot oc ol a n d st u d y  pr oce d ures.
1 5. 2.
Q u alit y Ass ur a nce
D uri n g a n d/ or after c o m pleti o n of t he st u d y , q ualit y ass ura nce officers na me d b y  Bi o ge n or t he 
re g ulat or y a ut h orities ma y wis h t o perf or m o n-site a u dits.  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 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
Bi o ge n or its desi g nee re prese ntati ves ma y c o n d uct o nsite visits at t he st u d y  facilities f or t he 
p ur p ose of m o nit ori n g vari o us as pects of t he st u d y.  T he I n vesti gat or m ust a gree t o Bi o ge n -
a ut h orize d pers o n nel ha vi n g direct access t o s u bject ( or ass ociate d) files f or t he p ur p ose of 
verif y i n g e ntries ma de i n t he C R F, a n d assist wit h t heir acti vities, if re q ueste d.  A de q uate s pace 
a n d ti me f or m o nit ori n g visits s h o ul d be ma de a vaila ble b y t he I n vesti gat or or st u d y  staff.  T he 
site m ust c o m plete t he C R Fs i n a ti mel y ma n ner a n d o n a n o n g oi n g basis t o all o w re g ular re vie w 
b y  t he st u d y tea m.
1 5. 4.
St u d y F u n di n g
Bi o ge n is t he S p o ns or of t he st u d y a n d is f u n di n g t he st u d y.  All fi na ncial details are pr o vi de d i n 
t he se parate c o ntract(s) bet wee n t he i nstit uti o n, In vesti gat or, a n d Bi o ge 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 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 5 8
1 6.
F U R T H E R R E Q UI R E M E N T S A N D G E N E R A L I N F O R M A T I O N
1 6. 1.
E xter n al C o ntr act Or g a niz ati o ns
1 6. 1. 1.
C o ntr act Rese arc h Or g a niz ati o n 
 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, m o nit ori n g, a n d ma na ge me nt of S A E re p orts a n d data ma na ge me nt.  Bef ore 
s u bjects are scree ne d at eac h st u d y site, t he c o ntract researc h or ga nizati o n ( C R O ) will re vie w 
st u d y res p o nsi bilities wit h t he In vesti gat ors a n d ot her st u d y  site staff, as a p pr o priate.
1 6. 1. 2.
Electr o nic D at a C a pt ure
S u bject i nf or mati o n will be ca pt ure d a n d ma na ge d b y  st u d y sites o n electr o nic C R Fs b y a 
we b -base d E D C t o ol de vel o pe d a n d s u p p orte d b y  E D C ve n d or a n d c o nfi g ure d b y Bi o g e n.
1 6. 1. 3.
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 Bi o ge n t o a nal yze he mat ol o g y, bl o o d c he mistr y, 
i m m u n ol o g y a n d uri ne sa m ples c ollecte d f or t his st u d y.
1 6. 1. 4.
Ce ntr al F acilit y f or M RI Assess me nts
 has bee n selecte d b y Bi o ge n t o rea d a n d i nter pret all M RIs.
All of t he M RI  sca ns wit h a n d wit h o ut G d will be e val uate d at a ce ntral M RI rea di n g ce nter, 
. All i n vesti gati o nal sites will be re q uire d t o se n d a test sca n of a healt h y
v ol u nteer s u bje ct t o t he M RI ce ntral rea di n g ce nter f or e val uati o n i n or der t o e ns ure t hat t he 
site’s sca n ni n g tec h ni q ues are a p pr o priate. T his re vie w will ta ke place bef ore t he i n vesti gati o nal 
site is per mitte d t o e nr oll a n y s u bjects i nt o t he st u d y.
M RI  di gital data s ho ul d be se nt o ver t he i nter net, if p ossi ble . If n ot p ossi ble, M RI di gital data ca n 
be se nt o n a c o m pact dis k . 
Refer t o t he M RI Ac q uisiti o n a n d Pr oce d ures Ma n ual f or m ore i nf or mati o n a n d detaile d 
i nstr ucti o ns.
1 6. 2.
A d vis or y C o m mittee
A n A d vis or y  C o m mittee will be f or me d t o pr o vi de scie ntific a n d me dical directi o n f or t he st u d y 
a n d t o o versee t he a d mi nistrati ve pr o gress of t he st u d y .  T he A d vis or y C o m mittee will meet at 
re g ular i nter vals t o m o nit or s u bject accr ual a n d t o m o nit or c o m plia nce wit h t he pr ot oc ol at 
in di vi d ual st u d y  sites.  T he A d vis or y C o m mittee will deter mi ne w het her t he st u d y s h o ul d be 
st o p pe d or a me n de d.
Me m bers of t he A d vis or y C o m mittee will i ncl u de t he Me dical Direct or, Cli nical Trial Ma na ger, 
a n d Pr oject Statisticia n fr o m Bi o ge n (a n d/ or t heir de si g nees), a n d partici pati n g I n vesti gat ors.  
Bi o ge n will desi g nate o ne of t he partici pati n g I n vesti gat ors t o be t he C hair pers o n of t he 
A d vis or y C o m mittee .

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 5 9
1 6. 3.
D at a S afet y M o nit ori n g B o ar d
A n i n de pe n de nt Data Safet y  M o nit ori n g B oar d ( D S M B) will be f or me d t o m o nit or be nefit/ris k 
d uri n g t he c o urse of t he trial. T he D S M B will re vie w all A Es , cli nical o bser vati o ns, vital si g ns, 
a n d la b orat or y tests f or all s u bjects. T he D S M B ma y  als o re q uest a n d re vie w data a n d m o nit or 
efficac y e n d p oi nts. T he D S M B will be c o m prise d of me m bers wit h a p pr o priate e x pertise w h o 
are all i n de pe n de nt of t he S p o ns or. Me m bers will n ot be bli n de d t o s u bject treat me nt assi g n me nt 
as t his is a n o pe n -la bel trial. I nvesti gati o nal sites will be n otifie d of a n y  rele va nt safet y fi n di n gs 
t hat ma y jeo par dize s u bject safet y . T he D S M B will meet r o uti nel y t hr o u g h o ut t he st u d y  
d urati o n. A c harter will be esta blis he d bet wee n Bi o ge n a n d t he D S M B t o o utli ne t he D S M B’s 
res p o nsi bilities a n d pr oce d ures.
1 6. 4.
C h a n ges t o Fi n al St u d y Pr ot oc ol
All pr ot oc ol a me n d me nts m ust be s u b mitte d t o t he E C a n d Re g ulat or y A ut h orities if re q uire d by 
l ocal la w.  Pr ot oc ol m o dificati o ns t hat affect s u bject safety, 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 E C 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, Bi o ge n m a y , at a n y ti me, a me n d t his pr ot oc ol t o eli mi nate a n a p pare nt i m me diate 
hazar d t o a s u bject.  I n t his case, t he a p pr o priate re g ulat or y a ut h orities will be n otifie d 
s u bse q ue nt t o t he m o dificati o n.
I n t he e ve nt of a pr ot oc ol m o dificati o n, t he s u bject c o nse nt f or m ma y re q uire si milar 
m o dificati o ns (see Secti o ns 1 4. 1 a nd 1 4. 2 ).
1 6. 5.
I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee N otific ati o n of St u d y 
C o m pleti o n or Ter mi n ati o n
W here re q uire d, t he Healt h A ut h orities a n d I RBs/ E Cs m ust be n otifie d of c o m pleti o n or 
ter mi nati o n of t his st u d y, a n d se nt a c o py of t he st u d y s y n o psis i n a cc or da nce wit h necessar y  
ti meli nes.
1 6. 6.
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 by a n y i nstit uti o nal re q uire me nts or l ocal la ws or re g ulati o ns.  Pri or t o 
pr ocee d i n g wit h destr ucti o n of rec or ds, t he I n vesti gat or m ust n otif y Bi o ge n i n writi n g a n d 
recei ve writte n a ut h orizati o n fr o m Bi o ge n t o destr o y st u d y rec or ds.  I n a d diti o n, t he In vesti gat or 
m ust n otif y  Bi o ge n of a n y  c ha n ges i n t he arc hi val arra n ge me nts i ncl u di n g, b ut n ot li mite d t o, 
arc hi val at a n off -site facilit y or tra nsfer of o w ners hi p if t he In vesti gat or lea ves t he site.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 6 0
1 7.
R E F E R E N C E S
A mara va di L M, O.; Me hta, D.; Reister, K.; S heri da n, J.; El ki ns, J. Earl y , S ustai ne d, a n d 
Re versi ble P har mac o d y na mic Effects of Dacliz u ma b H Y P i n M S S u p p ort Mec ha nis m of Acti o n 
via M o d ulati o n of t he I L -2 Pat h wa y. Ma n uscri pt s u b mitte d 2 0 1 5.
Be ne dict R C, S; L y nc h, S; Wa n g, P; Castr o -B orrer o, W; El ki ns, J. Dacliz u ma b H Y P Pr o vi de d 
Cli nicall y  Mea ni n gf ul Be nefits o n Co g niti ve O utc o mes vs. I ntra m usc ular I nterfer o n Beta -1a 
O ver 2 Years: Res ults Fr o m t he D E CI D E St u d y . Ma n uscri pt s u b mitte d 2 0 1 5.
Be ver C T, Jr., Gratta n L, Pa nitc h H S, et al. T he Brief Re peata ble Batter y  of Ne ur o psyc h ol o gical 
Tests f or M ulti ple Scler osis: a p reli mi nar y serial st u d y. M ult Scler. 1 9 9 5; 1( 3): 1 6 5-9. E p u b 
1 9 9 5/ 1 1/ 0 1.
Biele k o va B. Dacliz u ma b t hera p y f or m ulti ple scler osis. Ne ur ot hera pe utics. 2 0 1 3; 1 0( 1): 5 5 - 6 7.
Biele k o va B, Catalfa m o M, Reic hert -Scri v ner S, et al. Re g ulat or y  C D 5 6( bri g ht) nat ural killer
cells me diate i m m u n o m o d ulat or y  effects of I L-2 R α -tar gete d t hera p y ( dacliz u ma b) i n m ulti ple 
scler osis. Pr oc Natl Aca d Sci U S A. 2 0 0 6; 1 0 3( 1 5): 5 9 4 1- 6.
Bl o o m gre n G, Ric h ma n S, H oter ma ns C, et al. Ris k of nataliz u ma b-ass ociate d pr o gressi ve 
m ultif ocal le u k oe nc e p hal o pat h y. N E n gl J Me d. 2 0 1 2; 3 6 6( 2 0): 1 8 7 0- 8 0.
B utz k ue ve n H, Ka p p os L, Pelle gri ni F, et al. Efficac y  a n d safety of nataliz u ma b i n m ulti ple 
scler osis: i nteri m o bser vati o nal pr o gra m me res ults. J Ne ur ol Ne ur os ur g Ps yc hiatr y. 
2 0 1 4; 8 5( 1 1): 1 1 9 0 - 7.
Ca m p bell J D, G h us hc h ya n V, Brett Mc Q uee n R, et al. B ur de n of m ulti ple scler osis o n direct, 
i n direct c osts a n d q ualit y of life: Nati o nal U S esti mates. M ult Scler Relat Dis or d. 2 0 1 4; 3( 2): 2 2 7-
3 6.
Ce nt o nze D, R ossi S, Ri nal di F, et al. Se vere rela pses u n der fi n g oli m o d tre at me nt prescri be d 
after nataliz u ma b. Ne ur ol o g y . 2 0 1 2; 7 9( 1 9): 2 0 0 4-5. E p u b 2 0 1 2/ 1 0/ 0 5.
Cleric o M, Sc hia vetti I, De Merca nti S F, et al. Treat me nt of rela psi n g -re mitti n g m ulti ple 
scler osis after 2 4 d oses of nataliz u ma b: e vi de nce fr o m a n Italia n s p o nta ne o us, pros pecti ve, a n d 
o bser vati o nal st u d y  (t he T Y-S T O P St u d y ). J A M A Ne ur ol. 2 0 1 4; 7 1( 8): 9 5 4- 6 0.
C o ha n S M, H; Cal k w o o d, J; L a Ga n ke, C; S m o ot, K E; Ma n n, M; Me ka, V; O k w u o ke n y a, M; 
H oter ma ns, C; Meltzer, L. Real -W orl d Cli nical O utc o mes i n Rela psi n g -Re mitti n g M ulti ple
Scler osis Patie nts W h o S witc h Fr o m Nataliz u ma b t o Dela y e d-Release Di met h y l F u marate: 
Preli mi nar y  A nalys is of a M ultice nter, Retr os pecti ve, O bser vati o nal St u d y ( S T R A T E G Y). 
Ma n uscri pt s u b mitte d 2 0 1 5.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 6 1
C o he n M, Maillart E, T o ur ba h A, et al. S witc hi n g fr o m nat aliz u ma b t o fi n g oli m o d i n m ulti ple 
scler osis: a Fre nc h pr os pecti ve st u d y. J A M A Ne ur ol. 2 0 1 4; 7 1( 4): 4 3 6 - 4 1.
C o mi G, G ol d R, Da hl ke F, et al. Rela pses i n patie nts treate d wit h fi n g oli m o d after pre vi o us 
e x p os ure t o nataliz u ma b. M ult Scler. 2 0 1 5; 2 1( 6): 7 8 6- 9 0. E p u b 2 0 1 4/ 0 9/ 2 7.
C o mi G G, Ralf; Da hl ke, Fra n k; Si n ha, Arijit; v o n R ose nstiel, P hili p p; T o mic, Da v or ka; Ka p p os, 
L u d wi g. Rela pse O utc o mes i n Fi n g oli m o d -Treate d Patie nts wit h M ulti ple Scler osis Pre vi o usl y  
E x p ose d t o Nataliz u ma b: P ost H oc A nal y sis fr o m t he 4-m o nt h, O pe n -La bel FI R S T St u d y . 
Ma n uscri pt s u b mitte d 2 0 1 3.
C o nfa vre u x C, L i D K, Free d ma n M S, et al. L o n g-ter m f oll o w-u p of a p hase 2 st u d y  of oral 
terifl u n o mi de i n rela psi n g m ulti ple scler osis: safet y a n d efficac y res ults u p t o 8. 5 years. M ult 
Scler. 2 0 1 2; 1 8( 9): 1 2 7 8 -8 9. E p u b 2 0 1 2/ 0 2/ 0 7.
Cree B. S 4 1. 0 0 3 Nataliz u ma b effects d uri n g a 6 - m o nt h d ose i nterr u pti o n: relati o ns hi p of 
p har mac o ki netic ( P K), p har mac o d y n a mic ( P D), a n d M RI meas ure me nts. Ma n uscri pt s u b mitte d 
2 0 1 3.
De v o ns hire V, La pierre Y, Mac d o nell R, et al. T he Gl o bal A d here nce Pr oject ( G A P): a 
m ultice nter o bser vati o nal st u d y  o n a d here nce t o disease-m o dif y i n g t hera pies i n patie nts wit h 
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( 1): 6 9- 7 7.
El ki ns J, S heri da n J, A mara va di L, et al. C D 5 6( bri g ht ) nat ural killer cells a n d res p o nse t o 
dacliz u ma b H Y P i n rela psi n g -re mitti n g M S. Ne ur ol Ne ur oi m m u n ol Ne ur oi nfla m m. 
2 0 1 5; 2( 2):e 6 5.
E ur o pea n Me dici nes A ge nc y. E M A c o nfir ms rec o m me n dati o ns t o mi ni mise ris k of brai n 
i nfecti o n P M L wit h T ysa bri. P u blis he d 2 0 1 6 [Accesse d A pril 2 0 1 5]. A vaila ble fr o m: 
htt p:// w w w.e ma.e ur o pa.e u/e ma/i n de x.js p?c url = pa ges/ ne ws a n d e ve nts/ ne ws/ 2 0 1 6/ 0 2/ ne ws det
ail 0 0 2 4 7 6.js p & mi d = W C 0 b 0 1ac 0 5 8 0 0 4 d 5c 1
Faiss ner S, H oe p ner R, L u kas C, et al. T u mefacti ve m ulti ple scler osis lesi o ns i n t w o patie nts 
after cessati o n of fi n g oli m o d treat me nt. T her A d v Ne ur ol Dis or d. 2 0 1 5; 8( 5): 2 3 3 - 8.
Flac he nec ker P, St u ke K. Nati o nal M S re gistries. J Ne ur ol. 2 0 0 8; 2 5 5 S u p pl 6: 1 0 2- 8. E p u b 
2 0 0 9/ 0 3/ 2 8.
F o x RJ, Cree B A, De Sèze J, et al. M S disease acti vit y  i n R E S T O R E: a ra n d o mize d 2 4-wee k 
nataliz u ma b treat me nt i nterr u pti o n st u d y . Ne ur ol o g y. 2 0 1 4; 8 2( 1 7): 1 4 9 1- 8.
F o x RJ, Miller D H, P hilli p s J T, et al. Place b o-c o ntr olle d p hase 3 st u d y of oral B G -1 2 or 
glatira mer i n m ulti ple scler osis. N E n gl J Me d. 2 0 1 2; 3 6 7( 1 2): 1 0 8 7 -9 7. Errat u m i n: N E n gl J 
Me d. 2 0 1 2 Oct 2 5; 3 6 7( 1 7): 1 6 7 3.
F o x RJ, R u dic k R A. Ris k stratificati o n a n d patie nt c o u nseli n g f or natal iz u ma b i n m ulti ple 
scler osis. Ne ur ol o g y. 2 0 1 2; 7 8( 6): 4 3 6-7. E p u b 2 0 1 2/ 0 1/ 2 8.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 6 2
Gaffe n S L , Li u K D. O ver vie w of i nterle u ki n-2 f u ncti o n, pr o d ucti o n a n d cli nical a p plicati o ns. 
C y t o ki ne. 2 0 0 4; 2 8( 3): 1 0 9-2 3. E p u b 2 0 0 4/ 1 0/ 1 2.
Gile n y a ( Fi n g oli m o d) Pac ka ge I nsert. East Ha n o ver, NJ: N o vartis.
Gi o va n n o ni G, G ol d R, Sel maj K, et al. Dacliz u ma b hi g h- yi el d pr ocess i n rela psi n g -re mitti n g 
m ulti ple scler osis ( S E L E C TI O N): a m ultice ntre, ra n d o mise d, d o u ble -bli n d e xte nsi o n trial. 
La ncet Ne u r ol. 2 0 1 4; 1 3( 5): 4 7 2- 8 1.
G ol d R, Gi o va n n o ni G, Sel maj K, et al. Dacliz u ma b hi g h- yi el d pr ocess i n rela psi n g -re mitti n g 
m ulti ple scler osis ( S E L E C T): a ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d trial. La ncet. 
2 0 1 3; 3 8 1( 9 8 8 4): 2 1 6 7 -7 5.
G ol d R, Ka p p os L , Ar n ol d D L , et al. Place b o-c o ntr olle d p hase 3 st u d y of oral B G-1 2 f or 
rela psi n g m ulti ple scler osis. N E n gl J Me d. 2 0 1 2; 3 6 7( 1 2): 1 0 9 8- 1 0 7.
G o o di n D S. C ha pter 1 1 - T he e pi de mi ol o g y of m ulti ple scler osis: i nsi g hts t o disease 
pat h o ge nesis. I n: D o u glas S G, e dit or. Ha n d b o o k of Cli nical Ne ur ol o g y . V ol u me 1 2 2. Else vier; 
2 0 1 4. p 2 3 1 - 2 6 6.
G o o di n D S, Fr o h ma n E M, Gar ma n y G P, et al. Disease m o dif y i n g t hera pies i n m ulti ple scler osis: 
re p ort of t he T hera pe utics a n d Tec h n ol o g y Assess me nt S u bc o m mittee of t he A merica n Aca de my 
of Ne ur ol o g y  a n d t he M S C o u ncil f or Cli nical Practice G ui deli nes. Ne ur ol o g y. 2 0 0 2; 5 8( 2): 1 6 9-
7 8.
Ha ns o n K, A gas hi vala N, W y r wic h W. Treat me nt selecti o n a n d e x perie nce i n m ulti ple scler osis: 
s ur ve y of ne ur ol o gists. Patie nt Prefere nce a n d A d here nce. 2 0 1 4; 8: 8. E p u b 3 A pril 2 0 1 4.
Ha vr d o va E, Galetta S, H utc hi ns o n M, et al. Effect of nataliz u ma b o n cli nical a n d ra di ol o gical 
disease acti vit y  i n m ulti ple scler osis: a retr os pecti ve a nalys is of t he Nataliz u ma b Safety a n d 
Efficac y  i n Rela psi n g-Re mitti n g M ulti ple Scler osis ( A F FI R M) st u d y. La ncet Ne ur ol. 
2 0 0 9; 8( 3): 2 5 4 - 6 0.
Ka p p os L. Dacliz u ma b H Y P Vers us I nterfer o n Beta- 1a i n Rela psi n g -Re mitti n g M ulti ple 
Scler osis: Pri mar y  Res ults of t he D E CI D E St u d y. Ma n uscri pt s u b mitte d 2 0 1 5a.
Ka p p os L, Bates D, E da n G, et al. Nataliz u ma b treat me nt f or m ulti ple scler osis: u p date d 
rec o m me n dati o ns f or patie nt selecti o n a n d m o nit ori n g. La ncet Ne ur ol. 2 0 1 1; 1 0( 8): 7 4 5- 5 8.
Ka p p os L, Ra d ue E W, C o mi G, et al. S witc hi n g fr o m nataliz u ma b t o fi n g oli m o d: A ra n d o mize d, 
place b o -c o ntr olle d st u d y i n R R M S. Ne ur ol o g y. 2 0 1 5 b; 8 5( 1): 2 9- 3 9.
Ka p p os L, Wie n dl H, Sel maj K, et al. Dacliz u ma b H Y P vers us I nterfer o n Beta -1a i n Rela psi n g 
M ulti ple Scler osis. N E n gl J Me d. 2 0 1 5c; 3 7 3( 1 5): 1 4 1 8 - 2 8.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 6 3
Ka wasa ki R, Yas u da M, S o n g SJ, et al. T he pre vale nce of a ge -relate d mac ular de ge nerati o n i n 
Asia ns: a s y ste matic re vie w a n d meta-a nal ys is. O p ht hal m ol o g y. 2 0 1 0; 1 1 7( 5): 9 2 1-7. E p u b 
2 0 1 0/ 0 1/ 3 0.
K hatri B, Bar k h of F, C o mi G, et al. C o m paris o n of fi n g oli m o d wit h i nterfer o n beta -1a i n 
rela psi n g-re mitti n g m ulti ple scler osis: a ra n d o mise d e xte nsi o n of t he T R A N S F O R M S st u d y. 
La ncet Ne ur ol. 2 0 1 1; 1 0( 6): 5 2 0 - 9.
K o belt G, Ber g J, At herl y D, et al. C osts a n d q ualit y  of life i n m ulti ple scler osis: a cr oss-
secti o nal st u d y i n t he U nite d States. Ne ur ol o g y. 2 0 0 6a; 6 6( 1 1): 1 6 9 6- 7 0 2.
K o belt G, Ber g J, L i n d gre n P, et al. C osts a n d q ualit y of life of patie nts wit h m ulti ple scler osis i n 
E ur o pe. J Ne ur ol Ne ur os ur g Ps yc hiatr y . 2 0 0 6 b; 7 7( 8): 9 1 8- 2 6.
Lee P, Pla vi na T, Castr o A, et al. A sec o n d- ge nerati o n E LI S A ( S T R A TI F Y J C V D x Select) f or 
detecti o n of J C vir us a nti b o dies i n h u ma n ser u m a n d plas ma t o s u p p ort pr o gressi ve m ultif ocal 
le u k oe nce p hal o pat hy ris k stratificati o n. J Cli n Vir ol. 2 0 1 3; 5 7( 2): 1 4 1 -6. E p u b 2 0 1 3/ 0 3/ 0 8.
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 n s. Ne ur ol o g y. 2 0 1 4; 8 3( 3): 2 7 8- 8 6.
Mc D o nal d WI , C o m pst o n A, E da n G, et al. Rec o m me n de d dia g n ostic criteria f or m ulti ple 
scler osis: g ui deli nes fr o m t he Inter nati o nal pa nel o n t he dia g n osis of m ulti ple scler osis. A n n 
Ne ur ol. 2 0 0 1; 5 0( 1): 1 2 1 - 1 2 7.
Miller R M, Ha p p e L E, Me yer K L, et al. A p pr oac hes t o t he ma na ge me nt of a ge nts use d f or t he 
treat me nt of m ulti ple scler osis: c o nse ns us state me nts fr o m a pa nel of U. S. ma na ge d care 
p har macists a n d p h ys icia ns. J Ma na g Care P har m. 2 0 1 2; 1 8( 1): 5 4- 6 2.
Mil o R. T he efficac y  a n d safety of dacliz u ma b a n d its p ote ntial r ole i n t he treat me nt of m ulti ple 
scler osis. T her A d v Ne ur ol Dis or d. 2 0 1 4; 7( 1): 7-2 1.
Nati o nal C olla b orati n g Ce ntre f or C hr o nic C o n diti o ns. M ulti ple Scler osis: Nati o nal Cli nical 
G ui deli ne f or Dia g n osis a n d Ma na ge me nt i n Pri mar y  a n d Sec o n dar y Care. L o n d o n: R o yal 
C olle ge of P h ys icia ns of L o n d o n.; 2 0 0 4.
Nati o nal M ulti ple Scler osis S ociet y . Case of P M L Re p orte d i n Pers o n Recei vi n g Gile nya( R): 
U P D A T E D. P u blis he d 2 0 1 5 [ Accesse d A pril 2 0 1 5]. A vaila ble fr o m: 
htt p:// w w w. nati o nal mss ociet y . or g/ A b o ut-t he-S ociet y / Ne ws/ Case-of -P M L -Re p orte d -i n-Pers o n -
Recei vi n g -Gile n ya % C 2 % A E
Nie u w ka m p DJ, M ur k J L, va n O oste n B W. P M L  i n Patie nts Treate d wit h Di met h yl F u marate. N 
E n gl J Me d. 2 0 1 5; 3 7 3( 6): 5 8 4. E p u b 2 0 1 5/ 0 8/ 0 6.
Per u mal J, K ha n O. E mer gi n g disease -m o dif y i n g t hera pies i n m ulti ple scler osis. C urr Treat 
O pti o ns Ne ur ol. 2 0 1 2; 1 4( 3): 2 5 6 - 6 3.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 6 4
Pfe n der N, Marti n R. Dacliz u ma b (a n ti- C D 2 5) i n m ulti ple scler osis. E x p Ne ur ol. 2 0 1 4; 2 6 2 Pt 
A: 4 4 -5 1. E p u b 2 0 1 4/ 0 4/ 2 9.
Pla vi na T, S u bra ma n ya m  M, Bl o o m gre n G, et al. A nti-J C vir us a nti b o d y le vels i n ser u m or 
plas ma f urt her defi ne ris k of nataliz u ma b-ass ociate d pr o gressi ve m ultif ocal 
le u k oe nce phal o pat h y . A n n Ne ur ol. 2 0 1 4; 7 6( 6): 8 0 2-1 2. E p u b 2 0 1 4/ 1 0/ 0 3.
P oli A, Mic hel T, T hérési ne M, et al. C D 5 6( bri g ht) nat ural killer ( N K) cells: a n i m p orta nt N K 
cell s u bset. Im m u n ol o g y . 2 0 0 9; 1 2 6( 4): 4 5 8- 6 5.
P ol ma n C H, O' C o n n or P W, Ha vr d o va E, et al. A ra n d o mize d, p lace b o-c o ntr olle d trial of 
nataliz u ma b f or rela psi n g m ulti ple scler osis. N E n gl J Me d. 2 0 0 6; 3 5 4( 9): 8 9 9 - 9 1 0.
P ol ma n C H, Rei n g ol d S C, Ba n well B, et al. Dia g n ostic criteria f or m ulti ple scler osis: 2 0 1 0 
Re visi o ns t o t he Mc D o nal d criteria. A n n Ne ur ol. 2 0 1 1; 6 9( 2 ): 2 9 2- 3 0 2.
P ol ma n C H, R u dic k R A. T he m ulti ple scler osis f u ncti o nal c o m p osite: a cli nicall y  mea ni n gf ul 
meas ure of disa bilit y . Ne ur ol o g y. 2 0 1 0; 7 4 S u p pl 3: S 8- 1 5.
P oser C M, Pat y  D W, Sc hei n ber g L, et al. Ne w dia g n ostic criteria f or m ulti ple scler osis: 
g ui deli ne s f or researc h pr ot oc ols. A n n Ne ur ol. 1 9 8 3; 1 3( 3): 2 2 7- 3 1.
R oac h E S. I s m ulti ple scler osis a n a ut oi m m u ne dis or der? Arc h Ne ur ol. 2 0 0 4; 6 1( 1 0): 1 6 1 5 - 6. 
E p u b 2 0 0 4/ 1 0/ 1 3.
R ose n kra nz T, N o vas M, Ter b or g C. P M L  i n a patie nt wit h l ym p h oc y t o pe nia treate d wit h 
di met h y l f u marate. N E n gl J Me d. 2 0 1 5; 3 7 2( 1 5): 1 4 7 6-8. E p u b 2 0 1 5/ 0 4/ 0 9.
R ossi S, M otta C, St u der V, et al. Effect of glatira mer acetate o n disease reacti vati o n i n M S 
patie nts disc o nti n ui n g nataliz u ma b. E ur J Ne ur ol. 2 0 1 3; 2 0( 1): 8 7- 9 4. E p u b 2 0 1 2/ 0 6/ 3 0.
R u n mar ker B, A n derse n O. Pr o g n ostic fact ors i n a m ulti ple scler osis i nci de nce c o h ort wit h 
t we nt y-fi ve ye ars of f oll o w -u p. Brai n. 1 9 9 3; 1 1 6( Pt 1): 1 1 7 - 3 4.
Sa n galli F, M oi ola L, Ferrè L, et al. L o n g- ter m ma na ge me nt of nataliz u ma b disc o nti n uati o n i n a 
lar ge m o n oce ntric c o h ort of m ulti ple scler osis patie nts. M ult Scler Relat Dis or d. 2 0 1 4; 3( 4): 5 2 0-
6.
Sel maj K, L i D K, Hart u n g H P, et al. Si p o ni m o d f or patie nts wit h rela psi n g-re mitti n g m ulti ple 
scler osis ( B O L D): a n a da pti ve, d ose-ra n gi n g, ra n d o mise d, p hase 2 st u d y. La ncet Ne ur ol. 
2 0 1 3; 1 2( 8): 7 5 6 - 6 7.
S u mela hti M -L,  H ol m ber g M H A, M urt o ne n A, et al. Increasi n g I nci de nce i n Rela psi n g -
Re mitti n g M S a n d Hi g h Rates a m o n g Y o u n g W o me n i n Fi nla n d: A T hirt y- Year F oll o w -U p. 
M ulti ple Scler osis I nter nati o nal. 2 0 1 4; 2 0 1 4: 1 8 6 9 5 0.
T E C FI D E R A ™ ( di met h yl f u marate) Pac ka ge I nsert. Ca m bri d ge, M A: Bi o ge n I dec; Dece m ber 
2 0 1 4.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 6 5
Trea da wa y  K, C utter G, Salter A, et al. Fact ors t hat i nfl ue nce a d here nce wit h disease-m o dif y i n g 
t hera py i n M S. J Ne ur ol. 2 0 0 9; 2 5 6( 4): 5 6 8 - 7 6.
T ull ma n MJ. A re vie w of c urre nt a n d e mer gi n g t hera pe utic strate gies i n m ulti ple scler osis. A m J 
Ma na g Care. 2 0 1 3; 1 9( 2 S u p pl): S 2 1 - 7.
T y sa bri® S u m mar y  of Pr o d uct C haracteristics, 1 8 Fe br uar y 2 0 1 3, Bi o ge n I dec I nc.
T y sa bri® ( nataliz u ma b) Pac ka ge I nsert. Dec 2 0 1 3.
Wei ner H L. M ulti ple scler osis is a n i nfl a m mat or y T-cell- me diate d a ut oi m m u ne disease. Arc h 
Ne ur ol. 2 0 0 4; 6 1( 1 0): 1 6 1 3- 5. E p u b 2 0 0 4/ 1 0/ 1 3.
Wei ns he n ker B G, Bass B, Rice G P, et al. T he nat ural hist or y  of m ulti ple scler osis: a 
ge o gra p hicall y  base d st u d y. 2. Pre dicti ve val ue of t he early cli nical c o urse . Brai n. 1 9 8 9; 1 1 2( Pt 
6): 1 4 1 9 - 2 8.
Wie n dl H, Gr oss C C. M o d ulati o n of I L -2 Ral p ha wit h dacliz u ma b f or treat me nt of m ulti ple 
scler osis. Nat Re v Ne ur ol. 2 0 1 3; 9( 7): 3 9 4-4 0 4. E p u b 2 0 1 3/ 0 6/ 0 5.

Pr ot oc ol 2 0 5 M S 3 0 5
Versi o n 1. 0
Efficac y a n d Safet y of Dacliz u ma b i n S u bjects wit h R R M S S witc hi n g fr o m Nataliz u ma b
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d w it h o ut t he writte n c o nse nt of        
Bi o ge n M A I nc.
Pa ge 6 6
1 8.
I N V E S TI G A T O R S SI G N E D A G R E E M E N T O F 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 P hase 3 b, 1 2 -m o nt h, O pe n -la bel, M ultice nter St u d y t o 
E val uate t he Efficac y  a n d Safet y of BII B 0 1 9, Dacliz u ma b, i n S u bjects wit h Rela psi n g- Re mitti n g 
M ulti ple Scler osis ( R R M S) S witc hi n g fr o m Nataliz u ma b,” a n d a gree t o c o n d uct t he st u d y  
accor 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 l ocal 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)