Clinical trial NCT02881567
Conditions: Relapsing-Remitting Multiple Sclerosis (RRMS)
Keywords: Multiple Sclerosis Daclizumab Tysabri-Switch
Sponsor: Biogen
Start date: 2017-04-18; Completion date: 2018-09-12
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to evaluate the effects of treatment with daclizumab on the proportion of participants relapse-free at 6 months in Relapsing-Remitting Multiple Sclerosis (RRMS) participants, who switched from treatment with natalizumab to daclizumab due to safety concerns. The secondary objectives of this study in this study population are to evaluate the effects of daclizumab on the following: 1) Multiple Sclerosis (MS) relapse activity including the annualized relapse rate (ARR) and the proportion of participants experiencing relapses requiring hospitalization and/or steroid treatment; 2) MS-related outcomes measured using magnetic resonance imaging (MRI); 3) Safety and tolerability in participants previously treated with natalizumab.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Daclizumab
Intervention descriptions: intervention 1: High yield formulation

Protocol documents:
Prot_001.pdf: 




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


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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


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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


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C O N FI D E N TI A L
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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




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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
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Bi o ge n M A I nc.
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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
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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
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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


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C O N FI D E N TI A L
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Bi o ge n M A I nc.
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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.












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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
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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






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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
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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
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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
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I n vesti gat or’s Na me ( Pri nt)
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St u d y  Site ( Pri nt)

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St u d y 2 0 5 M S 3 0 5 Statistical A nal ysis Pla n 
St atistic al A n al ysis Pl a n
Versi o n N o.:  FI N A L v 1. 0 
 St u d y Title: 2 0 5 M S 3 0 5 ( S U S T AI N) 
Na me of St u d y Treat me nt: D A C LI Z U M A B 
Pr ot oc ol N o.:  2 0 5 M S 3 0 5/ N C T 0 2 8 8 1 5 6 7 
St u d y P hase: P H A S E III B 
C o nfi de nti al I nf or m ati o n 
T he i nf or m ati o n c o nt ai ne d i n t his St atisti c al A n alysis Pl a n ( S A P) is c o nfi de nti al a n d 
m ay n ot be re pr o d uce d or ot her wise disse mi n at e d wit h o ut t he a p pr ov al of Bi o ge n, I nc.  




St u d y 2 0 5 M S 3 0 5 Statistical A nal ysis Pla n  
  
 
 
 
A P hase 3 b, 1 2- m o nt h, O pe n-la bel, M ultice nte r 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 beta, 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) 
Pr ot oc ol 2 0 5 M S 3 0 5  
  
 
St u d y P h ase: 3 b  
  
 
Pr o d uct St u die d: Dacliz u ma b 
  
 
 D ate of Pr ot oc ol: 0 6 J ul y 2 0 1 1 ( versi o n 1. 0 ) 
  
 
 D ate of S A P:   1 4  J u ne 2 0 1 8 
Ke y w or ds : ( O pe n-la bel, m ultice nter, cli nical re la pses, c o nfir me d disa bilit y pr o gressi o n, 
M RI, a d verse e ve nts)  
Writte n B y: 
, P h D 
   
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o m pli a nce : T he st u d y descri be d i n t his re p ort was perf or me d acc or di n g t o t he pri nci ples of G o o d Cli nical Practice ( G C P) 
C o nfi de nti alit y St ate me nt 
T he i nf or mati o n i n t his d oc u me nt c o ntai ns tra de secrets a n d c o m mercial i nf or mati o n t hat are pri vile ge d or c o nfi de ntial a n d ma y n ot be 
discl ose d u nless s uc h discl os ure is re q uire d b y a p plica ble la w or  re g ulati o n. I n a n y e ve nt, pers o ns t o w h o m t he i nf or mati o n is discl ose d 
m ust be i nf or me d t hat t he i nf or mati o n is pri vile ge d or c o nfi de ntial a n d ma y n ot be f u rt her discl ose d b y t he m. T hese restri cti o ns o n 
discl os ure will a p pl y e q uall y t o all f ut ure i nf or mati o n s u p p lie d t o y o u w hic h is i n dicate d as pri vile ge d or c o nfi de ntial.


St u d y 2 0 5 M S 3 0 1 Statistical A nal ysis Pla n  
  
 3  
T A B L E O F C O N T E N T S 
 
1  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S ............................................................................. 4  
1. 1  
Pri mar y O bjecti ve a n d E n d p oi nt ................................................................................... 4  
1. 2  
Sec o n dar y O bjecti ves a n d E n d p oi nts ............................................................................ 4  
1. 3  
E x pl orat or y O bjecti ves a n d E n d p oi nts ......................................................................... 4  
2  
S T U D Y D E SI G N A N D S A M P L E SI Z E ................................................................................... 5  
3  
A N A L Y SI S P O P U L A TI O N S ................................................................................................... 6  
4  
G E N E R A L C O N SI D E R A TI O N S ............................................................................................. 6  
4. 1  
Treat me nt Peri o d Defi niti o ns ........................................................................................ 6  
4. 2  
Acc o u nti n g of S u bjects ................................................................................................. 7  
4. 3  
De m o gra p hics a n d Baseli n e C haracteristics ................................................................. 7  
4. 4  
St u d y Dr u g C o m plia nce ................................................................................................ 7  
4. 5  
C o nc o mita nt Me dicati o ns a n d N o n- dr u g T hera pies ..................................................... 7  
4. 6  
Ge neral I nf or mati o n o n Statistical A nal ysis ................................................................. 8  
4. 7  
Pr ot oc ol De viati o ns ....................................................................................................... 8  
4. 8  
Alter nati ve M ulti ple Scle r osis Me dicati o ns .................................................................. 8 
5  
S T A TI S TI C A L A N A L Y S E S .................................................................................................... 8  
5. 1  
Pri mar y A nal ysis ........................................................................................................... 8  
5. 2  
Sec o n dar y A nal ysis ....................................................................................................... 9  
5. 2. 1  A nal ysis f or 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 .......................................................................... 9  
5. 2. 2  A nal ysis f or A n n ualize d Rela pse Rate ( A R R) .............................................................. 9  
5. 2. 3  A nal ysis f or M RI e n d p oi nts .......................................................................................... 9  
5. 3  
E x pl orat or y A nal yses .................................................................................................. 1 0  
 1 0 
 1 0 
5. 4  
Safet y  A nal ysis ........................................................................................................... 1 0  
5. 4. 1  Cli nical A d verse E ve nts .............................................................................................. 1 0 
5. 4. 2  Cli nical La b orat or y Data ............................................................................................ 1 1  
5. 4. 3  Vital si g ns  
 ....................................................................................................... 1 2  


St u d y 2 0 5 M S 3 0 5 Statistical A nal ysis Pla n  
  
 
 
4 
  
 
1  
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 
1. 1  
Pri m ar y O bjecti ve a n d E n d p oi nt 
T he pri m ar y st u d y o bjecti ve  is t o e val uate t he effects of treat me nt wit h dacliz u ma b beta o n 
pr o p orti o n of s u bjects rela pse-fr ee at M o nt h 6, 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 beta d ue t o safet y c o ncer ns.  
T he pri m ar 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 d acliz u ma b beta w h o s witc he d fr o m treat me nt 
wit h nataliz u ma b. 
1. 2  
Sec o n d ar y O bjecti ves a n d E n d p oi nts 
T he sec o n d ar y o bjecti ves  are t o e val uate t he effects of dacliz u ma b beta o n t he f oll o wi n g:  
 M ulti ple Scler osis ( M S) rela pse acti vit y i n cl u di n g a n n ualize d rela pse rate ( 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 ma g netic res o na nce i ma gi 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 d ar y e n d p oi nts are:   
 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 re la 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 ga d oli ni u m e n ha nce d ( G 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 h y peri 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 beta at M o nt h 1 2. 
 T he i nci de nce of a d verse e ve nts ( A Es) a n d seri o us a d verse e ve nts ( S A Es) i ncl u di n g 
cli nicall y rele va nt.  
1. 3  
E x pl or at or y O bjecti ves a n d E n d p oi nts 
T he  e x pl or at or y o bjecti ves  of t his st u d y i n t his st u d y p o p ulatio n are t o e val uate t he effects of 
dacliz u ma b beta o n t he f oll o wi n g: 
 
 


St u d y 2 0 5 M S 3 0 5 Statistical A nal ysis Pla n  
  
 
 
5 
  
 
 
 
. 
 
 
 
 
 
T he e x pl or at or y e n d p oi nts  of t he st u d y are: 
 
 
 
 
 
 
. 
 
 
 
 
 
. 
 
 
 
 
 
 
 
. 
 
  
2  
S T U D Y D E SI G N A N D S A M P L E SI Z E 
T his is a m ultice nter, o pe n-l a bel st u d y of dac liz 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 wit h nataliz u ma b f or at least 1 2 m o nt hs. S u bjects will be 
e nr olle d o ver a n a p pr o xi matel y 1 2- m o nt h pe ri o d. S u bjects disc o nti n uin g fr o m nataliz u ma b 
treat me nt d ue t o safet y c o ncer ns will c o m me nce treat me nt wit h dacliz u ma b beta f oll o wi n g 
c o nse nt a n d e val uati o n of eli gi bil it y. S u bjects will i nitiate treat me nt wit h dacliz u ma b beta at 
2 8 ( + 3) da ys f oll o wi n g t he last i nf usi o n of nataliz u ma b. Assess me nts will be c o m plete 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.  




St u d y 2 0 5 M S 3 0 5 Statistical A nal ysis Pla n  
  
 
 
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 Tre at me nt peri o d, or, ti me o n (st u d y) tre at me nt , is defi ne d as t he ti me bet wee n t he 
first d osi n g date a n d t he last d osi n g date; it is calc ulate d as  t he last d osi n g date mi n us 
t he first d osi n g date + 1; als o k n o wn as t he ti me e x p ose d t o st u d y dr u g; 
 
Ti me o n st u d y, or st u d y peri o d , is defi ne d as t he ti me bet wee n t he first d osi n g date 
a n d t he e n d of st u d y date, calc ulate d as t he la st visit date – t he first d osi n g date + 1.  
4. 2  
Acc o u nti n g of S u bjects 
Dis p ositi o n  of  t he  s u bjects  will  be  s u m mari ze d.  T he  ke y  c o nte nts  i ncl u de  n u m ber  (a n d  
perce nta ge) of s u bjects, n u m ber of s u bject s d ose d, me dia n f oll o w- u p ti me, me dia n ti me o n 
st u d y treat me nt, t he n u m ber of s u bjects w h o c o m plete d st u d y f oll o w- u p. I n a d diti o n, al o n g 
wit h reas o ns, n u m bers (a n d pe rce nta ge) of s u bjects disc o ntin ue d treat me nt a n d wit h dra w n 
fr o m  t he  st u d y  will  be  prese nte d.  Listin gs  of  t hese  s u bjects  a n d  reas o ns  f or  
disc o nti n uati o n/ wit h dra wal will be prese nte d 
4. 3  
De m o gr a p hics a n d B aseli ne C h ar acteristics 
De m o gra p hic data, i ncl u di n g a ge ( years),  a ge cate g or y ( < 1 8, 1 8- 1 9, 2 0- 2 9, 3 0- 3 9, 4 0- 4 9, 5 0-
5 5, a n d > 5 5, als o < 3 5 , > 3 5), ge n der, race cate g or y, baseli ne hei g ht (c m) a n d wei g ht ( k g) will 
be s u m mari ze d.  
Baseli ne data are defi ne d as data c ollecte d o n t he cl osest date pri or t o or o n t he first d osi n g 
date. Baseli ne disease c haracteristics will be  s u m marize d. T hese i ncl u de years si nce disease 
( M S) o nset, years si nce dia g n osis, Mc D o nal d criteria, n u m ber of rela pses i n t he past 1 2 m o nt hs 
a n d i n t he past 3 years, 
 
, baseli ne M RI, pri or M S treat me nt hist or y, me dical hist or y, t o bacc o 
use, a n d stat us of i nterfer o n bi n di n g a n d ne utralizi n g a nti b o dies.  A d diti o nal varia bles ma y be 
i ncl u de d w here a p plica ble.  
All de m o gra p hic a n d baseli ne data will be s u m marize d f or t he f ull a nal ysis set.  
4. 4  
St u d y Dr u g C o m pli a nce  
St u d y  dr u g  c o m plia nce  will  be  s u m marize d,  i ncl u di n g  t he  t otal  n u m ber  of  i njecti o ns  of  
dacliz u ma b beta, t he perce nta ge of t he treat me nt i njecti o ns recei ve d.   
4. 5  
C o nc o mit a nt Me dic ati o ns a n d N o n- dr u g T her a pies 
C o nc o mita nt me dicati o n is defi ne d as prescri b e d or o ver-t he-c o u nter me dicati o n use d d uri n g 
t he st u d y (e. g. eit her starte d pri or t o t he st u d y a n d c o nti n ue d d uri n g t he st u d y or starte d after 
t he first d ose of st u d y dr u g).  T he W H O dictio nar y will be use d f or c o di n g c o nc o mita nt 
me dicati o n.  Me d D R A is use d f or c o di n g c o nc o mita nt n o n- dr u g t hera pies.   
N u m ber a n d perce nta ge of s u bjects ta ki n g c o nc o mita nt me di ca ti o n a n d n o n- dr u g t hera pies will 
be  s u m marize d.  I n  a d diti o n,  n u m ber  a n d  perc e nta ge  of  s u bjects  ta ki n g  (s witc hi n g  t o)  
alter nati ve me dicati o n will als o be s u m marize d.  


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4. 6  
Ge ner al I nf or m ati o n o n St atistic al A n al ysis 
S u m mar y  statistics  will  be  ge nerate d  f o r  all  efficac y,  safet y,  P K/ P D  para meters,  
de m o gra p hic/ baseli ne  varia bles  a n d  ot her  vari a bles  w here  a p plica ble.  F or  t he  c o nti n u o us  
e n d p oi nts, t he s u m mar y statistics will ge nerall y i ncl u de n u m ber of s u bjects, 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,  mi ni m u m  a n d  ma xi m u m.   F or  cate g orical  
e n d p oi nts, t he s u m mar y statistics will ge nerall y  i ncl u de  n u m ber of s u bjects i n c orres p o n di n g 
a nal ysis p o p ulati o n, n u m ber a n d t he per ce nta ge of s u bjects i n eac h cate g or y. 
I n ge neral, all efficac y e n d p oi nt a nal yses w here a p plica ble will i ncl u de t he baseli ne c o variates; 
t he c o variates i ncl u de d i n t he statistical m o dels f or efficac y e n d p oi nts are selecte d t o be 
c o nsiste nt wit h a nal ysis m o dels i n ot her pre vi o usl y re p orte d P h ase 3 M S st u dies.   
All statistical tests will be 2-si de d wit h a n o vera ll t y pe I err or rate of 0. 0 5;  n o m ulti ple testi n g 
a dj ust me nt will be perf or me d i n t his st u d y. 
4. 7  
Pr ot oc ol De vi ati o ns 
Pr ot oc ol de viati o ns i de ntifie d d uri n g site m o n it ori n g will be ca pt ure d i n a pr ot oc ol de viati o n 
l o g a n d cate g orize d as maj or or mi n or de viati o ns.  T hese de viati o ns will be liste d.  
4. 8  
Alter n ati ve M ulti ple Scler osis Me dic ati o ns 
I n t his st u d y, alter nati ve M S me dicati o ns refers t o a list of me dicati o ns i ncl u di n g b ut n ot 
li mite d  t o  met h otre xate,  glati mer  acetate,  m yc o p he n ol oate  m ofetil,  azat hi o pri ne,  
nataliz u ma b,   ale mt uz u ma b,  terifl u n o mi de,  mit o xa ntr o ne,   fi n g oli m o d, di met h yl  f u marate,  
rit u xi ma b, ocreliz u ma b, la q ui ni m o d, a n d i nterfero n beta t hr o u g h o ut t his d oc u me nt.   Patie nts 
w h o ta ke alter nati ve M S me dicati o ns  d uri n g t he st u d y will be liste d.   
5  
  S T A TI S TI C A L A N A L Y S E S  
5. 1  
Pri m ar y A n al ysis 
Defi niti o n of rel a pses.  Rela pses are defi ne d as ne w or rec urre nt ne ur ol o gical s y m pt o ms n ot 
ass ociate d wit h fe ver or i nfecti o n, lasti n g at  least 2 4 h o urs, a n d acc o m pa nie d b y ne w o bjecti ve 
ne ur ol o gical  fi n di n gs  u p o n  e xa mi nati o n  b y  t h e  E xa mi ni n g  Ne ur ol o gist.  Pr ot oc ol- defi ne d  
rela pses u p t o t he e n d of treat me nt peri o d visit will be i ncl u de d i n t he pri mar y a nal yses.  Ne w 
or rec urre nt ne ur ol o gical s y m p t o ms t hat occ urre d less t ha n 3 0 da ys f oll o wi n g t he o nset of a 
pr ot oc ol- defi ne d rela pse will be c o nsi dere d part of t he sa me rela pse (i.e., rela pses wit h o nset 
da ys ≤2 9 da ys of o ne a n ot her, will be c o u nte d as 1 rela pse). 
Ce ns ori n g. If  a  s u bject  pre mat urel y  disc o nti n ues  t he  treat me nt  a n d  t he  s u bject  d oes  n ot  
e x perie nce a pr ot oc ol- defi ne d rela pse pri or t o disc o nti n uati o n, t he s u bject will be ce ns ore d o n 
t he last d osi n g date.    
A n al ysis met h o d.  T he n u m ber of rela pses per s u bject will be s u m marize d. T he pr o p orti o n of 
s u bjects  w h o  are  rela pse-free  at  6  m o nt hs  will  be  esti mate d  as  1  mi n us  t he  c u m ulati ve  


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pr o ba bilit y of rela pses fr o m t he Ka pla n- Meier  pr o d uct li mit met h o d. T he ti me t o rela pse is t he 
n u m ber of da ys fr o m t he first d osi n g date t o t he date of first rela pse, or e n d of treat me nt peri o d, 
w hic he ver  c o mes  first.  Ti me  t o  first  rela pse  will  be  s u m marize d  b y  1 0 t h,  2 5t h a n d  5 0 t h 
perce ntile.  
5. 2  
Sec o n d ar y A n al ysis 
D ue t o t he earl y ter mi nati o n of t he st u d y, t he pe r ma ne nt disc o nti n uati o n rate of dacliz u ma b is 
n ot a nal yze d.  
5. 2. 1  A n al ysis f or t he pr o p orti o n of s u bj ects e x perie nci n g rel a pse re q uiri n g 
h os pit aliz ati o n a n d/ or ster oi d tre at me nt at M o nt h 1 2 
Rela pses re q uiri n g h os pitalizati o n a n d/ or ster oi d treat me nt will be liste d b y s u bject wit h 
rela pse e val uati o n date a n d o nset date.  
5. 2. 2  A n al ysis f or A n n u ali ze d Rel a pse R ate ( A R R) 
A R R will be a nal yze d f or b ot h treat me nt peri o d a n d st u d y peri o d. Please see secti o n 4. 1 f or 
t heir defi niti o ns.  
T he n u m ber of rela pses o bser ve d d uri n g t he treat me nt peri o d ( or d uri n g t he st u d y peri o d) 
will be s u m marize d as a cate g orical varia ble ( n u m ber of rela pse bei n g 0, 1, 2, 3 a n d ≥4).   
T he u na dj uste d rela pse rate will be calc ulate d  as t he t otal n u m ber of rela pses o bser ve d 
di vi de d b y t he t otal n u m ber of da ys o n treat me nt ( or o n st u d y) m ulti plie d b y 3 6 5. 2 5.  
If t here is s ufficie nt data, t he a dj uste d mea n a n n ualize d rela pse rate a n d its 9 5 % c o nfi de nce 
i nter val ( CI) d uri n g t he treat me nt peri o d will be esti mate d b y a ne gati ve bi n o mial m o del; 
pr o per c o variates are a dj uste d i n  t he m o del.  T he l o garit h mic tra nsf or mati o n of t he n u m ber of 
da ys i n t he st u d y will be i ncl u de d i n t he m o del as t he “ offset” para meter. If t he data is u n der-
dis perse d or if t he ne gati ve bi n o mial re gressi o n m o del d oes n ot c o n ver ge, a P oiss o n m o del will 
be use d i nstea d of t he ne gati ve bi n o mial re gressi o n m o del.  Dis persi o n will be e val uate d fr o m 
t he Pears o n C hi- S q uare statistic. If t he rati o of t he  Pears o n C hi- S q uare statistic t o t he de grees 
of free d o m is < 1 t he n a P oiss o n re gressi o n m o del will be use d.  
5. 2. 3  A n al ysis f or M RI e n d p oi nts 
M RI is meas ure d fr o m all s u bject s i n t his st u d y.. Rec or ds u p t o 2 8 da ys after t he first d ose ca n 
be use d as baseli ne assess me nts. If t here are m u lti ple rec or ds, t he n t he o ne cl osest t o t he first 
d osi n g date will be selecte d; if tie d, t he n t he rec or d pri or t o t he first d ose will be defi ne d as 
baseli ne.     
At eac h visit w here M RI data is  a vaila ble, t he n u m ber of G d+ lesi o ns , t he n u m ber of T 1 
h y p oi nte nse lesi o ns, a n d t he n u m ber of ne w or ne wl y e nlar ge d T 2 h y peri nte nse lesi o ns, 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 ble s ( n u m ber of lesi o ns 
bei n g 0, 1, 2, 3 a n d ≥4).  


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5. 3  
E x pl or at or y A n al yses 
Beca use t he st u d y is n ot f ull y e nr olle d d ue t o  t he gl o bal wit h dra wal of dacliz u ma b, t he 
 
  
5. 3. 1  A n al ysis f or dis a bilit y pr o gressi o n 
D ue t o t he earl y ter mi nati o n of t his st u d y, 
 
 
 
 
 
  
 
; 
 
 
 
.  
5. 3. 2  A n al ysis f or e x pl or at or y bi o m ar kers 
 
 
 
 
 
 
  
5. 4  
S afet y A n al ysis  
Safet y a nal ysis will be perf or me d wi t h data fr o m t he e ntire st u d y peri o d.  
5. 4. 1  Cli nic al A d verse E ve nts 
Tre at me nt-e mer ge nt  a d verse e ve nt ( T E A E) is defi ne d as a n a d verse e ve nt ha vi n g o nset date 
o n or after t he first d osi n g date a n d pri or t o t he 1 8 0 da ys after t he last d osi n g date, or if it was 
prese nt pri or t o start of st u d y treat me nt a n d s u bs e q ue ntl y w orse ne d. If it ca n n ot be deter mi ne d 
w het her a n e ve nt is treat me nt e mer ge nt d ue t o a missi n g or partial date, t h e n t he e ve nt will be 
ta b ulate d as treat me nt e mer ge nt. A d verse e ve nts 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 ( Me d D RA).  O nl y treat me nt-e mer ge nt a d verse e ve nts ( T E A E) will 
be prese nte d i n t he s u m mar y ta bles.   
I n ge neral, A E ta bles i ncl u de t he f oll o wi n g ( b ut n ot li mite d t o): 


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 i nci de nce of treat me nt-e mer ge nt a d verse e ve nts will be s u m marize d o verall a n d b y 
se verit y ( mil d, m o derate a n d se vere);  
 T E A E’s will als o be prese nte d b y s yste m or ga n class ( S O C) a n d preferre d ter ms ( P T) 
a n d s orte d b y decreasi n g fre q ue nc y of P T w it hi n S O C, if t here is s ufficie nt data. If a 
patie nt e x perie nces a n e ve nt m ore t ha n o nce wit h var yi n g se verit y d uri n g t he st u d y, 
he/s he will be c o u nte d o nl y o nce wit h t he ma xi m u m se verit y wit hi n eac h S O C a n d P T; 
 t he i nci de nce of seri o us a d verse e ve nts ( S A E) will be s u m marize d b y s yste m or ga n 
class ( S O C) a n d preferre d ter ms ( P T) a n d s o rte d b y fre q ue nc y if t here is s ufficie nt 
data;  ot her wise  listi n gs  f or  i n di vi d ual  patie nts  w h o  e x perie nce d  S A Es  will  be  
ge nerate d; 
 a n y i nci de nce of a d verse e ve nts t hat lea d  t o t he d ose i nterr u pti o n, disc o nti n uati o n of 
st u d y dr u g or pre mat ure wit h dra wal fr o m t he st u d y will be prese nte d; a listi n g of t hese 
a d verse e ve nts ma y als o be prese nte d; 
 a n y deat hs t hat occ urre d d ur i n g t he st u d y will be liste d a n d rele va nt i nf or mati o n 
i ncl u di n g ti mi n g of t he deat h relati ve t o stu d y treat me nt, reas o n of deat h, c o nc o mita nt 
me dicati o ns, t he i n vesti gat or assess me nt of t he ca use of deat h will be pr o vi de d; 
 i nci de nces of a d verse e ve nts of s pecial i nterest ( A E SI) will als o be prese nte d, if t here 
is s ufficie nt data; ot her wise listi n gs of A E SI will be ge nerate d. T hese a d verse e ve nt of 
s pecial i nterest cate g ories are defi ne d mai nl y base d o n Sta n dar dize d Me d D R A Q ueries 
( S M Qs), S O C’s, a n d/ or P T’s. T he A Es of s pecial i nterest cate g ories ma y i ncl u de b ut 
are n ot li mite d t o t he f oll o wi n g:  
o  I nfecti o ns, i ncl u di n g seri o us i nfecti o ns a n d p ote ntial o p p ort u nistic i nfecti o ns 
o  C uta ne o us e ve nts, i ncl u di n g seri o us e ve nts 
o  He patic dis or ders 
o  Gastr oi ntesti nal e ve nts  
o  A ut oi m m u ne dis or ders 
o  I njecti o n site reacti o ns 
o  De pressi o n a n d s uici de i deati o n 
o  Mali g na ncies, p ote ntial a n d t h os e c o nfir me d u p o n me dical re vie w 
5. 4. 2  Cli nic al L a b or at or y D at a 
T he f oll o wi n g cli nical la b orat or y para me ters are assesse d i n t he pr ot oc ol: 
 He mat ol o g y ( C B C):  he m o gl o bi n, he mat ocrit, platelet c o u nt, re d bl o o d cell c o u nt, W B C 
c o u nt ( wit h differe ntial).  
 Bl o o d  c he mistr y:  s o di u m,  p otassi u m,  c h l ori de,  al kali ne  p h os p hatase,  lactate  
de h y dr o ge nase, ga m ma gl uta m yl tra n sferase, bl o o d urea nitr o gen, creati ni ne, bicar b o nate.  
 Li ver f u ncti o n tests: ser u m tra nsa mi nase s ( A L T a n d A S T), a n d bilir u bi n le vels.  


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He m at ol o g y. Cli nicall y si g nifica nt a b n or malities f or se lecte d he mat ol o g y para meters will be 
ta b ulate d a n d liste d; t he n u m ber a n d perce nt of s u bjects f or t hese a b n or malities will be 
pr o vi de d. T he criteria of t he p ote ntiall y si g nifica nt he mat ol o g y la b orat or y a b n or malities are 
pr o vi de d bel o w.  
T a ble 1 Criteria f or P ote ntiall y Cli nicall y Si g nifica nt He mat ol o g y A b n or malities  
Test 
Criteri a 
W hite bl o o d cell c o u nt ( 1 0 ^ 9 cells/ L)  
< 3. 0; > = 1 6. 0 
L y m p h oc ytes ( 1 0 ^ 9 cells/ L) 
< 0. 8; < 0. 5; > 1 2. 0 
Se g me nte d ne utr o p hils ( 1 0 ^ 9 cells/ L)  
< = 1. 0; < 1. 5; > = 1 2. 0 
Re d bl o o d cell c o u nt ( 1 0 ^ 1 2 cells/ L)  
< = 3. 3; > = 6. 8 
He m o gl o bi n ( g/ L) 
< = 1 0 0 
Platelets ( 1 0 ^ 9 cells/ L) 
< = 1 0 0; > = 6 0 0 
F urt her m ore, selecte d he mat ol o g y para meters will be liste d a n d fl a g ge d b y C T C A E gra de, 
usi n g t he f oll o wi n g  cate g orizati o n, if t here is s ufficie nt data.  
T a ble 2 Se verit y Gra des f or He mat ol o g y 
Test 
Gr a de 1  
Gr a de 2  
Gr a de 3  
Gr a de 4 
He m o gl o bi n ( g/ L) 
[ 1 0 0, L L N)  
[ 8 0, 1 0 0)  
[ 6 5, 8 0)  
< 6 5 
L y m p h oc ytes ( 1 0 ^ 9 cells/ L) 
[ 0. 8, L L N)  
[ 0. 5, 0. 8)  
[ 0. 2, 0. 5)  
< 0. 2 
Platelets ( 1 0 ^ 9 cells/ L) 
[ 7 5, L L N)  
[ 5 0, 7 5)  
[ 2 5, 5 0)  
< 2 5 
Se g me nte d ne utr o p hils ( 1 0 ^ 9 cells/ L)  
[ 1. 5, L L N)  
[ 1. 0, 1. 5)  
[ 0. 5, 1. 0)  
< 0. 5 
W hite bl o o d cell c o u nt ( 1 0 ^ 9 cells/ L)  
[ 3. 0, L L N)  
[ 2. 0, 3. 0)  
[ 1. 0, 2. 0)  
< 1. 0 
 
Li ver f u ncti o n tests ( L F T).  Listi n gs will be ge nerate d f or al kali ne p h os p hatase, A L T, A S T, 
G G T a n d t otal bilir u bi n f or eac h s u bjects b y visit, w here se verit y of a b n or mal val ues will be 
fla g ge d  base d  o n  t he  f oll o wi n g  ta ble.  A d ditio nall y,  t he  i nci de nce  of  A L T  a n d/ or  A S T  
ele vati o ns > = 3 X U L N b y c o nc urre ntl y ele vate d  t otal bilir u bi n will als o be s u m marize d.  
T a ble 3 Se verit y Gra des f or Li ver F u ncti o n Tests  
Test 
Gr a de 1  
Gr a de 2 
Gr a de 3 
Gr a de 4 
A L T 
( 1. 0, 3. 0)  
[ 3. 0, 5. 0]  
( 5. 0, 1 0. 0]  
( 1 0. 0, 2 0. 0]  
> 2 0. 0 
A S T 
( 1. 0, 3. 0)  
[ 3. 0, 5. 0]  
( 5. 0, 1 0. 0]  
( 1 0. 0, 2 0. 0]  
> 2 0. 0 
Al kali ne p h os p hatase  
( 1. 0, 2. 5] 
( 2. 5, 5. 0]  
( 5. 0, 2 0. 0]  
> 2 0. 0 
G G T 
( 1. 0, 2. 5]  
( 2. 5, 5.0]
 ( 5. 0,
 
2 0. 0]
 > 2 0. 0
 
T otal bilir u bi n 
( 1. 0, 1. 5]  
( 1. 5, 3. 0] 
( 3. 0, 1 0. 0] 
> 1 0. 0 
5. 4. 3  Vit al si g ns 
Vital si g n data will be liste d  f or eac h s u bject b y visit.