Clinical trial NCT01194570
Conditions: Multiple Sclerosis, Primary Progressive
Sponsor: Hoffmann-La Roche
Start date: 2011-03-02; Completion date: 2022-12-31
Enrollment: 735 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, parallel group, double-blind, placebo controlled study will evaluate the efficacy and safety of ocrelizumab in participants with primary progressive multiple sclerosis. Eligible participants will be randomized 2 : 1 to receive either ocrelizumab or placebo.

Detailed description:

Arms: arm 1: Participants with primary progressive multiple sclerosis (PPMS) received placebo matched to ocrelizumab at a schedule interval of 24 weeks up to at least 120 weeks. arm 2: Participants with PPMS received ocrelizumab as two IV infusions of 300 mg separated by 14 days at a scheduled interval of every 24 weeks up to at least 120 weeks.
Interventions: intervention 1: Ocrelizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Two IV infusions of 300 mg in each treatment cycle of double blind treatment period; two IV infusions of ocrelizumab 300 mg for Cycle 1 and single IV infusion of ocrelizumab 600 mg for subsequent cycles in OLE phase. intervention 2: Two IV infusions of placebo matched to ocrelizumab in each treatment cycle of double blind treatment period.

Protocol documents:
Prot_000.pdf: 
P R O T O C O L A M E N D M E N T A P P R O V A L
C O N FI D E N TI A L
T hi s cli ni c al st u d y i s b ei n g s p o n s or e d gl o b all y b y F. H off m a n n-L a R o c h e Lt d of B a s el, S wit z erl a n d. 
H o w e v er, it m a y b e i m pl e m e nt e d i n i n di vi d u al c o u ntri e s b y R o c h e' s l o c al a ffili at e s, i n cl u di n g 
G e n e nt e c h, I n c. i n t h e U nit e d St at e s.  T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt, e s p e ci all y a n y 
u n p u bli s h e d d at a, i s t h e pr o p ert y of F. H off m a n n -L a R o c h e Lt d ( or u n d er it s c o ntr ol) a n d ; t h er ef or e, i s 
pr o vi d e d t o y o u i n c o nfi d e n c e a s a n i n v e sti g at or, p ot e nti al i n v e sti g at or, or c o n s ult a nt, f or r e vi e w b y y o u, 
y o ur st aff, a n d a n a p pli c a bl e Et hi c s C o m mitt e e or I n stit uti o n al R e vi e w B o ar d.  It i s u n d er st o o d t h at t hi s 
i nf or m ati o n will n ot b e di s cl o s e d t o ot h er s wit h o ut writt e n a ut h ori z ati o n fr o m R o c h e e x c e pt t o t h e e xt e nt 
n e c e s s ar y t o o bt ai n i nf or m e d c o n s e nt fr o m p er s o n s t o w h o m t h e dr u g m a y  be a d mi ni st er e d.
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
Pr ot o c ol W A 2 5 0 4 6 K, V er si o n 1 1
P R O T O C O L
P R O T O C O L TI T L E: 
A P H A S E III, M U L TI C E N T E R , R AN D O MI Z E D, 
P A R A L L E L -G R O U P, D O U B L E -B LI N D E D, 
P L A C E B O -C O N T R O L L E D S T U D Y T O E V A L U A T E 
T H E E F FI C A C Y A N D S A F E T Y O F O C R E LI Z U M A B I N 
A D U L T S WI T H P RI M A R Y P R O G R E S SI V E M U L TI P L E 
S C L E R O SI S
P R O T O C O L N U M B E R:
W A 2 5 0 4 6
V E R SI O N N U M B E R: 
K
T E S T C O M P O U N D: 
O cr eli z u m a b ( R O 4 9 6 4 9 1 3)
S T U D Y P H A S E: 
P h a s e III
E U D R A C T N U M B E R: 
2 0 1 0 -0 2 0 3 3 8 -2 5
I N D N U M B E R: 
1 0 0, 5 9 3
N C T N U M B E R: 
N C T 0 1 1 9 4 5 7 0
M E DI C A L M O NI T O R:
, M. D.
S P O N S O R N A M E A N D 
L E G A L R E GI S T E R E D 
A D D R E S S:
F. H off m a n n -L a R o c h e, Lt d
Gr e n z a c h er str a s s e 1 2 4
4 0 7 0 B a s el, S wit z erl a n d
A P P R O V A L  D AT E: 
S e e el e ctr o ni c d at e st a m p b el o w.
 
A p pr o v er' s N a m e
Titl e
D at e a n d Ti m e ( U T C)
2 0- N o v- 2 0 2 1 0 1: 3 9: 3 1


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
P R O T O C O L HI S T O R Y
Pr ot o c ol
V er si o n
D at e Fi n al
K
S e e el e ctr o ni c d at e st a m p o n titl e p a g e .
J
1 3 J ul y 2 0 2 0
I
1 7 D e c e m b er 2 0 1 9
H
3 A u g u st 2 0 1 8
G
2 4 S e pt e m b er 2 0 1 7
F
2 3 M ar c h 2 0 1 6
E
6 F e br u ar y 2 0 1 5
D
1 5 J u n e 2 0 1 2
C
9 A pril 2 0 1 2
B
3 M ar c h 2 0 1 1
A
2 3 J u n e 2 0 1 0


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
P R O T O C O L A M E N D M E N T, V E R SI O N K
R A TI O N A L E
Pr ot o c ol W A 2 5 0 4 6 ( O R A T O RI O) h a s b e e n a m e n d e d t o i ntr o d u c e t h e o pti o n of a r oll o v er 
st u d y ( M N 4 3 9 6 4), i nt o w hi c h all o n g oi n g p arti ci p a nt s c a n e nr oll d uri n g t h e c o ur s e of 
2 0 2 2.  A s alr e a d y st at e d i n t h e c urr e nt pr ot o c ol, o cr eli z u m a b tr e at m e nt vi a t hi s st u d y i s 
d u e t o fi ni s h b y D e c e m b er 2 0 2 2.  T h e S p o n s or h a s n o w m a d e t h e d e ci si o n n ot t o e xt e n d 
t hi s st u d y f urt h er a n d; t h er ef or e, t hi s st u d y will e n d o n 3 1 D e c e m b er 2 0 2 2.  I n st e a d, t h e 
n e w r oll o v er e xt e n si o n st u d y ( M N 4 3 9 6 4) i s b ei n g s et u p t o e n s ur e t h at p arti ci p a nt s of 
St u d y W A 2 5 0 4 6 (t o g et h er wit h p arti ci p a nt s fr o m ot h er P ar e nt st u di e s) c a n c o nti n u e t h eir 
o cr eli z u m a b tr e at m e nt or s af et y f oll o w -u p a s a p pli c a bl e wit h o ut i nt err u pti o n a n d all o wi n g 
f or v al u a bl e l o n g-t er m d at a t o c o nti n u e t o b e c oll e ct e d.
I n a d diti o n, a r e d u cti o n i n t h e s af et y f oll o w-u p p eri o d a n d t h e i n c or p or ati o n of t h e ri s k 
a s s e s s m e nt of v a c ci n ati o n a g ai n st s e v er e a c ut e r e s pir at or y s y n dr o m e c or o n a vir u s 2 
( S A R S-C o V -2) f or t h e p arti ci p a nt p o p ul ati o n ar e i m pl e m e nt e d t hr o u g h t hi s a m e n d m e nt.  
Pl e a s e s e e b el o w f or a s u m m ar y of t h e s u b st a nti v e c h a n g e s t o t h e pr ot o c ol, al o n g wit h a 
r ati o n al e f or e a c h c h a n g e:
 
T o i ntr o d u c e t h e o pti o n f or all o n g oi n g p arti ci p a nt s of St u d y W A 2 5 0 4 6 t o e nr oll i nt o 
a n e w o p e n -l a b el e xt e n si o n st u d y ( M N 4 3 9 6 4) pri or t o or f oll o wi n g t h e cl o s ur e of 
St u d y W A 2 5 0 4 6
 
T o cl arif y t h at p arti ci p a nt s w h o di s c o nti n u e tr e at m e nt e arl y f or a n y r e a s o n a n d t h at
p arti ci p a nt s w h o c o m pl et e t h e st u d y tr e at m e nt p eri o d will b e f oll o w e d u p f or a u p t o
4 8 w e e k s aft er t h e l a st i nf u si o n of o cr eli z u m a b.  T h e r e q uir e m e nt f or c o nti n u e d 
B c ell m o nit ori n g f or p arti ci p a nt s w h o s e B c ell s ar e n ot r e pl et e d (i. e., r et ur n e d t o 
b a s eli n e l e v el s or t h e l o w er li mit of n or m al, w hi c h e v er i s l o w er) at t h e e n d of t h e 
s af et y f oll o w -u p p eri o d h a s b e e n r e m o v e d b e c a u s e n o i n cr e a s e d s af et y ri s k w a s 
i d e ntifi e d i n t h e o cr eli z u m a b cli ni c al d e v el o p m e nt pr o gr a m f oll o wi n g c e s s ati o n of 
tr e at m e nt.
 
T o cl arif y t h at aft er e nt eri n g s af et y f oll o w -u p a n d u p o n tr e at m e nt i niti ati o n wit h 
a n ot h er di s e a s e -m o dif yi n g t h er a p y ( D M T), p arti ci p a nt s will b e di s c o nti n u e d fr o m t h e 
s af et y f oll o w -u p a n d fr o m t h e st u d y.  T h e r ati o n al e f or t hi s c h a n g e i s t h at, gi v e n t h e 
l o w n u m b er s of p arti ci p a nt s i n t h e cli ni c al d e v el o p m e nt pr o gr a m w h o h a v e s wit c h e d 
t o alt er n ati v e D M T s, a n d d at a c o n si sti n g of s e v er al diff er e nt D M T s wit h v ari o u s 
tr e at m e nt d ur ati o n s, t h e S p o n s or c o n si d ers t h at s u c h d at a w o ul d n ot all o w f or a n y 
m e a ni n gf ul i nt er pr et ati o n a n d it i s u nli k el y t h at pr ol o n g e d d at a c oll e cti o n w o ul d 
f a cilit at e t hi s.  P arti ci p a nt s w h o s wit c h t o c o m m er ci al o cr eli z u m a b ( O C R E V U S )
af t er e nt eri n g s af et y f oll o w-u p, will al s o b e di s c o nti n u e d fr o m s af et y f oll o w -u p a n d 
t h e st u d y.
 
T o i n c or p or at e t h e ri s k a s s e s s m e nt f or c o n c o mit a nt u s e of S A R S -C o V -2 v a c ci n e s:  
S e cti o n 2. 2 h a s b e e n u p d at e d t o i n cl u d e t h e b e n efit ri s k a s s e s s m e nt of t h e 
c o n c o mit a nt u s e of S A R S -C o V -2 v a c ci n e s o n t h e c o n d u ct of t h i s st u d y.  B a s e d o n 
t h at a s s e s s m e nt, n o i m p a ct i s a nti ci p at e d o n t h e effi c a c y a n d s af et y i n p arti ci p a nt s 
e nr oll e d i n o cr eli z u m a b cli ni c al tri al s.  T h e e xi sti n g i nf or m ati o n o n i d e ntifi e d ri s k s, 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
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s af et y m o nit ori n g, a n d ri s k miti g ati o n m e a s ur e s r el at e d t o a d mi ni str ati o n of v a c ci n e s 
(i n cl u di n g t h o s e f or S A R S-C o V -2) pr o vi d e d i n t h e st u d y pr ot o c ol ar e c o n si d er e d 
a d e q u at e.
A d diti o n al mi n or c h a n g e s h a v e b e e n m a d e t o i m pr o v e cl arit y a n d c o n si st e n c y. 
S u b st a nti v e n e w i nf or m ati o n a p p e ar s i n it ali c s.  T hi s a m e n d m e nt r e p r e s e nt s c u m ul ati v e 
c h a n g e s t o t h e ori gi n al pr ot o c ol.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
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T A B L E O F C O N T E N T S
1. 
P R O T O C O L S U M M A R Y ............................................................................. 1 6
1. 1 
S y n o p si s ................................................................................ 1 6
1. 2 
S c h e d ul e of A cti viti e s ............................................................ 1 9
2. 
B A C K G R O U N D A N D R A TI O N A L E ............................................................ 3 6
2. 1 
B a c k gr o u n d ........................................................................... 3 6
2. 1. 1 
M ulti pl e S cl er o si s ................................................................... 3 6
2. 1. 2 
O c r eli z u m a b .......................................................................... 3 7
2. 1. 2. 1 
Hi st or y of O cr eli z u m a b .......................................................... 3 7
2. 1. 3 
R a tio n al e f o r T a rg e tin g B C ell s i n M ulti pl e 
S cl er o si s ................................................................................ 3 8
2. 1. 4 
S p o n s or E x p eri e n c e wit h A n ti-C D 2 0  Co m p o u n d s 
i n M ulti pl e S cl er o si s............................................................... 3 9
2. 1. 4. 1 
O cr eli z u m a b i n R R M S ........................................................... 3 9
2. 1. 4. 2 
Rit u xi m a b i n R R M S ............................................................... 4 1
2. 1. 4. 3 
Rit u xi m a b i n P P M S ................................................................ 4 2
2. 2 
R ati o n al e f or t h e St u d y a n d Be nefit Ris k 
Assess me nt ............................................................................ 4 3
2. 2. 1 
St at e m e nt of T h er a p e uti c E q ui p oi s e ...................................... 4 4
2. 2. 2 
S tat e m e n t o n  th e U s e of Pl a c e b o  C o m p ar at or ...................... 4 5
3. 
O B J E C T I V E S.............................................................................................. 4 6
3. 1 
Pri m ar y O bj e cti v e .................................................................. 4 6
3. 2 
S e c o n d ar y O bj e cti v e s ............................................................ 4 6
3. 3 
E x pl or at or y O b j ect i v e s........................................................... 4 7
3. 4 
R e s e ar c h  B io s a m pl e R e p o sit or y O bj e cti v e s .......................... 4 8
3. 5 
O pti o n al E x pl or at or y S u b st u di e s ........................................... 4 8
3. 5. 1 
O p tic al C o h er e n c e  T o m o gr a p h y E x pl or at or y 
S u b st u d y ................................................................................ 4 8
4. 
S T U D Y D E SI G N ......................................................................................... 4 9
4. 1 
O v e rv ie w  of St u d y D e si g n a n d D o si n g R e gi m e n ................... 4 9
4. 1. 1 
S cr e e ni n g P eri o d ................................................................... 4 9
4. 1. 2 
Bli n d e d Tr e at m e nt P eri o d ...................................................... 4 9
4. 1. 3 
O p e n -L a b el E xt e n si o n P h a s e ................................................ 5 0


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4. 1. 4 
S af et y F oll o w -U p P eri o d ........................................................ 5 1
4. 1. 5 
R at io n a le  f or St u d y D e si g n.................................................... 5 4
4. 1. 5. 1 
R a ti o n al e f or Bli n de d  S tu d y ................................................... 5 4
4. 1. 5. 2 
R a ti o n al e f or Pl a ce b o  C o m p ar at or ........................................ 5 5
4. 1. 5. 3 
R a ti o n al e f or St u d y P o p ul ati o n .............................................. 5 5
4. 1. 5. 4 
R ati o n al e f or St u d y E n d p oi nt s ............................................... 5 6
4. 1. 5. 5 
R ati o n al e f or t h e Tr e at m e nt D ur ati o n .................................... 5 6
4. 1. 5. 6 
R ati o n al e f or t h e S af et y F oll o w -U p P eri o d ............................. 5 6
4. 1. 5. 7 
R ati o n al e f or O p e n -L a b el E xt e n si o n P h a s e ........................... 5 6
4. 1. 5. 8 
R ati o n al e f or t h e U s e of M et h yl pr e d ni s ol o n e a n d 
A nti hi st a mi n e s ....................................................................... 5 7
4 . 1. 6 
R a ti o n al e f or D o s e S el e cti o n a n d D o si n g 
I nt er v al s................................................................................. 5 7
4. 1. 7 
R ati o n al e f or S wit c hi n g t o Si n gl e I nf u si o n s ............................ 5 8
4. 1 . 8 
E n d of Bli n d e d Tr e at m e nt P eri o d of t h e St u d y ....................... 5 9
4. 1. 9 
E n d of St u d y .......................................................................... 5 9
4. 2 
N u m b er of P arti ci p a nt s/ A s si g n m e nt t o Tr e at m e nt 
Gr o u p s f or t h e Bli n d e d Tr e at m e nt P eri o d .............................. 5 9
4. 2. 1 
P arti ci p a nt R a n d o mi z ati o n a n d E nr oll m e nt ............................ 5 9
4. 3 
C e nt er s .................................................................................. 6 0
5. 
S T U D Y P O P U L A TI O N ................................................................................ 6 0
5. 1 
O v er vi e w ................................................................................ 6 0
5. 2 
I n cl u si o n Crit eri a f or Bli n d e d Tr e at m e nt P eri o d..................... 6 0
5. 3 
E x c lu s io n Crit eri a f o r B lin d e d  T re at m e nt P eri o d .................... 6 2
5. 3. 1 
E x cl u si o n s R el at e d t o G e n er al H e alt h ................................... 6 3
5. 3. 2 
E x cl u si o n s R el at e d t o M e di c ati o n s ........................................ 6 4
5. 3. 3 
E x c lu s io n s R el at e d  to  M e di c ati o n s P ot e n tia lly  
U s e d f or t h e Tr e at m e nt of M ulti pl e S cl er o si s ......................... 6 4
5. 3. 4 
E x cl u si o n s R el at e d t o L a b or at or y Fi n di n g s ............................ 6 4
5. 4 
E ligi bilit y Crit eri a f or O p e n -L a b el E xt e n si o n 
P h a s e .................................................................................... 6 5
5. 5 
C o n c o m ita nt M e d i cat i o n a n d Tr e at m e nt................................ 6 6
5. 5. 1 
D efi niti o n s .............................................................................. 6 6


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5. 5. 2 
Tr e at m e nt of M ulti pl e S cl er o si s a n d It s 
S y m pt o m s .............................................................................. 6 6
5. 5. 3 
I m m u ni z ati o n ......................................................................... 6 7
5. 6 
Crit eri a f or Pr e m at ur e W it h dr a w al ......................................... 6 8
5. 6. 1 
Wi th d ra w a l of  Su bj e ct s f r om t he R o c h e Cl i ni c al 
R e p o sit or y ............................................................................. 6 9
5. 6. 2 
Wi t h dr a w al fr o m t h e R e s e ar c h Bi o s a m pl e 
R e p o sit or y ............................................................................. 7 0
5. 6. 3 
R e -C o n s e nt R ul e (I n C a s e of C o nfir m e d 
Di s a bilit y Pr o gr e s si o n) ........................................................... 7 0
5. 7 
R e p la c e m e nt P oli c y ( E n s uri n g A d e q u at e 
N u m b er s of E v al u a bl e P arti ci p a nt s) ...................................... 7 0
5. 7. 1 
F or P arti ci p a nt s ..................................................................... 7 0
5. 7. 2 
F or C e nt er s ............................................................................ 7 0
5. 8 
S cr e e ni n g E x a mi n ati o n a n d Eli gi bilit y S cr e e ni n g 
F or m ...................................................................................... 7 1
5. 9 
Pr o c e d ur e s f or E nr oll m e nt of Eli gi bl e P arti ci p a nt s ................. 7 1
5. 1 0 
Cli ni c al A s s e s s m e nt s a n d Pr o c e d ur e s .................................. 7 2
5. 1 0. 1 
O v er vi e w o f S tu d y  V is its ........................................................ 7 2
5. 1 0. 1. 1 
B a s eli n e Vi sit ( Vi sit 2) f or t h e Bli n d e d Tr e at m e nt 
P eri o d .................................................................................... 7 2
5. 1 0. 1. 2 
S u b s e q u e nt Vi sit s D uri n g t h e Bli n d e d Tr e at m e nt 
P eri o d .............................................................................................7 2
5 . 1 0. 1. 3 
Vi sit s D uri n g t h e O p e n -L a b el E xt e n si o n P h a s e ..................... 7 3
5. 1 0. 1. 4 
Vi sit s D uri n g t h e S af et y F oll o w -U p P eri o d ......................................7 3
5 . 1 0. 1. 5 
D el a y e d D o si n g Vi sit s a n d U n s c h e d ul e d N o n -
D o si n g Vi sit s D uri n g t h e Bli n d e d Tr e at m e nt 
P eri o d .................................................................................... 7 4
5 . 1 0. 1. 6 
Wi t h dr a w al Vi sit s D uri n g t h e Bli n d e d Tr e at m e nt 
P eri o d .................................................................................... 7 4
5. 1 1 
C lini c al A s s e s s m e nt s of Effi c a c y ........................................... 7 5
5. 1 1. 1 
Cl in i c al A s s e s s m e nt s Du rin g  th e Bli n d e d 
Tr e at m e nt P eri o d ................................................................... 7 5
5. 1 1. 1. 1 
A s s e s s m e nt of Di s a bilit y ........................................................ 7 6
5. 1 1. 2 
Br ai n M RI I m a gi n g ................................................................. 7 7
5. 1 2 
S a fe ty  A s s e s s m e nt s .............................................................. 7 8


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5. 1 2. 1 
Vit al Si g n s .............................................................................. 7 8
5. 1 2. 2 
El e ctr o c ar di o gr a m s ................................................................ 7 8
5. 1 2. 3 
P h y si c al E x a mi n ati o n ............................................................ 7 9
5. 1 2. 4 
N e ur ol o gi c al E x a mi n ati o n ...................................................... 7 9
5. 1 2. 4. 1 
T el e p h o n e I nt er vi e w f or N e w/ W o rs e ni n g 
N e ur ol o gi c al S y m pt o m s ......................................................... 8 0
5. 1 2. 4. 2 
A s s e s s m e nt of R el a p s e ......................................................... 8 0
5. 1 3 
L a b or at or y  A s s e s s m e nt s ....................................................... 8 1
5. 1 3. 1 
S p e cifi c S cr e e ni n g L a b or at or y T e st s f or 
I n cl u si o n/ E x cl u si o n................................................................ 8 1
5. 1 3. 1. 1 
H e p atiti s S cr e e ni n g a n d Li v er F u n cti o n 
M o nit ori n g .............................................................................. 8 1
5. 1 3. 1. 2 
Ot h er S p e cifi c S cr e e ni n g T e st s ............................................. 8 1
5. 1 3. 2 
St a n d ar d L a b or at or y A s s e s s m e nt s ........................................ 8 2
5. 1 4 
P h ar m a c o ki n eti c A s s e s s m e nt s .............................................. 8 4
5. 1 4. 1 
Bli n d e d Tr e at m e nt P eri o d ...................................................... 8 4
5. 1 4. 2 
O p e n -L a b el  Ext e n si o n P h a s e ................................................ 8 4
5. 1 5 
R o c h e Cli ni c al R e p o s ito ry ...................................................... 8 4
5. 1 5. 1 
S p e ci m e n T y p e s .................................................................... 8 5
5. 1 5. 1. 1 
Bl o o d f or R N A E x pr e s si o n Pr ofili n g ....................................... 8 5
5. 1 5. 1. 2 
Bl o o d S a m pl e f or G e n eti c A n al y si s ....................................... 8 6
5. 1 5. 1. 3 
Bl o o d f or Pl a s m a A s s a y s ....................................................... 8 6
5. 1 6 
O pti o n al S a m pl e s f or R e s e ar c h Bi o s a m pl e 
R e p o sit or y ............................................................................. 8 6
5. 1 6. 1 
O v e rv ie w  of t h e R o c h e R e s e ar c h Bi o s a m pl e 
R e p o s it ory ............................................................................. 8 6
5. 1 6. 2 
A p pr o v al b y t h e I n stit uti o n al R e vi e w B o ar d or 
Et hi c s C o m mitt e e .................................................................. 8 7
5. 1 6. 3 
S a m pl e C oll e cti o n .................................................................. 8 7
5. 1 6. 4 
C o nfi d e nti alit y ........................................................................ 8 7
5. 1 6. 5 
C o n s e n t t o P arti ci p at e i n t h e R e s e ar c h 
Bi o s a m pl e R e p o sit or y ............................................................ 8 8
5. 1 6. 6 
W it h dr a w al fr o m t h e R e s e ar c h Bi o s a m pl e 
R e p o s it ory ............................................................................. 8 8
5. 1 6. 7 
M o nit ori n g a n d O v er si g ht ....................................................... 8 9


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
9 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
5. 1 7 
Pr ot ei n Bi o m ar k er S a m pl e ..................................................... 8 9
5. 1 8 
Cli ni c al G e n ot y pi n g ................................................................ 8 9
5. 1 9 
Pl a s m a a n d Uri n e B a n ki n g f or J o h n C u n ni n g h a m 
Vir u s ...................................................................................... 9 0
5. 2 0 
P arti ci p a nt -R e p ort e d O ut c o m e s ............................................ 9 0
5. 2 1 
P h ar m a c o e c o n o mi c A s s e s s m e nt s ......................................... 9 1
5. 2 2 
O p ti o n al E x pl or at or y Su b s tu di e s ........................................... 9 1
5. 2 2. 1 
O pt i c al C o h e re n c e  T o m o gr a p h y E x pl or at or y 
S u b st u d y ................................................................................ 9 2
5. 2 3   
O p e n -L a b el  Ext e n si o n P h a s e ................................................ 9 2
5. 2 3. 1 
O v er vi e w of S c h e d ul e of A cti viti e s i n t h e O p e n -
L a b el E xt e n si o n P h a s e .......................................................... 9 3
5. 2 3. 2 
D el a y e d D o si n g Vi sit i n t h e O p e n -L a b el 
E xt e n si o n P h a s e .................................................................... 9 4
5. 2 3. 3 
U n s c h e d ul e d Vi sit s i n t h e O p e n -L a b el E xt e n si o n  
P h a s e .................................................................................... 9 4
5. 2 3. 4 
W ith d ra w al Vi sit s i n t h e O p e n -L a b el E xt e n si o n 
P h a s e .................................................................................... 9 4
5. 2 3. 5 
C o nti n u e d A c c e s s t o St u d y Tr e at m e nt A fte r th e  
E n d of t h e St u d y .................................................................... 9 5
6. 
I N VE S T IG A TI O N A L M E DI CI N A L P R O D U C T ............................................. 9 6
6. 1 
D o s e a n d S c h e d ul e of O cr eli z u m a b ...................................... 9 6
6. 2 
Pr e p ar ati o n a n d A d mi ni str ati o n of O cr eli z u m a b 
I nf u si o n s ................................................................................ 9 6
6. 2. 1 
A d mi ni str ati o n of t h e I V I nf u si o n s .......................................... 9 6
6. 2. 1. 1 
Pr e p ar ati o n of I nf u si o n ........................................................... 9 7
6. 2. 1. 2 
In fu s io n  Pr o c e d ur e s ............................................................... 9 7
6. 2. 1. 3 
D u al I nf u si o n C y cl e ( Bli n d e d Tr e at m e nt P eri o d 
a n d Fir st C y cl e of O p e n L a b el E xt e n s io n  P h a s e) ................. 9 7
6. 2. 1. 4 
S i n gl e I nf u si o n C y cl e ( O p e n-L a b el E xt e n si o n  
C y cl e 2 O n w ar d s) .................................................................. 9 7
6. 2. 1. 5 
Al ter n ati v e S h o rte r In f u si o n of S u b s eq u e nt 6 0 0 
m g O cr eli z u m a b D o s e s ......................................................... 9 8
6. 2. 2 
O cr eli z u m a b D o s e M o difi c ati o n s, I nt err u pti o n s, 
a n d D el a y s ............................................................................. 9 9
6. 2. 2. 1 
H a n dli n g I nf u si o n -R e l at e d R e a cti o n s .................................... 9 9


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 0 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
6. 2. 3 
Crit eri a f or R e -tr e at m e nt wit h O cr eli z u m a b.......................... 1 0 0
6. 3 
F o rm ul ati o n,  P a c k a gi n g, a n d L a b eli n g ................................ 1 0 1
6. 3. 1 
S tor a g e o f O c re liz u m a b  a n d Pl a c e b o V ia ls  for  
I nf u si o n................................................................................ 1 0 2
6. 4 
Pr e v e n tio n  a n d  T re at m e nt of I nf u s io n- R e l at e d 
R e a cti o n s ............................................................................. 1 0 2
6. 5 
Bli n di n g a n d U n bli n di n g (f or t h e Bli n d e d 
Tr e at m e nt P eri o d) ................................................................ 1 0 3
6. 6 
A s s e s s m e nt of C o m p lia n c e ................................................. 1 0 4
6. 7 
D e str u cti o n of t h e I n v e sti g ati o n al M e di ci n al 
Pr o d u ct ................................................................................ 1 0 4
7. 
S A F E T Y I N S T R U C TI O N S A N D G UI D A N C E ............................................ 1 0 5
7. 1 
A d v er s e E v e nt s a n d L a b or at or y A b n or m aliti e s .................... 1 0 5
7. 1. 1 
Cli ni c al A d v er s e E v e nt s ....................................................... 1 0 5
7. 1. 1. 1 
I nt e n sit y ............................................................................... 1 0 6
7. 1. 1. 2 
D r u gA d v e r s e E v e nt R el ati o n s hi p ....................................... 1 0 6
7. 1. 1. 3 
S eri o u s A d v er s e E v e nt s (I m m e di at el y R e p ort a bl e 
t o S p o n s or).......................................................................... 1 0 6
7. 1. 1. 4 
A d v er s e E v e nt s of S p e ci al I nt er e st (I m m e di at el y 
R e p ort a bl e t o S p o n s or) ........................................................ 1 0 7
7. 1. 2 
Tr e at m e nt a n d F oll o w -U p of A d v er s e E v e nt s ...................... 1 0 7
7. 1. 3 
L a b or at or y T e st A b n or m aliti e s ............................................. 1 0 7
7. 1. 3. 1 
A b n or m al Li v er F u n cti o n T e st s ............................................ 1 0 8
7. 1. 3. 2 
F o ll o w-U p of A b n or m al L a b or at or y T e st V al u e s .................. 1 0 8
7. 2 
H a n dli n g of S af et y P ar a m et er s ............................................ 1 0 9
7. 2. 1 
R e p orti n g o f A d v e rs e  E v e nt s............................................... 1 0 9
7. 2. 2 
R e p orti n g o f S e rio u s  A d v er s e E v e nt s .................................. 1 0 9
7. 2. 2. 1 
Im m e di at e R e p orti n g R e q uir e m e nt s t o t h e 
S p o n s or ............................................................................... 1 0 9
7. 2. 2. 2 
M e di c al M o nit or s a n d E m er g e n c y M e di c al 
C o nt a ct s .............................................................................. 1 1 0
7. 2. 2. 3 
E x p e dit e d R e p orti n g t o H e alt h A ut h oriti e s, 
I n v e sti g at or s, I n stit uti o n al R e vi e w B o ar d s, a n d 
Et hi c s C o m mitt e e s ............................................................... 1 1 1
7. 2. 3 
Pr e g n a n c y a n d L a ct ati o n ..................................................... 1 1 1
7. 3 
W a r ni n g s a n d Pr e c a uti o n s................................................... 1 1 3


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
7. 3. 1 
O cr eli z u m a b ........................................................................ 1 1 3
7. 3 .1 .1 
I d e ntifi e d Ri s k s a n d A d v er s e Dr u g R e a cti o n s 
A s s o ci at e d wit h O cr eli z u m a b U s e ....................................... 1 1 3
7. 3. 1. 2 
P ot e nti al Ri s k s A s s o ci at e d wit h O cr eli z u m a b U s e ............... 1 1 6
7. 3. 2 
C orti c o st er oi d s ..................................................................... 1 1 7
7. 3. 3 
A nti hi st a mi n e s ..................................................................... 1 1 7
7. 3 . 4 
P ro gr e s si v e M ultif o c al L e u k o e n c e p h al o p at h y ...................... 1 1 7
7. 3. 4. 1 
G ui d a n c e f or Di a g n o si s of  PM L ........................................... 1 1 8
8. 
S T A TI S T IC A L  C O N S ID E R A TI O N S A N D A N A L Y TI C A L P L A N ................ 1 2 2
8. 1 
St u d y E n d p oi nt s .................................................................. 1 2 3
8. 1. 1 
Pri m ar y Effi c a c y E n d p oi nt .................................................... 1 2 3
8. 1 . 2 
S e c o n d ar y Effi c a c y E n d p oi nt s ............................................. 1 2 3
8. 1. 3 
E x pl or at or y Effi c a c y E n d p oi nt s ............................................ 1 2 3
8. 1. 4 
S a fe ty .................................................................................. 1 2 4
8. 2 
St ati sti c al a n d A n al yti c al M et h o d s ....................................... 1 2 5
8. 2 . 1 
P rim a ry  E ffi ca c y A n al y si s .................................................... 1 2 5
8. 2. 2 
S e c o n d ar y Ef fic a c y  An al y s e s .............................................. 1 2 6
8. 2. 2. 1 
Ti m e t o O n s et of C o nfir m e d Di s a bilit y 
Pr o gr e s si o n C o nfir m e d f or 2 4 W e e k s ............................... 1 2 6
8. 2. 2. 2 
C h a n g e i n Ti m e d 2 5 -F o ot W a l k T e st fr o m 
B a s eli n e t o W e e k 1 2 0 .......................................................... 1 2 7
8. 2. 2. 3 
C h a n g e i n  T o ta l V ol u m e of T 2 L e si o n s  o n M R I 
S c a n s of t h e Br ai n fr o m B a s eli n e t o W e e k  12 0 ................... 1 2 7
8. 2. 2. 4 
P er c e nt C h a n g e o n M RI fr o m W e e k 2 4  to W e e k  
1 2 0 i n T ot al Br ai n V ol u m e ................................................... 1 2 7
8. 2. 2. 5 
C h a n g e fr o m B a s eli n e i n Q u alit y of Lif e a s 
M e a s ur e d b y t h e S F -3 6 ( Ph y si c a l C o m p o n e nt 
S u m m ar y) ............................................................................ 1 2 7
8. 2. 3 
E x p lo ra to r y An al y s e s ........................................................... 1 2 7
8. 2. 4 
S a m pl e Si z e ........................................................................ 1 2 7
8. 2. 5 
H y p o th e s i s T e sti n g.............................................................. 1 2 7
8. 2. 6 
A n al y si s P o p ul ati o n s ........................................................... 1 2 8
8. 2. 6. 1 
S a fe t y P o p ul ati o n ................................................................ 1 2 8
8. 2. 6. 2 
I nt e nt-t o-Tr e at P o p ul ati o n .................................................... 1 2 8
8. 2. 6. 3 
P er Pr ot o c ol P o p ul ati o n ....................................................... 1 2 8


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
8. 2. 7 
I nt eri m A n al y si s ................................................................... 1 2 9
8. 2. 8 
S a fe ty  D at a A n al y si s ........................................................... 1 2 9
8. 2. 9 
S a fe ty  F oll o w -U p P e rio d ...................................................... 1 3 0
8. 2. 1 0 
O p e n -L a b el  Ext e n si o n P h a s e .............................................. 1 3 0
8. 2. 1 1 
Ot h er A n al y s e s .................................................................... 1 3 0
8. 2. 1 1. 1 
P h ar m a c o ki n eti c A n al y si s .................................................... 1 3 0
8. 2. 1 1. 2 
P h a rm a c o d y n a mi c A n al y si s ................................................. 1 3 0
8. 2. 1 1. 3 
Bi o m ar k er S a m pl e R e p o sit or y/ Bi o m ar k er 
R e s e ar c h S a m pl e s .............................................................. 1 3 1
8. 2. 1 1. 4 
Cli ni c al G e n ot y pi n g .............................................................. 1 3 1
9. 
D A T A C O L L E C TI O N, M A N A G E M E N T, A N D Q U A LI T Y 
A S S U R A N C E ............................................................................................ 1 3 1
9. 1 
A s si g n m e nt of Pr ef err e d T er m s a n d Ori gi n al 
T er mi n ol o g y ......................................................................... 1 3 2
1 0.
S T U D Y C O M MI T T E E S ............................................................................. 1 3 2
1 0. 1 
St e eri n g C o m mitt e e ............................................................. 1 3 2
1 0. 2 
D a t a M o nit ori n g C o m mitt e e................................................. 1 3 2
1 1.
R E F E R E N C E S ......................................................................................... 1 3 4
1 2.
E T HI C A L A S P E C T S ................................................................................. 1 3 8
1 2. 1 
L o c al R e g ul ati o n s/ D e cl ar ati o n of H el si n ki ............................ 1 3 8
1 2. 2 
In fo r m e d C o n s e nt ................................................................ 1 3 8
1 2. 3 
I n stit uti o n al R e vi e w B o ar d/ Et hi c s C o m mitt e e ...................... 1 3 9
1 3.
C O N D IT I O N S F O R M O DI F YI N G T H E P R O T O C O L................................ . 1 3 9
1 4.
C O N DI TI O N S F O R T E R MI N A TI N G T H E S T U D Y .................................... 1 4 0
1 5.
S T U D Y D O C U M E N T A TI O N, E L E C T R O NI C C R F S, A N D 
R E C O R D K E E PI N G .................................................................................. 1 4 0
1 5. 1 
I n v e sti g at or' s Fil e s/ R et e nti o n of D o c u m e nt s........................ 1 4 0
1 5. 2 
S o ur c e D o c u m e n ts  a n d B a c k gr o u n d D at a ........................... 1 4 1
1 5. 3 
A u dit s a n d I n s p e cti o n s ......................................................... 1 4 1
1 5. 4 
E le ctr o ni c  C a s e R e p ort F or m s ............................................. 1 4 1
1 6.
M O NI T O RI N G T H E S T U D Y
..................................................................... 1 4 1


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
1 7.
C O N FI D E N TI A LI T Y O F T RI A L D O C U M E N T S A N D 
P A R TI CI P A N T R E C O R D S ....................................................................... 1 4 2
1 8.
P U B LI C A TI O N O F D A T A A N D P R O T E C TI O N O F T R A D E 
S E C R E T S ................................................................................................. 1 4 3
LI S T O F T A B L E S
T a bl e 1 
S c h e d ul e of A cti viti e s:  S cr e e ni n g t hr o u g h t h e E n d of 
Tr e at m e nt P eri o d ........................................................................ 1 9
T a bl e 2 
S c h e d ul e of A cti viti e s:  A d diti o n al Tr e at m e nt C y cl e s, 
D el a y e d D o si n g, U n s c h e d ul e d Vi sit s, a n d Wi t h dr a w al fr o m 
Tr e at m e nt .................................................................................... 2 5
T a bl e 3 
S c h e d ul e of A c ti viti e s:  S af et y F oll o w-U p .................................... 2 9
T a bl e 4  
S c h e d ul e of A cti viti e s:  O p e n- L a b el E xt e n si o n P h a s e ................ 3 2
T a bl e 5 
O v er vi e w of t h e St u d y D e si g n a n d D o si n g R e gi m e n .................. 5 2
T a bl e 6  
Tr e at m e nt Gr o u p s a n d S c h e d ul e of St u d y M e di c ati o n d uri n g 
t h e Bli n d e d Tr e at m e nt P eri o d ..................................................... 9 6
T a bl e 7  
I nf u si o n s of O cr eli z u m a b/ Pl a c e b o 3 0 0 m g .................................. 9 7
T a bl e 8 
I nf u si o n R at e s f or Si n gl e I nf u si o n of O cr eli z u m a b 6 0 0 m g ......... 9 8
T a bl e 9 
Alt er n ati v e S h ort er I nf u si o n s of O cr eli z u m a b 6 0 0 m g ................. 9 8
T a bl e 1 0 
Cli ni c al Si g n s a n d S y m pt o m s T y pi c al of M S a n d P M L .............. 1 2 1
T a bl e 1 1 
M RI L e si o n C h ar a ct eri sti c s T y pi c al of M S a n d P M L ................. 1 2 1
LI S T O F FI G U R E S
Fi g ur e 1 
Di a g n o sti c Al g orit h m Fr a m e w or k f or P M L ................................. 1 2 0
LI S T O F A P P E N DI C E S
A p p e n di x 1 
R e vi s e d M c D o n al d Crit eri a 2 0 0 5 .............................................. 1 4 5
A p p e n di x 2 
A d v er s e E v e nt C at e g ori e s f or D et er mi ni n g R el ati o n s hi p t o 
T e st Dr u g .................................................................................. 1 4 6
A p p e n di x 3 
I C H G ui d eli n e s f or Cli ni c al S af et y D at a M a n a g e m e nt, 
D efi niti o n s a n d St a n d ar d s f or E x p e dit e d R e p orti n g, T o pi c E 2 .. 1 4 7
A p p e n di x 4 
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s ................... 1 4 9
A p p e n di x 5 
T el e p h o n e I nt er vi e w .................................................................. 1 5 0
A p p e n di x 6 
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y ............ 1 5 3
A p p e n di x 7 
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y 
S c h e d ul e of A cti viti e s ................................................................ 1 6 1


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A p p e n di x 8 
O p e n -L a b el E xt e n si o n S u b st u d y i n P arti ci p a nt s W h o 
Di s c o nti n u e d Tr e at m e nt i n t h e Bli n d e d P h a s e of 
St u d y W A 2 5 0 4 6 ........................................................................ 1 6 2
A p p e n di x 9 
A b br e vi ati o n s ............................................................................ 1 7 4


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
P R O T O C O L A M E N D M E N T A C C E P T A N C E F O R M
TI T L E:
A P H A S E III, M U L TI C E N T E R , R A N D O MI Z E D , 
P A R A L L E L - G R O U P, D O U B L E -B LI N D E D , 
P L A C E B O -C O N T R O L L E D S T U D Y T O E V A L U A T E 
T H E E F FI C A C Y A N D S A F E T Y O F O C R E LI Z U M A B 
I N A D U L T S WI T H P RI M A R Y P R O G R E S SI V E 
M U L TI P L E S C L E R O SI S
P R O T O C O L N U M B E R: 
W A 2 5 0 4 6
V E R SI O N N U M B E R: 
K
T E S T C O M P O U N D : 
O cr eli z u m a b ( R O 4 9 6 4 9 1 3)
M E DI C A L M O NI T O R:
, M. D.
S P O N S O R N A M E : 
F. H off m a n n -L a R o c h e Lt d
I a gr e e t o c o n d u ct t h e st u d y i n a c c or d a n c e wit h t h e c urr e nt pr ot o c ol.
Pri n ci p al I n v e sti g at or’ s N a m e ( pri nt)
Pri n ci p al I n v e sti g at or’ s Si g n at ur e
D at e
Pl e a s e r et ai n t h e si g n e d ori gi n al of t hi s f or m f or y o ur st u d y fil e s.  Pl e a s e r et ur n a c o p y of
t h e si g n e d f or m t o t h e S p o n s or or t h eir d e si g n e e.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 6 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
1.
P R O T O C O L S U M M A R Y
1. 1 
S Y N O P SI S
P R O T O C O L TI T L E:
A P H A S E III, M U L TI C E N T E R, R A N D O MI Z E D, P A R A L L E L -G R O U P, 
D O U B L E -B LI N D E D, P L A C E B O -C O N T R O L L E D S T U D Y T O 
E V A L U A T E T H E E F FI C A C Y A N D S A F E T Y O F O C R E LI Z U M A B  I N 
A D U L T S WI T H P RI M A R Y P R O G R E S SI V E M U L TI P L E S C L E R O SI S
St u d y R ati o n al e
T hi s st u d y ( W A 2 5 0 4 6) i s a pi v ot al P h a s e III cli ni c al tri al c o m p o s e d of a bli n d e d tr e at m e nt p eri o d, 
a n o p e n -l a b el e xt e n si o n ( O L E) p h a s e, a n d a s af et y f oll o w-u p p eri o d.  T h e bli n d e d tr e at m e nt 
p eri o d i s d e si g n e d t o d e m o n str at e t h e effi c a c y a n d s af et y of o cr eli z u m a b i n pri m ar y pr o gr e s si v e 
m u lti pl e s cl er o si s (P P M S ) i n c o m p ari s o n wit h pl a c e b o.  T h e O L E s er v e s t o e v al u at e l o n g-t er m 
s af et y, t ol er a bilit y, a n d effi c a c y of o cr eli z u m a b tr e at m e nt i n p arti ci p a nt s wit h P P M S.
T hi s st u d y i s p art of a br o a d er, c o nfir m at or y  cli ni c al d e v el o p m e nt pr o gr a m i n v e sti g ati n g t h e s af et y 
a n d effi c a c y  of o cr eli z u m a b i n p arti ci p a nt s wit h b ot h r el a p si n g m u lti pl e s cl er o si s ( R M S) a n d 
P P M S.  A n O L E p h a s e of t h e P h a s e II St u d y W A 2 1 4 9 3/ A C T 4 4 2 2 G i s o n g oi n g f or eli gi bl e 
p arti ci p a nt s wit h r el a p si n g-r e mitti n g m ulti pl e s cl er o si s (R R M S) .  T h er e ar e 3 o n g oi n g P h a s e III 
pi v ot al tri al s (i n cl u di n g t h e o n e pr e s e nt e d i n t hi s pr ot o c ol), 2 tri al s i n R M S a n d 1 tri al i n P P M S.
O bj e cti v e s
Pri m ar y
T o i n v e sti g at e t h e effi c a c y of o cr eli z u m a b c o m p ar e d wit h pl a c e b o i n p arti ci p a nt s wit h P P M S, a s 
m e a s ur e d b y t h e ti m e t o o n s et of c o nfir m e d di s a bilit y pr o gr e s si o n o v er t h e tr e at m e nt p eri o d, 
d efi n e d a s a n i n cr e a s e i n E x p a n d e d Di s a bilit y St at u s S c al e ( E D S S ) t h at i s s u st ai n e d f or at l e a st 
1 2 w e e k s, b a s e d o n r e g ul arl y s c h e d ul e d vi sit s.
Di s a bilit y pr o gr e s si o n i s d efi n e d a s a n i n cr e a s e of 1. 0 -p oi nt fr o m t h e b a s eli n e E D S S w h e n t h e 
b a s eli n e s c or e i s 5. 5 or l e s s, a n d 0. 5 w h e n t h e b a s eli n e s c or e i s m o r e t h a n 5. 5, t h at i s n ot 
attri b ut a bl e t o a n ot h er eti ol o g y ( e. g., f e v er, c o n c urr e nt ill n e s s, or c o n c o mit a nt m e di c ati o n).
S e c o n d ar y O bj e cti v e s
T h e s e c o n d ar y o bj e cti v e s of t hi s st u d y ar e t o e v al u at e t h e effi c a c y a n d s af et y of o cr eli z u m a b 
c o m p ar e d wit h pl a c e b o, a s r efl e ct e d b y t h e f oll o wi n g:
 
T h e ti m e t o o n s et of c o nfir m e d di s a bilit y pr o gr e s si o n o v er t h e tr e at m e nt p eri o d, d efi n e d a s 
a n i n cr e a s e i n E D S S t h at i s s u st ai n e d f or at l e a st 2 4 w e e k s, b a s e d o n r e g ul arl y s c h e d ul e d 
vi sit s
 
T h e c h a n g e i n Ti m e d 2 5 - F o ot W a l k Te st ( T 2 5 F W T) fr o m b a s eli n e t o W e e k  1 2 0
 
T h e c h a n g e i n t ot al v ol u m e of T 2 l e si o n s o n m a g n eti c r e s o n a n c e i m a gi n g ( M RI ) s c a n s of t h e 
br ai n fr o m b a s eli n e t o W e e k 1 2 0
 
T h e p er c e nt a g e c h a n g e i n t ot al br ai n v ol u m e a s d et e ct e d b y br ai n M RI fr o m W e e k 2 4 1 2 0
 
T h e c h a n g e i n S h ort F or m -3 6 ( S F -3 6 ) H e alt h S ur v e y v er si o n 2 P h y si c al C o m p o n e nt 
S u m m ar y  ( P C S) s c or e fr o m b a s eli n e t o We e k  1 2 0
 
T o e v al u at e t h e s af et y a n d t ol er a bilit y of o cr eli z u m a b 3 0 0 m g 2 ( o v er 2 4 -w e e k tr e at m e nt 
c y cl e s) c o m p ar e d wit h pl a c e b o i n p arti ci p a nt s wit h P P M S
O v er all D e si g n
T hi s i s a P h a s e III, r a n d o mi z e d, d o u bl e -bli n d, p ar all el -gr o u p, m ulti c e nt er st u d y t o e v al u at e t h e 
s af et y a n d effi c a c y  of t w o 3 0 0 m g o cr eli z u m a b I V i nf u si o n s of s e p ar at e d b y 1 4 d a y s at a 
s c h e d ul e d i nt er v al of e v er y 2 4 w e e k s a s c o m p ar e d wit h pl a c e b o i n a d ult s wit h P P M S.  
P arti ci p a nt s will b e tr e at e d f or a mi ni m u m of 1 2 0 w e e k s r e pr e s e nti n g at l e a st fi v e 2 4 -w e e k 
tr e at m e nt c ycl e s.  T h e st u d y will e nr oll a p pr o xi m at el y 6 3 0 p arti ci p a nt s i n a 2: 1 r a n d o mi z ati o n 
( o cr eli z u m a b: pl a c e b o), gl o b all y.  R a n d o mi z ati o n will b e p erf or m e d t hr o u g h a n I nt er a cti v e v oi c e or 
W e b- b a s e d r e s p o n s e s y s t e m (I x R S) a n d will b e str atifi e d b y r e gi o n ( U. S. v s. R e st of W o rl d 
[ R O W]) a n d a g e (4 5 v s. 4 5) .


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T hi s st u d y c o n si st s of t h e f oll o wi n g st u d y p eri o d s:  a s cr e e ni n g p eri o d, a bli n d e d tr e at m e nt p eri o d, 
a n O L E p h a s e, a n d a s af et y f oll o w -u p p eri o d.  T h e st u d y d ur ati o n will v ar y f or e a c h p arti ci p a nt t o 
m a xi m i ze t h e s af et y a n d effi c a c y d at a c oll e ct e d, a s d e s cri b e d b el o w.
S cr e e ni n g P eri o d
T h e s cr e e ni n g p eri o d l a st s u p t o 4 w e e k s.
Bli n d e d Tr e at m e nt P eri o d
All p arti ci p a nt s will u n d er g o at l e a st 1 2 0 w e e k s of st u d y tr e at m e nt r e pr e s e nti n g 5 tr e at m e nt 
c y cl e s, e a c h of 2 4 w e e k s’ d ur ati o n.  T h e st u d y will b e u n bli n d e d w h e n t h e l a st e nr oll e d p arti ci p a nt 
c o m pl et e s at l e a st 1 2 0 w e e k s ( 5 c y cl e s) of st u d y tr e at m e nt, pr o vi d e d t h e t ot al n u m b er of 
c o nfir m e d di s a bilit y pr o gr e s si o n e v e nt s i s a p pr o xi m at el y 2 5 3 ( b a s e d o n t h e S p o n s or’ s b e st 
e sti m ati o n aft er t h e l a st p arti ci p a nt fi ni s h e s W e e k 1 0 8 vi sit), or at t h e l at e st w h e n t h e l a st 
r a n d o mi z e d parti ci p a nt h a s b e e n i n t h e bli n d e d tr e at m e nt p eri o d f or 3 y e ar s.
If t h e pr oj e ct e d n u m b er of c o nfir m e d di s a bilit y pr o gr e s si o n e v e nt s h a s n ot b e e n r e a c h e d b y 
W e e k 1 2 0 b e c a u s e of sl o w er t h a n a nti ci p at e d di s a bilit y pr o gr e s si o n r at e s, t h e tr e at m e nt p eri o d 
will b e e xt e n d e d u ntil a p pr o xi m at el y 2 5 3 c o nfir m e d di s a bilit y pr o gr e s si o n e v e nt s h a v e o c c urr e d, 
wit h a d diti o n al tr e at m e nt c y cl e s e v er y 2 4 w e e k s, i n or d er t o m ai nt ai n st ati sti c al p o w er t o d et e ct a 
tr e at m e nt diff er e n c e.  B e c a u s e it i s a nti ci p at e d t h at it m a y t a k e 1 2 1 8 m o nt h s t o r e cr uit 
p arti ci p a nt s, t hi s bli n d e d tr e at m e nt p eri o d m a y e xt e n d t o u p t o 3. 5 4 y e ar s f or t h e fir st gr o u p of 
p arti ci p a nt s e nr oll e d i nt o t h e st u d y.
If t h e l a st p arti ci p a nt e nr oll e d di s c o nti n u e s t h e tr e at m e nt p eri o d b ef or e We e k  1 2 0 or b ef or e 
3 y e ar s of bli n d e d tr e at m e nt, t h e d at e of 1 2 0 w e e k s or 3 y e ar s aft er hi s/ h er r a n d o mi z ati o n d at e 
will b e u s e d.
R a n d o mi z ati o n ( D a y 1) will o c c ur o nl y aft er t h e p arti ci p a nt h a s m et all i n cl u si o n a n d e x cl u si o n 
crit eri a.  F or t h e fir st tr e at m e nt c y cl e a n d i n s u b s e q u e nt tr e at m e nt c y cl e s of st u d y dr u g 
e v er y 2 4 w e e k s, p arti ci p a nt s will b e d o s e d 1 4 d a y s a p art ( 3 0 0 m g
o cr eli z u m a b or pl a c e b o 
i nf u si o n2).  All p arti ci p a nt s will al s o r e c ei v e a 1 0 0 m g  m et h yl pr e d ni s ol o n e I V i nf u si o n o n D a y 1 
a n d wit h e a c h s u b s e q u e nt o cr eli z u m a b or pl a c e b o i nf u si o n.  I n p arti ci p a nt s w h er e 
m e t h yl pr e d ni s ol o n e i s c o ntr ai n di c at e d, e q ui v al e nt d o s e s of ot h er I V st er oi d s 
( e. g., d e x a m et h a s o n e) s h o ul d b e u s e d a s pr e m e di c ati o n.
O p e n -L a b el E xt e n si o n P h a s e
F oll o wi n g d at a b a s e l o c k of t h e bli n d e d tr e at m e nt p eri o d, p arti ci p a nt s s h o ul d c o nti n u e t o r e c ei v e 
bli n d e d tr e at m e nt u ntil t h e pri m ar y  a n al y si s i s c o m pl et e d a n d t h e d e ci si o n t o st art t h e O L E p h a s e
i s c o m m u ni c at e d b y t h e S p o n s or.
U p o n t h e di s cl o s ur e of r e s ult s a n d a p o siti v e b e n efit – ri s k a s s e s s m e nt of t h e u s e of o cr eli z u m a b 
t h er a p y, p arti ci p a nt s w h o c o m pl et e d t h e bli n d e d tr e at m e nt p eri o d a n d w h o, i n t h e o pi ni o n of t h e 
i n v e sti g at or, c o ul d b e n efit fr o m tr e at m e nt m a y r e c ei v e o p e n-l a b el o cr eli z u m a b.  U nl e s s t h e 
S p o n s or d e ci d e s t o t er mi n at e t h e o cr eli z u m a b pr o gr a m f or m u lti pl e s cl er o si s, t h e O L E p h a s e will 
c o nti n u e a s p er l o c al r e g ul ati o n.  T hi s d e ci si o n will b e b a s e d o n t h e c h a n g e of b e n efit ri s k a n d 
s af et y m o nit ori n g.  Eli gi bl e p arti ci p a nt s n e e d t o pr o vi d e c o n s e nt f or p arti ci p ati o n i n t h e 
O L E p h a s e.  U nl e s s dis c o nti n ue d e arl y , all p arti ci p a nt s m a y  c o nti n u e t h eir tr e at m e nt wit h 
o p e n -l a b el o cr eli z u m a b a s p er t h e pr ot o c ol u ntil 3 1 D e c e m b er 2 0 2 2.  All p arti ci p a nts m ust 
dis c o nti n ue o pe n -l a bel o creli z u m a b tre at me nt wit hi n t his st u d y bef ore 3 1 De ce m ber 2 0 2 2.  
H o we ver,
p arti ci p a nts will be offere d c o nti n u ati o n of o creli z u m a b tre at me nt or a s afet y 
f oll o w-u p peri o d vi a a r oll o ver st u d y ( M N 4 3 9 6 4, O L E R O).
P arti ci p a nt s w h o st art tr e at m e nt wit h c o m m er ci al o cr eli z u m a b or a n ot her D M T will di s c o nti n u e 
fr o m t h e st u d y c o m pl et el y a n d will n ot e nt er t h e s af et y f oll o w-u p p eri o d.
P arti ci p a nt s w h o ar e n ot willi n g t o p arti ci p at e i n t h e O L E p h a s e of t h e st u d y will e nt er t h e s af et y 
f oll o w-u p p eri o d ( s e e b el o w).  I n t h e c a s e of a p arti ci p a nt w h o i niti all y d e cli n e s p arti ci p ati o n i n t h e 
O L E p h a s e a n d s u b s e q u e ntl y c h a n g e s t h eir d e ci si o n, t h e p arti ci p a nt m a y  b e d e e m e d eli gi bl e t o 
e nt er t h e O L E p h a s e u p t o 2 4 w e e k s aft er t h e O L E p h a s e b e gi n s.  T hi s will o c c ur o n a 
c a s e -b y -c a s e b a si s i n c o n s ult ati o n wit h t h e S p o n s or. 
P arti ci p a nt s w h o c o n s e nt t o p arti ci p at e i n t h e O L E p h a s e will b e r e q uir e d t o m e et t h e 
tr e at m e nt/r e-tr e at m e nt crit eri a pri or t o i nf u si o n wit h o cr eli z u m a b.  D uri n g t h e O L E p h a s e, all 
p arti ci p a nt s will r e c ei v e d u al I V i nf u si o n s of o cr eli z u m a b 3 0 0 m g 2 f or t h e fir st c y cl e.  F or t h e 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
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s u b s e q u e nt c y cl e s, p arti ci p a nt s will c o nti n u e o p e n -l a b el tr e at m e nt wit h a si n gl e 6 0 0 m g 
o cr eli z u m a b I V i nf u si o n e v er y 2 4 w e e k s .  P arti ci p a nt s w h o wit h dr a w fr o m t h e O L E p h a s e will b e 
e nt er e d i nt o t h e s af et y f oll o w -u p p eri o d .
S af et y F oll o w -U p P eri o d
T h e s af et y  f oll o w-u p p eri o d will b e gi n w h e n t h e p arti ci p a nt c o m pl et e s or di s c o nti n u e s fr o m t h e 
bli n d e d tr e at m e nt p eri o d or O L E p h a s e f or a n y r e a s o n.  P arti ci p a nt s s h o ul d r e m ai n i n t h e s af et y 
f oll o w-u p p eri o d f or u p t o 4 8 w e e k s f oll o wi n g t h e l a st i nf u si o n of st u d y dr u g/ o p e n -l a b el 
o cr eli z u m a b ( a s a p pli c a bl e). D uri n g t h e s af et y f oll o w -u p p eri o d, p arti ci p a nt s will b e a s s e s s e d at 
cli ni c al vi sit s e v er y 1 2 w e e k s.  T el e p h o n e i nt er vi e w s will b e p erf or m e d e v er y 4 w e e ks
bet wee n 
vi sits.
P arti ci p a nt s w h o st art c o m m er ci al o cr eli z u m a b or a n ot her D M T will b e di s c o nti n u e d fr o m t h e 
st u d y c o m pl et el y a n d will n ot e nt er or c o nti n u e i n t h e s af et y f oll o w-u p p eri o d.
Be c a use t his st u d y will be cl ose d o n 3 1 De ce m ber 2 0 2 2, p arti ci p a nts alre a d y i n s afet y f oll o w-u p 
m a y c o m plete t his st u d y peri o d i n t he r oll o ver St u d y
M N 4 3 9 6 4.
It i s i m p ort a nt t o di sti n g ui s h b et w e e n “ wit h dr a w al fr o m tr e at m e nt” a n d “ wit h dr a w al fr o m st u d y”.  
P arti ci p a nt s w h o wit h dr a w fr o m tr e at m e nt s h o ul d b e e n c o ur a g e d t o r e m ai n i n t h e s t u d y f or t h e f ull 
d ur ati o n of t h e s af et y f oll o w -u p p eri o d ( u p t o 4 8 w e e k s fr o m t h e l a st i nf u si o n).
E v er y eff ort s h o ul d b e m a d e t o e n s ur e t h at p arti ci p a nt s w h o wit h dr a w fr o m st u d y tr e at m e nt 
c o m pl et e t h e s af et y f oll o w -u p p eri o d a n d all r el at e d a s s e s s m e nt s, r e g ar dl e s s of w h et h er or n ot 
t h e y r e c ei v e alt er n ati v e tr e at m e nt f or M S
N u m b er of P arti ci p a nt s
A p pr o xi m at el y 6 3 0 p arti ci p a nt s will b e r a n d o mi z e d i n 2 gr o u p s i n a 2: 1 r ati o.  A n i n d e p e n d e nt 
I x R S pr o vi d er will c o n d u ct r a n d o mi z ati o n a n d h ol d t h e tr e at m e nt a s sig n m e nt c o d e.  
P arti ci p a nt s will b e str atifi e d b y r e gi o n ( U. S. v s. R O W) a n d a g e (4 5 v s. 4 5) .
T h er e will b e n o r e pl a c e m e nt of p arti ci p a nt s s h o ul d a p arti ci p a nt’ s tr e at m e nt b e di s c o nti n u e d f or 
a n y r e a s o n.
St u d y Tr e at m e nt
D uri n g t h e bli n d e d tr e at m e nt p eri o d, p arti ci p a nt s will b e r a n d o ml y  a s si g n e d t o eit h er o cr eli z u m a b 
3 0 0 m g 2 or pl a c e b o.  T h e fir st I V i nf u si o n of o cr eli z u m a b or pl a c e b o will b e a d mi ni st er e d o n 
st u d y D a y 1.
D uri n g t h e O L E p h a s e, all p arti ci p a nt s will r e c ei v e 2 I V i nf u si o n s of 3 0 0 m g  o cr eliz u m a b 
s e p ar at e d b y 1 4 d a y s f or t h e fir st c y cl e.  F or t h e s u b s e q u e nt c y cl e s, p arti ci p a nt s will c o nti n u e 
o p e n -l a b el tr e at m e nt wit h a si n gl e i nf u si o n of 6 0 0 m g o cr eli z u m a b e v ery 2 4 w e e k s.
T o r e d u c e p ot e nti al i nf u si o n-r el at e d r e a cti o n s, all p arti ci p a nt s will r e c ei v e pr o p h yl a cti c tr e at m e nt 
wit h 1 0 0 m g  met h yl pr e d ni s ol o n e, a d mi ni st er e d b y sl o w I V i nf u si o n, a n d a n or al or I V 
a nti hi st a mi n e ( s u c h a s di p h e n h y dr a mi n e 5 0 m g or e q ui v al e nt d o s e of alt er n ati v e).  
T h e m e t h yl pr e d ni s ol o n e a d mi ni str ati o n i s t o b e c o m pl et e d a ppr o xi m at el y 3 0 mi n ut e s b ef or e t h e 
st art of e a c h o cr eli z u m a b i nf u si o n; a nti hi st a mi n e s s h o ul d b e a d mi ni st er e d 3 0 6 0 mi n ut e s pri or t o 
t h e st art of a n i nf u si o n.  I n p arti ci p a nt s w h er e m et h yl pr e d ni s ol o n e i s c o ntr ai n di c at e d, 
c orr e s p o n di n g d o s e s of ot h er I V st er o i d s ( e. g., d e x a m et h a s o n e) s h o ul d b e u s e d a s 
pr e m e di c ati o n .
E n d of St u d y
T h e e n d of st u d y i s n o w d efi n e d a s 3 1 De ce m ber 2 0 2 2 or u p u ntil t he a p pr o v al of 
St u d y M N 4 3 9 6 4 ( O L E R O).
Irres pe cti vel y, t he S p o ns or m a y de ci de t o ter mi n ate t he st u d y at a n y ti me.
T he S p o ns or h as de ci de d t o pr o vi de t he o p p ort u nit y t o all p arti ci p a nts t o r oll o ver a n d c o nti n ue 
t heir tre at me nt a n d/ or s afet y f oll o w-u p u n der t he ne w e xte nsi o n pr ot o c ol. 
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e
A n i n d e p e n d e nt D at a M o nit ori n g C o m mitt e e i s n ot b ei n g u s e d.










O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
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T a bl e 1 
S c h e d ul e of A c ti viti e s:  S cr e e ni n g t hr o u g h t h e E n d of Tr e at m e nt P eri o d ( c o nt.)
d
Aft er i nf or m e d c o n s e nt, b ut pri or t o i niti ati o n of st u d y m e di c ati o n s, o nl y s eri o u s a d v er s e e v e nt s c a u s e d b y a pr ot o c ol -m a n d at e d i nt er v e nti o n will 
b e c oll e ct e d ( e. g., s eri o u s a d v er s e e v e nt s r el at e d t o i n v a si v e pr o c e d ur e s s u c h a s bi o p si e s, m e di c ati o n w a s h o ut, or n o tr e at m e nt r u n-i n).
e
A str u ct ur e d t el e p h o n e i nt er vi e w will b e d o n e o n a 4 -w e e k b a si s b et w e e n vi sit s u p t o 4 8 w e e k s aft er t h e l a st i nf u si o n t o i d e ntif y a n d c oll e ct 
i nf or m ati o n o n a n y c h a n g e s in t h e p arti ci p a nt’ s h e alt h st at u s (i n cl u di n g, n e w or w or s e ni n g n e ur ol o gi c al s y m pt o m s) t h at w arr a nt a n u n s c h e d ul e d 
vi sit.
f
M RI s c a n s :  br ai n M RI s c a n s s h o ul d o c c ur wit hi n a wi n d o w of 4 w e e k s of t h e s c h e d ul e d vi sit.  Br ai n M RI s c a n s will al s o b e o bt ai n e d i n 
p arti ci p a nt s wit h dr a w n fr o m t h e tr e at m e nt p eri o d ( at a wit h dr a w al vi sit) if n ot p erf or m e d d uri n g t h e pr e vi o u s 4 w e e k s.
g
S er u m -h C G m u st b e p erf or m e d at s cr e e ni n g i n w o m e n of c hil d b e ari n g p ot e nti al.  S u b s e q u e ntl y, uri n e -h C G [ s e n siti vit y of at l e a st 25 mI U/ m L] 
will b e d o n e.  O n i nf u si o n vi sit s, t h e uri n e pr e g n a n c y t e st s h o ul d b e p erf or m e d pri or t o m et h yl pr e d ni s ol o n e i nf u si o n i n all w o m e n of c hil d b e ari n g 
p ot e nti al.  If p o siti v e, d o n ot d o s e a n d c o nfir m wit h a s er u m pr e g n a n c y t e st.
h
A n ti b o d y tit er s:  M e a s ur e m e nt of a nti b o d y tit er s a g ai n st c o m m o n a nti g e n s ( m u m p s, r u b ell a, v ari c ell a, a n d S. p n e u m o ni a e ) will b e p erf or m e d.
I
R C R ( D N A) 6 m L w h ol e bl o o d s a m pl e t o b e t a k e n fr o m c o n s e nti n g p arti ci p a nt s f or g e n eti c a n al y si s.  If n ot d o n e at B a s eli n e ( Vi sit 2), s a m pl e c a n 
b e c oll e ct e d at n e xt vi sit ( Vi sit 3)
j
R C R ( R N A) 2 2. 5 m L w h ol e bl o o d s a m pl e s t o b e t a k e n fr o m c o n s e nti n g p arti ci p a nt s f or e x pr e s si o n pr ofili n g a n al y si s.  O n i nf u si o n vi sit s, 
s a m pl e s s h o ul d b e t a k e n pri or t o m et h yl pr e d ni s ol o n e i nf u si o n.
k
R C R ( Pr ot ei n) 6 m L bl o o d s a m pl e s i n E D T A t u b e f or pl a s m a will b e t a k e n fr o m c o n s e nti n g p arti ci p a nt s f or a n aly s i s of pr ot ei n bi o m ar k er s.  
O n i nf u si o n vi sit s, s a m pl e s s h o ul d b e t a k e n pri or t o m et h yl pr e d ni s ol o n e i nf u si o n.
l
H A H A :  O n i nf u si o n vi sit s, s a m pl e s ar e c oll e ct e d pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n.
m
P K s a m pl e s:   O n t h e i nf u si o n d a y s ( D a y 1 a n d 1 5) of t h e fir st tr e at m e nt c ycl e a n d o n i nf u si o n d a y 5 0 5 (f o urt h tr e at m e nt c ycl e), 2 bl o o d s a m pl e s 
s h o ul d b e c oll e ct e d, o n e pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n, a n d t h e s e c o n d 3 0 mi n ut e s ( 1 0 mi n ut e s) f oll o wi n g t h e c o m pl eti o n of t h e 
o cr eli z u m a b/ pl a c e b o i nf u si o n.  F or all ot h er i nf u si o n vi sit s, a bl o o d s a m pl e s h o ul d b e t a k e n b ef or e t h e m et h yl pr e d ni s ol o n e i n f u si o n.  At ot h er 
ti me s ( n o n -i nf u si o n vi sit s), s a m pl e s m a y  b e t a k e n at a n y ti m e d uri n g t h e vi sit.
n
Cli ni c al g e n ot y pi n g :  a 3 m L w h ol e bl o o d s a m pl e will b e t a k e n fr o m all p arti ci p a nt s f or a n al y si s of H L A-D R a n d F c p ol y m o r p hi s m s.  If n ot d o n e 
at B a s eli n e ( Vi sit 2), s a m pl e c a n b e c oll e ct e d at n e xt vi si t ( Vi sit 3).
o
Pr ot ei n bi o m ar k er s a m pli n g :  a 6 m L  bl o o d s a m pl e i n a pl ai n t u b e wit h o ut E D T A f or s er u m s a m pl e will b e t a k e n fr o m all p arti ci p a nt s f or 
a n al y si s of pr ot ei n bi o m ar k er s; t h e s a m pl e s h o ul d b e t a k e n pri or t o m et h yl pr e d ni s ol o n e i nf u si o n.
p
F S H :  FS H o nl y a p pli c a bl e t o w o m e n t o c o nfir m t h e p o st -m e n o p a u s al st at u s.
q
H e p atiti s s cr e e ni n g a n d m o nit ori n g: all p arti ci p a nt s m u st h a v e n e g ati v e H B s A g r e s ult a n d n e g ati v e H e p C A b s cr e e ni n g t e st s pri or t o e nr oll m e nt.  
If t ot al H B c A b i s p o siti v e at s cr e e ni n g, H B V D N A m e a s ur e d b y P C R m u st b e n e g ati v e t o b e eli gi bl e.  F or t h o s e p arti ci p a nt s e nr oll e d wit h 
n e g ati v e H B s A g a n d p o siti v e t ot al H B c A b, H B V D N A ( P C R) m u st b e r e p e at e d e v er y 1 2 w e e k s.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
2 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T a bl e 1 
S c h e d ul e of A c ti viti e s:  S cr e e ni n g t hr o u g h t h e E n d of Tr e at m e nt P eri o d ( c o nt.)
r
F A C S :  i n cl u di n g C D 1 9 a n d ot h er cir c ul ati n g B c ell s u b s et s, T c ell s, n at ur al kill er c ell s a n d ot h er l e u k o c yt e s.  O n t h e i nf u si o n d a y s, F A C S 
s a m pl e s s h o ul d b e c oll e ct e d pri or t o i nf u si o n.  S e e S e cti o n 5. 1 3. 2 f or s p e cifi c t e st s.
s
R o uti n e s af et y l a b or at or y t e st s .  H e m at ol o g y, c h e mi str y, a n d uri n al y si s: O n i nf u si o n vi sit s, all uri n e a n d bl o o d s a m pl e s s h o ul d b e c oll e ct e d 
pri or t o t h e i nf u si o n of m et h yl pr e d ni s ol o n e.  At ot h er ti m e s, s a m pl e s m a y  b e t a k en at a n y ti m e d uri n g t h e vi sit.
t
L u m b ar p u n ct ur e will b e p erf or m e d at s cr e e ni n g t o d et er mi n e eli gi bilit y f or t h e st u d y o nl y i n p arti ci p a nt s w h o d o n ot h a v e d o c u m e nt e d C S F 
r e s ult s, i n cl u di n g ori gi n al l a b or at ory r e p ort a n d m et h o d, d e m o n str ati n g pr e s e n c e of eit h er a n el e v at e d I g G i n d e x or o n e or m or e oli g o cl o n al 
b a n d s b y i s o el e ctri c f o c u si n g.
u
Pl a s m a a n d uri n e s a m pl e s f or J C V will b e c oll e ct e d at s p e cifi e d ti m e p oi nt s.
v
All p arti ci p a nt s will r e c ei v e pr o p h yl a cti c tr e at m e nt wit h 1 0 0 m g of m et h yl pr e d ni s ol o n e I V.  I n p arti ci p a nt s w h er e m et h yl pr e d ni s ol o n e i s 
c o ntr ai n di c at e d, e q ui v al e nt d o s e s of ot h er I V st er oi d s ( e. g., d e x a m et h a s o n e) s h o ul d b e u s e d a s pr e m e di c ati o n.  It i s al s o r e c o m m e n d e d t h at
p arti ci p a nt s r e c ei v e a n a n al g e si c/ a nti p yr eti c s u c h a s a c et a mi n o p h e n / p ar a c et a m ol ( 1 g) a n d a n I V or or al a nti hi st a mi n e, s u c h a s 
di p h e n h y dr a mi n e 5 0 m g, 3 0 6 0 mi n ut e s pri or t o o cr eli z u m a b or pl a c e b o i nf u si o n s.
w
St u d y d r u g a d mi ni str ati o n :  T h e Tr e ati n g I n v e sti g at or m u st r e vi e w t h e cli ni c al a n d l a b or at or y r e-tr e at m e nt crit eria pri or t o r e -d o si n g p arti ci p a nt s 
wit h st u d y  dr u g i n tr e at m e nt Cy cl e 2 a n d all s u b s e q u e nt tr e at m e nt c y cl e s.






O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
2 7 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T a bl e 2 
S c h e d ul e of A c ti viti e s:  Ad diti o n al Tr e at m e nt C y cl e s, D el a y e d D o si n g, U n s c h e d ul e d Vi sit s, a n d 
Wit h dr a w al fr o m Tr e at m e nt
( c o nt.)
-h C G h u m a n c h ori o ni c g o n a d otr o pi n; C D cl u st er of diff er e nti ati o n; e C R F el e ctr o ni c C a s e R e p ort F or m; E D S S E x p a n d e d Di s a bilit y St at u s 
S c al e; F A C S fl u or e s c e n c e-a cti v at e d c ell s orti n g; H A H A h u m a n a nti -h u m a n a nti b o d y; H B c A b h e p atiti s B c or e a nti b o d y; H B s A g h e p atiti s B 
s urf a c e a nti g e n; H B V h e p atiti s B vir u s; H e p C A b h e p atiti s C vir u s a nti b o d y; J C V J o h n C u n ni n g h a m vir u s; M FI S M o difi e d F ati g u e I m p a ct 
S c al e; M RI m a g n eti c r e s o n a n c e i m a gi n g; M S
m u lti pl e s cl er o si s; M S F C S
M ulti pl e S cl er o si s F u n cti o n al C o m p o sit e; O L E o p e n -l a b el 
e xt e n si o n; P C R p ol y m e r a s e c h ai n r e a cti o n; P K p h ar m a c o ki n eti c; R C R R o c h e Cli ni c al R e p o sit or y; S F -3 6 S h ort F or m -3 6; w w e e k.
a
A d diti o n al tr e at m e nt c y cl e s : P arti ci p a nt s will c o nti n u e wit h bli n d e d 2 4 -w e e k tr e at m e nt c y cl e s u ntil t h e l a st p arti ci p a nt r e c ei v e s hi s/ h er fi n al 
c o ur s e of tr e at m e nt s c h e d ul e d at W e e k  9 8.  At t h at p oi nt, all p arti ci p a nt s will c o nti n u e t o t h e e n d of t h eir c urr e nt ( 2 4 -w e e k) c y cl e.  If t h e pr oj e ct e d 
t ot al n u m b er of c o nfir m e d di s a bilit y pr o gr e s si o n e v e nt s h a s n ot b e e n r e a c h e d at W e e k  1 2 0, t h e n all p arti ci p a nt s will c o nti n u e wit h a d diti o n al 
bli n d e d 2 4 -w e e k tr e at m e nt c y cl e s u n til t h e pr oj e ct e d n u m b er of c o nfir m e d di s a bilit y e v e nt s h a s b e e n r e a c h e d.
b
P arti ci p a nt s u n d er g oi n g t h e fir st i nf u si o n of t h e fir st a d diti o n al tr e at m e nt c y cl e at W e e k 1 2 0 s h o ul d al s o c o m pl e t e all a s s e s s m e nt s f or t h e 
W e e k 1 2 0 v i sit o utli n e d i n T a bl e 1 .
c
A d el a y e d d o si n g vi sit will b e p erf or m e d a n d r e c or d e d i n t h e D el a y e d D o si n g Vi sit e C R F w h e n d o si n g c a n n ot b e a d mi ni st er e d at t h e s c h e d ul e d
d o si n g vi sit.  Ot h er t e st s/ a s s e s s m e nt s m a y  b e d o n e a s a p pr o pri at e.
d
U n s c h e d ul e d Vi sit ( n o n-d o si n g): A s s e s s m e nt s p erf or m e d at u n s c h e d ul e d ( n o n -d o si n g) vi sit s will d e p e n d o n t h e cli ni c al n e e d s of t h e 
p arti ci p a nt .  All p arti ci p a nt s wit h n e w n e ur ol o gi c al s y m pt o m s s u g g e sti v e of M S w or s e ni n g or of a r el a p s e s h o ul d h a v e E D S S p erf or m e d b y 
E x a mi ni n g I n v e sti g at or.  Ot h er t e st s/ a s s e s s m e nt s m a y b e d o n e a s a p pr o pri at e.  U n s c h e d ul e d vi sit s m a y  al s o t a k e pl a c e d uri n g t he s af et y 
foll o w -u p p eri o d.
e
Vit al si g n s will b e o bt ai n e d w hil e t h e p arti ci p a nt i s i n t h e s e mi-s u pi n e p o siti o n ( aft er 5 mi n ut e s), i. e., p ul s e r at e, s y st oli c a n d di a st oli c bl o o d 
pr e s s ur e, r e s pir ati o n r at e a n d t e m p er at ur e.  O n i nf u si o n vi sit s, t h e vit al si g n s s h o ul d b e t a k e n wit hi n 4 5 mi n ut e s pri or t o t h e m et h yl pr e d ni s ol o n e 
i nf u si o n i n all p arti ci p a nt s.  I n a d diti o n, vit al si g n s s h o ul d b e o bt ai n e d pri or t o t h e st u d y dr u g or pl a c e b o i nf u si o n, t h e n e v er y 1 5 mi n ut e s 
(5 mi n ut e s) f or t h e fir st h o ur; t h e n e v er y 3 0 mi n ut e s ( 1 0 mi n ut e s) u ntil 1 h o ur aft er t h e e n d of t h e i nf u si o n.  O n n o n -i nf u si o n d a y s, t h e vit al 
si g n s m a y  b e t a k e n at a n y ti m e d uri n g t h e vi sit.
f
A str u ct ur e d t el e p h o n e i nt er vi e w will b e d o n e o n a 4 -w e e k b a si s b et w e e n vi sit s u p t o 4 8 w e e k s aft er t h e l a st i nf u si o n t o i d e ntif y a n d c oll e ct 
i nf or m ati o n o n a n y c h a n g e s i n t h e p arti ci p a nt ’ s h e alt h st at u s (i n cl u di n g, n e w or w or s e ni n g n e ur ol o gi c al sy m pt o m s t h at w arr a nt a n u n s c h e d ul e d
vi sit.  F or O L E, t el e p h o n e i nt er vi e w s will b e d o n e o n a 4 -w e e k b a s i s f or t h e fir st y e ar a n d e v ery 8 -w e e k s s u b s e q u e ntl y.
g
M RI s c a n s :  br ai n M RI s c a n s will b e o bt ai n e d i n p arti ci p a nt s wit h dr a w n fr o m t h e tr e at m e nt p eri o d ( at a wit h dr a w al vi sit) if n ot p erf or m e d d uri n g 
t h e pr e vi o u s 4 w e e k s.  O n c e t h e p arti ci p a nt h a s p a s s e d t h e W e e k 1 2 0 vi sit, br ai n M RI s c a n s will b e p erf or m e d a n n u all y.
h
S er u m -h C G m u st b e p erf or m e d at s cr e e ni n g i n w o m e n of c hil d b e ari n g p ot e nti al.  S u b s e q u e ntl y, uri n e -h C G [ s e n siti vit y of at l e a st 2 5 mI U/ m L] 
will b e d o n e.  O n i nf u si o n vi sit s, t h e uri n e pr e g n a n c y t e st s h o ul d b e p erf or m e d pri or t o m et h yl pr e d ni s ol o n e i nf u si o n i n all w o m e n of c hil d b e ari n g
p ot e nti al.  If p o siti v e, d o n ot d o s e a n d c o nfir m wit h a s er u m pr e g n a n c y t e st.  
i
A n ti b o d y tit er s: M e a s ur e m e nt of a nti b o d y tit er s a g ai n st c o m m o n a nti g e n s ( m u m p s, r u b ell a, v ari c ell a, a n d S. p n e u m o ni a e ) will b e p erf or m e d.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
2 8 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T a bl e 2 
S c h e d ul e of A c ti viti e s:  Ad diti o n al Tr e at m e nt C y cl e s, D el a y e d D o si n g, U n s c h e d ul e d Vi sit s, a n d 
Wit h dr a w al fr o m Tr e at m e nt
( c o nt.)
j
R C R ( R N A) 2 2. 5 m L w h ol e bl o o d s a m pl e s t o b e t a k e n fr o m c o n s e nti n g p arti ci p a nt s f or e x pr e s si o n pr ofili n g a n al y si s.  O n i nf u si o n vi sit s, 
s a m pl e s s h o ul d b e t a k e n pri or t o m et h yl pr e d ni s ol o n e i nf u si o n.
k
R C R ( Pr ot ei n) 6 m L bl o o d s a m pl e s i n E D T A t u b e f or pl a s m a will b e t a k e n fr o m c o n s e nti n g p arti ci p a nt s f or a n al y s i s of pr ot ei n bi o m ar k er s.  
O n i nf u si o n vi sit s, s a m pl e s s h o ul d b e t a k e n pri or t o m et h yl pr e d ni s ol o n e i nf u si o n.
l
H A H A  a n d P K s a m pl e s :  O n i nf u si o n vi sit s , s a m pl e s ar e c oll e ct e d pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n
m
H e p atiti s s cr e e ni n g a n d m o nit ori n g : all p arti ci p a nt s m u st h a v e n e g ati v e H B s A g r e s ult a n d n e g ati v e H e p C A b s cr e e ni n g t e st s pri or t o e nr oll m e nt.  
If t ot al H B cA b i s p o siti v e at s cr e e ni n g, H B V D N A m e a s ur e d b y P C R m u st b e n e g ati v e t o b e eli gi bl e.  F or t h o s e p arti ci p a nt s e nr oll e d wit h 
n e g ati v e H B s A g a n d p o siti v e t ot al H B c A b, H B V D N A ( P C R) m u st b e r e p e at e d e v er y 1 2 w e e k s.
n
F A C S : i n cl u di n g C D 1 9 a n d ot h er cir c ul ati ng B c ell s u b s et s , T c ell s, n at ur al kill er c ell s a n d ot h er l e u k o c yt e s.  O n t h e i nf u si o n d a y s, F A C S 
s a m pl e s s h o ul d b e c oll e ct e d pri or t o i nf u si o n.  S e e S e cti o n 5. 1 3. 2 f or s p e cifi c t e st s.
o
R o uti n e s af et y l a b or at or y t e st s .  H e m at ol o g y, c h e mi str y, a n d uri n al y si s : O n i nf u si o n vi sit s, all uri n e a n d bl o o d s a m pl e s s h o ul d b e c oll e ct e d 
pri or t o t h e i nf u si o n of m et h yl pr e d ni s ol o n e.  At ot h er ti m e s, s a m pl e s m a y  b e t a k e n at a n y ti m e d uri n g t h e vi sit.  S a m pl e s c oll e ct e d d uri n g 
u n s c h e d ul e d vi sit s s h o ul d pr ef er a bl y b e s e nt t o a n d a n al y z e d b y t h e c e ntr al l a b or at or y u nl e s s r e s ult s ar e r e q uir e d ur g e ntl y.
p
Pl a s m a a n d uri n e s a m pl e s f or J C V will b e c oll e ct e d at s p e cifi e d ti me p oi nt s.
q
All p arti ci p a nt s will r e c ei v e pr o p h yl a cti c tr e at m e nt wit h 1 0 0 m g of m et h yl pr e d ni s ol o n e I V.  I n p arti ci p a nt s w h er e m et h yl pr e d ni s ol o n e i s 
c o ntr ai n di c at e d, e q ui v al e nt d o s e s of ot h er I V st er oi d s ( e. g., d e x a m et h a s o n e) s h o ul d b e u s e d a s pr e m e di c ati o n.  It i s al s o r e c o m m e n d e d t h at
p arti ci p a nt s r e c ei v e a n a n al g e si c/ a nti p yr eti c s u c h a s a c et a mi n o p h e n/ p ar a c et a m ol ( 1 g) a n d a n I V or or al a nti hi st a mi n e , s u c h a s 
di p h e n h y dr a mi n e 5 0 m g , 3 0 6 0 mi n ut e s pri or t o o cr eli z u m a b or pl a c e b o i nf u si o n s.
r
St u d y d r u g a d mi ni str ati o n : T h e Tr e ati n g I n v e sti g at or m u st r e vi e w t h e cli ni c al a n d l a b or at or y r e-tr e at m e nt crit eri a pri or t o r e-d o si n g p arti ci p a nt s 
wit h st u d y dr u g i n all s u b s e q u e nt tr e at m e nt c y cl e s.






O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
3 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T a bl e 3 
S c h e d ul e of A c ti viti e s: S af et y  F oll o w-U p ( c o nt.)
g
A d e di c at e d ( s c h e d ul e d or u n s c h e d ul e d) s af et y f oll o w -u p vi sit dir e ctl y pri or t o t h e st art of a n alt er n ati v e M S tr e at m e nt i s r e q uir e d f or p arti ci p a nt s 
w h o b e gi n a n alt er n ati v e tr e at m e nt f or M S w hil e i n s af et y f oll o w -u p i n or d er t o a s s e s s t h e p arti ci p a nt’ s c li ni c al st at u s a n d s af et y p ar a m et er s 
( a s s e s s m e nt s t o b e p erf or m e d a s p er s c h e d ul e of a cti viti e s (T a bl e 3 ) d e p e n di n g o n t h e st u d y p eri o d i n w hi c h t h e p arti ci p a nt w a s i n w h e n t h e 
alt er n ati v e tr e at m e nt b e g a n).
h
R o uti n e s af et y l a b or at or y t e st s :  H e m at ol o g y, c h e mi str y, a n d uri n al y si s.  S a m pl e s c oll e ct e d d uri n g u n s c h e d ul e d vi sit s s h o ul d pr ef er a bl y b e 
s e nt t o a n d a n al y z e d b y t h e c e ntr al l a b or at o r y u nl e s s r e s ult s ar e r e q uir e d ur g e ntl y.
i
F A C S i n cl u di n g C D 1 9 a n d ot h er cir c ul ati n g B c ell s u b s et s, T c ell s, n at ur al kill er c ell s a n d ot h er l e u k o c y t e s.
j
Uri n e -h C G [s e n siti vit y of at l e a st 2 5 mI U/ m L] m u st b e p erf or m e d i n w o m e n of c hil d b e ari n g p ot e nti al d uri n g s af et y f oll o w -u p w hil e B c ell s 
r e m ai n d e pl et e d b el o w n or m al l e v el s.  If p o siti v e c o nfir m wit h a s er u m pr e g n a n c y t e st.  
k
H e p atiti s m o nit ori n g :  If t ot al H B c A b i s p o siti v e at s cr e e ni n g, H B V D N A m e a s ur e d b y P C R m u st b e n e g ati v e t o b e eli gi bl e.  F or t h o s e 
p arti ci p a nt s e nr oll e d wit h n e g ati v e H B s A g a n d p o siti v e t ot al H B c A b, H B V D N A ( P C R) m u st b e r e p e at e d e v er y 1 2 w e e k s. 
l
H A H A a n d P K s a m pl e s:   I n a n y c a s e of a n a p h yl a xi s, a n a p h yl a ct oi d r e a cti o n, or s eri o u s or s e v er e h y p er s e n siti vit y r e a cti o n, H A H A a n d 
o cr eli z u m a b c o n c e ntr ati o n s a m pl e s s h o ul d b e c oll e ct e d a s cl o s e a s p o s si bl e t o t h e e v e nt a n d t h e n at 4 a n d 1 6 w e e k s p o st d o s e.
m
A str u ct ur e d t el e p h o n e i nt er vi e w will b e d o n e o n a 4 - we e k b a si s b et w e e n vi sit s u p t o 4 8 w e e k s aft er t h e l a st i nf u si o n t o i d e ntif y a n d c oll e ct 
i nf or m ati o n o n a n y c h a n g e s i n t h e p arti ci p a nt’ s h e alt h st at u s t h at w arr a nt a n u n s c h e d ul e d vi sit (i n cl u di n g n e w or w or s e ni n g ne ur ol o gi c al 
s y m p t o m s t h at w arr a nt a n u n s c h ed ul e d vi sit).
n
R C R ( Pr ot ei n) 6 m L bl o o d s a m pl e s i n E D T A t u b e f or pl a s m a will b e t a k e n fr o m c o n s e nti n g p arti ci p a nt s f or a n al ysi s of pr ot ei n bi o m a r k er s. 
o
M RI s h o ul d o nl y b e p erf or m e d f or p arti ci p a nt s w h o b e gi n a n alt er n ati v e tr e at m e nt f or M S, wit hi n t h e t i me wi n d o w of 1 m o nt h pri or t o t h e st art of 
a n alt er n ati v e M S tr e at m e nt ( u nl e s s M RI h a s alr e a d y b e e n p erf or m e d wit hi n pri or 8 w e e k s).






O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
3 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T a bl e 4 
S c h e d ul e of A c ti viti e s: O p e n -L a b el E xt e n si o n P h a s e ( c o nt.)
-h C G h u m a n c h ori o ni c g o n a d otr o pi n; C D cl u st er of diff er e nti ati o n; C S F c er e br o s pi n al fl ui d; D D a y ; e C R F el e ctr o ni c C a s e R e p ort F or m; 
E D S S E x p a n d e d Di s a bilit y St at u s S c al e; F A C S fl u or e s c e n c e-a cti v at e d c ell s orti n g; F c fr a g m e nt cr yst alli z a bl e; H A H A h u m a n a nti -h u m a n 
a nti b o d y; H B c A b h e p atiti s B c or e a nti b o d y; H B s A g h e p atiti s B s urf a c e a nti g e n; H B V h e p atiti s B vir u s; M FI S
M o difi e d F ati g u e I m p a ct S c al e; 
M RI
m a g n eti c r e s o n a n c e i m a gi n g; M S m u lti pl e s cl er o si s; M S F C S
M ulti pl e S cl er o si s F u n cti o n al C o m p o sit e S c al e; O L E
o p e n -l a b el 
e xt e n si o n; P C R p ol y m e r a s e c h ai n r e a cti o n; P K p h ar m a c o ki n eti c; R B R R e s e ar c h Bi o s a m pl e R e p o sit or y; R C R R o c h e Cli ni c al 
R e p o sit or y ; S F-3 6 S h ort F or m -3 6;  w w e e k .
a
O L E p h a s e c y cl e s:  T h e O L E p h a s e will st art aft er t h e pri m ar y  a n al y si s a n d c o m m u ni c ati o n fr o m t h e S p o n s or.  T h e O L E p h a s e c a n t er mi n at e at 
a n y m o m e nt or c y cl e ( s e e S e cti o n 4. 1. 9 ).  I n c a s e t h e st u d y i s e n d e d, a Wit h dr a w al fr o m Tr e at m e nt Vi sit s h o ul d o c c ur f or a n y p arti ci p a nts n ot 
r olli n g o ver t o S t u d y M N 4 3 9 6 4.
b
All p arti ci p a nt s e nt eri n g t h e O L E will r e c ei v e a d u al o cr eli z u m a b i nf u si o n ( 3 0 0 m g
I V i nf u si o n s a d mi ni st er e d 1 4 d a y s a p art) f or t h e fir st c y cl e.  
F or t h e s u b s e q u e nt cy c l e s, p arti ci p a nt s will c o nti n u e o p e n-l a b el tr e at m e nt wit h a si n gl e i nf u si o n of 6 00 m g  o cr eli z u m a b I V e v er y 2 4 w e e k s.
c
T h e a s s e s s m e nt s r e q u e st e d f or N r e pr e s e nt t h e t y pi c al s c h e d ul e of a cti viti e s d uri n g a c y cl e.
d
A d el a y e d d o si n g vi sit will b e p erf or m e d a n d r e c or d e d i n t h e D el a y e d D o si n g Vi sit e C R F w h e n d o si n g c a n n ot b e a d mi ni st er e d at t h e s c h e d ul e d 
d o si n g vi sit.  Ot h er t e st s/ a s s e s s m e nt s m a y b e d o n e a s a p pr o pri at e.
e
U n s c h e d ul e d Vi sit ( n o n -d o si n g):   A s s e s s m e nt s p erf or m e d at u n s c h e d ul e d ( n o n -d o si n g) vi sit s will d e p e n d o n t h e cli ni c al n e e d s of t h e 
p arti ci p a nt.  All p arti ci p a nt s wit h n e w n e ur ol o gi c al s y m pt o m s s u g g e sti v e of M S w or s e ni n g or of a r el a p s e s h o ul d h a v e E D S S p erf or m e d b y 
E x a mi ni n g I n v e sti g at or.  Ot h er t e st s/ a s s e s s m e nt s m a y b e d o n e a s a p pr o pri at e.
f
I nf or m e d C o n s e nt f or O L E m u st b e si g n e d b y t h e p arti ci p a nt pri or t o t h e fir st i nf u si o n i n t h e O L E p h a s e.
g
Vit al si g n s will b e o bt ai n e d w hil e t h e p arti ci p a nt i s i n t h e s e mi -s u pi n e p o siti o n ( aft er 5 mi n ut e s), i n cl u di n g p ul s e r at e, s y st oli c a n d di a st oli c bl o o d 
pr e s s ur e, r e s pir ati o n r at e, a n d t e m p er at ur e.  At i nf u si o n vi sit s, t h e vit al si g n s f or all p arti ci p a nt s s h o ul d b e t a k e n wit hi n 4 5 mi n ut e s pri or t o t h e 
m e t h yl pr e d ni s ol o n e i nf u si o n.  I n a d diti o n, vit al si g n s s h o ul d b e o bt ai n e d pri or t o t h e st u d y dr u g or pl a c e b o i nf u si o n, t h e n ev er y 1 5 mi n ut e s 
(5 mi n ut e s) f or t h e fir st h o ur; t h e n e v er y 3 0 mi n ut e s ( 1 0 mi n ut e s) u ntil 1 h o ur aft er t h e e n d of t h e i nf u si o n.  At n o n -i nf u si o n vi sit s, t h e vit al 
si g n s m a y  b e t a k e n at a n y ti m e d uri n g t h e vi sit.
h
E C G s ( pr e - a n d p o st d o s e) :  E C G s h o ul d b e p erf or m e d wit hi n 4 5 mi n ut e s pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n i n all p arti ci p a nt s a n d wit hi n 
6 0 mi n ut e s aft er c o m pl eti o n of t h e o cr eli z u m a b i nf u si o n.  Fr o m O L E W e e k  7 2 o n w ar d s, E C G a s s e s s m e nt i s n ot m a n d at ory; it s h o ul d o nl y b e 
p erf or m e d if cli ni c all y i n di c at e d.
i
T el e p h o n e i nt er vi e w:   A str u ct ur e d t el e p h o n e i nt er vi e w will b e c o n d u ct e d b y si t e p er s o n n el e v er y 4 w e e k s bet wee n visits t o i d e ntif y a n d 
c oll e ct i nf or m ati o n o n a n y c h a n g e s i n t h e p arti ci p a nt’ s h e alt h st at u s t h at w arr a nt a n u n s c h e d ul e d vi sit (i n cl u di n g n e w or w or s e ni n g n e ur ol o gi c al 
s y m p t o m s).
j
M RI s c a n s:   A br ai n M RI s c a n s h o ul d b e p erf or m e d at t h e st art of O L E p h a s e if n ot d o n e i n t h e pr e vi o u s 1 2 w e e k s.  I n t h e O L E p h a s e, br ai n 
M RI s s h o ul d b e d o n e o n c e a y e ar.  Br ai n M RI s c a n s s h o ul d o c c ur wit hi n a wi n d o w of 4 w e e k s of t h e s c h e d ul e d vi sit.  Al s o, br ai n M RI s c a n s will 
b e o bt ai n e d i n p arti ci p a nt s wit h dr a w n fr o m t h e O L E p h a s e ( at a wit h dr a w al vi sit) if n ot p erf or m e d d uri n g t h e pr e vi o u s 4 w e e k s.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
3 5 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
k
A n ti b o d y tit er s:  M e a s ur e m e nt of a nti b o d y tit er s a g ai n st c o m m o n a nti g e n s ( m u m p s, r u b ell a, v ari c ell a, a n d S. p n e u m o ni a e ) will b e p erf or m e d.
l
H A H A :  I n a n y c a s e of a n a p h yl a xi s, a n a p h yl a ct oi d r e a cti o n, or s eri o u s or s e v er e h y p er s e n siti vit y r e a cti o n, H A H A a n d o cr eli z u m a b c o n ce ntr ati o n 
s a m pl e s s h o ul d b e c oll e ct e d a s cl o s e a s p o s si bl e t o t h e e v e nt a n d t h e n at 4 a n d 1 6 w e e k s p o st d o s e.
P K s a m pl e s:
I n a n y c a s e of a n a p h yl a xi s, a n a p h yl a ct oi d r e a cti o n, or s eri o u s or s e v er e h y p er s e n siti vit y r e a cti o n, H A H A a n d o cr eli z u m a b 
c o n c e ntr ati o n s a m pl e s s h o ul d b e c oll e ct e d a s cl o s e a s p o s si bl e t o t h e e v e nt a n d t h e n at 4 a n d 1 6 w e e k s p o st d o s e.
m
H e p atiti s m o nit ori n g :  F or t h o s e p arti ci p a nt s e nr oll e d wit h n e g ati v e H B s A g a n d p o siti v e t ot al H B c A b, H B V D N A ( P C R) m u st c o nti n u e t o b e 
r e p e at e d e v er y 1 2 w e e k s d uri n g t h e O L E p h a s e.
n
F A C S:   I n cl u di n g C D 1 9 a n d ot h er cir c ul ati n g B c ell s u b s et s, T c ell s, n at ur al kill er c ell s a n d ot h er l e u k o c yt e s.  F A C S s a m pl e s s h o ul d b e c oll e ct e d 
pri or t o i nf u si o n.  S e e S e cti o n 5. 1 3. 2 f or s p e cifi c t e st s.
o
R o uti n e s af et y l a b o r at or y t e st s:  H e m at ol o g y, c h e mi str y , a n d uri n al y si s:  O n t h e i nf u si o n vi sit ( C y cl e 1, D a y 1), uri n e a n d bl o o d s a m pl e s 
s h o ul d b e c oll e ct e d pri or t o t h e i nf u si o n of m e t h yl pr e d ni s ol o n e.  At all ot h er ti m e s, s a m pl e s m a y b e t a k e n at a n y ti m e d uri n g t h e vi sit. 
S a m pl e s c oll e ct e d d uri n g u n s c h e d ul e d vi sit s s h o ul d pr ef er a bl y b e s e nt t o a n d a n al y z e d b y t h e c e ntr al l a b or at or y a n d n ot l o c al u nl e s s r e s ult s ar e 
r e q uir e d ur g e ntl y. 
p
R C R ( Pr ot ei n) 6 m L bl o o d s a m pl e s i n E D T A t u b e f or pl a s m a will b e t a k e n fr o m c o n s e nti n g parti ci p a nt s f or a n al y si s of pr ot ei n bi o m ar k er s.   
S a m pl e s s h o ul d b e c oll e ct e d 5 3 0 mi n ut e s pri or t o m et h yl pr e d ni s ol o n e i nf u si o n.
q
O p e n -la b el cli ni c al g e n ot y pi n g:  A 3 m L w h ol e bl o o d s a m pl e will b e t a k e n o n e ti m e fr o m p arti ci p a nt s t h at di d n ot h a v e a s a m pl e c oll e ct e d f or 
D N A a n al y si s of H L A -D R a n d F c p ol y m o r p hi s m s d uri n g t h e bli n d e d tr e at m e nt p eri o d.  If n ot c oll e ct e d at t h e fir st O L E p h a s e vi sit ( Vi sit 1), t h e 
s a m pl e m a y  b e c oll e ct e d at a n y s u b s e q u e nt vi sit.
r
All p arti ci p a nt s will r e c ei v e pr o p h yl a cti c tr e at m e nt wit h 1 0 0 m g  of m et h yl pr e d ni s ol o n e I V a n d a n or al or I V a nti hi st a mi n e, s u c h a s 
di p h e n h y dr a mi n e 5 0 m g  or e q ui v al e nt d o s e of alt er nati v e, pri or t o i nf u si o n wit h o cr eli z u m a b .  T he met h yl pre d nis ol o ne a d mi nistr ati o n is t o be 
c o m plete d a p pr o xi m atel y 3 0 mi n utes bef ore t he st art of e a c h o creli z u m a b i nf usi o n; a nti hist a mi nes s h o ul d be a d mi nistere d 3 0 6 0 mi n utes 
pri or t o t he st art of a n i nf usi o n.  I n t h e r ar e c a s e w h e n t h e u s e of m et h yl pr e d ni s ol o n e i s c o ntr ai n di c at e d f or t h e p arti ci p a nt, u s e of a n e q ui v al e nt 
d o s e of a n alt er n ati v e st er oi d ( e. g., d e x a m et h a s o n e) s h o ul d b e u s e d a s pr e m e di c ati o n pri or t o t h e i nf u si o n .  It i s al s o r e c o m m e n d e d t h at
p arti ci p a nt s r e c ei v e a n a n al g e si c/ a nti p yr eti c s u c h a s a c et a mi n o p h e n/ p ar a c et a m ol ( 1 g) 3 0 – 6 0 mi n ut e s p ri or t o o cr eli z u m a b i nf u si o n s.
s
St u d y dr u g a d mi ni str ati o n:   T h e Tr e ati n g I n v e sti g at or m u st r e vi e w t h e cli ni c al a n d l a b or at or y r e -tr e at m e nt crit eri a pri or t o r e-d o si n g p arti ci p a nt s 
wit h st u d y dr u g i n all s u b s e q u e nt tr e at m e nt c y cl e s.  T h e p arti ci p a nt will n e e d t o r e m ai n u n d er o b s er v ati o n at t h e cli ni c f or at l e a st 1 h o ur aft er 
i nf u si o n.  It i s a nti ci p at e d t h at t h e p arti ci p a nt will n e e d t o st a y at t h e h o s pit al or cli ni c f or a f ull d a y f or t h e i nf u si o n vi sit.
t
O n e -ti me o pti o n al C S F, p air e d pl a s m a s a m pl e s, a n d bl o o d s a m pl e s f or t h e R B R c oll e ct e d at a n y ti m e p oi nt i n t h e O L E p h a s e.  T h e s e s a m pl e s 
s h o ul d b e c oll e ct e d aft er t h e p arti ci p a nt' s c o n s e nt a n d at t h e n e xt p o s si bl e vi sit d uri n g t h e O L E p h a s e.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
3 6 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
P A R T I: 
S T U D Y D E SI G N A N D C O N D U C T
2.
B A C K G R O U N D A N D R A TI O N A L E
2. 1 
B A C K G R O U N D
2. 1. 1 
M ulti pl e S cl er o si s
M u lti pl e s cl er o si s ( M S) i s a n i nfl a m m at or y a n d d e g e n er ati v e d e m y eli n ati n g di s e a s e of 
t h e h u m a n C N S.  It i s a gl o b al di s e a s e t h at aff e ct s a n e sti m at e d 1. 3 milli o n p e o pl e 
w orl d wi d e, i n cl u di n g a p pr o xi m at el y 6 3 0, 0 0 0 i n E ur o p e a n d 5 2 0, 0 0 0 i n t h e A m eri c a s 
(I nt ern ati o n al F e d er ati o n of M ulti pl e S cl er o si s S o ci eti e s 2 0 0 9) .  T h e c o n diti o n m a nif e st s 
a s n e ur ol o gi c al d efi cit s r el at e d t o d a m a g e t o t h e s pi n al c or d, br ai n st e m, o pti c n er v e s, 
c er e b ell u m, a n d c er e br u m.  R e s ulti n g s y m pt o m s m a y i n cl u d e w e a k n e s s, p ai n, vi s u al 
l o ss, b o w el/ bl a d d er d y sf u n cti o n, a n d c o g niti v e d y sf u n cti o n.  Di a g n o si s of M S t y pi c all y 
o c c ur s t hr o u g h t h e a p pli c ati o n of hi g hl y str u ct ur e d di a g n o sti c crit eri a t h at r el y o n cli ni c al 
o b s er v ati o n, n e ur ol o gi c al e x a mi n ati o n, br ai n a n d s pi n al c or d m a g n eti c r e s o n a n c e 
i m a gi n g ( M RI) s c a n s, e v o k e d p ot e nti al s, a n d c er e br o s pi n al fl ui d ( C S F) st u di e s 
(M c D o n al d et al. 2 0 0 1;
P ol m a n et al. 2 0 0 5 ).
M u lti pl e s cl er o si s i s cli ni c all y s u b c at e g ori z e d i nt o 3 p h e n ot y pi c di s e a s e p att er n s 
di sti n g ui s h e d b y t h e o c c urr e n c e a n d ti mi n g of r el a p s e s r el ati v e t o di s e a s e o n s et a n d 
di s a bilit y pr o gr e s si o n ( L u bli n et al. 2 0 1 4).  T h e s e i n cl u d e r el a p si n g-r e mitti n g M S 
( R R M S), pri m ar y pr o gr e s si v e M S ( P P M S) a n d s ec o n d ar y pr o gr e s si v e M S ( S P M S).
Pri m ar y pr o gr e s si v e M S i s a r el ati v el y r ar e f or m of M S, a c c o u nti n g f or a p pr o xi m at el y 
1 0 % 1 5 % of all p e o pl e wit h M S.  Pri m ar y pr o gr e s si v e M S i s c h ar a ct eri z e d b y a 
pr o gr e s si v e c o ur s e fr o m di s e a s e o n s et wit h o ut s u p eri m p o s e d di s cr et e cli ni c al a tt a c k s or 
r el a p s e s ( E b er s 2 0 0 4, Mill er a n d L e ar y 2 0 0 7).  U nli k e R R M S, t h e t y pi c al a g e of o n s et f or 
P P M S i s ol d er at a p pr o xi m at el y 4 0 y e ar s, a n d m e n ar e aff e ct e d n e arl y a s oft e n a s 
w o m e n ( C ottr ell et al. 1 9 9 9).  T h e a b s e n c e of r el a p s e s i m p o s e s s p e ci al c h all e n g e s f or 
di a g n o si s , r e q uiri n g cli ni c al e vi d e n c e t h at t h e di s e a s e h a s a d v a n c e d f or at l e a st 1 y e ar 
fr o m s y m pt o m o n s et ( M c D o n al d et al. 2 0 0 1; P ol m a n et al. 2 0 0 5).
N at ur al hi st or y st u di e s of p ati e nt s wit h P P M S s u g g e st a di s a bli n g c o ur s e fr o m s y m pt o m 
o n s et.  I n a w ell-c h ar a ct eri z e d c o h ort of p ati e nt s wit h P P M S fr o m O nt ari o, C a n a d a, t h e 
m e di a n ti m e t o t h e u s e of a u nil at er al c a n e or br a c e ( Di s a bilit y St at u s S c al e 6 [ D S S 6 ]) 
w a s 8 y e ar s a n d t h e m e di a n ti m e t o w h e el c h air u s e ( D S S 7) w a s u n d er 2 0 y e ar s 
( C ottr ell et al. 1 9 9 9) .  A hi g h er pr o p orti o n of p ati e nt s wit h P P M S pr e s e nt i niti all y wit h 
m ot or i m p air m e nt, c er e b ell ar at a xi a a n d br ai n st e m s y m pt o m s t h a n p ati e nt s wit h 
r el a p si n g-o n s et, a n d s p a sti c p ar a p ar e si s i s a c o m m o n e arl y cli ni c al pr e s e nt ati o n 
( A n d er s s o n et al. 1 9 9 9) .
N o tr e at m e nt h a s b e e n d e m o n str at e d t o si g nifi c a ntl y sl o w t h e pr o gr e s si o n of di s a bilit y i n 
p ati e nt s wit h P P M S, i n cl u di n g t h er a pi e s a p pr o v e d f or t h e tr e at m e nt of r el a p si n g f or m s of 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
3 7 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
M S.  A l ar g e P h a s e III r a n d o mi z e d , c o ntr oll e d tri al wit h gl atir a m er a c et at e 
( Woli n s k y et al. 2 0 0 7) a n d s m all er r a n d o mi z e d , c o ntr oll e d cli ni c al tri al s e v al u ati n g 
mit o x a ntr o n e ( Kit a et al. 2 0 0 4), i nt erf er o n (I F N)--1 a i ntr a m u s c ul arl y 
(I M; L e ar y et al. 2 0 0 3) , a n d I F N--1 b ( M o nt al b a n 2 0 0 4) di d n ot d e m o n str at e a si g nifi c a nt 
i m p act o n cli ni c al pr o gr e s si o n i n t h e P P M S p o p ul ati o n.  T h e m o st r e c e ntl y c o m pl et e d 
r a n d o mi z e d, c o ntr oll e d P P M S cli ni c al tri al w a s t h e 4 3 9 -p arti ci p a nt P h a s e II/III 
St u d y U 2 7 8 6 g ( O L Y M P U S ), c o m p ari n g rit u xi m a b wit h pl a c e b o o v er a 9 6 -w e e k tr e at m e nt 
p eri o d.  O v er all , t hi s st u d y di d n ot d e m o n str at e a si g nifi c a nt tr e at m e nt eff e ct.  S u b gr o u p 
a n al y s e s s u g g e st e d t h at a y o u n g er, m or e a cti v e s u b s et of p arti ci p a nt s wit h P P M S 
( d efi n e d b y t h e pr e s e n c e of g a d oli ni u m [ G d]-e n h a n ci n g l e si o n s s e e n o n M RI s c a n s at 
b a s eli n e a n d hi g h er lif eti m e r at e s of di s a bilit y pr o gr e s si o n) m a y h a v e b e n efitt e d cli ni c all y 
fr o m a nti-C D 2 0 t h er a p y ( H a w k er et al. 2 0 0 9).  C urre ntl y, P P M S r e m ai n s a s e v er el y 
di s a bli n g c o n diti o n wit h v er y hi g h u n m et m e di c al n e e d.
2. 1. 2 
O cr eli z u m a b
O cr eli z u m a b (r h u M A b 2 H 7, RO 4 9 6 4 9 1 3, P R O 7 0 7 6 9) i s a h u m a ni z e d, gl y c o s yl at e d 
m o n o cl o n al a nti b o d y
dir e ct e d a g ai n st t h e C D 2 0 a nti g e n pr e s e nt o n s el e ct n or m al , a s 
w e ll a s m ali g n a nt B c ell s.  C l u st er of diff er e nti ati o n ( C D)2 0 i s a B c ell s urf a c e m ol e c ul e 
t h at i s r e stri ct e d i n e x pr e s si o n t o pr eB c ell s a n d m at ur e B c ell s b ut i s n ot e x pr e s s e d 
e arli er i n t h e d e v el o p m e nt of B c ell s ( B a n c h er e a u a n d R o u s s et 1 9 9 2) .  O cr eli z u m a b 
s h ar e s a si mil ar b a si c m e c h a ni s m of a cti o n a s rit u xi m a b ( M a b T h er a /Rit u x a n ), a 
c hi m eri c m o n o cl o n al a nti b o d y al s o dir e ct e d a g ai n st t h e C D 2 0 a nti g e n.  Cli ni c al 
e x p eri e n c e wit h rit u xi m a b h a s d e m o n str at e d B c ell d e pl eti o n t o b e of m aj or cli ni c al 
b e n efit f or t h e tr e at m e nt of c ert ai n l y m p h o m a t y p e s a n d r h e u m at oi d art hriti s ( R A).  
T h e s af et y a n d effi c a c y of o cr eli z u m a b w a s e v al u at e d i n m ulti pl e r a n d o mi z e d, c o ntr oll e d 
P h a s e III cli ni c al tri al s i n M S a n d
R A ( s e e b el o w) a n d a P h a s e II st u d y i n R R M S 
( s e e S e cti o n 2. 1. 4 ).
2. 1. 2. 1 
Hi st or y  of O cr eli z u m a b
T h e fir st h u m a n e x p eri e n c e wit h o cr eli z u m a b i n a ut o i m m u n e c o n diti o n s w a s fr o m 
2 P h a s e I/II d o s e -e s c al ati n g st u di e s (A C T 2 8 4 7 g [G e n o v e s e et al. 2 0 0 8 ] a n d WA 1 8 2 3 0 )
i n p a rti ci p a nt s wit h a cti v e R A.  I n t h e s e st u di e s, o cr eli z u m a b w a s f o u n d t o b e g e n er all y 
w e ll-t ol er at e d i n p arti ci p a nt s wit h R A, a n d n o u n a nti ci p at e d s af et y c o n c er n s w er e 
o b s er v e d w h e n c o m p ar e d wit h d at a fr o m p arti ci p a nt s wit h R A tr e at e d wit h rit u xi m a b.  
M or e d et ail e d i nf or m ati o n fr o m c o m pl et e d st u di e s r e g ar di n g t h e n o n cli ni c al a n d cli ni c al 
r e s ult s wit h o cr eli z u m a b i s pr o vi d e d i n t h e O cr eli z u m a b I n v e sti g at or’ s Br o c h ur e.
T h e d e v el o p m e nt pr o gr a m s f or R A a n d l u p u s h a v e b e e n t er mi n at e d.  T h e a n al y s e s of 
effi c a c y a n d s af et y d at a fr o m t h e P h a s e III st u di e s i n R A l e d t h e S p o n s or s t o c o n cl u d e 
t h at o cr eli z u m a b 2 0 0 m g 2 pr o vi d e d n o a d diti o n al b e n efit t o c urr e ntl y a v ail a bl e 
t h er a pi e s i n t h e t ar g et p o p ul ati o n of p ati e nt s wit h T N F -I R, w hil e o cr eli z u m a b 5 0 0 m g 2 
d e m o n str at e d a n u nf a v or a bl e s af et y pr ofil e ( hi g h er s eri o u s i nf e cti o n r at e). T h e 
u nf a v or a bl e s af et y pr ofil e of o cr eli z u m a b 5 0 0 m g 2 w a s dri v e n m ai nl y ( alt h o u g h n ot 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
3 8 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
e ntir el y) b y p arti ci p a nt s r e cr uit e d fr o m A si a. T h e S p o n s or c o n cl u d e d t h at t h e s e 
o b s er v ati o n s d o n ot s u p p ort f urt h er d e v el o p m e nt of t hi s t h er a p y i n R A.
A s a r e s ult of t h e li mit e d n u m b er of p arti ci p a nt s ( 3 3 p arti ci p a nt s ) e nr oll e d i n 
St u d y W A 2 0 4 9 9 ( s y st e mi c lu p u s e r yt h e m at o s u s st u d y) at t h e ti m e of t h e st u d y 
t er mi n ati o n; n o m e a ni n gf ul a n al y si s of effi c a c y c o ul d b e c o n d u ct e d. St u d y W A 2 0 5 0 0 
( L N st u d y) w a s t er mi n at e d pri or t o t h e ti mi n g of t h e pri m ar y e n d p oi nt.
2. 1. 3 
R ati o n al e f or T ar g eti n g B C ell s i n M ulti pl e S cl er o si s
H u m or al i m m u nit y h a s b e e n i m pli c at e d i n M S f or d e c a d e s, a s e vi d e n c e d b y i n cl u si o n of 
C S F oli g o cl o n al b a n d s a n d i n cr e a s e d i ntr at h e c al I g G s y nt h e si s i n di a g n o sti c crit eri a f or 
M S ( M c D o n al d et al. 2 0 0 1; P ol m a n et al. 2 0 0 5; Si d é n 1 9 7 9).  Alt h o u g h , u ntil v er y 
r e c entl y, t h e pr e v aili n g vi e w of M S p at h o p h y si ol o g y h el d t h at t h e C N S i nfl a m m ati o n s e e n 
i n M S i s pri n ci p all y m e di at e d b y C D 4pr o -i nfl a m m at or y ( T h 1, T h 1 7) T c ell s, r a pi dl y 
e x p a n di n g e vi d e n c e s u g g e st s t h at B c ell s m a y c o ntri b ut e t o M S p at h o g e n e si s m u c h 
m or e t h a n w a s pr e vi o u sl y b eli e v e d, p ot e nti all y t hr o u g h eit h er a nti b o d y-d e p e n d e nt or 
i n d e p e n d e nt m e c h a ni s m s ( M ei nl et al. 2 0 0 6; Fr a n ci ott a et al. 2 0 0 8; M c F arl a n d 2 0 0 8).
B l y m p h o c yt e s h a v e b e e n d et e ct e d wit hi n M S l e si o n s a n d i n t h e C S F of p ati e nt s wit h 
M S.  M ol e c ul ar a n al y si s of b ot h l e si o n al a n d C S F B c ell r e p ert oir e s r e v e al e d d o mi n a nt, 
cl o n all y -e x p a n d e d B c ell p o p ul ati o n s e x hi biti n g s o m ati c h y p er m ut ati o n i n t h e 
a nti g e n -r e c o g ni zi n g C D R 3 r e gi o n s of I g h e a v y c h ai n s, pr e d o mi n at el y wit hi n t h e V H 4
g e n e f amil y ( O w e n s et al. 1 9 9 8; Qi n et al. 1 9 9 8; B ar a n zi ni et al. 1 9 9 9; 
C ol o m b o et al. 2 0 0 0; Rit c hi e et al. 2 0 0 4; L a m br a c ht -W a s hi n gt o n et al. 2 0 0 7; 
O w e n s et al. 2 0 0 7) .  D et e cti o n of t h e s e affi nit y-m at ur e d, cl o n all y -e x p a n d e d r e p ert oir e s i n 
t h e C S F b ut n ot i n t h e p eri p h er al bl o o d of p ati e nt s wit h M S s u g g e st s t h at a l o c ali z e d, 
a nti g e n -dri v e n B c ell r e s p o n s e i s pr e s e nt i n t h e C N S c o m p art m e nt.  C er e br o s pi n al fl ui d
cl o n al B c ell e x p a n si o n h a s b e e n r e p ort e d i n p arti ci p a nt s wit h b ot h R R M S a n d P P M S 
s h ortl y aft er di a g n o si s, i m pl yi n g a r ol e f or B c ell s e arl y i n M S p at h o g e n e si s r at h er t h a n 
a s a l at e r e s p o n s e t o l o n g st a n di n g ti s s u e d a m a g e ( M o n s o n et al. 2 0 0 5).  M or e r e c e ntl y, 
c D N A tr a n s cri pt o m e s of cl o n a ll y-e x p a n d e d affi nit y -m at ur e d B
c ell s i s ol at e d fr o m t h e C S F 
of  p arti ci p a nt s wit h M S h a v e b e e n s e q u e n c e -m at c h e d t o s p e cifi c I g G oli g o cl o n al b a n d s
fr o m t h e s a m e C S F s a m pl e s, i n di c ati n g t h at t hi s l o n g st a n di n g h all m ar k of M S di a g n o si s 
d eri v e s fr o m i d e ntifi a bl e B c ell cl o n e s pr e s e nt i n t h e C N S c o m p art m e nt 
( O b er m ei er et al. 2 0 0 8) .
M a n y h y p ot h e s e s f or t h e r ol e of B c ell s i n M S h a v e b e e n p o st ul at e d.  B c ell s m a y 
diff er e nti at e i nt o pl a s m a c ell s a n d pr o d u c e C N S -dir e ct e d a ut o a nti b o di e s , p ot e nti all y 
tri g g eri n g c ell ul ar a n d c o m pl e m e nt-d e p e n d e nt c yt ot o xi cit y.  Alt h o u g h a p at h o g e ni c r ol e 
of  a nti m y eli n a nti b odi e s i n M S h a s n ot b e e n e st a bli s h e d, t h e y h a v e b e e n d et e ct e d i n t h e 
C S F of p ati e nt s wit h M S ( R ei n dl et al. 1 9 9 9; E g g et al. 2 0 0 1; A n d er s s o n et al. 2 0 0 2) a n d 
i n a cti v e M S l e si o n s ( G e n ai n et al. 1 9 9 9), a n d r e m ai n p ot e nti al c a n di d at e s a s eff e ct or s of 
m y eli n s h e at h d a m a g e.  B c ell s m a y al s o f u n cti o n a s a nti g e n pr e s e nti n g c ell s a n d 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
3 9 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
t h er e b y m o d ul at e eff e ct or T c ell r e s p o n s e s, a s t h e y e x hi bit r e g ul at e d s e cr eti o n of b ot h 
pr o -i nfl a m m at or y a n d a nti-i nfl a m m at or y c yt o ki n e s, a f u n cti o n t h at a p p e ar s t o b e 
a b n or m al i n p at i e nt s wit h M S ( M ei nl et al. 2 0 0 6) .  Fi n all y, B c ell s m a y b e a sit e of l at e nt 
vir al i nf e cti o n s s u c h a s E p st ei n -B arr v ir u s, w hi c h m a y dri v e C N S a ut oi m m u n e r e s p o n s e s 
t hr o u g h m ol e c ul ar mi mi cr y or ot h er pr o-i nfl a m m at or y m e c h a ni s m s 
( Fr a n ci ott a et al. 2 0 0 8) .
P o st -m ort e m p at h ol o gi c al st u di e s h a v e i d e ntifi e d t h e pr e s e n c e of e ct o pi c f olli c ul ar 
l y m p h oi d str u ct ur e s i n t h e m e ni n g e s a n at o mi c all y pr o xi m al t o sit e s of gr e y-m att er 
d e m y eli n ati o n i n a s u b s et of p ati e nt s wit h S P M S ( S er afi ni et al. 2 0 0 4; 
K ut z el ni g g et al. 2 0 0 7; M a gli o z zi
et al. 2 0 0 7) .  Si mil ar t erti ar y l y m p h oi d str u ct ur e s f or m 
d e n o v o i n v ari o u s ti s s u e s of m a n y a ut oi m m u n e di s or d er s a n d r e pr e s e nt p ot e nti al d e 
n o v o sit e s of c hr o ni c a ut o a nti g e ni c B c ell a cti v ati o n, m at ur ati o n a n d cl o n al e x p a n si o n 
( Al oi si a n d P uj ol-B orr ell 2 0 0 6) .  P ati e nt s wit h S P M S e x hi biti n g t h e s e l y m p h oi d str u ct ur e s 
h a v e b e e n f o u n d t o h a v e w or s e pr o gr e s si o n r at e s, w h e n c o m p ar e d wit h c o ntr ol s wit h o ut 
s u c h f olli c ul ar str u ct ur e s ( H o w ell et al. 2 0 0 9) a n d a p at h o m e c h a ni sti c li n k t o gr e y-m att er 
d e m y eli n ati o n t y pi c al f or S P M S h a s b e e n s u g g e st e d.  Alt h o u g h t erti ar y l y m p h oi d 
str u ct ur e s h a v e n ot b e e n d e s cri b e d i n t h e s m all n u m b er of p ati e nt s wit h P P M S st u di e d, 
gr e y -m att er d e m y eli n ati o n i s pr o mi n e nt i n br ai n s p e ci m e n s fr o m b ot h p ati e nt s wit h 
S P M S a n d P P M S, a n d it i s c o n c ei v a bl e t h at t h e s a m e p at h o m e c h a ni s m a s s u g g e st e d i n 
S P M S m a y a p pl y f or P P M S.  W h et h er or n ot a n a nti -C D 2 0 t h er a p e uti c a nti b o d y c a n 
aff e ct t h e f or m ati o n or p er si st e n c e of m e ni n g e al l y m p h oi d f olli cl e s or t h e gr e y -m att er 
d e m y eli n ati o n pr o mi n e nt i n pr o gr e s si v e f or m s of M S i s u n k n o w n.
I n s u m m ar y, B l y m p h o c yt e s ar e b eli e v e d t o c o ntri b ut e t o t h e p at h o g e n e si s of all 
s u bt y p e s of M S, i n cl u di n g P P M S.  R e m o vi n g s el e ct p eri p h er al B c ell s fr o m cir c ul ati o n 
m a y b e n efi ci all y di sr u pt i nfl a m m at or y pr o c e s s e s
t h at p ot e nti all y i n v ol v e c hr o ni c a nti g e ni c 
sti m ul ati o n or ot h er r e g ul at or y f u n cti o n s pr o m oti n g c hr o ni c a ut oi m m u nit y.  
O cr eli z u m a b s p e cifi c all y d e pl et e s C D 2 0 B c ell s, m a ki n g it a p ot e nti all y attr a cti v e 
p h ar m a c ol o gi c al a g e nt t o t e st t h er a p e uti c p ot e nti al i n p ati e nt s wit h P P M S.
2. 1. 4 
S p o n s or E x p eri e n c e wit h A nti -C D 2 0 C o m p o u n d s i n M ulti pl e 
S cl er o si s
2. 1. 4. 1 
O cr eli z u m a b i n R R M S
St u d y W A 2 1 4 9 3/ A C T 4 4 2 2 G w a s a 2 2 0 -p arti ci p a nt P h a s e II, m ulti c e nt er, r a n d o mi z e d, 
p ar all el -gr o u p, pl a c e b o -c o ntr oll e d, pr o of -of -c o n c e pt st u d y t o e v al u at e t h e s af et y a n d 
effi c a c y of 2 d o s i n g r e gi m e n s of o cr eli z u m a b (1 0 0 0 m g 2 [a d mi ni st er e d o n D a y 1 a n d 
D a y 1 5, f oll o w e d b y si n gl e i nf u si o n s of 1 0 0 0 m g f or s u b s e q u e nt c y cl e s ] a n d 
3 0 0 m g 2 [ a d mi ni st er e d o n D a y 1 a n d D a y 1 5 , f oll o w e d b y si n gl e i nf u si o n s of 6 0 0 m g 
f or s u b s e q u e nt c y cl e s]), wit h a n a d diti o n al r a n d o mi z e d o p e n -l a b el arm of I F N 1- a 
3 0 g I M e v er y w e e k.  T h e pri m ar y o bj e cti v e w a s t o e v al u at e t h e effi c a c y of 2 d o s i n g
r e gi m e n s of o cr eli z u m a b c o m p ar e d wit h pl a c e b o i n r e d u ci n g br ai n i nfl a m m ati o n, a s 
m e a s ur e d b y t h e t ot al n u m b er of G d -e n h a n ci n g T 1 l e si o n s o b s er v e d o n s eri al M RI s c a n s 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
4 0 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
of  t h e br ai n at We e k s 1 2, 1 6, 2 0, a n d 2 4.  K e y s e c o n d ar y o bj e cti v e s w er e t o e v al u at e t h e 
effi c a c y of b ot h d o s i n g r e gi m e n s of o cr eli z u m a b c o m p ar e d wit h pl a c e b o i n r e d u ci n g 
a n n u ali z e d r el a p s e r at e ( A R R ) at W e e k 2 4 a n d t o e v al u at e t h e s af et y a n d t ol er a bilit y of 
b ot h d o si n g r e gi m e n s of o cr eli z u m a b i n p arti ci p a nt s wit h R R M S.  E x pl or at or y o ut c o m e s 
in cl u d e d a n al y si s of b ot h d o si n g r e gi m e n s of o cr eli z u m a b c o m p ar e d wit h I F N - 1-a 
3 0 g I M w e e kl y f or v ari o u s st u d y m e a s ur e s.  Tr e at m e nt wit h o cr eli z u m a b w a s pl a n n e d 
f or 7 29 6 w e e k s t ot al, d e p e n di n g o n t h e st u d y ar m ( p arti ci p a nt s fr o m b ot h t h e pl a c e b o 
a n d t h e I F N -1 a gr o u p s wit c h e d t o o cr eli z u m a b 3 0 0 m g 2 aft er W e e k 2 4).  
A d diti o n al M RI s c a n s of t h e br ai n will b e o bt ai n e d at W e e k s 9 6 a n d 1 4 4 f or a s u b gr o u p 
of  p arti ci p a nt s.
W e e k 2 4 r e s ult s d e m o n str at e d t h at b ot h d o s e s of o cr eli z u m a b a c hi e v e d t h e pri m ar y 
e n d p oi nt b y si g nifi c a ntl y r e d u ci n g t h e n u m b er of G d -e n h a n ci n g l e si o n s c o m p ar e d wit h 
pl a c e b o ( p 0. 0 0 0 1).  B ot h o cr eli z u m a b d o s e gr o u p s s h o w e d st ati sti c all y si g nifi c a nt 
r e d u cti o n s i n A R R c o m p ar e d wit h t h e pl a c e b o gr o u p ( A R R 0. 1 2 5 f or t h e o cr eli z u m a b 
3 0 0 m g 2 gr o u p [ p 0. 0 0 0 5] a n d A R R 0. 1 6 9 f or t h e o cr eli z u m a b 1 0 0 0 m g 2 gr o u p 
[ p0. 0 0 1 4] c o m p ar e d wit h A R R 0. 6 3 7 f or t h e pl a c e b o gr o u p), r e pr e s e nti n g a r el ati v e 
r e d u cti o n ( R R) of 8 0 % a n d of 7 3 % i n A R R v s. t h e pl a c e b o gr o u p f or t h e l o w d o s e a n d 
t h e hi g h-d o s e o cr eli z u m a b gr o u p s, r e s p e cti v el y.  I n e x pl or at or y a n al y s e s, b ot h 
o cr eli z u m a b gr o u p s w er e s u p eri or t o t h e I F N -1 a gr o u p f or t h e pri m ar y e n d p oi nt 
( p 0. 0 0 0 1) a n d t h e 3 0 0 m g 2 gr o u p f or A R R ( A R R 0. 3 6 4 f or t h e I F N -1 a gr o u p, 
r e pr es e nti n g a n R R of 6 6 % i n A R R wit h p 0. 0 3 f or t h e o cr eli z u m a b 3 0 0 m g 2 gr o u p 
v s. t h e I F N -1 a gr o u p a n d a R R of 5 3. 6 % i n t h e A R R wit h p 0. 0 8 6 f or t h e o cr eli z u m a b 
1 0 0 0 m g 2 gr o u p v s. t h e I F N -1 a gr o u p; K a p p o s et al. 2 0 1 1).
P arti ci p a nt s fr o m b ot h t h e pl a c e b o a n d I F N -1 a gr o u p s s wit c h e d t o o cr eli z u m a b 
3 0 0 m g 2 aft er W e e k  2 4.  B y 4 8 w e e k s, t h e l e v el of b e n efit of o cr eli z u m a b i n r e d u cti o n 
of  A R R w a s m ai nt ai n e d; p arti ci p a nt s i n t h e o cr eli z u m a b 3 0 0 m g 2 gr o u p c o nti n u e d t o 
h a v e a s u p pr e s s e d A R R of 0. 0 8 6 fr o m W e e k s 2 4 4 8, a n d p arti ci p a nt s w h o s wit c h e d t o 
o cr eli z u m a b fr o m eit h er pl a c e b o or I F N -1 a d eri v e d a si mil ar d e gr e e of effi c a c y t o t h o s e 
r a n d o mi z e d t o o cr eli z u m a b fr o m o n s et ( A R R f or pl a c e b o-t o-o cr eli z u m a b 0. 1 6 1 a n d f or 
I F N -1 a -t o-o cr eli z u m a b 0. 1 3 7 aft er t h e s wit c h, r e pr e s e nti n g a R R of 7 4 % a n d 6 2. 4 % 
c o m p ar e d wit h A R R b ef or e t h e s wit c h, r e s p e cti v el y).  Fr o m W e e k s 0 7 2, p arti ci p a nt s 
ori gi n all y r a n d o mi z e d t o o cr eli z u m a b 3 0 0 m g 2 m ai nt ai n e d cli ni c al effi c a c y wit h a n A R R
of  0. 1 8 6.
T h e m o st c o m m o nl y r e p ort e d a d v er s e e v e nt s i n o cr eli z u m a b -tr e at e d p arti ci p a nt s w er e 
i nf u si o n-r el at e d r e a cti o n s (I R R s).  Inf u si o n -r el at e d r e a cti o n s w er e r e p ort e d d uri n g/ aft er 
t h e fir st i nf u si o n ( D a y 1) f or 3 0 % 4 3. 6 % of p arti ci p a nt s tr e at e d wit h o c r eli z u m a b.  
F e w er p arti ci p a nt s ( 2. 1 % 9. 4 %) e x p eri e n c e d I R R s d uri n g/ aft er t h e s e c o n d i nf u si o n 
( D a y 1 5).  T h e m o st c o m m o n s y m pt o m s w er e r a s h, pr urit u s, fl u s hi n g, t a c h y c ar di a, 
h e a d a c h e, p yr e xi a, a n d t hr o at irrit ati o n.  N o u n a nti ci p at e d, cli ni c all y si g nifi c a nt


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4 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
a b n or m aliti e s i n vit al si g n s, E C G s, or l a b or at or y p ar a m et er s w er e o b s er v e d i n 
a s s o ci ati o n wit h o cr eli z u m a b tr e at m e nt.
O n r e vi e w of t h e pl a c e b o -c o ntr oll e d, d o u bl e -bli n d e d, 2 4 -w e e k s af et y d at a, n o i m b al a n c e 
i n a d v er s e e v e nt s ( or i nf e cti o n a d v er s e e v e nt s) or s eri o u s a d v er s e e v e nt s ( or i nf e cti o n 
s eri o u s a d v er s e e v e nt s) b et w e e n t h e pl a c e b o a n d t h e a cti v e o cr eli z u m a b ar m s w a s 
o b s er v e d.   T h e r at e of a d v er s e e v e nt s ( or i nf e cti o n a d v er s e e v e nt s) a n d s eri o u s a d v er s e 
e v e nt s ( or i nfe cti o n s eri o u s a d v er s e e v e nt s) di d n ot i n cr e a s e i n o cr eli z u m a b -tr e at e d 
p arti ci p a nt s at W e e k 4 8 c o m p ar e d wit h W e e k 2 4.  N o tr e n d t o w ar d a n i n cr e a s e d ri s k of 
a d v er s e e v e nt s ( or i nf e cti o n a d v er s e e v e nt s ) or s eri o u s a d v er s e e v e nt s ( or i nfe cti o n 
s eri o u s a d v er s e e v e nt s) w a s f o u n d f or o cr eli z u m a b-tr e at e d p arti ci p a nt s wit h pr e vi o u s 
I F N tr e at m e nt (f or 6 m o nt h s).
B y t h e ti m e all p arti ci p a nt s fi ni s h e d W e e k 4 8 of tr e at m e nt, t h e i n ci d e n c e of i nf e cti o n s a n d 
s eri o u s i nf e cti o n s w a s 9 2. 4 1/ 1 0 0 p arti ci p a nt -y e ar s ( P Y) ( 9 5 % CI: 7 6. 5 9, 1 1 1. 5) a n d 
3. 3 9/ 1 0 0 P Y ( 9 5 % CI:
1. 2 7, 9. 0 4) i n p arti ci p a nt s e x p o s e d t o l o w -d o s e o cr eli z u m a b, 
i n cl u di n g p arti ci p a nt s w h o s wit c h e d fr o m pl a c e b o or I F N -1 a .  T h e i n ci d e n c e of 
i nf e cti o n s a n d s eri o u s i nf e cti o n s w a s 9 7. 3 8/ 1 0 0 P Y ( 9 5 % CI: 7 4. 7 6, 1 2 6. 8 4) a n d 
5. 3 1/ 1 0 0 P Y ( 9 5 % CI: 1. 7 1, 1 6. 4 7) i n t h o s e e x p o s e d t o t h e hi g h d o s e of o cr eli z u m a b.  
T h e m o st c o m m o n i nf e cti o n s i n o cr eli z u m a b -tr e at e d p arti ci p a nt s i n cl u d e d uri n ar y tr a ct 
i nf e cti o n s, u p p er r e s pir at or y i nf e cti o n s, a n d n a s o p h ar y n giti s.
T o d at e, i n S t u d y WA 2 1 4 9 3, aft er o v er 2 5 0 p arti ci p a n t-y e ar s of e x p o s ur e t o o cr eli z u m a b, 
n o r e p ort s of o p p ort u ni sti c or f at al i nf e cti o n s h a v e b e e n m a d e .
Pl e a s e r ef er t o t h e O cr eli z u m a b I n v e sti g at or’ s Br o c h ur e f or m or e i nf or m ati o n.
2. 1. 4. 2 
Rit u xi m a b i n R R M S
T w o cli ni c al tri al s of rit u xi m a b h a v e b e e n c o n d u ct e d i n p arti ci p a nt s wit h R R M S . 
R it u xi m a b i s a c hi m eri c m o u s e/ h u m a n m o n o cl o n al a nti b o d y t h at s h ar e s t h e s a m e b a si c 
m e c h a ni s m of a cti o n a s o cr eli z u m a b.  Fi n di n g s bri efl y hi g hli g ht e d b el o w off er a d diti o n al 
s u p p ort f or t h e t h er a p e uti c p ot e nti al of t h e a nti -C D 2 0 m e c h a ni s m i n M S.
St u d y U 3 2 6 4 g ( H E R M E S Jr.) w a s a P h a s e I, o p e n-l a b el, m ulti c e nt er st u d y i n 2 6 a d ult s 
wit h R R M S t o e v al u at e t h e s af et y a n d t ol er a bilit y of 2 tr e at m e nt c y cl e s of rit u xi m a b 
a d mi ni st er e d at b a s eli n e a n d aft er 2 4 w e e k s.  R e -tr e at m e nt wit h rit u xi m a b ( 1 0 0 0 m g 2) 
at 2 4 w e e k s w a s s af e a n d w ell -t ol er at e d a n d r e s ult e d i n a n o b s er v e d d e cr e a s e i n 
r el a p s e s a n d G d-e n h a n ci n g l e si o n s t hr o u g h 7 2 w e e k s ( B ar -Or et al. 2 0 0 8).
St u d y U 2 7 8 7 g ( H E R M E S) w a s a P h a s e II, pr o of -of -c o n c e pt, r a n d o mi z e d, d o u bl e -bli n d, 
p ar all e l-gr o u p, pl a c e b o -c o ntr oll e d, m ulti c e nt er st u d y t o e v al u at e t h e s af et y a n d effi c a c y 
of  rit u xi m a b i n 1 0 4 a d ult s wit h R R M S.  T h e pri m ar y o bj e cti v e s w er e t o i n v e sti g at e t h e 
effi c a c y of rit u xi m a b c o m p ar e d wit h pl a c e b o, a s m e a s ur e d b y t h e t ot al n u m b er of 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
4 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
G d -e n h a n ci n g T 1 l e si o n s o b s er v e d o n s eri al M RI s c a n s of t h e br ai n at W e e k s 1 2, 1 6, 
2 0, a n d 2 4, a n d t o e v al u at e t h e s af et y a n d t ol er a bilit y of rit u xi m a b i n p arti ci p a nt s wit h 
R R M S.  S e c o n d ar y o bj e cti v e s w er e t o e v al u at e a d diti o n al M RI p ar a m et er s a n d t h e 
pr o p orti o n of p arti ci p a nt s r el a p si n g.  T h e tri al m et it s pri m ar y effi c a c y e n d p oi nt a n d all 
s e c o n d ar y e n d p oi nt s.  Rit u xi m a b w a s s af e a n d g e n er all y w ell -t ol er at e d i n t hi s st u d y 
t hr o u g h 4 8 w e e k s , al t h o u g h t h e r at e of i nf u si o n-a s s o ci at e d a d v er s e e v e nt s, p arti c ul arl y 
af t er t h e fir st i nf u si o n, w a s hi g h er i n rit u xi m a b-tr e at e d p arti ci p a nt s ( 7 8 %) t h a n i n 
p arti ci p a nt s w h o r e c ei v e d pl a c e b o ( 4 0 %) .
Corti c o st er oi d pr e m e di c ati o n w a s n ot 
a d mi ni st er e d b ef or e or at t h e ti m e of i nf u si o n.  St u d y U 2 7 8 7 g pr o vi d e s pr o of of t h e 
pri n ci pl e t h at a n a nti -C D 2 0 t h er a p e uti c a p pr o a c h c a n r e d u c e b ot h M RI a n d cli ni c al 
e vi d e n c e of i nfl a m m at or y a cti vit y i n a d ult s wit h R R M S ( H a u s er et al. 2 0 0 8).
2. 1. 4. 3 
Rit u xi m a b i n P P M S
A si n gl e, P h a s e II/III, r a n d o mi z e d, d o u bl e -bli n d e d, pl a c e b o -c o ntr oll e d tri al of rit u xi m a b 
f or P P M S w a s c o n d u ct e d.  T h e fi n di n g s s u m m ari z e d b el o w r e pr e s e nt t h e l ar g e st a n d 
l o n g e st d ur ati o n tri al e x p eri e n c e t o d at e e v al u ati n g t h e s af et y a n d effi c a c y of a nti-C D 2 0 
t h er a p y i n i n di vi d u al s wit h M S .
St u d y U 2 7 8 6 g ( O L Y M P U S) w a s a P h a s e II/III, r a n d o mi z e d, d o u bl e -bli n d, p ar all el -gr o u p, 
pl a c e b o -c o ntr oll e d, m ulti c e nt er st u d y e v al u ati n g t h e s af et y a n d effi c a c y of rit u xi m a b i n 
p arti ci p a nt s wit h P P M S o v er a 9 6 -w e e k tr e at m e nt p eri o d c o n si sti n g of 4 tr e at m e nt c y cl e s 
wit h d u al i nf u si o n s of 1 0 0 0 m g ( 2 0 0 0 m g/ c y cl e).  Alt h o u g h t h e tri al di d n ot d e m o n str at e 
si g nifi c a nt pri m ar y effi c a c y o n ti m e t o c o nfir m e d di s e a s e pr o gr e s si o n a s m e a s ur e d b y 
t h e E x p a n d e d Di s a bilit y St at u s S c al e ( E D S S), a diff er e n c e w a s o b s er v e d:  3 8. 5 % of 
p arti ci p a nt s i n t h e pl a c e b o gr o u p e x p eri e n c e d c o nf ir m e d di s e a s e pr o gr e s si o n v s. 3 0. 2 % 
i n t h e rit u xi m a b gr o u p.  Bi ol o gi c al a cti vit y w a s e vi d e n c e d b y si g nifi c a ntl y l o w er T 2 l e si o n 
v ol u m e a c c u m ul ati o n o n br ai n M RI, a s e c o n d ar y effi c a c y e n d p oi nt, i n rit u xi m a b -tr e at e d 
p arti ci p a nt s c o m p ar e d wit h t h o s e w h o r e c eiv e d pl a c e b o ( p 0. 0 0 0 8).  
S u b gr o u p a n al y s e s s u g g e st t h at p arti ci p a nt s wit h P P M S a n d e vi d e n c e of a cti v e di s e a s e 
m a y h a v e s h o w n si g nifi c a nt cli ni c al tr e at m e nt r e s p o n s e a s m e a s ur e d b y ti m e t o 
c o nfir m e d di s e a s e pr o gr e s si o n o v er a 9 6 -w e e k ti m efr a m e.  F a ct or s t h at a p p e ar e d 
pr o g n o sti c f or di s e a s e pr o gr e s si o n a n d p ot e nti all y pr e di cti v e of tr e at m e nt r e s p o n s e i n 
t h e rit u xi m a b gr o u p i n cl u d e d y o u n g er a g e, pr e s e n c e of c o ntr a st-e n h a n ci n g l e si o n s at 
b a s eli n e o n br ai n M RI, a n d hi g h er M S s e v erit y s c or e .
Rit u xi m a b w a s g e n e r all y s af e a n d w ell-t ol er at e d i n St u d y U 2 7 8 6 g.  T h e pr o p orti o n s of 
p arti ci p a nt s wit h at l e a st 1 a d v er s e e v e nt ( 1 0 0 % f or pl a c e b o v s . 9 9 % f or rit u xi m a b) a n d 
1 s eri o u s a d v er s e e v e nt ( 1 3. 6 % f or pl a c e b o v s . 1 6. 1 % f or rit u xi m a b) w er e c o m p ar a bl e 
b et w e e n tr e at m e nt gr o u p s.  T hr e e a d v er s e e v e nt s t h at o c c urr e d d uri n g t h e st u d y l e d t o 
d e at h: 1 a d v er s e e v e nt i n t h e rit u xi m a b gr o u p f oll o wi n g r e c urr e nt a s pir ati o n p n e u m o ni a s 
a n d 2 a d v er s e e v e nt s i n t h e pl a c e b o gr o u p b e c a u s e of p n e u m o ni a a n d c ar di o p ul m o n ar y 
f ail ur e.  M or e i nfu si o n -a s s o ci at e d a d v er s e e v e nt s w er e o b s er v e d i n rit u xi m a b -tr e at e d 
p arti ci p a nt s ( 7 3. 6 % f or rit u xi m a b v s . 4 0. 3 % f or pl a c e b o), p arti c ul arl y aft er t h e fir st 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
4 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
i nf u si o n, b ut r at e s d e cli n e d i n b ot h gr o u p s t o si mil ar l e v el s u p o n s u c c e s si v e i nf u si o n s.  
P arti ci p a nt s w er e n ot pr e -m e di c at e d
wit h gl u c o c orti c oi d s b ef or e rit u xi m a b i nf u si o n s i n 
St u d y U 2 7 8 6 g.  T h e v a st m aj orit y ( 9 2 %) of i nf u si o n -a s s o ci at e d e v e nt s i n 
rit u xi m a b-tr e at e d p arti ci p a nt s w er e mil d t o m o d er at e i n s e v erit y; n o Gr a d e 4 or 5 
i nf u si o n-a s s o ci at e d e v e n t s w er e o b s er v e d.  T h e pr o p orti o n of p arti ci p a nt s wit h at l e a st 
1 i nfe cti o n w a s c o m p ar a bl e b et w e e n gr o u p s ( 6 8. 2 % f or rit u xi m a b v s. 6 5. 3 % f or pl a c e b o), 
b ut a hi g h er pr o p orti o n of p arti ci p a nt s wit h at l e a st 1 s eri o u s i nf e cti o n w a s o b s er v e d i n 
t h e rit u xi m a b-tr e at e d gr o u p ( 4. 5 %) c o m p ar e d wit h pl a c e b o (1 %).  N o o p p ort u ni sti c 
i nf e cti o n s o c c urr e d.
Tr e at m e nt wit h rit u xi m a b w a s a s s o ci at e d wit h r a pi d a n d n e ar -c o m pl et e d e pl eti o n of 
cir c ul ati n g C D 1 9 B l y m p h o c yt e s b e gi n ni n g 2 w e e k s p o st -tr e at m e nt t hr o u g h 9 6 w e e k s.  
A p pr o xi m at el y 3 5 % of rit u xi m a b -tr e at e d p arti ci p a nt s h a d r e c o v er e d p eri p h er al C D 1 9 
B c ell c o u nt s t o 8 0 c ell s/ L (t h e l a b or at or y d efi n e d l o w er li mit of n or m al [ L L N] i n h e alt h y 
v ol u nt e er s) wit hi n 4 8 w e e k s aft er t h e l a st d o s e.  M e d i a n cir c ul ati n g C D 3 T -l y m p h o c yt e 
c o u nt s w er e n ot a p pr e ci a bl y alt er e d b y rit u xi m a b.  At a n y ti m e i n t h e tri al, I g M l e v el s 
w er e b el o w t h e L L N i n 3 1. 7 % of rit u xi m a b -tr e at e d p arti ci p a nt s a n d 5. 9 % of 
pl a c e b o -tr e at e d p arti ci p a nt s.  T h e pr o p orti o n s of p arti ci p a nts wit h I g G a n d I g A l e v el s 
b el o w L L N w er e n ot diff er e nt b et w e e n gr o u p s.  T h e i n ci d e n c e of i nf e cti o u s a d v er s e 
e v e nt s a n d i nf e cti o u s s eri o u s a d v er s e e v e nt s di d n ot a p p e ar hi g h er i n p arti ci p a nt s wit h 
I g l e v el s ( all i s ot y p e s) b el o w L L N i n eit h er tr e at m e nt gr o u p c o m p ar e d wit h p arti ci p a nt s 
wit h I g l e v el s i n t h e n or m al r a n g e or a b o v e u p p er li mit of n or m al 
( U L N; H a w k er et al. 2 0 0 9).
2. 2 
R A TI O N A L E F O R T H E S T U D Y A N D B E N E FI T R I S K 
A S S E S S M E N T
T hi s st u d y ( W A 2 5 0 4 6) i s a pi v ot al P h a s e III cli ni c al tri al c o m p o s e d of a b li n d e d tre at m e nt 
p eri o d, a n o p e n -la b el e xt e n si o n ( O L E ) p h a s e, a n d a s af et y foll o w -u p p eri o d.  
T h e b li n d e d tr e at m e nt p eri o d i s d e si g n e d t o d e m o n str at e t h e effi c a c y a n d s af et y of 
o cr eli z u m a b i n P P M S i n c o m p ari s o n wit h pl a c e b o.  T h e O L E s er v e s t o e v al u at e 
l o n g-t er m s af et y, t ol er a bilit y, a n d effi c a c y of o cr eli z u m a b tr e at m e nt i n p arti ci p a nt s wit h 
P P M S.
T hi s st u d y i s p art of a br o a d er, c o nfir m at or y cli ni c al d e v el o p m e nt pr o gr a m i n v e sti g ati n g 
t h e s af et y a n d effi c a c y of o cr eli z u m a b i n p arti ci p a nt s wit h b ot h r el a p si n g M S
( RM S)
a n d 
P P M S .  A n O L E p h a s e of t h e P h a s e II S t u d y WA 2 1 4 9 3/ A C T 4 4 2 2 G i s o n g oi n g f or 
eli gi bl e p arti ci p a nt s wit h R R M S.  T h er e ar e 3 o n g oi n g P h a s e III pi v ot al tri al s (i n cl u di n g 
t h e o n e pr e s e nt e d i n t hi s pr ot o c ol), 2 tri al s i n R M S a n d 1 tri al i n P P M S.  Pl e a s e s e e
S e cti o n 4. 1. 5 f or f urt h er d et ail s o n st u d y d e si g n a n d t o t h e O cr eli z u m a b I n v e sti g at or’ s 
Br o c h ur e , f or m or e i nf or m ati o n o n effi c a c y a n d s af et y .
A be nefit ris k assess me nt w as c o n d ucte d t o deter mi ne w het her t here is a n y i m p act o n 
t he c o nc o mit a nt use of S A R S-C o V -2 v acci nes o n t he c o n d uct of t his st u d y.  B ase d o n 


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t his assess me nt, n o i m p act is a ntici p ate d t o affect t he effic ac y a nd s afet y i n p artici p a nts 
e nr olle d i n ocreli z u m a b cli nic al tri als.  E xisti n g i nf or m ati o n o n i de ntifie d ris ks, s afet y 
m o nit ori n g, a n d ris k miti g ati o n me as ures rel ate d t o a d mi nistr ati o n of v acci nes 
(i ncl u di n g t h ose f or S A R S-C o V -2) pr o vi de d i n t he st u d y pr ot oc ol 
( n a mel y, i m m u ni z ati o n [Secti o n 5. 5. 3 ], c o nc o mit a nt t her a p y [Secti o n 5. 5 ], a n d 
i m p aire d res p o nse t o v acci n ati o n [Secti o n 7. 3. 1. 1 ]) are c o nsi dere d a de q u ate.
D at a fr o m t he pi v ot al P h ase III st u dies of ocreli z u m a b i n R M S a n d P P M S s h o w t h at 
pree xisti n g h u m or al i m m u nit y t o c o m m o n vir al a n d b acteri al a nti ge ns is n ot affecte d 
b y ocreli z u m a b tre at me nt.  T he v acci n ati o n st u d y ( B N 2 9 7 3 9, V E L O C E) s h o we d t h at 
p arti ci p a nts wit h M S tre ate d wit h ocreli z u m a b were a ble t o m o u nt a h u m or al i m m u ne 
res p o nse t o n o n-li ve v acci nes a n d ne w a nti ge ns.  T he a nti b o d y i m m u ne res p o nse w as 
c o nsi dere d pr otecti ve, al beit wit h re d uce d le vels of a nti b o dies c o m p are d wit h c o ntr ols.  
I n t his st u d y, v accines were gi ve n as e arl y as 1 2 wee ks after t he first ocreli z u m a b 
i nf usi o n ( a n d as e arl y as 1 0 wee ks after t he sec o n d ocreli z u m a b i nf usi o n of t he first 
d ose).  B o osters were gi ve n at le ast 4 wee ks bef ore t he ne xt d ose of ocreli z u m a b.  
Ot her
i m m u ne res p o nses s uc h as cell ul ar res p o nses were n ot i n vesti g ate d i n t he 
St u d y B N 2 9 7 3 9.
R oc he is c o nti n u all y c ollecti n g e vi de nce fr o m cli nic al a n d bi ol o gic al s o urces t o better 
u n derst a n d i m m u ne res p o nse mec h a nis ms of t he S A R S -C o V -2 v acci ne i n 
ocreli z u m a b -tre ate d p artici p ants.
As wit h a n y ot her me dic ati o n or v acci ne, S A R S -C o V -2 v acci nes s h o ul d be re p orte d as 
c o nc o mit a nt me dic ati o n b y usi n g t he st a n d ar d fiel ds i n t he cli nic al d at a b ase 
(see Secti o n 5. 5 ).
2. 2. 1 
St at e m e nt of T h er a p e uti c E q ui p oi s e
T h e et hi c s of c o ntr oll e d cli ni c al tri al s r e q uir e t h at t h er a p e uti c e q ui p oi s e e xi st b et w e e n 
c o m p ar ati v e tr e at m e nt s.  I n t h e c a s e of St u d y W A 2 5 0 4 6, t h er a p e uti c e q ui p oi s e d o e s 
e xi st f or a pl a c e b o -c o ntr oll e d tri al of o cr eli z u m a b d e s pit e a n e g ati v e pri m ar y r e s u lt of t h e 
St u d y U 2 7 8 6 g i n P P M S c o m p ari n g pl a c e b o wit h rit u xi m a b ( s e e S e cti o n 2. 1. 4. 3 ), a 
m ol e c ul e t h at s h ar e s a si mil ar b a si c m e c h a ni s m of a cti o n t o o cr eli z u m a b.  Alt h o u g h t h e 
st u d y di d n ot d e m o n str at e si g nifi c a nt pri m ar y effi c a c y o n ti m e t o c o nfir m e d di s e a s e 
pr o gr e s si o n a s m e a s ur e d b y E D S S, a l o w er pr o p orti o n of p arti ci p a nt s i n t h e rit u x i m a b 
gr o u p e x p eri e n c e d c o nfir m e d di s e a s e pr o gr e s si o n ( 3 0. 2 %) c o m p ar e d wit h pl a c e b o 
( 3 8. 5 %).  Rit u xi m a b di d d e m o n str at e bi ol o gi c al a cti vit y b y si g nifi c a ntl y r e d u ci n g T 2 l e si o n 
v ol u m e a c c u m ul ati o n o n br ai n M RI o v er 9 6 w e e k s c o m p ar e d wit h pl a c e b o.  Pr e -
s p e cif i e d s u b gr o u p a n al y s e s al s o s u g g e st t h at y o u n g er p arti ci p a nt s wit h P P M S wit h 
e vi d e n c e of a cti v e di s e a s e ( pr e s e n c e of G d -e n h a n ci n g l e si o n s a n d/ or d ur ati o n o f 
di s e a s e 3 y e ar s) m a y h a v e s h o w n si g nifi c a nt cli ni c al si g n s of tr e at m e nt -r el at e d b e n efit 
a s m e a s ur e d b y ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n o v er a 9 6 -w e e k ti m efr a m e.


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Cli ni c al tri al d e si g n c o n si d er ati o n s m a y al s o h a v e c o ntri b ut e d t o t h e n e g ati v e r e s ult of 
St u d y U 2 7 8 6 g , r e n d eri n g pr e m at ur e a n y d efi niti v e c o n cl u si o n t h at t h e a nti-C D 2 0 
t h er a p e uti c m e c ha ni s m i s i n eff e cti v e i n P P M S.  T h e d ur ati o n of t h e tr e at m e nt p eri o d i n 
St u d y U 2 7 8 6 g w a s 9 6 w e e k s, w hil e m o st P h a s e III tri al s u si n g si mil ar E D S S o ut c o m e 
m e a s ur e s i n pr o gr e s si v e f or m s of M S (i. e. , P P M S a n d S P M S) h a v e b e e n d e si g n e d wit h 
a mi ni m u m 3 -y e ar tr e a t m e nt p eri o d.  S u b gr o u p a n al y s e s al s o s u g g e st t h at s o m e 
p arti ci p a nt s w h o w er e l e s s li k el y t o b e n efit fr o m a n a nti -C D 2 0 t h er a p e uti c a p pr o a c h w er e 
i n cl u d e d i n t h e st u d y, a s w ell a s m a n y l e s s a cti v e p arti ci p a nt s w h o s e E D S S di d n ot 
w or s e n o v er 9 6 w e e k s d e s pit e r e c ei vi n g pl a c e b o tr e at m e nt.  Fi n all y, t h e st u d y w a s 
d e si g n e d i n t h e a b s e n c e of pri or tri al d at a o n t h e eff e ct of a nti -C D 2 0 a nti b o di e s i n 
i n di vi d u al s wit h P P M S.  T h u s, a st ati sti c al p o w eri n g a s s u m pti o n t ar g eti n g a 5 0 % R R i n 
c o nfir m e d di s e a s e pr o gr e s si o n o v er 9 6 w e e k s a p p e ar s t o h a v e b e e n o v erl y o pti mi sti c.
T h e pri m ar y h y p ot h e si s t h at a n a nti -C D 2 0 m o n o cl o n al a nti b o d y , s u c h a s o cr eli z u m a b ,
m a y c o nf er cli ni c al b e n efit s a s c o m p ar e d wit h pl a c e b o i n a P P M S p o p ul ati o n h a s n eit h er 
b e e n a d e q u at el y pr o v e n n or di s pr o v e n.  B a s e d o n t h e s e c o n si d er ati o n s, a r a n d o mi z e d ,
c o ntr oll e d P h a s e III tr e at m e nt tri al c o m p ari n g o cr eli z u m a b wit h pl a c e b o i s et hi c all y 
j u stifi e d wit hi n t h e fr a m ew or k of t h er a p e uti c e q ui p oi s e.
2. 2. 2  
St at e m e nt o n t h e U s e of Pl a c e b o C o m p ar at or
Pri m ar y pr o gr e s si v e M S
i s a n e ur ol o gi c all y di s a bli n g c o n diti o n wit h o ut a D M T .  T o d at e, 
n o t h er a pi e s h a v e s h o w n eff e cti v e n e s s i n P P M S a n d n o n e ar e r e gi st er e d f or it s 
tr e at m e nt i n a n y gl o b al r e gi o n.  P ur s u a nt t o t h e H el si n ki D e cl ar ati o n, w h e n st a n d ar d 
tr e at m e nt of a di s e a s e e xi st s, pl a c e b o s h o ul d g e n er all y n ot b e u s e d i n cli ni c al tri al s 
( Worl d M e di c al A s s o ci ati o n 2 0 0 8) .  H o w e v er, P ar a gr a p h 3 2 of t h e D e cl ar ati o n s u p p ort s 
t h e st a n c e t h at pl a c e b o c a n b e a c c e pt a bl e i n t h e s etti n g w h er e n o pr o v e n st a n d ar d 
t h er a p y e xi st s:
T h e b e n efit s, ri s k s, b ur d e n s a n d eff e cti v e n e s s of a n e w i nt er v e nti o n m u st b e t e st e d 
a g ai n st t h o s e of t h e b e st c urr e nt pr o v e n i nt er v e nti o n, e x c e pt i n t h e f oll o wi n g 
cir c u m st a n c e s:
 
T h e u s e of pl a c e b o, or n o tr e at m e nt, i s a c c e pt a bl e i n st u di e s w h er e n o c urr e nt 
pr o v e n i nt er v e nti o n e xi st s; or
 
W h er e f or c o m p elli n g a n d s ci e ntifi c all y s o u n d m et h o d ol o gi c al r e a s o n s t h e u s e of 
pl a c e b o i s n e c e s s ar y t o d et er mi n e t h e effi c a c y or s af et y of a n i nt er v e nti o n a n d t h e 
p arti ci p a nt s w h o r e c ei v e pl a c e b o or n o tr e at m e nt will n ot b e s u bj e ct t o a n y ri s k of 
s eri o u s or irr e v er si bl e h ar m.  E xtr e m e c ar e m u st b e t a k e n t o a v oi d a b u s e of t hi s 
o pti o n.
Gi v e n t h at n o st a n d ar d t h er a p y e xi st s f or t h e tr e at m e nt of P P M S, a pl a c e b o -c o ntr oll e d 
tri al i s a c c e pt a bl e pr o vi d e d t h at a p pr o pri at e p arti ci p a nt c o n s e nt a n d s af e g u ar d s ar e 
i n stit ut e d t o mi ni mi z e t h e ri s k of s eri o u s or irr e v er si bl e h ar m r e s ulti n g fr o m e x p o s ur e t o 
pl a c e b o.


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T h e u s e of pl a c e b o i n a P P M S cli ni c al tri al i s al s o et hi c all y j u stifi e d a c c or di n g t o t h e 
gl o b al M S s ci e ntifi c c o m m u nit y.  I n r e c e nt y e ar s, et hi c al c o n si d er ati o n s r e g ar di n g 
pl a c e b o -c o ntr oll e d cli ni c al tri al s i n t h e s u bt y p e s of M S h a v e b e e n p u bli cl y di s c u s s e d a n d 
d e b at e d.  A r e c e nt p u bli c ati o n, “ Et hi c s of pl a c e b o -c o ntr oll e d tri al s i n m ulti pl e s cl er o si s” 
( P ol m a n et al. 2 0 0 8), r efl e ct s a c o n s e n s u s p o siti o n of i nt er n ati o n al cli ni c al a n d s ci e ntifi c 
M S e x p ert s f oll o wi n g a 2 0 0 7 m e eti n g s p o n s or e d b y t h e U. S. -b a s e d N ati o n al M ulti pl e 
S cl er o si s S o ci et y.  T h e r ef er e n c e cl e arl y n ot e s t h at n o e st a bli s h e d eff e cti v e t h er a p y 
c urr e ntl y e xi st s f or P P M S a n d s u p p ort s t h e et hi c alit y of a p pr o pri at el y d e si g n e d 
pl a c e b o -c o ntr oll e d tri al s i n t hi s p arti ci p a nt p o p ul ati o n.
3.
O B J E C TI V E S
3. 1 
P RI M A R Y O B J E C TI V E
T o i n v e sti g at e t h e effi c a c y of o cr eli z u m a b c o m p ar e d wit h pl a c e b o i n p arti ci p a nt s wit h 
P P M S , a s m e a s ur e d b y t h e ti me t o o n s et of c o nfir m e d di s a bilit y pr o gr e s si o n o v er t h e 
tr e at m e nt p eri o d, d efi n e d a s a n i n cr e a s e i n E D S S t h at i s s u st ai n e d f or at l e a st 1 2 w e e k s, 
b a s e d o n r e g ul arl y s c h e d ul e d vi sit s.
Di s a bilit y pr o gr e s si o n i s d efi n e d a s a n i n cr e a s e of 1. 0 -p oi nt fr o m t h e b a s eli n e E D S S 
w h e n t h e b a s eli n e s c or e i s 5. 5 or l e s s, a n d 0. 5 w h e n t h e b a s eli n e s c or e i s 
m or e
t h a n 5. 5, t h at i s n ot attri b ut a bl e t o a n ot h er eti ol o g y ( e. g., f e v er, c o n c urr e nt ill n e s s, 
or c o n c o mit a nt m e di c ati o n).  S e e S e cti o n 8 f or f urt h er d et ail s.
3. 2 
S E C O N D A R Y O B J E C TI V E S
T h e s e c o n d ar y o bj e cti v e s of t hi s st u d y ar e t o e v al u at e t h e effi c a c y a n d s af et y of 
o cr eli z u m a b c o m p ar e d wit h pl a c e b o, a s r efl e ct e d b y t h e f oll o wi n g:
 
T h e ti m e t o o n s et of c o nfir m e d di s a bilit y pr o gr e s si o n o v er t h e tr e at m e nt p eri o d, 
d ef i n e d a s a n i n cr e a s e i n E D S S t h at i s s u st ai n e d f or at l e a st 2 4 w e e k s, b a s e d o n 
r e g ul arl y s c h e d ul e d vi sit s
 
T h e c h a n g e i n Ti m e d 2 5 - Fo ot W al k T e st ( T 2 5 F W T) fr o m b a s eli n e t o W e e k 1 2 0
 
T h e c h a n g e i n t ot al v ol u m e of T 2 l e si o n s o n M RI s c a n s of t h e br ai n fr o m b a s eli n e t o 
W e e k 1 2 0
 
T h e p er c e nt a g e c h a n g e i n t ot al br ai n v ol u m e a s d et e ct e d b y br ai n M RI fr o m 
W e e k 2 4 1 2 0
 
T h e c h a n g e i n S F -3 6 H e alt h S ur v e y ( S F-3 6) v er si o n 2 P h y si c al C o m p o n e nt 
S u m m ar y ( P C S) s c or e fr o m b a s eli n e t o W e e k  1 2 0
 
T o e v al u at e t h e s af et y a n d t ol er a bilit y of o cr eli z u m a b 3 0 0 m g 2 ( o v er 2 4 -w e e k 
tr e at m e nt c y cl e s) c o m p ar e d wit h pl a c e b o i n p arti ci p a nt s wit h P P M S


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3. 3 
E X P L O R A T O R Y O B J E C TI V E S
T h e e x pl or at or y o bj e cti v e s i n t hi s st u d y will i n cl u d e, b ut m a y n ot b e li mit e d t o, t h e 
f oll o wi n g e v al u ati o n s.
Cli ni c al:
 
T h e pr o p orti o n of p arti ci p a nt s wit h c o nfir m e d 1 2 -w e e k di s a bilit y pr o gr e s si o n at 
W e e k 1 2 0
 
T h e c h a n g e i n E D S S s c or e ( m e a n c h a n g e a n d ar e a u n d er t h e c o n c e ntr ati o n ti m e 
c ur v e [ A U C]) fr o m b a s eli n e t o W e e k s 4 8, 9 6, a n d 1 2 0
 
T h e c h a n g e i n M ulti pl e S cl er o si s F u n cti o n al C o m p o sit e S c al e ( M S F C S) s c or e fr o m 
b a s eli n e t o W e e k s 4 8, 9 6, a n d 1 2 0
 
T h e ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n o v er t h e tr e at m e nt p eri o d, d efi n e d a s a n 
i n cr e a s e i n E D S S t h at i s s u st ai n e d f or at l e a st 1 2 w e e k s ( 0. 5 or 1, s a m e crit eri a a s 
f or t h e pri m ar y e n d p oi nt ti m e t o 1 2 -w e e k C D P) or a 2 0 % i n cr e a s e i n T 2 5 F W T t h at i s 
s u st ai n e d f or at l e a st 1 2 w e e k s, or a 2 0 % i n cr e a s e i n t h e 9- H ol e P e g T e st ( 9-H P T) 
t h at i s s u st ai n e d f or at l e a st 1 2 w e e k s
 
T h e ti m e t o s u st ai n e d 2 0% i n cr e a s e i n t h e T 2 5 F WT a n d 9 -H P T
 
T h e pr o p orti o n of p arti ci p a nt s wit h a 2 0 % i n cr e a s e i n T 2 5 F W T  ti m e
 
T h e pr o p orti o n of p arti ci p a nt s wit h a 2 0 % i n cr e a s e i n 9-H P T ti m e
 
T h e c h a n g e i n P a c e d A u dit or y S eri al A d diti o n T e st ( P A S A T) fr o m b a s eli n e t o 
W e e k 1 2 0
I m a gi n g:
 
T h e n u m b er of G d -e n h a n ci n g T 1 l e si o n s a n d n u m b er of n e w or e nl ar gi n g T 2 l e si o n s 
a s d et e ct e d b y br ai n M RI
 
T h e p er c e nt a g e c h a n g e i n c orti c al gr e y m att er v ol u m e fr o m b a s eli n e t o W e e k 1 2 0
 
T h e p er c e nt a g e c h a n g e i n w hit e -m att er v ol u m e fr o m b a s eli n e t o W e e k  1 2 0
 
T h e c h a n g e fr o m b a s eli n e i n t ot al n o n -e n h a n ci n g T 1 l e si o n v ol u m e o n M RI s c a n of 
t h e br ai n
P arti ci p a nt -R e p ort e d O ut c o m e s:
 
T h e c h a n g e i n f ati g u e, a s m e a s ur e d b y t h e M o difi e d F ati g u e I m p a ct S c al e ( M FI S) 
t ot al s c or e a n d s u b s c al e s c or e s ( P h y si c al I m p a ct, C o g niti v e I m p a ct, a n d 
P s y c h ol o gi c al I m p a ct) fr o m b a s eli n e t o W e e k 1 2 0
 
T h e c h a n g e i n q u alit y of lif e, a s m e a s ur e d b y t h e S F -3 6 M e nt al C o m p o n e nt 
S u m m ar y ( M C S) s c or e fr o m b a s eli n e t o W e e k 1 2 0
Bi o m ar k er s:
 
T o i n v e sti g at e t h e p h ar m a c o ki n eti c s a n d ot h er p h ar m a c o d y n a mi c st u d y e n d p oi nt s of 
o cr eli z u m a b


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 
T o e x pl or e t h e i m p a ct of o cr eli z u m a b t h er a p y o n bi o m ar k er s a s s o ci at e d wit h t h e 
pr o p o s e d i nfl a m m at or y or n e ur o d e g e n er ati v e pr o c e s s i n P P M S
O L E P h a s e :
 
T o e v al u at e t h e l o n g -t er m s af et y of o cr eli z u m a b tr e at m e nt d uri n g t h e O L E p h a s e of 
t h e st u d y
 
T o e v al u at e t h e l o n g -t er m eff e ct s of o cr eli z u m a b o n cli ni c al a n d M RI p ar a m et er s of 
di s e a s e a cti vit y a n d pr o gr e s si o n d uri n g t h e OL E p h a s e of t h e st u d y
3. 4 
R E S E A R C H BI O S A M P L E R E P O SI T O R Y O B J E C TI V E S
T h e R e s e ar c h Bi o s a m pl e R e p o sit or y ( R B R) i s a c e ntr all y a d mi ni st er e d gr o u p of f a ciliti e s 
u s e d f or t h e l o n g -t er m st or a g e of h u m a n bi ol o gi c al s p e ci m e n s, i n cl u di n g b o d y fl ui d s, 
s oli d ti s s u e s, a n d d eri v ati v e s t h er e of ( e. g., D N A, R N A, pr ot ei n s, p e pti d e s).
S peci me ns st ore d i n t he R B R will be use d t o:
 
St u d y t he ass oci ati o n of bi o m ar kers wit h effic ac y a n d/ or a d verse e ve nts ass oci ate d 
wit h ocreli z u m a b
 
I ncre ase t he k n o wle d ge a n d t he u n derst a n di n g of t he bi ol o g y of M S a n d m o de of 
acti o n of ocreli z u m a b
Si mil arl y, t h e R B R s a m pl e s c oll e ct e d i n t h e O L E p h a s e of t hi s st u d y will b e u s e d f or 
r e s e ar c h i nt o M S di s e a s e pr o gr e s si o n m e c h a ni s m s, i d e ntifi c ati o n of n e w M S di s e a s e 
pr o gr e s si o n bi o m ar k er s, a n d t h e d e v el o p m e nt of n e w t h er a p e uti c a g e nt s.  
S e e S e cti o n 5. 1 6 f or d et ail s o n t h e R B R.
3. 5 
O P TI O N A L E X P L O R A T O R Y S U B S T U DI E S
C o n s e nti n g p arti ci p a nt s w h o e nr oll e d i n t h e m ai n S t u d y WA 2 5 0 4 6 a n d w h o ar e eli gi bl e 
will b e off er e d t h e o p p ort u nit y t o p arti ci p at e i n o pti o n al s u b st u di e s, w hi c h ar e r u n u n d er 
s e p ar at e pr ot o c ol s.  S e e S e cti o n 5. 2 2 f or d et ail s.
3. 5. 1 
O pti c al C o h er e n c e T o m o gr a p h y  E x pl or at or y S u b st u d y
T hi s s u b st u d y i s r u n u n d er t h e m ai n st u d y pr ot o c ol a n d will b e c o n d u ct e d at c ert ai n 
s el e ct e d c e nt er s a n d will b e u s e d t o e v al u at e t h e n e ur o pr ot e cti v e eff e ct of o cr eli z u m a b 
a s m e a s ur e d b y r eti n al n er v e fi b er l a y er ( R N F L) t hi c k n e s s a n d m a c ul ar v ol u m e i n b ot h
e y e s ( s e e S e cti o n 5. 2 2. 1 a n d A p p e n di x 6 ).
I n J ul y 2 0 1 7, R o c h e d et er mi n e d t h at s uffi ci e nt d at a h a d b e e n c oll e ct e d fr o m t h e o pti c al 
c o h er e n c e t o m o gr a p h y ( O C T) s u b st u d y.  D uri n g 2 0 1 7 a n d 2 0 1 8, p arti ci p a nt s will b e 
di s c o nti n u e d fr o m t h e O C T s u b st u d y b ut m a y c o nti n u e i n t h e O L E.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
4 9 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
4.
S T U D Y D E SI G N
4. 1 
O V E R VI E W O F S T U D Y D E SI G N A N D D O SI N G R E GI M E N
T hi s i s a P h a s e III, r a n d o mi z e d, d o u bl e -bli n d, p ar all el -gr o u p, m ulti c e nt er st u d y t o 
e v al u at e t h e s af et y a n d effi c a c y of t w o 3 0 0 m g o cr eli z u m a b I V i nfu si o n s of s e p ar at e d b y 
1 4 d a y s at a s c h e d ul e d i nt er v al of e v er y 2 4 w e e k s a s c o m p ar e d wit h pl a c e b o i n a d ult s 
wit h P P M S.  P arti ci p a nt s will b e tr e at e d f or a mi ni m u m of 1 2 0 w e e k s r e pr e s e nti n g at 
l e a st fi v e 2 4-w e e k tr e at m e nt c y cl e s.  T h e st u d y will e nr oll a p pr o xi m at el y 6 3 0 p arti ci p a nt s
i n a 2: 1 r a n d o mi z ati o n ( o cr eli z u m a b: pl a c e b o), gl o b all y.  R a n d o mi z ati o n will b e 
p erf or m e d t hr o u g h a n I nt er a cti v e v oi c e or W e b- b a s e d re s p o n s e s y st e m (Ix R S) a n d will 
b e str atifi e d b y r e gi o n ( U.S. v s. R e st of W orl d [ R O W ]) a n d a g e (4 5 v s. 4 5) .
T hi s st u d y c o n si st s of t h e f oll o wi n g st u d y p eri o d s: a s cr e e ni n g p eri o d, a b li n d e d 
tr e at m e nt p eri o d, a n O L E p h a s e , a n d a s af et y foll o w -u p p eri o d.  T h e st u d y d ur ati o n will 
v ar y f or e a c h p arti ci p a nt t o m a xi mi z e t h e s af et y a n d effi c a c y d at a c oll e ct e d, a s d e s cri b e d 
b el o w .
4. 1. 1 
S cr e e ni n g P eri o d
T h e s cr e e ni n g p eri o d l a st s u p t o 4 w e e k s.
4. 1. 2 
Bli n d e d Tr e at m e nt P eri o d
A ll p arti ci p a nt s will u n d er g o at l e a st 1 2 0 w e e k s of st u d y tr e at m e nt r e pr e s e nti n g 
5 tr e at m e nt c y cl e s, e a c h of 2 4 w e e k s’ d ur ati o n.  T h e st u d y will b e u n bli n d e d w h e n t h e 
l a st e nr oll e d p arti ci p a nt c o m pl et e s at l e a st 1 2 0 w e e k s ( 5 c y cl e s) of st u d y tr e at m e nt, 
pr o vi d e d t h e t ot al n u m b er of c o nfir m e d di s a bilit y pr o gr e s si o n e v e nt s i s a p pr o xi m at el y 
2 5 3 ( b a s e d o n t h e Sp o n s or ’s b e st e sti m ati o n aft er t h e l a st p arti ci p a nt fi ni sh e s W e e k 1 0 8 
vi sit) , or at t h e l at e st w h e n t h e l a st r a n d o mi z e d p arti ci p a nt h a s b e e n i n t h e b li n d e d
tr e at m e nt p eri o d f or 3 y e ar s.
If t h e pr oj e ct e d n u m b er of c o nfir m e d di s a bilit y pr o gr e s si o n e v e nt s h a s n ot b e e n r e a c h e d 
b y W e e k 1 2 0 b e c a u s e of sl o w er t h a n a nti ci p at e d di s a bilit y pr o gr e s si o n r at e s, t h e 
tr e at m e nt p eri o d will b e e xt e n d e d u ntil a p pr o xi m at el y 2 5 3 c o nfir m e d di s a bilit y 
pr o gr e s si o n e v e nt s h a v e o c c urr e d, wit h a d diti o n al tr e at m e nt c y cl e s e v er y 2 4 w e e k s, i n 
or d er t o m ai nt ai n st ati sti c al p o w er t o d et e ct a tr e at m e nt diff er e n c e.  B e c a u s e it i s 
a nti ci p at e d t h at it m a y t a k e 1 2 1 8 m o nt h s t o r e cr uit p arti ci p a nt s , t hi s bli n d e d tr e at m e nt 
p eri o d m a y e xt e n d t o u p t o 3. 5 4 y e ar s f or t h e fir st gr o u p of p arti ci p a nt s e nr oll e d i nt o t h e 
st u d y.
If t h e l a st p arti ci p a nt e nr oll e d di s c o nti n u e s t h e tr e at m e nt p eri o d b ef or e W e e k 1 2 0 or 
b ef or e 3 y e ar s of bli n d e d tr e at m e nt, t h e d at e of 1 2 0 w e e k s or 3 y e ar s aft er hi s/ h er 
r a n d o mi z ati o n d at e will b e u s e d.
R a n d o mi z ati o n ( D a y 1) will o c c ur o nl y aft er t h e p arti ci p a nt h a s m et all i n cl u si o n a n d 
e x cl u si o n crit eri a.  F or t h e fir st tr e at m e nt c y cl e a n d i n s u b s e q u e nt tr e at m e nt c y cl e s of 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
5 0 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
st u d y dr u g e v er y 2 4 w e e k s, p arti ci p a nt s will b e d o s e d 1 4 d a y s a p art 
( 3 0 0 m g
o cr eli z u m a b or pl a c e b o i nf u si o n 2).  All p arti ci p a nt s will al s o r e c ei v e a 1 0 0 m g 
m et h yl pr e d ni s ol o n e I V i nf u si o n o n D a y 1 a n d wit h e a c h s u b s e q u e nt o cr eli z u m a b or 
pl a c e b o i nf u si o n.  I n p arti ci p a nt s w h er e m et h yl pr e d ni s ol o n e i s c o ntr ai n di c at e d, 
e q ui v al e nt d o s e s of ot h er I V st er oi d s ( e. g., d e x a m et h a s o n e) s h o ul d b e u s e d a s 
pr e m e di c ati o n.  M or e d et ail e d i nf or m ati o n o n st u d y dr u g a d mi ni str ati o n i s c o nt ai n e d i n 
S e cti o n 6 .
4. 1. 3 
O p e n -L a b el E xt e n si o n P h a s e
F oll o wi n g d at a b a s e l o c k of t h e b li n d e d tr e at m e nt p eri o d, p arti ci p a nt s s h o ul d c o nti n u e t o 
r e c ei v e bli n d e d tr e at m e nt, a s p er t h e s c h e d ul e of a cti viti e s (T a bl e 2 ), u ntil t h e pri m ar y 
a n al y si s i s c o m pl et e d a n d t h e d e ci si o n t o st art t h e O L E p h a s e i s c o m m u ni c at e d b y t h e 
S p o n s or.
U p o n t h e di s cl o s ur e of r e s ult s a n d a p o siti v e b e n efit – ri s k a s s e s s m e nt of t h e us e of 
o cr eli z u m a b t h er a p y, p arti ci p a nt s w h o c o m pl et e d t h e b li n d e d tr e at m e nt p eri o d a n d w h o, 
i n t h e o pi ni o n of t h e in v e sti g at or, c o ul d b e n efit fr o m tr e at m e nt m a y r e c ei v e o p e n -l a b el 
o cr eli z u m a b . U nl e s s t h e S p o n s or d e ci d e s t o t er mi n at e t h e o cr eli z u m a b pr o gr a m f or M S, 
t h e O L E p h a s e will c o nti n u e a s p er l o c al r e g ul ati o n . T hi s d e ci si o n will b e b a s e d o n t h e 
c h a n g e of b e n efit ri s k a n d s af et y m o nit ori n g.  Eli gi bl e p arti ci p a nt s n e e d t o pr o vi d e 
c o n s e nt f or p arti ci p ati o n i n t h e O L E p h a s e.  U nl e s s disc o nti n ue d e arl y , all p arti ci p a nt s
m a y c o nti n u e t h eir tr e at m e nt wit h o p e n -l a b el o cr eli z u m a b a s p er t h e pr ot o c ol u ntil 
3 1 D e c e m b er 2 0 2 2 .  All p arti ci p a nt s m u st di s c o nti n u e o p e n -l a b el o cr eli z u m a b tr e at m e nt 
wit hi n t his st u d y b ef or e 3 1 D e c e m b er 2 0 2 2 .  H o we ver,
p arti ci p a nts will be offere d 
c o nti n u ati o n of ocreli z u m a b tre at me nt or a s afet y f oll o w -u p peri o d vi a a r oll o ver st u d y 
( M N 4 3 9 6 4, O L E R O).
P arti ci p a nt s w h o st art tr e at m e nt wit h c o m m er ci al o cr eli z u m a b or a n ot her D M T will 
di s c o nti n u e fr o m t h e st u d y c o m pl et el y a n d will n ot e n t er t h e s af et y f oll o w- up p eri o d.
P arti ci p a nt s w h o ar e n ot willi n g t o p arti ci p at e i n t h e O L E p h a s e of t h e st u d y will e nt er t h e 
s af et y foll o w -u p p eri o d ( s e e b el o w).  I n t h e c a s e of a p arti ci p a nt w h o i niti all y d e cli n e s 
p arti ci p ati o n i n t h e O L E p h a s e a n d s u b s e q u e ntl y c h a n g e s t h eir d e ci si o n, t h e p arti ci p a nt
m a y b e d e e m e d eli gi bl e t o e nt er t h e O L E p h a s e u p t o 2 4
w e e k s aft er t h e O L E p h a s e 
b e gi n s.  T hi s will o c c ur o n a c a s e -b y -c a s e b a si s i n c o n s ult ati o n wit h t h e S p o n s or. 
P arti ci p a nt s w h o c o n s e nt t o p arti ci p at e i n t h e O L E p h a s e will b e r e q uir e d t o m e et t h e 
tr e at m e nt/r e-tr e at m e nt crit eri a pri or t o i nf u si o n wit h o cr eli z u m a b.  D uri n g t h e O L E p h a s e, 
all p arti ci p a nt s will r e c ei v e d u al I V i nfu si o n s of o cr eli z u m a b 3 0 0 m g 2 f or t h e fir st c y cl e. 
F or t h e s u b s e q u e nt c y cl e s , p arti ci p a nt s will c o nti n u e o p e n -l a b el tr e at m e nt wit h a si n gl e 
6 0 0 m g o cr eli z u m a b I V i nfu si o n e v er y 2 4 w e e k s (s e e T a bl e 4 a n d S e cti o n 5. 2 3 f or m or e 
d et ail s). T h e r ati o n al e f or t h e s wit c hi n g t o a si n gl e i nf u si o n f or t h e s u b s e q u e nt c y cl e s i s 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
5 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
pr o vi d e d i n S e cti o n 4. 1. 6 . P arti ci p a nt s w h o wit h dr a w fr o m t h e O L E p h a s e will b e 
e nt er e d i nt o t h e s af et y foll o w - up p eri o d ( s e e b el o w).
4. 1. 4 
S af et y  F oll o w-U p P eri o d
T h e s af et y foll o w - up p eri o d will b e gi n w h e n t h e p arti ci p a nt c o m pl et e s or di s c o nti n u e s 
fr o m t h e b li n d e d tr e at m e nt p eri o d or O L E p h a s e f or a n y r e a s o n.  P arti ci p a nt s s h o ul d 
r e m ai n i n t h e s af et y foll o w - u p peri o d f or u p t o 4 8 w e e k s f oll o wi n g t h e l a st i nfu si o n of 
st u d y dr u g/ o p e n -l a b el o cr eli z u m a b ( a s a p pli c a bl e).D uri n g t h e s af et y foll o w -u p p eri o d, 
p arti ci p a nt s will b e a s s e s s e d at cli ni c al vi sit s e v er y 1 2 w e e k s.  T el e p h o n e i nt er vi e w s will 
b e p erf or m e d e v er y 4 w e e k s bet wee n visits .
P arti ci p a nt s w h o st art c o m m er ci al o cr eli z u m a b or a n ot her D M T will b e di s c o nti n u e d
fr o m t h e st u d y c o m pl et el y a n d will n ot e nt er or c o nti n u e i n t h e s af et y foll o w -u p p eri o d .
Bec a use t his st u d y will be cl ose d o n 3 1 Dece m ber 2 0 2 2, p artici p a nts alre a d y i n s afet y 
f oll o w-u p m a y c o m plete t his st u d y peri o d i n t he r oll o ver St u d y M N 4 3 9 6 4.
It i s i m p ort a nt t o di sti n g ui s h b et w e e n “ wit h dr a w al fr o m tr e at m e nt” a n d “ wit h dr a w al fr o m 
st u d y”.  P arti ci p a nt s w h o wit h dr a w fr o m tr e at m e nt s h o ul d b e e n c o ur a g e d t o r e m ai n i n t h e 
st u d y f or t h e f ull d ur ati o n of t h e s af et y foll o w - up p eri o d ( u p t o 4 8 w e e k s fr o m t h e l a st 
i nf u si o n).
E v er y eff ort s h o ul d b e m a d e t o e n s ur e t h at p arti ci p a nt s w h o wit h dr a w fr o m st u d y 
tr e at m e nt c o m pl et e t h e s af et y foll o w - up p eri o d a n d all r el at e d a s s e s s m e nt s, r e g ar dl e s s 
of  w h et h er or n ot t h e y r e c ei v e alt er n ati v e tr e at m e nt f or M S.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
5 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T a bl e 5 
O v er vi e w  of t h e St u d y D e si g n a n d D o si n g R e gi m e n
Bli n d e d Tr e at m e nt P eri o d
O L E P h a s e
5 Tr e at m e nt C y cl e ( 1 2 0 W k s ) Mi ni m u m a, b, c, d, h
V ari a bl e
a, c , e ,f , g, h
1 st C y cl e 
(W k s 0 2 4)
2 n d C y cl e
(W k s 2 4 4 8)
3 r d C y cl e
(W k s 4 8 7 2)
4 t h C y cl e
(W k s 7 2 9 6)
5 t h C y cl e
(W k s 9 6 1 2 0)
A d diti o n al 
Tr e at m e nt 
C y cl e s
b, d
( E v er y 2 4 W k s )
O p e n -L a b el Tr e at m e nt 
C y cl e 1
f, h
O p e n -L a b el 
Tr e at m e nt 
C y cl e s
b , c ... N f, h
( E v er y 2 4 W k s )
R a n d o mi z ati o n 
gr o u p
D a y 1
D a y 1 5
W k
2 4 W k
2 6
W k
4 8
W k
5 0
W k
7 2
W k
7 4 W k
9 6
W k
9 8
W k
1 2 0 
( D a y 1)
W k
1 2 0 
( D a y 1 5)
O p e n -l a b el 
D a y 1
O p e n -l a b el 
D a y 1 5
O p e n -l a b el 
D a y 1
A
O cr eli z u m a b
O cr eli z u m a b 3 0 0 m g I V
B
Pl a c e b o
Pl a c e b o I V
O cr eli z u m a b 3 0 0 m g I V
O L E o p e n -l a b el e xt e n si o n; W k w e e k( s).
a
E a c h tr e at m e nt c y cl e h a s a d ur ati o n of 2 4 w e e k s.
b
T h e bli n d e d tr e at m e nt p eri o d c o n si st s of a 1 2 0 w e e k mi ni m u m p eri o d .  P arti ci p a nt s e nr oll e d e arl y i n t h e st u d y will u n d er g o u p t o a n e sti m at e d 
2 3 a d diti o n al tr e at m e nt c y cl e s, d e p e n di n g o n t h e d ur ati o n of e nr oll m e nt a n d t h e t ot al n u m b er of di s a bilit y pr o gr e s si o n e v e nt s.
c
Aft er t h e fir st i nf u si o n, a n e v al u ati o n will b e p erf or m e d b ef or e e a c h s u b s e q u e nt i nf u si o n t o e n s ur e t h at t h e p arti ci p a nt r e m ai n s eli gi bl e f or r e -tr e at m e nt 
( s e e S e cti o n 6. 2. 3 ).
d
Tri al p arti ci p a nt s e n t eri n g t h e st u d y e arl y will u n d er g o m or e t h a n 5 tr e at m e nt c ycl e s.  W h e n a p pli c a bl e, s u b s e q u e nt d o si n g c y cl e s will c o n si st of t h e s a m e 
d o si n g r e gi m e n at 2 4 -w e e k i nt er v al s a s C y cl e s 2 5.
e
T h e O L E p h a s e f or eli gi bl e p arti ci p a nt s b e gi n s aft er t h e pri m ar y  d at ab a s e l o c k at t h e c o m pl eti o n of t h e bli n d e d tr e at m e nt p eri o d.  T h e O L E p h a s e c a n 
t er mi n at e at a n y m o m e nt or c ycl e ( s e e S e cti o n 4. 1. 9 ).
f
D uri n g t h e O L E p h a s e, all p arti ci p a nt s will r e c ei v e d u al i nf u si o n s of o cr eli z u m a b 3 0 0 m g 2 f or t h e fir st c y cl e.  F or t h e s u b s e q u e nt c y cl e s, p arti ci p a nt s will 
c o nti n u e o p e n -l a b el tr e at m e nt wit h a si n gl e i nf u si o n of 6 0 0 m g o cr eli z u m a b I V e v er y 2 4 w e e k s.  F or p arti ci p a nt s r a n d o mi z e d t o t h e o cr eli z u m a b gr o u p, 
t h e fir st i nf u si o n of o cr eli z u m a b i n t h e O L E p h a s e s h o ul d r e s p e ct a mi ni m u m of 2 0 w e e k s fr o m l a st i nf u si o n i n t h e bli n d e d tr eat m e nt p eri o d.  
F or p arti ci p a nt s r a n d o mi z e d t o t h e pl a c e b o gr o u p, t h e fir st i nf u si o n of o cr eli z u m a b i n t h e O L E p h a s e c a n o c c ur o n c e a p arti ci p a nt m e et s t h e r e-tr e at m e nt 
crit eri a ( s e e S e cti o n 6. 2. 3 ) at a s c h e d ul e d vi sit f oll o wi n g c o m m u ni c ati o n wit h t h e S p o n s or.


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T a bl e 5 
O v er vi e w  of t h e St u d y D e si g n a n d D o si n g R e gi m e n ( c o nt.)
g
T h e s af et y  foll o w - up p eri o d st art s aft er t h e l a st 2 4 w e e k tr e at m e nt c y cl e h a s b e e n c o m pl et e d ( eit h er d uri n g t h e b li n d e d tr e at m e nt p eri o d or t h e 
O L E p h a s e).  P arti ci p a nt s w h o wit h dr a w fr o m tr e at m e nt will al s o e nt er t h e s af et y foll o w- u p p eri o d.  T h e s af et y foll o w- u p p eri o d will l a st u p t o 
4 8 w e e k s f oll o wi n g t h e l a st i nf u si o n.   P arti ci p a nts w h o st art tre at me nt wit h c o m mer ci al o creli z u m a b or a n ot her D M T will dis c o nti n ue fr o m 
t he st u d y c o m pletel y a n d will n ot e nt er t he s afet y f oll o w -u p peri o d .
h
A d o s e of 1 0 0 m g  m et h yl pr e d ni s ol o n e I V a n d or al or I V a nti hi st a mi n e , s u c h a s di p h e n h y dr a mi n e 5 0 m g
or e q ui v al e nt d o s e of alt er n ati v e , will b e 
a d m i ni st er e d pri or t o o cr eli z u m a b or pl a c e b o i nf u si o n s.  I n p arti ci p a nt s w h er e m et h yl pr e d ni s ol o n e i s c o ntr ai n di c at e d, e q ui v al e nt d o s e s of ot h er I V
st er oi d s ( e. g., d e x a m et h a s o n e) s h o ul d b e u s e d a s pr e m e di c ati o n.


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5 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
R o uti n e l a b or at or y st u di e s will b e o bt ai n e d t hr o u g h o ut t h e st u d y, wit h a d diti o n al t e st s 
f oll o wi n g c y cl e s of st u d y dr u g tr e at m e nt.  I m m u n e p a n el (I g M, I g G, I g A) a n d s er u m 
h u m a n a nti -h u m a n a nti b o d y ( H A H A) t e st s will al s o b e c o n d u ct e d.  All p arti ci p a nt s will 
h a v e s er u m s a m pl e s c oll e ct e d f or P K a n al y si s a n d bl o o d s a m pl e s will b e c oll e ct e d f or 
C D 1 9 B c ell c o u nt s, a P D m ar k er of o cr eli z u m a b.  S er u m, pl a s m a a n d bl o o d R N A a n d 
pr ot ei n bi o m ar k er s a m pl e s will b e c oll e ct e d i n c o n s e nti n g p arti ci p a nt s f or t h e 
m e a s ur e m e nt of c a n di d at e pr o g n o sti c or pr e di cti v e bi o m ar k er s at b a s eli n e a n d s el e ct e d 
f oll o w-u p vi sit s ( wit h t h e e x c e pti o n t h at R N A will n ot b e c oll e ct e d i n t h e O L E p h a s e).
D uri n g t h e b li n d e d tr e at m e nt p eri o d:  to pr e v e nt p ot e nti al u n bli n di n g a s a r e s ult of 
a d v er s e e v e nt s or l a b or at or y c h a n g e s, a “ d u al a s s e s s or” a p pr o a c h will b e u s e d t o 
e v al u at e effi c a c y a n d s af et y.  E a c h sit e will h a v e 2 bli n d e d in v e sti g at or s:  a 
P ri n ci p al I n v e sti g at or or Tr e ati n g I n v e sti g at or a n d a R ati n g I n v e sti g at or or 
E x a mi ni n g I n v e sti g at or.  T h e Tr e ati n g I n v e sti g at or i s t h e s af et y a s s e s s or a n d s h o ul d b e 
a n e ur ol o gi st wit h e x p eri e n c e i n t h e c ar e of p arti ci p a nt s wit h M S.  
T h e Tr e ati n g I n v e sti g at or will h a v e a c c e s s t o b ot h s af et y a n d effi c a c y d at a a n d will m a k e 
all tr e at m e nt d e ci si o n s b a s e d o n t h e p arti ci p a nt’ s cli ni c al r e s p o n s e a n d l a b or at or y 
fi n di n g s.  T h e E x a mi ni n g I n v e sti g at or i s t h e effi c a c y a s s e s s or a n d s h o ul d b e a 
n e ur ol o gi st or ot h er q u alifi e d h e alt h c ar e pr a ctiti o n er tr ai n e d a n d c ertifi e d i n 
a d mi ni st eri n g a n d s c ori n g t h e F u n cti o n al S y st e m S c or e s ( F S S) a n d K urt z k e E D S S.  
T h e E x a mi ni n g I n v e sti g at or will b e r e s p o n si bl e f or a d mi ni str ati o n of t h e E D S S , i n cl u di n g 
t h e s cr e e ni n g a s s e s s m e nt a n d will o nl y h a v e a c c e s s t o E D S S d at a.  
T h e Tr e ati n g I n v e sti g at or an d t h e E x a mi ni n g I n v e sti g at or will n ot b e all o w e d t o s wit c h 
r ol e s.
4. 1. 5 
R ati o n al e f or St u d y  D e si g n
T h e r ati o n al e f or t h e el e m e nt s of t h e st u d y d e si g n i s pr o vi d e d b el o w .
4. 1. 5. 1 
R ati o n al e f or Bli n d e d St u d y
T o mi ni mi z e p o s si bl e bi a s e s i n t h e st u d y o ut c o m e, t hi s i s a d o u b l e-bli n d e d 
(p arti ci p a nt a n d in v e sti g at or) r a n d o mi z e d , c o ntr oll e d tri al c o m p ari n g o cr eli z u m a b t h er a p y 
wit h pl a c e b o.  A d diti o n al f e at ur e s t o mi ni mi z e bi a s i n o ut c o m e m e a s ur e m e nt s i n cl u d e 
t h e f oll o wi n g:
 
A bli n d e d a s s e s s or ( E x a mi ni n g I n v e sti g at or) will p erf or m n e ur ol o gi c al e x a mi n ati o n s 
i n all p arti ci p a nt s t o a s s e s s t h e F S S/ E D S S ( s e e S e cti o n 5. 1 1. 1 )
 
M RI s c a n s i n all p arti ci p a nt s will b e r e a d i n a bli n d e d f a s hi o n at t h e c e ntr al r e a di n g 
c e nt er
 
O cr eli z u m a b a n d pl a c e b o tr e at m e nt all o c ati o n r e m ai n bli n d e d u ntil t h e pri m ar y 
d at a b a s e l o c k f or t h e pri m ar y a n al y si s
 
L a b or at or y p ar a m et er s w hi c h m a y b e u n bli n di n g t o tr e at m e nt a s si g n m e nt, s u c h a s 
fl u or e s c e n c e-a cti v at e d c ell s orti n g ( F A C S ) c ell c o u nt s , i n cl u di n g C D 1 9c ell s, 
l y m p h o c yt e c o u nt, a n d I g M a n d I g G l e v el s, ar e bli n d e d i n all p arti ci p a nt s , ex c e pt 


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t h o s e m e eti n g u n bli n di n g crit eri a f or s af et y r e a s o n s, u ntil t h e pri m ar y d at a b a s e l o c k 
f or t h e pri m ar y a n al y si s
4. 1. 5. 2 
R ati o n al e f or P l a c e b o C o m p ar at or
T h e a c c e pt a bilit y of pl a c e b o i n P P M S tri al s i s c o n si st e nt wit h c urr e nt st a n d ar d s i n M S 
cli ni c al tri al s a s o utli n e d i n S e cti o n 2. 2. 2 .  T h e st u d y S p o n s or r e c o g ni z e s t h at a 
tr e at m e nt p eri o d l a sti n g 2. 54 y e ar s p o s e s ri s k s t o p arti ci p a nt s r a n d o mi z e d t o b ot h 
pl a c e b o a n d a n a cti v e st u d y dr u g wit h u n pr o v e n cli ni c al eff e cti v e n e s s.  F or t hi s r e a s o n, 
s e v er al st u d y el e m e nt s ar e e m pl o y e d t o pr ot e ct t h e w ell -b ei n g of st u d y p arti ci p a nt s:
 
T h e Inf or m e d C o n s e nt F or m (I C F) cl e arl y d efi n e s t h e d ur ati o n of t h e st u d y i n cl u di n g 
t h e b li n d e d tr e at m e nt p eri o d, O L E p h a s e, a n d s af et y foll o w -u p p eri o d.  
T h e pr o b a biliti e s of a s si g n m e nt t o pl a c e b o a n d o cr eli z u m a b ar e i n di c at e d i n e a sil y 
u n d er st o o d t er m s i n m ulti pl e s e cti o n s of t h e I C F.  N o i m pli c ati o n i s m a d e t h at 
o cr eli z u m a b i s s ur e t o b e m or e eff e cti v e t h a n pl a c e b o.
 
A t h or o u g h m e di c al m o nit ori n g pl a n will b e i m pl e m e nt e d b y t h e st u d y S p o n s or t o 
e n s ur e t h e s af et y of all st u d y p arti ci p a nt s.  M or e o v er, a n i n d e p e n d e nt D at a 
M o nit ori n g C o m mitt e e (i D M C) will b e i n stit ut e d t o f urt h er pr ot e ct t h e w ell-b ei n g of 
p arti ci p a nt s i n t h e st u d y.
 
I n t h e e v e nt t h at p arti ci p a nt s e x p eri e n c e c o nfir m e d di s a bilit y pr o gr e s si o n p er si sti n g 
f or 2 4 w e e k s or m or e, p arti ci p a nt s will n e e d t o b e r e -c o n s e nt e d a b o ut t h e p ot e nti al 
b e n efit s a n d ri s k s of c o nti n ui n g i n t h e bli n d e d tr e at m e nt p eri o d of t h e st u d y, 
i n cl u di n g t h e ri s k of f urt h er di s a bilit y pr o gr e s si o n.  P arti ci p a nt s will n ot b e f or ci bl y 
wit h dr a w n fr o m t h e tr e at m e nt p eri o d b e c a u s e t h e y c o ul d still b e b e n efitti n g fr o m 
t h er a p y d e s pit e e vi d e n c e f or c o nti n u e d di s e a s e a cti vit y.  I n s u c h a c a s e, f or ci bl e 
wit h dr a w al of tr e at m e nt h a s p ot e nti al t o i n d u c e h ar m a s n o alt er n ati v e pr o v e n 
t h er a pi e s e xi st f or P P M S.
 
U p o n wit h dr a w al fr o m st u d y tr e at m e nt f or a n y r e a s o n, st u d y p arti ci p a nt s will b e 
r e c o m m e n d e d t o st a y i n t h e st u d y f or s af et y foll o w -u p b ut m a y b e eli gi bl e f or 
tr e at m e nt wit h s o m e alt er n ati v e t h er a pi e s at t h e di s cr eti o n of an d i n c o n s ult ati o n 
wit h t h eir Tr e ati n g I n v e sti g at or.
4. 1. 5. 3 
R ati o n al e f or S t u d y Po p ul ati o n
T hi s st u d y will e nr oll p arti ci p a nt s wit h P P M S wit h a n E D S S s c or e of 3. 0 6. 5 a n d d ur ati o n 
of  di se a s e l e s s t h a n 1 0 y e ar s if E D S S 5 or l e s s t h a n 1 5 y e ar s if E D S S 5.  
T h e s e crit eri a will b e i m pl e m e nt e d t o r e cr uit p arti ci p a nt s wit h P P M S wit h m or e di s e a s e 
a cti vit y a n d hi g h er s e v erit y.  T h e a g e r a n g e will b e li mit e d t o 5 5 y e ar s t o m a xi mi z e t h e 
b e n efit -ri s k pr ofil e of o cr eli z u m a b; it m a y al s o r e d u c e c o nf o u n di n g b y n e ur ol o gi c al 
c o n diti o n s pr e v al e nt i n ol d er i n di vi d u al s, i n cl u di n g b ut n ot li mit e d t o mi cr o v a s c ul ar 
di s e a s e.  S u b gr o u p a n al y si s fr o m St u d y U 2 7 8 6 g wit h rit u xi m a b i n p arti ci p a nt s wit h 
P P M S, St u d y U 2 7 8 6 g (O L Y M P U S ) s u g g e st s t h at p arti ci p a nt s wit h P P M S a g e d 5 5 or 
l e s s wit h G d -e n h a n ci n g l e si o n s m a y h a v e b e n efitt e d fr o m a nti -C D 2 0 t h er a p y, w hil e al s o 
e x hi biti n g a l o w er i n ci d e n c e of s eri o u s i nf e cti o n s t h a n ol d er p arti ci p a nt s
( H a w k er et al. 2 0 0 9) .


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4. 1. 5. 4 
R ati o n al e f or S t u d y En d p oi nt s
T h e pr o p o s e d st u d y e n d p oi nt s ar e wi d el y a c c e pt e d i n tri al s of p arti ci p a nt s wit h M S, 
i n cl u di n g P P M S.  T h e pri m ar y e n d p oi nt i n t hi s st u d y i s t h e ti m e t o c o nfir m e d di s a bilit y 
pr o gr e s si o n a s m e a s ur e d b y a pr e -s p e cifi e d i n cr e a s e i n E D S S, s u st ai n e d f or at l e a st 
1 2 w e e k s.  Ot h er cli ni c al e n d p oi nt s will i n cl u d e c h a n g e s i n E D S S a n d M S F C S, M RI 
p ar a m et er s a s s e s si n g f o c al l e si o n s a n d diff u s e c h a n g e s o n br ai n i m a gi n g, a n d 
p arti ci p a nt -r e p ort e d o ut c o m e s.  M or e i nf or m ati o n o n t h e st u d y effi c a c y e n d poi nt s i s 
pr o vi d e d i n S e c ti o n 8. 1 .
4. 1. 5. 5 
R ati o n al e f or t h e T r e at m e nt D ur ati o n
I n M S tri al s at l e a st 2 y e ar s of tr e at m e nt ar e c o n si d er e d a d e q u at e t o s h o w a tr e at m e nt 
eff e ct o n di s a bi lit y pr o gr e s si o n.  Cli ni c al tri al s i n pr o gr e s si v e f or m s of M S m a y n e e d t o b e 
l o n g er t h a n 2 y e ar s’ d ur ati o n b e c a u s e of h et er o g e n eit y i n di s a bilit y pr o gr e s si o n r at e s, 
w h i c h h a v e at ti m e s b e e n hi st ori c all y l o w er t h a n a nti ci p at e d r e s ulti n g i n i n a bilit y t o s h o w
a tr e at m e nt ef f e ct.  At t h e e n d of a fi x e d 9 6-w e e k tr e at m e nt p eri o d i n St u d y U 2 7 8 6 g wit h 
rit u xi m a b i n P P M S, a n o n-si g nifi c a nt diff er e n c e w a s o b s er v e d wit h 3 8. 5 % of 
pl a c e b o -tr e at e d p arti ci p a nt s d e m o n str ati n g s u st ai n e d di s a bilit y pr o gr e s si o n v er s u s 
3 0. 2 % of rit u xi m a b-tr e at e d p arti ci p a nt s.  It i s u n c ert ai n if a l o n g er tri al d ur ati o n w o ul d 
h a v e d e m o n str at e d a st ati sti c all y si g nifi c a nt diff er e n c e i n pr o gr e s si o n r at e s.  M o st pi v ot al 
P h a s e III pr o gr e s si v e M S ( P P M S a n d S P M S) tri al s h a v e e m pl o y e d a 3- y e ar mi ni m u m 
tr e at m e nt d ur ati o n.  B a s e d o n r e s ult s fr o m St u d y U 2 7 8 6 g (O L Y M P U S ), t h e mi ni m u m 
1 2 0 -w e e k tr e at m e nt p eri o d d ur ati o n i n t h e c urr e nt st u d y i s a nti ci p at e d t o a d e q u at el y 
d e m o n str at e a si g nifi c a nt tr e at m e nt eff e ct.  P arti ci p a nt s e nr oll e d at t h e b e gi n ni n g of t h e 
st u d y will b e tr e at e d a n d e v al u at e d f or m or e t h a n 1 2 0 w e e k s i n or d er t o m a xi mi z e t h e 
c oll e cti o n of effi c a c y a n d s af et y d at a i n t h e tri al.  I n a d diti o n, i n t h e e v e nt t h at t h e n u m b er 
of  di s a bilit y pr o gr e s si o n e v e nt s i s m u c h l o w er t h a n a nti ci p at e d, t h e b li n d e d tr e at m e nt 
p eri o d m a y b e e xt e n d e d b y a d diti o n al tr e at m e nt c y cl e s t o m ai nt ai n st ati sti c al p o w er t o 
d et e ct a tr e at m e nt diff er e n c e.
4. 1. 5. 6 
R ati o n al e f or t h e S af et y  Foll o w - Up P eri o d
D at a c oll e ct e d d uri n g t hi s p eri o d will all o w e v al u ati o n of t h e s af et y of B c ell r e pl eti o n 
af t er st o p pi n g a nti-C D 2 0 tr e at m e nt, a s w ell a s t h e m ai nt e n a n c e of eff e ct or p ot e nti al f or 
a wit h dr a w al eff e ct.
4. 1. 5. 7 
R ati o n al e f or O p e n -L a b el E xt e n si o n P h a s e
U p o n t h e c o m pl eti o n of t h e b li n d e d tr e at m e nt p eri o d, p arti ci p a nt s w h o ar e c o n si d er e d 
eli gi bl e a n d w h o m a y b e n efit fr o m tr e at m e nt wit h o cr eli z u m a b m a y b e off er e d t h e c h a n c e 
t o p arti ci p at e i n t h e O L E p h a s e.  T h e r ati o n al e f or t hi s pr o vi si o n i s b a s e d o n t h e v er y 
hi g h u n m et m e di c al n e e d i n P P M S, a c o n diti o n f or w hi c h t h er e ar e n o a p pr o v e d 
t h er a pi e s a n d f or w hi c h n o u n a p pr o v e d t h er a pi e s h a v e s h o w n e vi d e n c e of effi c a c y.
F oll o wi n g t h e pri m ar y a n al y si s a n d t h e p o siti v e o ut c o m e of t h e st u d y, t h e d e ci si o n b y t h e 
S p o n s or w a s t o pr o c e e d wit h t h e O L E. Pl e a s e s e e t h e O cr eli z u m a b I nv e sti g at or’ s 
B r o c h ur e f or m or e i nf or m ati o n o n effi c a c y a n d s af et y . T hi s will pr o vi d e a l o n g er-t er m 
s af et y pr ofil e f or o cr eli z u m a b.


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4. 1. 5. 8 
R ati o n al e f or t h e U s e of M et h yl pr e d ni s ol o n e a n d 
A nti hi st a mi n e s
In or d er t o r e d u c e t h e fr e q u e n c y a n d s e v erit y of I R R s, p arti ci p a nt s will b e pr e -m e di c at e d 
wit h 1 0 0 m g m et h yl pr e d ni s ol o n e I V a n d a n or al or I V a nti hi st a mi n e , s u c h a s 
di p h e n h y dr a mi n e 5 0 m g or e q ui v al e nt d o s e of alt er n ati v e, pri or t o a d mi ni str ati o n of 
o cr eli z u m a b .  M et h yl pr e d ni s ol o n e
a d mi ni str ati o n i s t o b e c o m pl et e d a p pr o xi m at el y 
3 0 mi n ut e s b ef or e t h e st art of e a c h o cr eli z u m a b i nf u si o n; a nti hi st a mi n e s s h o ul d b e 
a d mi ni st er e d 3 0 6 0 mi n ut e s b ef or e t h e st art of a n i nf u si o n.  ( s e e S e cti o n 6. 4 ).  A r e c e nt 
i nt e gr at e d a n al y si s of p arti ci p a nt s wit h M S tr e at e d wit h o cr eli z u m a b r e v e al e d t h at t h e 
a d diti o n of a nti hi st a mi n e s t o t h e pr e -tr e at m e nt wit h m et h yl pr e d ni s ol o n e d e cr e a s e d t h e 
i n ci d e n c e of I R R s b y 2- f ol d ( O C R E V U SU. S. P a c k a g e I n s ert [ U S PI ]). I n p arti ci p a nt s
w h er e m et h yl pr e d ni s ol o n e i s c o ntr ai n di c at e d, e q ui v al e nt d o s e s of ot h er I V st er oi d s 
( e. g., d e x a m et h a s o n e) s h o ul d b e u s e d a s pr e m e di c ati o n pri or t o t h e i nf u si o n.  
I n St u d y W A 2 1 4 9 3/ A C T 4 4 2 2 g, a p pr o xi m at el y 3 5 % of p arti ci p a nt s wit h R R M S r e c ei vi n g 
3 0 0 m g o cr eli z u m a b o n t h e fir st i nf u si o n o n D a y 1 e x p eri e n c e d a n i nf u si o n -a s s o ci at e d 
e v e nt, a n d a p pr o xi m at el y 4 % e x p eri e n c e d a n e v e nt wit h t h e s e c o n d 3 0 0 m g i nf u si o n o n 
D a y 1 5.  T h e s e p arti ci p a nt s w er e pr e -m e di c at e d wit h c orti c o st er oi d s pri or t o i nf u si o n, 
w h i c h m a y i n p art, h a v e c o ntri b ut e d t o a l o w er r at e of i nfu si o n e v e nt s t h a n t h o s e 
o b s er v e d i n t h e rit u xi m a b M S st u di e s ( U 2 7 8 6 g, U 2 7 8 7 g a n d U 3 2 6 4 g) i n w hi c h
p arti ci p a nt s w er e n ot pr e -m e di c at e d wit h c orti c o st er oi d s.  A d mi ni st er e d i nfr e q u e ntl y at a 
l o w d o s e, m et h yl pr e d ni s ol o n e i s n ot a nti ci p at e d t o aff e ct t h e effi c a c y or s af et y o ut c o m e s 
of  t h e st u d y.  M et h yl pr e d ni s ol o n e ( or a n alt er n ati v e st er oi d i n p arti ci p a nt s w h er e 
m et h yl pr e d ni s ol o n e i s
c o ntr ai n di c at e d) will b e a d mi ni st er e d t o p arti ci p a nt s i n b ot h 
tr e at m e nt gr o u p s d uri n g t h e tr e at m e nt p eri o d t o m ai nt ai n t h e tr e at m e nt bli n di n g.
4. 1. 6 
R ati o n al e f or D o s e S el e cti o n a n d D o si n g I nt er v al s
T h e b li n d e d tr e at m e nt p eri o d of t hi s st u d y will e v al u at e t h e s af et y a n d effi c a c y, 
c o m p ar e d wit h pl a c e b o, of t w o 3 0 0 m g o cr eli z u m a b I V i nf u si o n s s e p ar at e d b y 1 4 d a y s at 
a s c h e d ul e d i nt er v al of e v er y 2 4 w e e k s d uri n g t h e tr e at m e nt p eri o d .  Pr eli mi n ar y a n al y si s 
fr o m St u d y WA 2 1 4 9 3/ A C T 4 4 2 2 G, a P h a s e II st u d y of o cr eli z u m a b i n p arti ci p a nt s wit h 
R R M S, s u g g e st s t hi s d o si n g r e gi m e n s h o ul d r a pi dl y a n d p er si st e ntl y d e pl et e p eri p h er all y 
cir c ul ati n g C D 2 0 B c ell s a n d p ot e nti all y r e d u c e i nfl a m m ati o n wit hi n t h e C N S.  I n or d er 
t o a s s ur e a d e q u at e i niti al a n d s u st ai n e d B c ell d e pl eti o n, mi ni mi z e p ot e nti all y 
d o s e -d e p e n d e nt i nf u si o n -a s s o ci at e d e v e nt s p arti c ul arl y u p o n t h e fir st i nf u si o n, a v oi d 
e arl y pr o d u cti o n of H A H A, a n d m ai nt ai n p ot e nti al f or effi c a c y, a d u al i nf u si o n of 
o cr eli z u m a b i s a d mi ni st er e d f or all tr e at m e nt c y cl e s.
S o m e e x p er t s p o st ul at e a pr o mi n e nt r ol e f or n o n-a nti b o d y m e di at e d p at h o g e ni c 
m e c h a ni s m s of B
c ell f u n cti o n i n M S.  T h e s e m e c h a ni s m s mi g ht i n cl u d e a nti g e n 
pr e s e nt ati o n t o a n d a cti v ati o n of p at h o g e ni c T c ell s, s e cr eti o n of pr o -i nfl a m m at or y 
c yt o ki n e s a n d a cti v ati o n of i n n at e i m m u n e c ell s.  T h e s e n o n-a nti b o d y m e di at e d 
m e c h a ni s m s ar e t h o u g ht t o t a k e pl a c e wit hi n ti s s u e s, n ot a bl y t h e l y m p h o -r eti c ul ar 
s y st e m a n d ( p ot e nti all y) C N S.  If t hi s h y p ot h e si s i s c orr e ct, ti s s u e B c ell d e pl eti o n i s 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
5 8 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
p er h a p s m or e i m p ort a nt t h a n d e pl eti o n of cir c ul ati n g B c ell s.  W h et h er or n ot C N S 
p e n etr ati o n of a n a nti -C D 2 0 m o n o cl o n al a nti b o d y i s n e c e s s ar y t o d e pl et e B c ell s wit hi n 
t h e C N S or c o nf er cli ni c al effi c a c y i n M S r e m ai n s u n cl e ar.
D o si n g wit h o cr eli z u m a b i n all p arti ci p a nt s c o n si st s of a d u al I V i nf u si o n of 3 0 0 m g 2 
s e p ar at e d b y 1 4 d a y s.  T hi s r e gi m e n r e s ult s i n a l o w er a m o u nt of o cr eli z u m a b 
a d mi ni st er e d u p o n fir st e x p o s ur e, a n d it pr o vi d e s a n o p p ort u nit y f or a n e ar -t er m 
s c h e d ul e d s af et y a s s e s s m e nt 2 w e e k s aft er t h e fir st d o s e a d mi ni str ati o n.   
I n St u d y W A 2 1 4 9 3/ A C T 4 4 2 2 G i nf u si o n- a s s o ci at e d a d v er s e e v e nt s , w er e m o st 
fr e q u e ntl y o b s er v e d wit h t h e fir st i nf u si o n of o cr eli z u m a b ( s e e al s o S e cti o n 4. 1 ).  
T h e s e e v e nt s o c c urr e d m or e c o m m o nl y i n p arti ci p a nt s r e c ei vi n g a 1 0 0 0 m g d o s e o n t h e
fir st i nf u si o n.  R at e s of i nf u si o n-a s s o ci at e d a d v er s e e v e nt s i n b ot h d o s e ar m s di mi ni s h e d 
c o n si d er a bl y b y t h e s e c o n d i nf u si o n, a p att er n al s o o b s er v e d wit h st u di e s of o cr eli z u m a b 
a n d rit u xi m a b i n p arti ci p a nt s wit h R A a s w ell a s rit u xi m a b i n p arti ci p a nt s wit h M S .
T h e pr o p o s e d r e -tr e at m e nt r e gi m e n c o n si st s of t w o 3 0 0 m g o cr eli z u m a b I V i nfu si o n s 
a d mi ni st er e d 1 4 d a y s a p art at a s c h e d ul e d i nt er v al of e v er y 2 4 w e e k s.  T hi s d u al 
I V i nfu si o n s c h e d ul e i s a nti ci p at e d t o b e w ell -t ol er at e d a n d i s c o n si st e nt wit h t h e 
d o u bl e- bli n d e d , 2 4 -w e e k , pri m ar y tr e at m e nt p h a s e of t h e o cr eli z u m a b R R M S P h a s e II 
tri al ( St u d y W A 2 1 4 9 3/ A C T 4 4 2 2 G) a s w ell a s ot h er s u c c e s sf ul tri al s e m pl o yi n g a B c ell 
d e pl eti n g t h er a p e uti c a p pr o a c h e m pl o yi n g d u al i nf u si o n s wit h b ot h o cr eli z u m a b a n d 
rit u xi m a b i n p arti ci p a nt s wit h R A a n d wit h rit u xi m a b i n R R M S ( St u d y U 2 7 8 7 g, H E R M E S).  
Pri m ar y effi c a c y r e s ult s fr o m a r e c e nt P h a s e III tri al i n p arti ci p a nt s wit h R A 
( St u d y W A 2 0 4 9 6/ A C T 4 3 9 4 g, F E A T U R E) i n di c at e t h at a si n gl e i nf u si o n of 4 0 0 m g di d 
n ot s h o w a si g nifi c a nt diff er e n c e fr o m pl a c e b o i n r e d u ci n g si g n s a n d s y m pt o m s of R A, 
w h il e a d u al i nf u si o n of 2 0 0 m g o cr eli z u m a b a d mi ni st er e d 1 4 d a y s a p art di d s h o w 
si g nifi c a nt effi c a c y c o m p ar e d wit h pl a c e b o o n t h e pri m ar y effi c a c y e n d p oi nt.  
T h er ef or e , t o m ai nt ai n t h e p ot e nti al f or effi c a c y wit h o cr eli z u m a b i n P P M S, t h e 
d u al -i nf u si o n tr e at m e nt p ar a di g m f or a nti-C D 2 0 a nti b o di e s t h at h a s d e m o n str at e d 
effi c a c y i n R A a n d R R M S will b e u s e d f or all tr e at m e nt c y cl e s of t h e st u d y.
A 2 4 -w e e k r e -tr e at m e nt i nt er v al s h o ul d a d e q u at el y m ai nt ai n p eri p h er al B c ell d e pl eti o n 
a s o b s er v e d i n St u d y W A 2 1 4 9 3/ A C T 4 4 2 2 g a n d s h o ul d h a v e p ot e nti al t o c o n f er a 
tr e at m e nt b e n efit i n p arti ci p a nt s wit h P P M S.  A gr e at er ti m e i nt er v al b et w e e n d o s e s 
c o ul d r e s ult i n a r e d u cti o n or l o s s of effi c a c y.  N o cli ni c al i n di c e s or bi o m ar k er s e xi st t o 
r eli a bl y tr a c k t h e r et ur n of cli ni c al a cti vit y i n P P M S.  T h u s, a 2 4-w e e k r e-tr e at m e nt 
i nt er v al i s s el e ct e d b a s e d o n e x p e ct e d m ai nt e n a n c e of B c ell d e pl eti o n a n d t h e 
S p o n s or’ s cli ni c al e x p eri e n c e wit h o cr eli z u m a b i n R R M S a s w ell a s St u d y U 2 7 8 6 g wit h 
rit u xi m a b i n P P M S.
Pl e a s e s e e t h e O cr eli z u m a b In v e sti g at or’ s B r o c h ur e f or m or e 
d et ail s.
4. 1. 7 
R ati o n al e f or S wit c hi n g t o S i n gl e Inf u si o n s
I n t h e st u di e s i n R M S ; St u d y W A 2 1 0 9 2 a n d W A 2 1 0 9 3) a n d P P M S ( St u d y W A 2 5 0 4 6), 
b ot h t h e si n gl e a n d d u al i nf u si o n r e gi m e n s r e s ult e d i n s u p eri or effi c a c y v s. t h e 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
5 9 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
c o m p ar at or, a s e vi d e n c e d b y t h e eff e ct s of o cr eli z u m a b s e e n i n a wi d e r a n g e of effi c a c y 
m e a s ur e s i n t h e st u di e s. 
T h er e w er e n o diff er e n c e s i n s af et y o ut c o m e s b et w e e n t h e 
d u al a n d si n gl e r e gi m e n s , e. g., I R R s. Aft er t h e fir st d o s e ( w hi c h w a s gi v e n a s 
3 0 0 m g 2 i n b ot h R M S a n d P P M S), t h e r at e of I R R s w a s c o m p ar a bl e b et w e e n t h e 
3 0 0 m g i nf u si o n s i n P P M S a n d t h e 6 0 0 m g i nf u si o n s i n R M S. 
T h e o v er all e x p o s ur e 
( A U C o v er t h e 2 4w e e k d o si n g i nt er v al ) w a s i d e nti c al b et w e e n 3 0 0 m g 2 i n P P M S a n d 
6 0 0 m g i n R M S, a s e x p e ct e d wit h a n i d e nti c al d o s e a d mi ni st er e d.  Alt h o u g h t h e
m a xi m u m o b s er v e d c o n c e ntr ati o n
w a s o b vi o u sl y diff er e nt b et w e e n t h e 3 0 0 m g a n d
6 0 0 m g i nf u si o n s , t hi s di d n ot i m p a ct t h e I R R r at e .  T h e B c ell d e pl eti o n p att er n, a s t h e 
P D m ar k er, w a s al s o t h e s a m e f or b ot h r e gi m e n s.  T hi s d at a i n di c at e s t h at 3 0 0 m g 2
a n d 6 0 0 m g gi v e n e v er y 2 4 w e e k s l e a d s t o c o n si st e nt s af et y, P K , a n d P D o ut c o m e s, 
s u p p orti n g t h at t h e s a m e si n gl e d o si n g r e gi m e n of 6 0 0
m g e v er y 2 4 w e e k s w o ul d b e 
a p pr o pri at e f or b ot h p arti ci p a nt s wit h R M S a n d P P M S.
4. 1. 8 
E n d of Bli n d e d Tr e at m e nt P eri o d of t h e St u d y
T h e e n d of t h e b li n d e d tr e at m e nt p eri o d of t h e st u d y h a s b e e n d efi n e d a s t h e d at e at 
w h i c h t h e l a st d at a p oi nt fr o m t h e l a st p arti ci p a nt t h at i s r e q uir e d f or t h e pri m ar y effi c a c y 
a n al y si s, a s d efi n e d i n t h e St ati sti c al A n a l y si s Pl a n ( S A P), i s r e c ei v e d.
4. 1. 9 
E n d of St u d y
T h e e n d of st u d y i s n o w d ef i n e d a s 3 1 Dece m ber 2 0 2 2 or u p u ntil t he a p pr o v al of 
St u d y
M N 4 3 9 6 4 ( O L E R O) .
Irres pecti vel y, t he S p o ns or m a y deci de t o ter mi n ate t he st u d y at a n y ti me.
T he S p o ns or h as deci de d t o pr o vi de t he o p p ort u nit y t o all p artici p a nts t o r oll o ver a n d 
c o nti n ue t heir tre at me nt a n d/ or s afet y f oll o w -u p u n der t he ne w e xte nsi o n pr ot oc ol .
4. 2 
N U M B E R O F P A R TI CI P A N T S /A S SI G N M E N T T O T R E A T M E N T 
G R O U P S F O R T H E B LI N D E D T R E A T M E N T
P E RI O D
A p pr o xi m at el y 6 3 0 p arti ci p a nt s will b e r a n d o mi z e d i n 2 gr o u p s i n a 2: 1 r ati o.  
A n i n d e p e n d e nt Ix R S pr o vi d er will c o n d u ct r a n d o mi z ati o n a n d h ol d t h e tr e at m e nt 
a s si g n m e nt c o d e.  P arti ci p a nt s will b e str atifi e d b y r e gi o n ( U. S. v s. R O W ) a n d a g e
(4 5 v s. 4 5) .
T h er e will b e n o r e pl a c e m e nt of p arti ci p a nt s s h o ul d a p arti ci p a nt’ s tr e at m e nt b e 
di s c o nti n u e d f or a n y r e a s o n.
4. 2. 1  
P arti ci p a nt R a n d o mi z ati o n a n d E nr oll m e nt
R a n d o mi z ati o n a n d bli n di n g will b e e m pl o y e d t o mi ni mi z e bi a s i n tr e at m e nt a s si g n m e nt 
a n d t o pr o vi d e t h e b a si s f or v ali d st ati sti c al i nf er e n c e.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
6 0 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T o e n s ur e a c c ur at e a n d ti m el y m o nit ori n g of p arti ci p a nt e nr oll m e nt, t h e f oll o wi n g 
pr o c e d ur e s will b e i m pl e m e nt e d:
 
P arti ci p a nt s w h o ar e c a n di d at e s f or e nr oll m e nt i nt o t h e st u d y will b e e v al u at e d f or 
eli gi bili t y b y t h e in v e sti g at or t o e n s ur e t h at t h e crit eri a gi v e n i n S e cti o n s 5. 2 a n d 5. 3
h a v e b e e n s ati sfi e d, a n d t h at t h e p arti ci p a nt i s eli gi bl e f or p arti ci p ati o n i n t hi s cli ni c al 
st u d y.  A n eli gi bilit y w or k s h e et will b e pr o vi d e d f or t hi s e v al u ati o n.  All p arti ci p a nt s
m u s t si g n t h e I C F pri or t o s cr e e ni n g a n d pri or t o a n y c h a n g e s t o t h eir e xi sti n g 
m e di c ati o n f or t h e p ur p o s e s of e nr oll m e nt i nt o t h e tri al.
 
Eli gi bl e p arti ci p a nt s m u st b e r a n d o mi z e d t hr o u g h I x R S pri or t o r e c ei vi n g a n y st u d y 
m e di c ati o n
P arti ci p a nt s will b e r a n d o ml y a s si g n e d t o tr e at m e nt gr o u p s.  C e ntr al r a n d o mi z ati o n will 
b e p erf or m e d b y t h e I x R S a n d will b e str atifi e d b y r e gi o n ( U. S. v s. R O W ) a n d a g e 
(4 5 v s. 4 5) .
P arti ci p a nt eli gi bilit y i nf or m ati o n will b e pr o vi d e d b y t h e in v e sti g at or or t h e in v e sti g at or’ s 
r e s e ar c h st aff t o t h e Ix R S at r a n d o mi z ati o n.  T h e p arti ci p a nt will b e r a n d o mi z e d a n d 
a s si g n e d a u ni q u e m e di c ati o n n u m b er a n d r a n d o mi z ati o n n u m b er.  A s c o nfir m ati o n, t h e 
in v e sti g at or will b e pr o vi d e d wit h a f a x e d v erifi c ati o n of e a c h p arti ci p a nt’ s r e gi str ati o n.
N o p arti ci p a nt m a y b e gi n tr e at m e nt pri or t o r a n d o mi z ati o n a n d a s si g n m e nt of a 
m e di c ati o n n u m b er.  U n d er n o cir c u m st a n c e s ar e p arti ci p a nt s w h o e nr oll i n t hi s st u d y 
a n d w h o h a v e c o m pl et e d tr e at m e nt a s s p e cifi e d, p er mitt e d t o b e r e -r a n d o mi ze d t o t hi s 
st u d y.
T h e in v e sti g at or s will b e n otifi e d b y t h e S p o n s or if t h e st u d y i s pl a c e d o n cli ni c al h ol d 
a n d w h e n t h e st u d y i s c o m pl et e d or cl o s e d t o f urt h er p arti ci p a nt e nr oll m e nt .
4. 3 
C E N T E R S
T hi s will b e a m ulti c e nt er, i nt er n ati o n al st u d y.  It i s a nti ci p at e d t h at a p pr o xi m at el y 
2 1 0 sit e s will p arti ci p at e.
5.
S T U D Y P O P U L A TI O N
5. 1 
O V E R VI E W
M a l e s a n d f e m al e s a g e d 18 5 5 y e ar s , i n cl u si v e, w h o ar e di a g n o s e d wit h P P M S i n 
a c c or d a n c e wit h t h e r e vi s e d M c D o n al d crit eri a ( P ol m a n et al. 2 0 0 5; s e e A p p e n di x 1 ) a n d 
w h o m e et t h e i n cl u si o n/ e x cl u si o n crit eri a pr o vi d e d b el o w ar e eli gi bl e f or e nr oll m e nt i nt o 
t h e st u d y.  F or t h e eli gi bilit y crit eri a f or t h e O L E p h a s e, s e e S e cti o n 5. 4 .
5. 2 
I N C L U SI O N C RI T E RI A F O R B LI N D E D T R E A T M E N T P E RI O D
P arti ci p a nt s m u st m e et t h e f oll o wi n g crit eri a t o b e eli gi bl e f or st u d y e ntr y:
 
A bilit y t o pr o vi d e writt e n i nf or m e d c o n s e nt a n d t o b e a bl e t o f oll o w t h e s c h e d ul e of 
a cti viti e s


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
6 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
P arti ci p a nt s w h o ar e u n a bl e t o c o m pl et e e x pl or at or y a s s e s s m e nt s 
( e. g., e l e ctr o ni c p arti ci p a nt -r e p ort e d o ut c o m e s [P R O s ]) b e c a u s e of p h y si c al/ di s e a s e 
li mit ati o n s will not b e e x cl u d e d fr o m t h e st u d y.
 
Di a g n o si s of P P M S i n a c c or d a n c e wit h t h e r e vi s e d M c D o n al d crit eri a ( 2 0 0 5)
 
A g e d 1 8 5 5 y e ar s , i n cl u si v e
 
E D S S at s cr e e ni n g fr o m 3. 0 6. 5 p oi nt s
 
S c or e of 2. 0 o n t h e F S S f or t h e p yr a mi d al s y st e m t h at i s d u e t o l o w er e xtr e mit y 
fi n di n g s
 
Di s e a s e d ur ati o n fr o m t h e o n s et of M S s y m pt o m s:
– 
L e s s t h a n 1 5 y e ar s i n p arti ci p a nt s wit h a n E D S S at s cr e e ni n g 5. 0
– 
L e s s t h a n 1 0 y e ar s i n p arti ci p a nt s wit h a n E D S S at s cr e e ni n g 5. 0
 
D o c u m e nt e d hi st or y or pr e s e n c e at s cr e e ni n g of at l e a st 1 of t h e f oll o wi n g l a b or at or y 
fi n di n g s i n a C S F s p e ci m e n (s o ur c e d o c u m e nt ati o n of l a b or at or y r e s ult s a n d m et h o d 
m u st b e v erifi e d ):
– 
E l e v at e d I g G i n d e x
– 
O n e or m or e I g G oli g o cl o n al b a n d s d et e ct e d b y i s o el e ctri c f o c u si n g
 
F or s e x u all y a cti v e f e m al e a n d m al e p arti ci p a nt s of  r e pr o d u cti v e p ot e nti al, u s e of 
r eli a bl e m e a n s of c o ntr a c e pti o n a s d e s cri b e d b el o w a s a mi ni m u m ( a d h er e n c e t o 
l o c al r e q uir e m e nt s, if m or e stri n g e nt, i s r e q uir e d):
– 
F or f e m al e p arti ci p a n t s:  2 m et h o d s of c o ntr a c e pti o n t hr o u g h o ut t h e tri al, 
i n cl u di n g t h e a cti v e tr e at m e nt p h a s e A N D f or 4 8 w e e k s aft er t h e l a st d o s e of 
o cr eli z u m a b, or u ntil h er B c ell s h a v e r e pl et e d, w hi c h e v er i s l o n g er.  F or m al e 
p arti ci p a nt s :  2 m et h o d s of c o ntr a c e pti o n t hr o u g h o ut t h e tri al, i n cl u di n g t h e 
a cti v e tr e at m e nt p h a s e A N D f or 2 4 w e e k s aft er t h e l a st d o s e of o cr eli z u m a b.  
A c c e pt a bl e m et h o d s of c o ntr a c e pti o n i n cl u d e 1 pri m ar y 
( e. g., s y st e mi c h or m o n al c o ntr a c e pti o n or t u b al li g ati o n of t h e f e m al e p art n er, 
v a s e ct o m y of t h e m al e p art n er) A N D 1 s e c o n d ar y b arri er m et h o d 
( e. g., l at e x c o n d o m s, s p er mi ci d e) O R a d o u bl e -b arri er m et h o d 
( e. g., l at e x c o n d o m, i ntr a ut eri n e d e vi c e, v a gi n al ri n g or p e s s ar y pl u s s p er mi ci d e 
( e. g., f o a m, v a gi n al s u p p o sit or y, g el, cr e a m).
 
F or p arti ci p a nt s of n o n -r e pr o d u cti v e p ot e nti al ( a d h er e n c e t o l o c al r e q uir e m e nt s, if 
m or e stri n g e nt, i s r e q uir e d):
– 
F e m al e s of r e pr o d u cti v e p ot e nti al m a y b e e nr oll e d if p o st -m e n o p a u s al 
(i. e., s p o nt a n e o u s a m e n orr h e a f or 1 2 m o nt h s
c o nf ir m e d b y a n F S H l e v el 
4 0 mI U/ m L u nl e s s t h e p arti ci p a nt i s r e c ei vi n g a h or m o n al t h er a p y f orh er
m e n o p a u s e or i s s ur gi c all y st eril e [i. e., h y st er e ct o m y, c o m pl et e bil at er al 
o o p h or e ct o m y ])
– 
M a l e s of  r e pr o d u cti v e p ot e nti al m a y b e e nr oll e d if t h e y ar e s ur gi c all y st eril e 
( c a str ati o n)


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6 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
B a s e d o n l o c al E C s or N ati o n al C o m p et e nt A ut h orit y f e e d b a c k a d diti o n al 
r e q uir e m e nt s t o a s s ur e c o ntr a c e pti o n or t o c o nfir m m e n o p a u s e m a y b e 
r e q uir e d ( e. g., s er u m e str a di ol c o m p ati bl e wit h p o st-m e n o p a u s e st at u s, l o n g er 
d ur ati o n of a m e n orr h e a, hi g h er l e v el of F S H ).
5. 3 
E X C L U SI O N C RI T E RI A F O R B LI N D E D T R E A T M E N T P E RI O D
P arti ci p a nt s w h o m e et t h e f oll o wi n g crit eri a will b e e x cl u d e d fr o m st u d y e ntr y:
 
Hi st or y of R R M S , S P M S , or pr o gr e s si v e R M S at s cr e e ni n g
 
I n a bilit y t o c o m pl et e a n M RI ( c o ntr ai n di c ati o n s f or M RI, i n cl u d e b ut ar e n ot r e stri ct e d 
t o, w ei g ht 1 4 0 k g, p a c e m a k er, c o c hl e ar i m pl a nt s, i ntr a cr a ni al v a s c ul ar cli p s, 
s ur g er y wit hi n 6 w e e k s of e ntr y i nt o t h e st u d y, c or o n ar y st e nt i m pl a nt e d wit hi n 
8 w e e k s pri or t o t h e ti m e of t h e i nt e n d e d M RI, et c.).  P arti ci p a nt s wit h 
c o ntr ai n di c ati o n t o G d c a n b e e nr oll e d i nt o t h e st u d y b ut c a n n ot r e c ei v e G d c o ntr a st 
d y e s d uri n g t h eir M RI s c a n s.
 
C o ntr ai n di c ati o n s f or or i nt ol er a n c e t o or al or I V c orti c o st er oi d s, i n cl u di n g 
m et h yl pr e d ni s ol o n e a d mi ni st er e d I V, a c c or di n g t o t h e c ou ntr y l a b el, i n cl u di n g:
– 
P s y c h o si s n ot y et c o ntr oll e d b y a tr e at m e nt
– 
H y p er s e n siti vit y t o a n y of t h e c o n stit u e nt s
 
K n o w n pr e s e n c e of ot h er n e ur ol o gi c di s or d er s, i n cl u di n g b ut n ot li mit e d t o, t h e 
f oll o wi n g:
– 
Hi st or y of i s c h e mi c c er e br o v a s c ul ar di s or d er s ( e. g. , str o k e , tr a n si e nt i s c h e mi c 
att a c k) or i s c h e mi a of t h e s pi n al c or d
– 
Hi st or y or k n o w n pr e s e n c e of C N S or s pi n al c or d t u m or ( e. g. , m e ni n gi o m a, 
gli o m a)
– 
Hi st or y or k n o w n pr e s e n c e of p ot e nti al m et a b oli c c a u s e s of m y el o p at h y 
( e. g., u ntr e at e d vit a mi n B 1 2 d efi ci e n c y )
– 
Hi st or y or k n o w n pr e s e n c e of i nf e cti o u s c a u s e s of m y el o p at h y 
( e. g., s y p hili s, L y m e di s e a s e, h u m a n T -l y m p h otr o p hi c vir u s [H T L V ]-1, h er p e s 
z o st er m y el o p at h y)
– 
Hi st or y of g e n eti c all y i n h erit e d pr o gr e s si v e C N S d e g e n er ati v e di s or d er 
( e. g., h er e dit ar y p ar a p ar e si s; mit o c h o n dri al m y o p at h y, e n c e p h al o p at h y, l a cti c 
a ci d o si s, str o k e [M E L A S ] s y n dr o m e)
– 
N e ur o m y eliti s o pti c a
– 
Hi st or y or k n o w n pr e s e n c e of s y st e mi c a ut oi m m u n e di s or d er s p ot e nti all y 
c a u si n g pr o gr e s si v e n e ur ol o gi c di s e a s e ( e. g., l u p u s, a nti -p h o s p h oli pi d a nti b o d y 
s y n dr o m e, Sj ö gr e n’ s s y n dr o m e, B e h ç et’ s di s e a s e)
– 
Hi st or y or k n o w n pr e s e n c e of s ar c oi d o si s
– 
Hi st or y of s e v er e, cli ni c all y si g nifi c a nt br ai n or s pi n al c or d tr a u m a 
( e. g., c er e br al c o nt u si o n, s pi n al c or d c o m pr e s si o n)
– 
Hi st or y of pr o gr e s si v e m ultif o c al l e u k o e n c e p h al o p at h y ( P M L)


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
6 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
5. 3. 1 
E x cl u si o n s R el at e d t o G e n er al H e alt h
P arti ci p a nt s w h o m e et t h e f oll o wi n g crit eri a r el at e d t o t h eir g e n er al h e alt h will b e 
e x cl u d e d:
 
Pr e g n a n c y or l a ct ati o n
 
L a c k of p eri p h er al v e n o u s a c c e s s
 
Hi st or y of s e v er e all er gi c or a n a p h yl a cti c r e a cti o n s t o h u m a ni z e d or m uri n e 
m o n o cl o n al a nti b o di e s
 
Si g nifi c a nt, u n c o ntr oll e d di s e a s e, s u c h a s c ar di o v a s c ul ar (i n cl u di n g c ar di a c 
arr h yt h mi a), p ul m o n ar y (i n cl u di n g o b str u cti v e p ul m o n ar y di s e a s e), r e n al, h e p ati c, 
e n d o cri n e or g a str oi nt e sti n al or a n y ot h er si g nifi c a nt di s e a s e t h at m a y pr e cl u d e 
p arti ci p a nt fr o m p arti ci p ati n g i n t h e st u d y
 
C o n g e sti v e h e art f ail ur e ( N e w Y or k H e art A s s o ci ati o n III or I V f u n cti o n al s e v erit y)
 
K n o w n a cti v e b a ct eri al, vir al, f u n g al, m y c o b a ct eri al i nf e cti o n or ot h er i nf e cti o n 
(i n cl u di n g t u b er c ul o si s [ T B] or at y pi c al m y c o b a ct eri al di s e a s e, b ut e x cl u di n g f u n g al 
i nf e cti o n of n ail b e d s) or a n y m aj or e pi s o d e of i nf e cti o n r e q uiri n g h o s pit ali z ati o n or 
tr e at m e nt wit h I V a nti bi oti c s wit hi n 4 w e e k s pri or t o b a s eli n e vi sit ( Vi sit 2) or or al 
a nti bi oti c s wit hi n 2 w e e k s pri or t o b a s eli n e vi sit ( Vi sit 2)
 
Hi st or y or k n o w n pr e s e n c e of r e c urr e nt or c hr o ni c i nf e cti o n ( e. g., HI V, s y p hili s, T B )
Pl e a s e n ot e:
i n G er m a n y, t h e f oll o wi n g a d diti o n al e x cl u si o n crit eri a a p pl y:
 
P o siti v e a nti -HI V I at s cr e e ni n g
 
P o siti v e a nti - HI V II at s cr e e ni n g
 
P o siti v e Q u a nti F E R O N -T B G ol d t e st at s cr e e ni n g
P arti ci p a nt s wit h a n i n d et er mi n at e r e s ult ar e n ot eli gi bl e f or t h e st u d y u nl e s s a d diti o n al 
t e sti n g d e m o n str ati n g a n e g ati v e r e s ult i s pr o vi d e d. T h u s, t h e s e p arti ci p a nt s s h o ul d 
h a v e eit h er a t u b er c uli n s ki n t e st or h a v e t h e Q u a nti F E R O N -T B G ol d t e st r e p e at e d pri or 
t o e nr oll m e nt i nt o t h e st u d y. If a t u b er c uli n s ki n t e st i s p erf or m e d, a n i n d ur ati o n of 
6 m m i s “ p o siti v e” f or a p arti ci p a nt wit h hi st or y of B a cill e C al m ett e -G u eri n ( B C G )
v a c ci n e, w hi l e a n i n d ur ati o n of 1 0 m m i s “ p o siti v e” f or a p arti ci p a nt wit h o ut hi st or y of 
B C G v a c ci n e.
If n e c e s s ar y, a Q u a nti F E R O N -T B G ol d t e st mi g ht b e c o m pl e m e nt e d b y a d diti o n al 
s p e cifi c di a g n o sti c t e st s a s p er st a n d ar d pr o c e d ur e s i n t h e c o u ntr y.
 
Hi st or y of r e c urr e nt a s pir ati o n p n e u m o ni a r e q uiri n g a nti bi oti c t h er a p y
 
Hi st or y of c a n c er, i n cl u di n g s oli d t u m or s a n d h e m at o l o gi c al m ali g n a n ci e s 
( e x c e pt b a s al c ell, i n sit u s q u a m o u s c ell c ar ci n o m a s of t h e s ki n, a n d i n sit u 
c ar ci n o m a of t h e c er vi x of t h e ut er u s t h at h a v e b e e n e x ci s e d a n d r e s ol v e d, wit h 
d o c u m e nt e d cl e a n m ar gi n s o n p at h ol o g y)
 
A n y c o n c o mit a nt di s e a s e t h at m a y r e q uir e c hr o ni c tr e at m e nt wit h s y st e mi c 
c orti c o st er oi d s or i m m u n o s u p pr e s s a nt s d uri n g t h e c o ur s e of t h e st u d y


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
6 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
Hi st or y of al c o h ol or ot h er dr u g a b u s e wit hi n 2 4 w e e k s pri or t o r a n d o mi z ati o n
 
Hi st or y of or c urr e ntl y a cti v e pri m ar y or s e c o n d ar y i m m u n o d efi ci e n c y
 
Hi st or y or l a b or at or y e vi d e n c e of c o a g ul ati o n di s or d er s
5. 3. 2 
E x cl u si o n s R el at e d t o M e di c ati o n s
 
Tr e at m e nt wit h a n y i n v e sti g ati o n al a g e nt wit hi n 2 4 w e e k s of s cr e e ni n g ( Vi sit 1) or 
5 h alf -li v e s of t h e i n v e sti g ati o n al dr u g ( w hi c h e v er i s l o n g er), or tr e at m e nt wit h a n y 
e x p eri m e nt al pr o c e d ur e f or M S ( e. g., tr e at m e nt f or c hr o ni c c er e br o s pi n al v e n o u s 
i n s uffi ci e n c y)
 
R e c ei pt of a li v e v a c ci n e wit hi n 6 w e e k s pri or t o r a n d o mi z ati o n
V a c ci n ati o n s b ef or e b a s eli n e : i n r ar e c a s e s w h er e a li v e v a c ci n e m u st b e 
a d mi ni st er e d b y t h e p arti ci p a nt’ s p h y si ci a n, t h e s cr e e ni n g p eri o d m a y n e e d t o b e 
pr ol o n g e d b ut c a n n ot e x c e e d 8 w e e k s.
5. 3. 3 
E x cl u si o n s R el at e d t o M e di c ati o n s P ot e nti all y  U s e d f or t h e 
Tr e at m e nt of M ulti pl e S cl er o si s
 
Pr e vi o u s tr e at m e nt wit h B c ell -t ar g et e d t h er a pi e s ( e. g., rit u xi m ab, o cr eli z u m a b, 
at a ci c e pt, b eli m u m a b, or of at u m u m a b)
 
A n y pr e vi o u s tr e at m e nt wit h C a m p at h (al e mt u z u m a b ), a nti-C D 4, cl a dri bi n e, 
c y cl o p h o s p h a mi d e, mit o x a ntr o n e, a z at hi o pri n e, m y c o p h e n ol at e m of etil (M M F ), 
c y cl o s p ori n e, m et h otr e x at e, t ot al b o d y irr a di ati o n, or b o n e m arr o w tr a n s pl a nt ati o n
 
A n y pr e vi o u s tr e at m e nt wit h l y m p h o c yt e -tr affi c ki n g bl o c k er s 
( e. g., n at ali z u m a b, F T Y 7 2 0)
 
Tr e at m e nt wit h I F N s, gl atir a m er a c et at e, I V I g, pl a s m a p h er e si s, or ot h er 
i m m u n o m o d ul at or y t h er a pi e s wit hi n 1 2 w e e k s pri or t o r a n d o mi z ati on
P arti ci p a nt s s cr e e n e d f or t hi s st u d y s h o ul d n ot b e wit h dr a w n fr o m t h er a pi e s f or t h e 
s ol e p ur p o s e of m e eti n g eli gi bilit y f or t h e tri al.  P arti ci p a nt s w h o di s c o nti n u e t h eir 
c urr e nt t h er a p y f or n o n- m e di c al r e a s o n s s h o ul d s p e cifi c all y b e i nf or m e d b ef or e 
d e ci di n g t o e nt er t h e st u d y of t h eir tr e at m e nt o pti o n s a n d, t h at b y p arti ci p ati n g i n t hi s 
st u d y, t h e y m a y b e r a n d o mi z e d t o pl a c e b o f or a p eri o d of 1 2 0 w e e k s or gr e at er.
 
S y st e mi c c orti c o st er oi d t h er a p y wit hi n 4 w e e k s pri or t o s cr e e ni n g
T h e s cr e e ni n g p eri o d m a y b e e xt e n d e d ( b ut c a n n ot e x c e e d 8 w e e k s) f or p arti ci p a nt s
w h o h a v e u s e d s y st e mi c c orti c o st er oi d s f or t h eir M S b ef or e s cr e e ni n g.  F or a 
p arti ci p a nt t o b e eli gi bl e, s y st e mi c c orti c o st er oi d s s h o ul d n ot h a v e b e e n 
a d mi ni st er e d al s o b et w e e n s cr e e ni n g a n d b a s eli n e .
5. 3. 4  
E x cl u si o n s R el at e d t o L a b or at or y  Fi n di n g s
 
P o siti v e s er u m h u m a n c h ori o ni c g o n a d otr o pi n ( -h C G ) m e a s ur e d at s cr e e ni n g
 
P o siti v e s cr e e ni n g t e st s f or h e p atiti s B (h e p atiti s B s urf a c e a nti g e n [H B s A g ] p o siti v e, 
or p o siti v e h e p atiti s B c or e a nti b o d y [t ot al H B c A b ] c o nfir m e d b y a p o siti v e vir al D N A
p ol y m er a s e c h ai n r e a cti o n [P C R ] or h e p atiti s C vir u s a nti b o d y ([H e p C A b ]); 
s e e S e cti o n 5. 1 3. 1. 1 .


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
6 5 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
P o siti v e r a pi d pl a s m a r e a gi n ( R P R) if c o nfir m e d b y mi cr o h e m a g gl uti n ati o n a s s a y 
( M H A-T P) or fl u or e s c e nt tr e p o n e m al a nti b o d y a b s or pti o n ( F T A-A B S) t e st
 
C D 4 c o u nt 3 0 0/ L
 
S er u m cr e ati ni n e 1. 4 m g/ d L ( 1 2 4 m ol/ L) f or f em al e s
or 1. 6 m g/ d L 
(1 4 1 m ol/ L) f or m al e s
 
A S T/ S G O T or A L T/ S G P T 2. 0 U L N
 
Pl at el et c o u nt 1 0 0, 0 0 0/ L ( 1 0 0 1 0 9/ L)
 
H e m o gl o bi n 8. 5 g/ d L ( 5. 1 5 m m ol/ L)
 
A N C 1. 5 1 0 3 /L
 
L e v el s of s er u m I g G 1 8 % b el o w t h e L L N (f or c e ntr al l a bor at or y I g G 4. 6 g/ L)
 
L e v el s of s er u m I g M 8 % b el o w t h e L L N (f or c e ntr al l a bor at or y I g M 0. 3 7 g/ L)
R e -t e sti n g b ef or e b a s eli n e: in r ar e c a s e s i n w hi c h t h e s cr e e ni n g l a b or at or y s a m pl e s 
ar e r ej e ct e d b y t h e c e ntr al l a b or at or y ( e. g., a h e m ol y z e d s a m pl e) or t h e r e s ult n ot 
a s s e s s a bl e ( e. g., i n d et er mi n at e) or a b n or m al, t h e t e st s n e e d t o b e r e p e at e d wit hi n 
4 w e e k s.  A n y a b n or m al s cr e e ni n g l a b or at or y v al u e t h at i s cli ni c all y r el e v a nt s h o ul d 
b e r et e st e d i n or d er t o r ul e o ut a n y pr o gr e s si v e or u n c o ntr oll e d u n d erl yi n g c o n diti o n.   
T h e l a st v al u e b ef or e r a n d o mi z ati o n m u st m e et st u d y crit eri a.  I n s u c h 
cir c u m st a n c e s, t h e s cr e e ni n g p eri o d m a y n e e d t o b e pr ol o n g e d b ut c a n n ot e x c e e d 
8 w e e k s.
B a s e d o n l o c al E C s or N ati o n al C o m p et e nt A ut h orit y r e q uir e m e nt s, a d diti o n al di a g n o sti c 
t e sti n g m a y b e r e q uir e d f or s el e ct e d p arti ci p a nt s or s el e ct e d c e nt er s t o e x cl u d e T B
( e. g., c h e st X -r a y, t u b er c uli n s ki n or bl o o d t e st), L y m e di s e a s e, H T L V-1 a s s o ci at e d 
m y el o p at h y, A I D S, h er e dit ar y di s or d er s, c o n n e cti v e ti s s u e di s or d er s, or s ar c oi d o si s.  
Ot h er s p e cif i c di a g n o sti c t e st s m a y b e r e q u e st e d w h e n d e e m e d n e c e s s ar y b y t h e 
in v e sti g at or.
5. 4 
E LI GI BI LI T Y C RI T E RI A F O R O P E N -L A B E L E X T E N SI O N P H A S E
P arti ci p a nt s w h o m e et t h e f oll o wi n g e ntr y crit eri a m a y p arti ci p at e i n t h e O L E p h a s e:
 
C o m pl et e d t h e b li n d e d tr e at m e nt p eri o d of t h e tri al a n d w h o, i n t h e o pi ni o n of t h e 
in v e sti g at or, m a y b e n efit fr o m tr e at m e nt wit h o cr eli z u m a b
 
A bl e a n d willi n g t o pr o vi d e writt e n i nf or m e d c o n s e nt t o p arti ci p at e i n t h e O L E p h a s e 
a n d t o c o m pl y wit h t h e st u d y pr ot o c ol
 
C o ntr a c e pti o n r e q uir e m e nt s:
– 
F e m al e p arti ci p a nt s w h o ar e of r e pr o d u cti v e p ot e nti al a n d s e x u all y a cti v e m u st 
b e w illi n g t o c o nti n u e u s e of r eli a bl e m e a n s of c o ntr a c e pti o n a s d e s cri b e d 
b el o w a s a mi ni m u m ( a d h er e n c e t o l o c al r e q uir e m e nt s, if m or e stri n g e nt, i s 
r e q uir e d)
– 
O n e pri m ar y m et h o d of c o ntr a c e pti o n t hr o u g h o ut t h e O L E p h a s e
a n d 6 m o nt h s 
af t er t h e l a st d o s e of o cr eli z u m a b


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
6 6 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
– 
A c c e pt a bl e m et h o d s of c o ntr a c e pti o n i n cl u d e 1 pri m ar y 
( e. g., s y st e mi c h or m o n al c o ntr a c e pti o n or t u b al li g ati o n, v a s e ct o m y of t h e m al e 
p art n er) O R a d o u bl e -b arr i er m et h o d ( e. g., l at e x c o n d o m, i ntr a ut eri n e d e vi c e, 
v a gi n al ri n g or p e s s ar y pl u s s p er mi ci d e [ e. g., f o a m, v a gi n al s u p p o sit or y, g el, 
cr e a m])
– 
F or f e m al e p arti ci p a nt s wit h o ut r e pr o d u cti v e p ot e nti al:
W o m e n m a y b e e nr oll e d if p o st -m e n o p a u s al (i. e., s p o nt a n e o u s a m e n orr h e a f or 
t h e p a st y e ar c o nfir m e d b y a f olli cl e sti m ul ati n g h or m o n e l e v el 4 0 mI U/ m L) 
u nl e s s t h e p arti ci p a nt i s r e c ei vi n g a h or m o n al t h er a p y f or h er m e n o p a u s e; or 
s ur gi c all y st eril e (i. e., h y st er e ct o m y, c o m pl et e bil at er al o o p h or e ct o m y)
 
M e et t h e r e -tr e at m e nt crit eri a wit h o cr eli z u m a b ( s e e S e cti o n 6. 2. 3 )
5. 5 
C O N C O MI T A N T M E DI C A TI O N A N D T R E A T M E N T
5. 5. 1 
D efi niti o n s
A c o n c o mit a nt m e di c ati o n i s a n y dr u g or s u b st a n c e t a k e n d uri n g t h e st u d y, i n cl u di n g t h e 
s cr e e ni n g p eri o d.  O v er -t h e-c o u nt er m e di c ati o n s a n d pr e v e nt ati v e v a c ci n e s r e c ei v e d 
d uri n g t h e st u d y ar e c o n si d er e d c o n c o mit a nt m e di c ati o n s.  A c o n c o mit a nt pr o c e d ur e i s 
a n y t h er a p e uti c or el e cti v e i nt er v e nti o n ( e. g. , s ur g er y, bi o p s y) or di a g n o sti c e v al u ati o n 
( e. g., bl o o d g a s m e a s ur e m e nt s, b a ct eri al c ult ur e s) p erf or m e d d uri n g t h e st u d y, i n cl u di n g 
t h e s cr e e ni n g p eri o d.
C o n c o mit a nt m e di c ati o n s a n d pr o c e d ur e s will b e r e p ort e d at e a c h vi sit i n t h e r el e v a nt 
el e ctr o ni c C a s e R e p ort F or m s ( e C R F s ) st arti n g fr o m t h e b a s eli n e vi sit (f or m e di c ati o n 
a n d pr o c e d ur e s t a k e n b e t w e e n s cr e e ni n g a n d b a s eli n e).  M e di c ati o n s t a k e n f or t h e 
tr e at m e nt of M S
i n t h e 2-y e ar p eri o d pri or t o t h e b a s eli n e vi sit a n d m e di c ati o n s t a k e n f or 
t h e s y m pt o m s of M S
i n t h e 3- m o nt h
p eri o d pri or t o t h e b a s eli n e vi sit will b e r e c or d e d at 
t h e b a s eli n e vi sit.
5. 5. 2 
Tr e at m e nt of M ulti pl e S cl er o si s a n d It s S y m pt o m s
T h e Tr e ati n g I n v e sti g at or s h o ul d att e m pt t o m ai nt ai n t h er a pi e s or tr e at m e nt s f or 
s y m pt o m s r el at e d t o M S ( e. g., w al ki n g a bilit y, s p a sti cit y, i n c o nti n e n c e, p ai n, f ati g u e) 
r e a s o n a bl y c o n st a nt t hr o u g h o ut t h e st u d y.  H o w e v er, c h a n g e s m a y b e m a d e if 
a p pr o pri at e f or a p arti ci p a nt’ s w ell -b ei n g i n t h e cli ni c al j u d g m e nt of t h e 
Tr e ati n g I n v e sti g at or.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
6 7 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T h er a pi e s f or M S n ot e d i n S e cti o n 5. 3. 3 ar e N O T p er mitt e d d uri n g t h e bli n d e d tr e at m e nt 
p eri o d or t h e O L E p h a s e, wit h t h e e x c e pti o n of a s h ort (l e s s t h a n 5 d a y s) c o ur s e of 
s y st e mi c c orti c o st er oi d s f or t h e tr e at m e nt of a r el a p s e or w or s e ni n g of M S s y m pt o m s ; 
I V I g is als o per mitte d.  F or p arti ci p a nt s w h o di s c o nti n u e tr e at m e nt wit h o cr eli z u m a b 
a n d e nt er s af et y foll o w -u p p eri o d , alt er n ati v e tr e at m e nt s f or t h eir M S a s j u d g e d cli ni c all y 
a p pr o pri at e b y t h e Tr e ati n g I n v e sti g at or ar e all o w e d. H o w e v er , si n c e s uffi ci e nt d at a ar e 
n ot a v ail a bl e t o a s s e s s t h e ri s k s a s s o ci at e d wit h s wit c hi n g t o ot h er pr o d u ct s, t h e 
f oll o wi n g r e c o m m e n d ati o n s ar e gi v e n:
 
C a uti o n i s a d vi s e d w hil e p arti ci p a nt s r e m ai n B c ell d e pl et e d
 
B e c a u s e of t h e u n k n o w n s af et y ri s k of a d mi ni st eri n g D M T s f or MS aft er 
di s c o nti n u ati o n of o cr eli z u m a b, c ert ai n tr e at m e nt s f or M S , s u c h a s 
l y m p h o c yt e-d e pl eti n g a g e nt s or l y m p h o c yt e -tr affi c ki n g bl o c k er s 
(e. g. , al e mt u z u m a b, n at ali z u m a b, fi n g oli m o d, di m et h yl f u m ar at e, c y cl o p h o s p h a mi d e, 
a z at hi o pri n e, et c.) , ar e str o n gl y di s c o ur a g e d f or a s l o n g a s t h e p arti ci p a nt r e m ai n s 
B c ell d e pl et e d b e c a u s e of u n k n o w n eff e ct s o n t h e i m m u n e s y st e m 
( e. g., i n cr e a s e d ri s k, i n ci d e n c e, or s e v erit y of i nf e cti o n).
P arti ci p a nt s w h o st art tr e at m e nt wit h c o m m er ci al o cr eli z u m a b ( O C R E V U S ) or a n ot her 
D M T will b e di s c o nti n u e d fr o m t h e st u d y c o m pl et el y a n d will n ot e nt er or c o nti n u e i n t h e 
s af et y f oll o w -u p p eri o d .
Alt h o u g h a nti ci p at e d t o b e r ar e i n a P P M S p o p ul ati o n, p arti ci p a nt s w h o i niti all y pr e s e nt 
wit h a P P M S p h e n ot y p e c a n e x p eri e n c e a r el a p s e.  P arti ci p a nt s w h o e x p eri e n c e a 
r el a p s e d uri n g t h e tr e at m e nt p eri o d m a y r e c ei v e tr e at m e nt wit h I V or or al c orti c o st er oi d s, 
if j u d g e d t o b e cli ni c all y a p pr o pri at e b y t h e in v e sti g at or.  T h e f oll o wi n g st a n d ar di z e d 
tr e at m e nt r e gi m e n i s r e c o m m e n d e d, 1 g m et h yl pr e d ni s ol o n e I V p er d a y f or a m a xi m u m 
of  5 c o n s e c uti v e d a y s.  I n a d diti o n, at t h e di s cr eti o n of t h e in v e sti g at or, c orti c o st er oi d s 
m a y b e st o p p e d a br u ptl y or t a p er e d o v er a m a xi m u m of 1 0 d a y s.  S u c h p arti ci p a nt s
s h o ul d n ot di s c o nti n u e t h e tr e at m e nt p eri o d s ol el y b a s e d o n t h e o c c urr e n c e of a r el a p s e, 
u nl e s s t h e p arti ci p a nt or in v e sti g at or f e el s h e or s h e h a s m et t h e crit eri a f or wit h dr a w al 
( s e e S e cti o n 5. 6 ).
5. 5. 3 
I m m u ni z ati o n
R o c h e h a s c o m pl et e d a r a n d o mi z e d, o p e n -l a b el v a c ci n ati o n st u d y i n 
o cr eli z u m a b -tr e at e d p arti ci p a nt s wit h R M S ( St u d y B N 2 9 7 3 9).  T h e r e s ult s of t hi s st u d y 
i n di c at e t h at p arti ci p a nt s b ei n g tr e at e d wit h o cr eli z u m a b m a y h a v e a n att e n u at e d 
h u m or al r e s p o n s e w h e n i m m u ni z e d wit h a n i n a cti v at e d v a c ci n e.  D et ail e d 
St u d y B N 2 9 7 3 9 r e s ult s c a n b e f o u n d i n t h e c urr e nt v er si o n of t h e O cr eli z u m a b I B.
P h y si ci a n s ar e a d vi s e d t o r e vi e w t h e i m m u ni z ati o n st at u s of p arti ci p a nt s b ei n g 
c o n si d er e d f or tr e at m e nt wit h o cr eli z u m a b a n d f oll o w l o c al/ n ati o n al g ui d a n c e f or a d ult 
v a c ci n ati o n a g ai n st i nf e cti o u s di s e a s e.  I m m u ni z ati o n s s h o ul d b e c o m pl et e d at l e a st 
6 w e e k s pri or t o fir st a d mi ni str ati o n of o cr eli z u m a b.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
6 8 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T h e s af et y of i m m u ni z ati o n wit h li v e vir al v a c ci n e s f oll o wi n g o cr eli z u m a b or rit u xi m a b 
t h er a p y h a s n ot b e e n st u di e d.  I m m u ni z ati o n wit h a n y li v e or li v e-att e n u at e d v a c ci n e 
(i. e., m e a s l e s, m u m p s, r u b ell a, or al p oli o v a c ci n e, B C G, t y p h oi d, y ell o w f e v er, v a c ci ni a, 
c ol d a d a pt e d li v e i nfl u e n z a str ai n v a c ci n e , or a n y ot h er v a c ci n e s n ot y et li c e n s e d b ut 
b el o n gi n g t o t hi s c at e g or y) i s n ot r e c o m m e n d e d wit hi n 6 w e e k s pri or t o fir st d o si n g 
( s e e S e cti o n 5. 3 ), d uri n g o cr eli z u m a b tr e at m e nt a n d f or a s l o n g a s t h e p arti ci p a nt i s 
B c ell d e pl et e d.
P arti ci p a nt s r e q uiri n g d e n o v o h e p atiti s B v a c ci n ati o n ( w hi c h i n v ol v e s 3 s e p ar at e d o s e s 
of  v a c ci n e) s h o ul d h a v e c o m pl et e d t h e c o ur s e at l e a st 6 w e e k s pri or t o t h e fir st i nf u si o n 
of  st u d y dr u g.
T h e o cr eli z u m a b P h a s e II a n d III pr o gr a m c urr e ntl y s h o w s t h at aft er tr e at m e nt wit h 
o cr eli z u m a b o v er 2 y e ar s , t h e pr o p orti o n s of p arti ci p a nt s wit h p o siti v e a nti b o d y tit er s 
a g ai n st S tr e pt o c o c c u s p n e u m o ni a e , i nfl u e n z a, m u m p s, r u b ell a, v ari c ell a, a n d t et a n u s 
t o x oi d w er e g e n er all y si mil ar t o t h e pr o p orti o n s at b a s eli n e.
T h e in v e sti g at or s h o ul d r e vi e w t h e p arti ci p a nt’ s i m m u ni z ati o n hi st or y a n d v a c ci n ati o n 
st at u s.  K n o w n d at e s of i m m u ni z ati o n s c a n b e r e c or d e d o n s p e cifi c e C R F p a g e s.
5. 6 
C RI T E RI A  F O R P R E M AT U R E WI T H D R A W A L
P arti ci p a nt s h a v e t h e ri g ht t o wit h dr a w fr o m t h e st u d y at a n y ti m e f or a n y r e a s o n.
I n t h e c a s e t h at t h e p arti ci p a nt d e ci d e s t o pr e m at ur el y di s c o nti n u e st u d y tr e at m e nt 
(“r ef u s e s tr e at m e nt”), h e/ s h e s ho ul d c o m pl et e t h e s af et y foll o w -u p p eri o d.  If t h e 
p arti ci p a nt i n si sts o n di s c o nti n ui n g t h e st u d y, h e/ s h e s h o ul d b e a s k e d if h e/ s h e c a n still 
b e c o nt a ct e d f or f urt h er i nf or m ati o n.  T h e o ut c o m e of t h at di s c u s si o n s h o ul d b e 
d o c u m e nt e d i n b ot h t h e m e di c al r e c or d s a n d i n t h e e C R F.  If l o st t o f oll o w -u p, t h e 
in v e sti g at or s h o ul d c o nt a ct t h e p arti ci p a nt or a r e s p o n si bl e r el ati v e b y t el e p h o n e f oll o w e d 
b y r e gi st er e d m ail or t hr o u g h a p er s o n al vi sit t o e st a bli s h a s c o m pl et el y a s p o s si bl e t h e 
r e a s o n f or t h e wit h dr a w al.  A c o m pl et e fi n al e v al u ati o n at t h e ti m e of t h e p arti ci p a nt’ s
wit h d r a w al s h o ul d b e m a d e wit h a n e x pl a n ati o n of w h y t h e p arti ci p a nt i s wit h dr a wi n g 
fr o m t h e st u d y.
W h e n a p pli c a bl e, p arti ci p a nt s s h o ul d b e i nf or m e d of cir c u m st a n c e s u n d er w hi c h t h eir 
p arti ci p ati o n m a y b e t er mi n at e d b y t h e in v e sti g at or wit h o ut t h e p arti ci p a nt’ s c o n s e nt.  
T h e in v e sti g at or m a y wit h dr a w p arti ci p a nt s fr o m t h e st u d y i n t h e e v e nt of i nt er c urr e nt 
ill n e s s, a d v er s e e v e nt s, tr e at m e nt f ail ur e, aft er a pr e s cri b e d pr o c e d ur e, l a c k of 
c o m pli a n c e wit h t h e st u d y a n d/ or st u d y pr o c e d ur e s ( e. g., d o si n g i n str u cti o n s , st u d y 
vi sit s), c ur e or a n y r e a s o n w h er e it i s f elt b y t h e in v e sti g at or t h at it i s i n t h e b e st i nt er e st 
of  t h e p arti ci p a nt t o b e t er mi n at e d fr o m t h e st u d y.  A n y a d mi ni str ati v e or ot h er r e a s o n s 
f or wit h dr a w al m u st b e d o c u m e nt e d a n d e x pl ai n e d t o t h e p arti ci p a nt .  If t h e r e a s o n f or 
r e m o v al of a p arti ci p a nt fr o m t h e st u d y i s a n a d v er s e e v e nt, t h e pri n ci p al s p e cifi c e v e nt 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
6 9 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
will b e r e c or d e d o n t h e e C R F.  T h e p arti ci p a nt s h o ul d b e f oll o w e d u ntil t h e a d v er s e 
e v e nt h a s r e s ol v e d, if p o s si bl e.
A n e x c e s si v e r at e of wit h dr a w al s c a n r e n d er t h e st u d y n o n -i nt er pr et a bl e; t h er ef or e, 
u n n e c e s s ar y wit h dr a w al of p arti ci p a nt s s h o ul d b e a v oi d e d.  S h o ul d a p arti ci p a nt d e ci d e 
t o wit h dr a w, all eff ort s will b e m a d e t o c o m pl et e a n d r e p ort t h e o b s er v ati o n s pri or t o 
wit h dr a w al a s t h or o u g h l y a s p o s si bl e.
It i s i m p ort a nt t o di sti n g ui s h b et w e e n “ wit h dr a w al fr o m tr e at m e nt” a n d “ wit h dr a w al fr o m 
st u d y”.  P arti ci p a nt s w h o wit h dr a w fr o m tr e at m e nt s h o ul d b e e n c o ur a g e d t o r e m ai n i n t h e 
st u d y f or t h e f ul l d ur ati o n of t h e s af et y foll o w -u p p eri o d ( u p t o 4 8 w e e k s f oll o wi n g t h e l a st 
i nf u si o n).
P arti ci p a nt s w h o st art tr e at m e nt wit h c o m m er ci al o cr eli z u m a b or a n ot her D M T will 
di s c o nti n u e fr o m t h e st u d y c o m pl et el y a n d will n ot e nt er or c o nti n u e i n t h e s af et y 
foll o w -u p p eri o d.
P arti ci p a nt s m u st b e wit h dr a w n fr o m tr e at m e nt (r e g ar dl e s s of w h et h er t h e y ar e i n t h e 
b li n d e d tr e at m e nt p eri o d or i n t h e O L E p h a s e) u n d er t h e f oll o wi n g cir c u m st a n c e s:
 
Lif e -t hr e at e ni n g (C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s [ C T C A E] 
Gr a d e 4) i nf u si o n -r el at e d e v ent t h at o c c urr e d d uri n g a pr e vi o u s o cr eli z u m a b i nf u si o n
( s e e S e cti o n s 6. 2. 2 , 7. 1. 1. 3 , a n d 7. 3. 1 )
 
P arti ci p a nt s w h o d e m o n str at e a cti v e h e p atiti s B or C i nf e cti o n, eit h er n e w o n s et or 
r e a cti v ati o n i n t h e c a s e of h e p atiti s B ( s e e S e cti o n s 5. 1 3. 1. 1 a n d 7. 3. 1 )
 
P arti ci p a nt s wit h P M L ( s e e S e cti o n s 7. 3. 1 a n d 7. 3. 4 )
 
P arti ci p a nt s w h o d e ci d e t o di s c o nti n u e t h e tr e at m e nt
 
T h e p arti ci p a nt’ s Tr e ati n g I n v e sti g at or d e ci d e s t h at di s c o nti n u ati o n of tr e at m e nt i s i n 
t h e b e st cli ni c al i nt er e st of t h e p arti ci p a nt
It s h o ul d b e n ot e d t h at u p o n wit h dr a w al fr o m t h e st u d y, a n y u nt e st e d r o uti n e s a m pl e s 
will b e d e str o y e d.  H o w e v er, i nf or m ati o n alr e a d y o bt ai n e d fr o m s a m pl e s u p u ntil t h e ti m e 
of  wit h dr a w al will b e u s e d.
5. 6. 1 
Wit h dr a w al of S u bj e ct s fr o m t h e R o c h e Cli ni c al R e p o sit or y
P arti ci p a nt s w h o gi v e c o n s e nt t o pr o vi d e R C R s p e ci m e n s h a v e t h e ri g ht t o wit h dr a w 
t h eir s p e ci m e n fr o m t h e R C R at a n y ti m e f or a n y r e a s o n.  If a p arti ci p a nt wi s h e s t o 
wit h dr a w hi s/ h er c o n s e nt t o t h e t e sti n g of hi s/ h er s p e ci m e n( s), t h e in v e sti g at or m u st 
i nf or m t h e R o c h e m o nit or i n writi n g of t h e p arti ci p a nt’ s wi s h e s wit h u s e of t h e R C R 
P arti ci p a nt Wi t h dr a w al F or m a n d e nt er t h e d at e of wit h dr a w al i n t h e p arti ci p a nt’ s e C R F.  
A p arti ci p a nt wit h dr a w al fr o m t h e m ai n tri al d o e s n ot, b y it s elf, c o n stit ut e wit h dr a w al of 
t h e s p e ci m e n fr o m t h e R C R; li k e wi s e, a p arti ci p a nt wit h dr a w al fr o m t h e R C R d o e s n ot 
c o n stit ut e a wit h dr a w al fr o m t h e m ai n tri a l.


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7 0 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
5. 6. 2 
Wit h dr a w al fr o m t h e R e s e ar c h Bi o s a m pl e R e p o sit or y
P arti ci p a nt s w h o gi v e c o n s e nt t o pr o vi d e R B R s a m pl e s h a v e t h e ri g ht t o wit h d r a w t h eir 
c o n s e nt at a n y ti m e f or a n y r e a s o n ( s e e S e cti o n 5. 1 6 ).
5. 6. 3 
R e - Co n s e nt R ul e ( In C a s e of C o nfir m e d D i s a bilit y Pr o gr e s si o n)
D uri n g t h e bli n d e d tr e at m e nt p eri o d, i n t h e e v e nt of c o nfir m e d di s a bilit y pr o gr e s si o n o n 
E D S S s u st ai n e d f or 2 4 -w e e k s, t h e b e n efit s a n d ri s k s of st u d y tr e at m e nt s h o ul d b e 
r e a s s e s s e d wit h t h e p arti ci p a nt pri or t o a n y f urt h er d o si n g, i n cl u di n g a di s c u s si o n of
tr e at m e nt o pti o n s a v ail a bl e f or t h at p arti ci p a nt .  If t h e p arti ci p a nt d e sir e s t o c o nti n u e 
bli n d e d st u d y tr e at m e nt, t h e n p arti ci p a nt w o ul d b e r e -c o n s e nt e d.  Ot h er wi s e, t h e 
p arti ci p a nt s h o ul d b e di s c o nti n u e d fr o m a n y f urt h er tr e at m e nt a n d e nt er e d i nt o t h e s af et y 
foll o w -u p p eri o d.  T h e r e s ult of t h e di s c u s si o n a n d, w h e n a p pli c a bl e, a si g n e d r e n e w e d 
c o n s e nt f or m s h o ul d b e i n cl u d e d i n t h e p arti ci p a nt’ s fil e a n d t h e d at e of r e -c o n s e nt 
s h o ul d b e r e c or d e d i n t h e e C R F .
Di s a bilit y pr o gr e s si o n i s d efi n e d a s a n i n cr e a s e of 1. 0 p oi nt fr o m t h e b a s eli n e E D S S 
w h e n t h e b a s eli n e s c or e i s 5. 5 or l e s s, a n d 0. 5 w h e n t h e b a s eli n e s c or e i s m or e t h a n 
5. 5, t h at i s n ot attri b ut a bl e t o a n ot h er eti ol o g y ( e. g., f e v er, c o n c urr e nt ill n e s s, or 
c o n c o mit a nt m e di c ati o n).  S u st ai n e d m e a n s t h at t h e i n cr e a s e i s c o nfir m e d at a r e g ul arl y 
s c h e d ul e d vi sit at l e a st 2 4 w e e k s aft er t h e i niti al d o c u m e nt ati o n of t h e pr o gr e s si o n.  
I n v e sti g at or s will b e n otifi e d b y t h e S p o n s or w h e n a n E D S S s c or e i n cr e a s e m e et s 
crit eri a f or c o nfir m e d di s a bilit y pr o gr e s s i o n, aft er w hi c h r e-c o n s e nt t o c o nti n u e st u d y 
tr e at m e nt m u st b e o bt ai n e d.
I n t h e O L E p h a s e, t h e r e-c o n s e nt r ul e will n o l o n g er a p pl y.
5. 7 
R E P L A C E M E N T P O LI C Y ( E N S U RI N G A D E Q U A T E N U M B E R S 
O F E V A L U A B L E P A R TI CI P A N T S )
5. 7. 1 
F or P arti ci p a nt s
N o p arti ci p a nt pr e m at ur el y di s c o nti n u e d fr o m t h e st u d y f or a n y r e a s o n will b e r e pl a c e d.
5. 7. 2 
F or C e nt er s
A c e nt er m a y b e r e pl a c e d f or t h e f oll o wi n g a d mi ni str ati v e r e a s o n s:
 
E x c e s si v el y sl o w st art -u p or sit e -a cti v ati o n
 
E x c e s si v el y sl o w r e cr uit m e nt
 
P o or pr ot o c ol a d h er e n c e
 
S p o n s or’ s di s cr eti o n ( S p o n s or r ef er s t o F.  H off m a n n -L a R o c h e Lt d)


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5. 8 
S C R E E NI N G E X A MI N A TI O N A N D E LI GI BI LI T Y S C R E E NI N G 
F O R M
All p arti ci p a nt s m u st si g n a n d d at e t h e m o st c urr e nt I n stit uti o n al R e vi e w B o ar d 
(IR B )/E C -a p pr o v e d writt e n i nf or m e d c o n s e nt b ef or e a n y st u d y s p e cifi c a s s e s s m e nt s or 
pr o c e d ur e s ar e p erf or m e d.
A s cr e e ni n g e x a mi n ati o n ( m e di c al hi st or y a n d p h y si c al e x a mi n ati o n , i n cl u di n g vit al si g n s 
h ei g ht a n d w ei g ht a n d n e ur ol o gi c al e x a mi n ati o n wit h E D S S a s s e s s m e nt) s h o ul d b e 
p erf or m e d wit hi n 4 w e e k s pri or t o t h e st art of t h e st u d y.  A n E C G a n d l a b or at or y t e st s 
(r o uti n e s af et y, pr e g n a n c y t e st i n w o m e n of c hil d b e ari n g p ot e nti al, F S H f or m e n o p a u s al 
st at u s, t h yr oi d f u n cti o n t e st s, h e p atiti s s cr e e ni n g t e st s, I g s, R P R , HI V t e st, 
Q u a nti F E R O N -T B G ol d t e st ( G er m a n y o n l y) a n d C D 4 c o u nt will al s o b e p erf or m e d.  
T h e s cr e e ni n g p eri o d c a n b e e xt e n d e d t o a t ot al p eri o d of 8 w e e k s i n c a s e s w h e n a 
l a b or at or y bl o o d t e st or M RI s c a n n e e d t o b e r e p e at e d f or c o nfir m ati o n d uri n g t h e 
s cr e e ni n g i nt er v al or f or ot h er r el e v a nt cli ni c al , a d mi ni str ati v e, or o p er ati o n al r e a s o n s.  
P arti ci p a nt s m u st f ulfill all t h e e ntr y crit eri a f or p arti ci p ati o n i n t h e st u d y ( s e e
S e cti o n 5 ).
A n Eli gi bilit y S cr e e ni n g F or m d o c u m e nti n g t h e in v e sti g at or’ s a s s e s s m e nt of e a c h 
s cr e e n e d p arti ci p a nt wit h r e g ar d t o t h e pr ot o c ol’ s i n cl u si o n a n d e x cl u si o n crit eri a i s t o b e 
c o m pl et e d b y t h e in v e sti g at or.
E a c h p arti ci p a nt s cr e e n e d m u st b e r e gi st er e d i n t h e I x R S b y t h e in v e sti g at or or t h e 
in v e sti g at or’ s r e s e ar c h st aff at s cr e e ni n g.  A s cr e e n f ail ur e r e c or d m u st b e m ai nt ai n e d b y 
t h e in v e sti g at or a n d c a pt ur e d i n t h e I x R S.
It s h o ul d b e st at e d i n t h e m e di c al r e c or d t h at t h e p ar ti ci p a nt i s p arti ci p ati n g i n t hi s cli ni c al 
st u d y.
5. 9 
P R O C E D U R E S F O R E N R O L L M E N T O F E LI GI B L E 
P A R TI CI P A N T S
O n c e a p arti ci p a nt h a s f ulfill e d t h e e ntr y crit eri a, h e or s h e will b e r a n d o mi z e d vi a I x R S t o 
o n e of 2 tr e at m e nt gr o u p s: 3 0 0 m g 2 of o cr eli z u m a b or pl a c e b o.
P arti ci p a nt eli gi bilit y i nf or m ati o n will b e pr o vi d e d t o t h e I x R S b y t h e in v e sti g at or or t h e 
in v e sti g at or’ s r e s e ar c h st aff at r a n d o mi z ati o n.  T h e p arti ci p a nt will b e r a n d o mi z e d a n d 
a s si g n e d a u ni q u e tr e at m e nt b o x n u m b er ( m e di c ati o n n u m b er) a n d r a n d o mi z ati o n 
n u m b er.  A s c o nfir m ati o n, t h e sit e will b e pr o vi d e d wit h a v erifi c ati o n of e a c h p arti ci p a nt’ s
r a n d o mi z ati o n.
T h e p arti ci p a nt r a n d o mi z ati o n n u m b er s will b e g e n er at e d b y R o c h e or it s d e si g n e e a n d 
i n c or p or ate d i nt o d o u bl e -bli n d l a b eli n g.


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T h e p arti ci p a nt r a n d o mi z ati o n n u m b er s ar e t o b e all o c at e d s e q u e nti all y i n t h e or d er i n 
w h i c h t h e p arti ci p a nt s ar e e nr oll e d a c c or di n g t o t h e s p e cifi c ati o n d o c u m e nt a gr e e d wit h 
t h e e xt er n al r a n d o mi z ati o n c o m p a n y/ c e nt er.
Tr e at m e nt wit h t h e fir st st u d y dr u g i nf u si o n s h o ul d o c c ur wit hi n 2 4 h o ur s of 
r a n d o mi z ati o n.  I n e x c e pti o n al c a s e s w h er e all b a s eli n e a s s e s s m e nt s c a n n ot b e 
c o m pl et e d wit hi n 2 4 h o ur s, t h e fir st st u d y dr u g i nf u si o n c a n b e a d mi ni st er e d wit hi n 
4 8 h o ur s of r a n d o mi z ati o n pr o vi d e d t h at t h e in v e sti g at or a s s ur e s t h at all i n cl u si o n a n d 
e x cl u si o n crit eri a ar e still m et o n t h e d a y of d o si n g.  I n p arti c ul ar, t h er e s h o ul d b e n o 
e vi d e n c e of a n o n g oi n g i nf e cti o n at t h e ti m e of d o si n g.
N o p arti ci p a nt m a y b e gi n tr e at m e nt pri or t o r a n d o mi z ati o n a n d a s si g n m e nt of a 
m e di c ati o n n u m b er.
5. 1 0 
C LI NI C A L A S S E S S M E N T S A N D P R O C E D U R E S
5. 1 0. 1 
O v er vi e w  of St u d y Vi sit s
Aft er t h e s cr e e ni n g vi sit, p arti ci p a nt s f ulfilli n g t h e e ntr y crit eri a will b e s c h e d ul e d f or t h e 
b a s eli n e a s s e s s m e nt s wit hi n 4 w e e k s ( Vi sit 2).  R a n d o mi z ati o n will o c c ur o nl y aft er t h e 
p arti ci p a nt m e et s all i n cl u si o n a n d e x cl u si o n crit eri a o n D a y 1.  T h e s c h e d ul e of a cti viti e s
i s d e s cri b e d i n T a bl e 1 , T a bl e 2 , T a bl e 3 , a n d T a bl e 4 .  A n o v er all s u m m ar y of t h e st u d y 
vi sit s i s gi v e n b el o w f oll o w e d b y a d et ail e d d e s cri pti o n of effi c a c y a n d s af et y 
a s s e s s m e nt s.
5. 1 0. 1. 1 
B a s eli n e Vi sit ( Vi sit 2) f or t h e Bli n d e d Tr e at m e nt P eri o d
M o st a s s e s s m e nt s f or t hi s vi sit s h o ul d b e c o m pl et e d o n D a y 1 pri or t o t h e st art of st u d y 
tr e at m e nt (i. e., t h e fir st I V i nfu si o n of o cr eli z u m a b or p l a c e b o).  P arti ci p a nt s will h a v e 
t h eir vit al si g n s c h e c k e d at t h e s p e cifi e d ti m e p oi nt s b ef or e tr e at m e nt o n s et a n d d uri n g 
a n d aft er t h e i nf u si o n ( s e e S e cti o n 5. 1 2. 1 ).  I n a d diti o n, t h e s e p arti ci p a nt s will h a v e 
l a b or at or y s a m pl e s f or P K ( s e e S e cti o n 5. 1 4 ) a n d f or B c ell s u bt y pi n g 
( s e e S e cti o n 5. 1 3. 2 ) t a k e n b ef or e a n d aft er d o si n g.  T h e p arti ci p a nt s h o ul d r e m ai n i n 
o b s er v ati o n f or at l e a st 1 h o ur aft er t h e c o m pl eti o n of t h e i nf u si o n i s a d mi ni st er e d 
( s e e S e cti o n 6. 2. 1 ).
5. 1 0. 1. 2 
S u b s e q u e nt Vi sit s D uri n g t h e Bli n d e d Tr e at m e nt P eri o d
T h er e ar e a mi ni m u m of 5 tr e at m e nt c y cl e s, e a c h l a sti n g 2 4 w e e k s i n d ur ati o n, 
i. e., C y cl e b a s eli n e t o W e e k 2 4; C y cl e 2 W e e k 2 4 4 8; C y cl e 3 W e e k  4 87 2; 
C y cl e 4 W e e k 7 2 9 6; C y cl e 5 W e e k 9 6 1 2 0.  P arti ci p a nt s e nr oll e d e arli er i n t h e st u d y 
m a y u n d er g o 7 or 8 tr e at m e nt c y cl e s, c o nti n g e nt o n t h e ti m e p eri o d r e q uir e d t o e nr oll t h e 
e ntir e st u d y.  T h e tr e at m e nt p eri o d will e n d w h e n t h e l a st p arti ci p a nt e nr oll e d c o m pl et e s 
t h eir fift h tr e at m e nt c y cl e (W e e k 1 2 0).  I n t h e e v e nt t h at t h e a nti ci p at e d n u m b er of 
c o nfir m e d di s a bilit y pr o gr e s si o n e v e nt s i s n ot r e a c h e d w h e n t h e l a st p arti ci p a nt e nr oll e d 
c o m pl et e s t h e fift h tr e at m e nt c y cl e, t h e n all p arti ci p a nt s m a y u n d er g o a d diti o n al 
tr e at m e nt c y cl e s u ntil a p pr o xi m at el y 2 5 3 c o nfir m e d di s a bilit y pr o gr e s si o n e v e nt s h a v e 
o c c urr e d.


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T w o i nf u si o n vi sit s will o c c ur 1 4 d a y s a p art , e v er y 2 4 w e e k s t hr o u g h t h e e n d of t h e 
b li n d e d tr e at m e nt p eri o d (i. e. , D a y 1 a n d W e e k 2, W e e k s 2 4 a n d 2 6, W e e k s 4 8 a n d 5 0, 
a n d s o f ort h).  N o n -i nfu si o n vi sit s will o c c ur at W e e k 1 2 a n d at t h e mi d p oi nt of e a c h 
tr e at m e nt c y cl e t h er e aft er t hr o u g h t h e e n d of t h e b li n d e d tr e at m e nt p eri o d 
(i. e., W e e k s 3 6, 6 0, 8 4, a n d s o f ort h).  I n a d diti o n, a str u ct ur e d t el e p h o n e i nt er vi e w will 
b e d o n e o n a 4 -w e e k b a si s b et w e e n st u d y vi sit s fr o m W e e k 8 t hr o u g h t h e e n d of t h e 
b li n d e d tr e at m e nt p eri o d t o i d e ntif y a n y n e w or w or s e ni n g n e ur ol o gi c al s y m pt o m s t h at 
w arr a nt a n u n s c h e d ul e d vi sit.  All eff o rt s s h o ul d b e m a d e t o s c h e d ul e t h e vi sit s wit hi n t h e 
pr o vi d e d wi n d o w s.
Vi sit s s h o ul d b e s c h e d ul e d i n r el ati o n t o t h e b a s eli n e vi sit ( Vi sit 2) pr o vi di n g a 
2 0 w e e k p eri o d i s m ai nt ai n e d b et w e e n t h e l a st i nf u si o n of 1 tr e at m e nt c y cl e a n d t h e fir st 
i nf u si o n of t h e n e xt tr e at m e nt c y cl e.  T hi s a p pli e s t o all tr e at m e nt gr o u p s.  
P arti ci p a nt s s h o ul d n ot r e c ei v e t h eir i nf u si o n s wit hi n a s h ort er i nt er v al.  P arti ci p a nt s w h o 
c a n n ot r e c ei v e t h eir i nf u si o n at t h e vi sit, s h o ul d b e r e s c h e d ul e d f or a d el a y e d d o si n g vi sit
( s e e S e cti o n 5. 1 0. 1. 5 ).
A d diti o n al u n s c h e d ul e d vi sit s f or t h e a s s e s s m e nt of p ot e nti al r el a p s e s, n e w n e ur ol o gi c al 
s y m pt o m s or s af et y e v e nt s m a y o c c ur at a n y ti m e.  St arti n g at W e e k 8, all p arti ci p a nt s
will b e i nt er vi e w e d o v er t h e t el e p h o n e e v er y 4 w e e k s b et w e e n st u d y vi sit s t o i d e ntif y a n d 
c oll e ct i nf or m ati o n o n a n y c h a n g e s i n t h e p arti ci p a nt’ s h e alt h st at u s (i n cl u di n g a n y n e w 
or w or s e ni n g n e ur ol o gi c al s y m pt o m s) t h at w arr a nt a n u n s c h e d ul e d vi sit 
( s e e S e cti o n 5. 1 2. 4. 1 ).
5. 1 0. 1. 3 
Vi sit s D uri n g t h e O p e n -L a b el E xt e n si o n P h a s e
P arti ci p a nt s e nr oll e d i n t h e O L E p h a s e will r e c ei v e a d u al o cr eli z u m a b i nf u si o n 
( 3 0 0 m g
I V i nfu si o n s a d mi ni st er e d 1 4 d a y s a p art) f or t h e fir st c y cl e. F or t h e s u b s e q u e nt 
c y cl e s , p arti ci p a nt s will c o nti n u e o p e n -l a b el tr e at m e nt wit h a si n gl e i nf u si o n of 6 0 0 m g 
o cr eli z u m a b I V e v er y 2 4 w e e k s.   S e e T a bl e 4 f or d et ail e d i nf or m ati o n o n t h e 
a s s e s s m e nt s t h at will b e p erf or m e d d uri n g t h e O L E p h a s e.  All p arti ci p a nt s p arti ci p ati n g 
i n O L E p h a s e m u st c o nti n u e t o b e eli gi bl e f or r e-d o si n g a s o utli n e d i n t h e crit eri a f or 
r e-tr e at m e nt wit h o cr eli z u m a b ( S e cti o n 6. 2. 3 ).
5. 1 0. 1. 4 
Vi sit s D uri n g t h e S af et y  F oll o w-U p P eri o d
P arti ci p a nt s w h o di s c o nti n u e tr e at m e nt f or a n y r e a s o n (i n cl u di n g , b ut n ot li mit e d t o ,
wit h dr a w al fr o m bli n d e d tr e at m e nt, wit h dr a w al fr o m O L E p h a s e, or S p o n s or d e ci si o n t o 
t er mi n at e t h e st u d y) will b e f oll o w e d u p f or u p t o 4 8 w e e k s aft er t h e l a st i nf u si o n i n t h e 
s af et y foll o w -u p p eri o d wit h vi sit s e v er y 1 2 w e e k s.
P arti ci p a nt s s h o ul d b e e n c o ur a g e d t o c o m pl et e t h e s af et y foll o w - up p eri o d.


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5. 1 0. 1. 5 
D el a y e d D o si n g Vi sit s a n d U n s c h e d ul e d N o n- D o si n g Vi sit s
D uri n g t h e Bli n d e d Tr e at m e nt P eri o d
D el a y e d D o si n g Vi sit s
V i sit s will o nl y b e u s e d if t h e i nf u si o n c a n n ot b e a d mi ni st er e d at t h e ti m e p oi nt s d ef i n e d i n
T a bl e 2 . T h u s, a p arti ci p a nt w h o h a d all a s s e s s m e nt s of a d o si n g vi sit p erf or m e d, b ut 
c o ul d n ot r e c ei v e hi s/ h er i nf u si o n, s h o ul d b e r e s c h e d ul e d f or t h e i nf u si o n 
( s e e S e cti o n 5. 1 0. 1. 2 ).
If t h e d el a y e d i nf u si o n i s t h e fir st i nf u si o n of t h e tr e at m e nt c y cl e, t h e n t h e vi sit f or t h e 
s e c o n d i nf u si o n s h o ul d b e s c h e d ul e d 1 4 d a y s aft er t h e d el a y e d fir st i nf u si o n ( 2 d a y s).  
I n t h e e v e nt a n y i nf u si o n n e e d s t o b e d el a y e d, a 2 0w e e k p eri o d still m u st b e 
m ai nt ai n e d b et w e e n t h e l a st i nf u si o n of o n e tr e at m e nt
c y cl e a n d t h e fir st i nf u si o n of t h e 
n e xt tr e at m e nt c y cl e.  If a l o n g er p eri o d of ti m e i s r e q uir e d, t h e n t h e p arti ci p a nt s h o ul d 
w a it f or t h e n e xt tr e at m e nt c y cl e b ef or e t h e a d mi ni str ati o n of st u d y dr u g.
At t h e d el a y e d d o si n g vi sit, a p h y si c al e x a mi n ati o n , i n cl u di n g vit al si g n s a n d pr e g n a n c y 
t e st will b e r e p e at e d a n d a d ver s e e v e nt s, p ot e nti al r el a p s e s, a n d c o n c o mit a nt tr e at m e nt s 
r e c or d e d.  Ot h er t e st s or a s s e s s m e nt s, s u c h a s r o uti n e s af et y l a b or at or y t e st s, m a y b e 
p erf or m e d w h e n t h e in v e sti g at or j u d g e s t h at t h e s e ar e w arr a nt e d.  A n y a d diti o n al t e st s 
or a s s e s s m e nt s t h at ar e p erf or m e d a s a r e s ult of in v e sti g at or j u d g m e nt s h o ul d b e 
d o c u m e nt e d wit hi n t h e u n s c h e d ul e d p a g e s of t h e e C R F.
U n s c h e d ul e d N o n -D o si n g V i sit s
P arti ci p a nt s d e v el o pi n g n e w or w or s e ni n g n e ur ol o gi c al s y m pt o m s s h o ul d b e s e e n at t h e 
i n v e sti g ati o n al sit e a s s o o n a s p o s si bl e, r e g ar dl e s s of t h e d at e s of t h eir pr epl a n n e d
s c h e d ul e d st u d y vi sit s, a n d r e g ar dl e s s of t h e st u d y p eri o d (i. e., i n cl u di n g t h e f oll o w-u p 
a n d m o n it ori n g p eri o d s).
P arti ci p a nt s will u n d er g o a p h y si c al e x a mi n ati o n, a n e ur ol o gi c al e v al u ati o n a n d, if j u d g e d 
r el e v a nt b y t h e in v e sti g at or, ot h er t e st s or a s s e s s m e nt s ( s u c h a s s af et y l a b or at or y t e st s).  
T h e E D S S a s s e s s m e nt s h o ul d b e p erf or m e d f or a n y s u s p e c t e d n e ur ol o gi c al w or s e ni n g.  
If a r el a p s e i s s u s p e ct e d, t h e E D S S s h o ul d al s o b e p erf or m e d i n a d diti o n t o c o m pl eti n g 
t h e M S r el a p s e e C R F.
F or g ui d a n c e o n t h e di a g n o si s of P M L, s e e S e cti o n 7. 3. 4. 1 .
5. 1 0. 1. 6 
Wit h dr a w al Vi sit s
D uri n g t h e Bli n d e d Tr e at m e nt P eri o d
At t h e m o m e nt a p arti ci p a nt m e et s 1 or m or e of t h e wit h dr a w al crit eri a ( S e cti o n 5. 6 ), t h at 
p arti c ul ar p arti ci p a nt i s r e g ar d e d wit h dr a w n fr o m tr e at m e nt.  Eff ort s s h o ul d b e m a d e t o 
c o m pl et e t h e r e s p e cti v e s c h e d ul e of a cti viti e s a s s o o n a s p o s si bl e, if n e c e s s ar y at a n 
e xtr a v i sit w hi c h c o m pl et e s t h e wit h dr a w al vi sit.
At t h e t er mi n ati o n of t h e st u d y ( s e e S e cti o n 4. 1. 9 ), t h e p arti ci p a nt s will di s c o nti n u e 
o cr eli z u m a b tr e at m e nt a n d s h o ul d m o v e i nt o t h e s af et y foll o w -u p p eri o d or will r e c ei v e 
c o m m er ci al o cr eli z u m a b (if a v ail a bl e i n t h at c o u ntr y). All p arti ci p a nt s will u n d er g o a 


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c o m pl et e fi n al e v al u ati o n a c c or di n g t o t h e W it h dr a w al fr o m Tr e at m e nt Vi sit i n T a bl e 4 . 
T h er e aft er, all p arti ci p a nt s will b e tr e at e d a c c or di n g t o i n di vi d u al c e nt er pr a cti c e.
P arti ci p a nt s w h o wit h dr a w fr o m t h e b li n d e d tr e at m e nt p eri o d will c o m pl et e all 
a s s e s s m e nt s a s s h o w n i n T a bl e 2 a n d will e nt er t h e s af et y foll o w - up p eri o d.  
P arti ci p a nt s wit h dr a wi n g fr o m t h e O L E p h a s e will c o m pl et e all a s s e s s m e nt s a s s h o w n i n
T a bl e 4 a n d will e nt er t h e s af et y foll o w - up p eri o d.
F or p arti ci p a nt s w h o h a v e wit h dr a w n fr o m t h e b li n d e d tr e at m e nt p eri o d or t h e O L E 
p h a s e or w h o ar e n ot eli gi bl e f or tr e at m e nt wit h o cr eli z u m a b, it i s at t h e di s cr eti o n of t h e 
in v e sti g at or t o d e ci d e o n f urt h er tr e at m e nt of t h e u n d erl yi n g di s e a s e.
H o w e v er, si n c e s uffi ci e nt d at a ar e n ot a v ail a bl e t o i nf or m ri s k s a s s o ci at e d wit h s wi t c hi n g 
t o ot h er pr o d u ct s, c ert ai n tr e at m e nt s f or M S, s u c h a s l y m p h o c yt e -d e pl eti n g a g e nt s or 
l y m p h o c yt e-tr affi c ki n g bl o c k er s (e. g. , al e mt u z u m a b, n at ali z u m a b, fi n g oli m o d, di m et h yl 
f u m ar at e, c y cl o p h o s p h a mi d e, a z at hi o pri n e, et c.), ar e str o n gl y di s c o ur a g e d f or a s l o n g a s 
t h e p arti ci p a nt r e m ai n s B c ell d e pl et e d b e c a u s e of u n k n o w n eff e ct s o n t h e i m m u n e 
s y st e m ( e. g. , i n cr e a s e d ri s k, i n ci d e n c e, or s e v erit y of i nf e cti o n ; s e e S e cti o n 5. 5. 2 f or 
r e c o m m e n d ati o n s o n alt er n ati v e tr e at m e nt s f or M S a n d S e cti o n 5. 2 3. 5 f or pr ol o n g atio n 
of  s af et y m o nit ori n g p eri o d f or p arti ci p a nt s o n alt er n ati v e M S tr e at m e nt s).
D e s pit e all eff ort s, p arti ci p a nt s m a y wit h dr a w fr o m t h e
st u d y d uri n g t h e s af et y foll o w -u p 
p eri o d.  P arti ci p a nt s wit h dr a wi n g fr o m t h e s af et y foll o w - up p eri o d will u n d er g o t h e 
a s s e s s m e nt s s h o w n i n T a bl e 3 .
N ot e:  at t h e Wi t h dr a w al fr o m b li n d e d tr e at m e nt p eri o d Vi sit, a n M RI s c a n will b e 
r e q uir e d o nl y if n ot p erf or m e d i n t h e pr e vi o u s 4 w e e k s.
5. 1 1 
C LI NI C A L A S S E S S M E N T S O F E F FI C A C Y
5. 1 1. 1 
Cli ni c al A s s e s s m e nt s D uri n g t h e Bli n d e d Tr e at m e nt P eri o d
T hi s i s a n a s s e s s or bli n d e d st u d y.  E a c h sit e will h a v e 2 i n v e sti g at or s: 
a P ri n ci p al I n v e sti g at or or a Tr e ati n g I n v e sti g at or a n d a n E x a mi ni n g I n v e sti g at or or 
R ati n g I n v e sti g at or.
T h e Tr e ati n g I n v e sti g at or i s t h e p h y sici a n r e s p o n si bl e f or t h e p arti ci p a nt’ s c ar e a n d 
s h o ul d b e a n e ur ol o gi st e x p eri e n c e d i n t h e c ar e of p arti ci p a nt s wit h M S.  
T h e Tr e ati n g I n v e sti g at or will h a v e a c c e s s t o b ot h s af et y ( s e e S e cti o n s 5. 1 2 a n d 5. 1 3 ) 
a n d effi c a c y d at a a n d will m a k e tr e at m e nt d e ci si o n s b a s e d o n t h e p arti ci p a nt’ s cli ni c al 
r e sp o n s e a n d l a b or at or y fi n di n g s.
T h e E x a mi ni n g I n v e sti g at or s h o ul d b e a n e ur ol o gi st or ot h er h e alt h c ar e pr a ctiti o n er a n d 
m u st b e tr ai n e d a n d c ertifi e d i n a d mi ni st eri n g t h e F S S a n d E D S S pri or t o st u d y st art.  
T h e E x a mi ni n g I n v e sti g at or will b e r e s p o n si bl e f or t h e a d mi ni str ati o n of t h e F S S/ E D S S 


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a n d will o nl y h a v e a c c e s s t o t h e s e d at a.  W h e n e v er p o s si bl e, t h e s a m e i n di vi d u al s h o ul d 
p erf or m t h e e x a mi n ati o n f or t h e f ull st u d y d ur ati o n.
All eff ort s s h o ul d b e m a d e t o k e e p t h e E x a mi n i n g I n v e sti g at or bli n d e d t o t h e tr e at m e nt 
a s si g n m e nt.  P arti ci p a nt s will b e i n str u ct e d n ot t o di s c u s s a n y s y m pt o m s r el at e d t o t h e 
st u d y tr e at m e nt wit h t h e E x a mi ni n g I n v e sti g at or; t h e E x a mi ni n g I n v e sti g at or s h o ul d 
r e mi n d t h e p arti ci p a nt at t h e st art of t h e e x a mi n ati o n.  I n vi e w of t h e e xt e n d e d d ur ati o n of 
t hi s st u d y, e a c h sit e will i d e ntif y a pri m ar y a n d b a c k-u p T r e ati n g a n d 
E x a mi ni n g I n v e sti g at or.  T h e Tr e ati n g I n v e sti g at or a n d t h e E x a mi ni n g I n v e sti g at or will 
n ot b e all o w e d t o s wit c h r ol e s.
5. 1 1. 1. 1 
A s s e s s m e nt of Di s a bilit y
Di s a bilit y i n M S i s c o m m o nl y m e a s ur e d b y t h e E D S S.  T h e E D S S will b e a s s e s s e d i n all 
p arti ci p a nt s b y t h e i n d e p e n d e nt E x a mi ni n g I n v e sti g at or at s cr e e ni n g, b a s eli n e, a n d e v er y 
1 2 w e e k s (r e g ul arl y s c h e d ul e d vi sit) d uri n g t h e bli n d e d tr e at m e nt p eri o d of t h e st u d y, 
d uri n g t h e s af e ty foll o w -u p p eri o d , at a n y u n s c h e d ul e d vi sit, a n d at t h e wit h dr a w al fr o m 
tr e at m e nt a n d e n d of st u d y vi sit s.  A s n ot e d a b o v e, a d diti o n al E D S S a s s e s s m e nt s f or 
i n di vi d u al p arti ci p a nt s m a y b e r e q u e st e d b et w e e n vi sit s (i. e., d uri n g a n M S r el a p s e, 
n e ur ol o gi c al w or s e ni n g, et c.).
Di s a bilit y pr o gr e s si o n i s d efi n e d a s a n i n cr e a s e of 1. 0 p oi nt fr o m t h e b a s eli n e E D S S 
s c or e t h at i s n ot attri b ut a bl e t o a n ot h er eti ol o g y ( e. g. , f e v er, c o n c urr e nt ill n e s s, or 
c o n c o mit a nt m e di c ati o n) w h e n t h e b a s eli n e s c or e i s 5. 5 or l e s s, a n d 0. 5 w h e n t h e 
b a s eli n e s c or e i s a b o v e 5. 5.  Di s a bilit y pr o gr e s si o n i s c o n si d er e d c o nfir m e d w h e n t h e 
i n cr e a s e i n t h e E D S S is c o nf ir m e d at a r e g ul arl y s c h e d ul e d vi sit at l e a st 1 2 w e e k s aft er 
t h e i niti al d o c u m e nt ati o n of th e pr o gr e s si o n.  A n alt er n ati v e d efi niti o n of c o nfir m e d 
di s a bilit y pr o gr e s si o n r e q uir e s t h at t h e i n cr e a s e i n E D S S b e c o nfir m e d at l e a st 2 4 w e e k s 
af t er t h e i niti al d o c u m e nt ati o n of t h e pr o gr e s si o n.  T h e i niti al e v e nt of di s a bilit y 
pr o gr e s si o n m u st o c c ur d uri n g t h e b li n d e d tr e at m e nt p eri o d.
T h e E D S S i s b a s e d o n a st a n d ar d n e ur ol o gi c al e x a mi n ati o n, i n c or p or ati n g s e v e n 
f u n cti o n al s y st e m s ( p yr a mi d al, c er e b ell ar, br ai n st e m, s e n s or y, b o w el a n d bl a d d er, vis u al, 
a n d c er e br al [ or m e nt al], pl u s “ ot h er”) r at e d a n d s c or e d a s F S S .  E a c h F S S i s a n or di n al 
cli ni c al r ati n g s c al e r a n gi n g fr o m 0 5 or 6.  I n a d diti o n, t h er e i s a n a m b ul ati o n s c or e 
r a n gi n g fr o m 01 2.   T h e s e r ati n g s ar e t h e n u s e d i n c o nj u n cti o n wit h o b s er v ati o n s a n d 
i nf or m ati o n c o n c er ni n g a m b ul ati o n a n d u s e of a s si sti v e d e vi c e s t o d et er mi n e t h e E D S S 
s c or e.  T h e E D S S i s a di s a bilit y s c al e t h at r a n g e s i n 0. 5 -p oi nt st e p s fr o m 0 ( n or m al) t o 
1 0 ( d e at h).
T h e M S F C S c o n si st s of 3 s u b s c al e s, i n cl u di n g t h e 9- H P T , P AS A T, a n d T 2 5 F W T , w hi c h 
pr o vi d e a gl o b al q u a ntit ati v e e sti m at e of M S di s a bilit y pr o gr e s si o n ( Fi s c h er et al. 1 9 9 9; 
Fr o h m a n et al. 2 0 0 8;).   T h e M S F C S
s h o ul d b e p erf or m e d b y t h e E x a mi ni n g I n v e sti g at or 
or a q u alifi e d d e si g n e e w h o m u st r e m ai n bli n d e d t o t h e tr e a t m e nt a s si g n m e nt.


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5. 1 1. 2 
Br ai n M RI I m a gi n g
M a g n eti c r e s o n a n c e i m a gi n g
i s a u s ef ul t o ol f or m o nit ori n g C N S l e si o n s i n M S.  
Diff er e nt M RI -d eri v e d p ar a m et er s h a v e b e e n r el at e d t o cli ni c al a cti vit y a n d T 1 -w ei g ht e d 
G d -e n h a n ci n g l e si o n s or n e w a n d/ or e nl ar gi n g h y p eri nt e n s e T 2 l e si o n s h a v e b e e n 
r el at e d t o r el a p s e s.  It i s h y p ot h e si z e d t h at c h a n g e s i n br ai n v ol u m e m a y r efl e ct br ai n 
atr o p h y a s a r e s ult of M S -r el at e d ti s s u e l o s s a n d m a y t h er e b y c orr el at e wit h l o n g-t er m 
cli ni c al o ut c o m e i n t h e s e p arti ci p a nt s .
Br ai n M RI s c a n s will b e o bt ai n e d i n all p arti ci p a nt s at b a s eli n e a n d at W e e k s 2 4, 4 8 , a n d 
1 2 0.
S c a n s will b e p erf or m e d b y tr ai n e d a n d c ertifi e d M RI t e c h ni ci a n s.  T h e f oll o wi n g ti m e 
wi n d o w s a p pl y:
 
Vi sit 2 ( b a s eli n e ):  aft er s cr e e ni n g vi sit, b ut at l e a st 1 0 d a y s pri or t o t h e b a s eli n e vi sit
 
Vi sit 5 1 7 ( W e e k s 2 4 1 2 0 ):  s h o ul d b e p erf or m e d wit hi n a wi n d o w of 4 w e e k s of 
t h e s c h e d ul e d vi sit
 
I n a d diti o n al c y cl e s d uri n g t h e b li n d e d tr e at m e nt p eri o d , a n M RI s h o ul d b e 
p erf or m e d a n n u all y
 
I n t h e O L E p h a s e, M RI s h o ul d b e p erf or m e d a n n u all y
If p arti ci p a nt s r e c ei v e c orti c o st er oi d s f or a n M S r el a p s e, e v er y eff ort s h o ul d b e m a d e t o 
o bt ai n t h e s c a n pri or t o t h e fir st st er oi d d o s e if t h e pr e -st er oi d s c a n i s wit hi n 1 w e e k of 
t h e s c h e d ul e d vi sit.  I n p arti ci p a nt s r e c ei vi n g c orti c o st er oi d s f or a n M S r el a p s e, t h er e
s h o ul d b e a n i nt er v al of 3 w e e k s b et w e e n t h e l a st d o s e of c orti c o st er oi d s a n d t h e s c a n.
T h e M RI will i n cl u d e t h e a c q ui siti o n of s c a n s at e a c h ti m e p oi nt wit h a n d/ or wit h o ut I V
a d mi ni st er e d G d c o ntr a st e n h a n c e m e nt.
D uri n g t h e b li n d e d tr e at m e nt p eri o d, M RI s c a n s will b e r e a d b y  a c e ntr ali z e d r e a di n g 
c e nt er f or effi c a c y  e n d p oi nt s. T h e c e ntr ali z e d r e a di n g c e nt er i s bli n d e d t o t h e 
tr e at m e nt a s si g n m e nt a n d t h e r e a di n g i s p erf or m e d i n t h e a b s e n c e of cli ni c al 
i nf or m ati o n.  F urt h er d etail s o n s c a n ni n g a c q ui siti o n s e q u e n c e s, m et h o d s, h a n dli n g a n d 
tr a n s mi s si o n of t h e s c a n s, c ertifi c ati o n of sit e M RI r a di ol o gi st/t e c h ni ci a n s, a n d t h e 
pr o c e d ur e s f or t h e bli n d e d a n al y si s of t h e s c a n s at t h e c e ntr al r e a di n g c e nt er ar e 
d e s cri b e d i n a s e p ar at e M RI t e c h ni c al m a n u al.
D uri n g t h e b li n d e d tr e at m e nt p eri o d, a ll M RI s c a n s will al s o b e r e vi e w e d l o c all y b y a 
r a di ol o gi st f or s af et y a n d t h e M RI s c a n r e p ort c o nt ai ni n g o nl y n o n -M S p at h ol o g y will b e 
pr o vi d e d t o t h e Tr e ati n g I n v e sti g at or ( s e e S e cti o n 5. 1 1. 1 f or d efi niti o n).  At t h e 
i n v e sti g ati o n al sit e, o nl y t h e l o c al r a di ol o gi st/t e c h ni ci a n a s si g n e d t o t hi s st u d y m a y h a v e 
a c c e s s t o t h e M RI s c a n s, e x c e pt at b a s eli n e, w h e n t h e Tr e ati n g I n v e sti g at or m a y vi e w 
t h e M RI s c a n; t h e Tr e ati n g I n v e sti g at or s h o ul d n ot r e vi e w t h e M RI s c a n s o bt ai n e d aft er 
r a n d o mi z ati o n u nl e s s a s af et y c o n c er n ari s e s.  I n t h e e v e nt t h at t h e Tr e ati n g I n v e sti g at or 


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d o e s b e c o m e a w ar e of t h e s e M RI r e s ult s, t hi s s h o ul d b e d o c u m e nt e d i n t h e e C R F, 
i n di c ati n g t h e r e a s o n.
N ot e:  D uri n g t h e O L E p h a s e, it i s p o s si bl e f or t h e Tr e ati n g I n v e sti g at or t o h a v e a c c e s s 
t o M RI s c a n s p erf or m e d d uri n g t h e O L E p h a s e.
5. 1 2 
S A F E T Y A S S E S S M E N T S
T h e Tr e ati n g I n v e sti g at or i s t h e p h y si ci a n r e s p o n si bl e f or p arti ci p a nt c ar e a n d will h a v e 
a c c e s s t o effi c a c y a n d s af et y d at a c oll e ct e d d uri n g t h e st u d y.  T o m ai nt ai n t h e tr e at m e nt 
bli n d b et w e e n o cr eli z u m a b a n d pl a c e b o, s o m e l a b or at or y d at a will n ot b e r e v e al e d t o t h e 
i nv e sti g at or e x c e pt i n e x c e pti o n al c o n diti o n s a s d e s cri b e d i n t h e s af et y pl a n 
( s e e S e cti o n 6. 2. 3 ).
N ot e: s cr e e ni n g r e s ult s of I g s ( T ot al I g, I g G, I g M a n d I g A) a n d C D 4 c ell c o u nt s, w hi c h 
ar e r e q uir e d f or a s s e s s m e nt of t h e i n cl u si o n/ e x cl u si o n crit eri a, will b e pr o vi d e d t o t h e 
sit e s.
5. 1 2. 1 
Vit al Si g n s
Vit al si g n s ( p ul s e r at e, s y st oli c a n d di a st oli c bl o o d pr e s s ur e, r e s pir ati o n r at e a n d or al or 
a uri c ul ar t e m p er at ur e) will b e o bt ai n e d at s cr e e ni n g a n d at e a c h vi sit t h er e aft er, wit h t h e 
p arti ci p a nt i n t h e s e mi-s u pi n e p o siti o n ( aft er 5 mi n ut e s).  O n t h e d o si n g d a y s, t h e vit al 
si g n s s h o ul d b e t a k e n wit hi n 4 5 mi n ut e s pri or t o t h e pr e m e di c ati o n m et h yl pr e d ni s ol o n e
( or e q ui v al e nt) i nfu si o n i n all p arti ci p a nt s .  I n a d diti o n, t h e vit al si g n s f or p arti ci p a nt s o n
o cr eli z u m a b or m at c hi n g pl a c e b o s h o ul d b e o bt ai n e d pri or t o t h e st u d y dr u g i nf u si o n, 
t h e n e v er y 1 5 mi n ut e s (5 mi n ut e s) f or t h e fir st h o ur; t h e n e v er y 3 0 mi n ut e s 
(1 0 mi n ut e s) u ntil 1 h o ur aft er t h e e n d of t h e i nf u si o n.
O n n o n -i nfu si o n d a y s, t h e vit al s i g n s m a y b e t a k e n at a n y ti m e d uri n g t h e vi sit.
A d diti o n al vit al si g n s r e a di n g s m a y b e t a k e n at t h e di s cr eti o n of t h e in v e sti g at or i n t h e 
e v e nt of a n I R R s or if cli ni c all y i n di c at e d a n d s h o ul d b e r e c or d e d o n t h e u n s c h e d ul e d 
vit al si g n s e C R F.
G ui d a n c e f or t h e i nf u si o n s of o cr eli z u m a b i s gi v e n i n S e cti o n 6. 2 .  T hi s s e cti o n al s o 
pr o vi d e s g ui d a n c e o n t h e r e d u cti o n of t h e i nf u si o n r at e i n t h e e v e nt of I R R s.
5. 1 2. 2 
El e ctr o c ar di o gr a m s
A 1 2 -l e a d E C G s h o ul d b e t a k e n at t h e vi sit s i n di c at e d i n t h e s c h e d ul e of a cti viti e s
(T a bl e 1 , T a bl e 2 , a n d T a bl e 4 ).  C o m m e nt s g e n er at e d a ut o m ati c all y b y t h e E C G 
m a c hi n e s h o ul d n ot b e r e c or d e d i n t h e e C R F u nl e s s c o nfir m e d b y a p h y si ci a n.  A n E C G 
i s al s o r e q uir e d if t h e p arti ci p a nt pr e m at ur el y wit h dr a w s f r o m t h e st u d y.


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5. 1 2. 3 
P h y si c al E x a mi n ati o n
A g e n er al p h y si c al e x a mi n ati o n s h o ul d b e p erf or m e d at t h e s cr e e ni n g a n d b a s eli n e 
vi sit s, at all d o si n g vi sit s d uri n g tr e at m e nt, d uri n g t h e s af et y foll o w -u p p eri o d, a n d at t h e 
e n d of f oll o w -u p.  T h e p h y si c al e x a mi n ati o n w ill b e r e c or d e d a s “ n or m al” or “ a b n or m al”.  
If a b n or m al, t h e a b n or m aliti e s s h o ul d b e s p e cifi e d o n t h e e C R F a s eit h er a n a d v er s e 
e v e nt or a s a n o n g oi n g c o n diti o n o n t h e M e di c al Hi st or y f or m .  A s of t h e b a s eli n e vi sit, 
p er si sti n g a b n or m aliti e s s h o ul d b e st at e d e a c h ti m e t h e e x a mi n ati o n i s p erf or m e d.  
Di a g n o si s of n e w a b n or m aliti e s or cli ni c all y si g nifi c a nt w or s e ni n g of pr e e xi sti n g 
a b n or m aliti e s s h o ul d b e r e c or d e d a s a d v er s e e v e nt s if a p pr o pri at e ( s e e S e cti o n 7. 1 ).
5. 1 2. 4 
N e ur ol o gi c al E x a mi n ati o n
A n e ur ol o gi c al e x a mi n ati o n will b e p erf or m e d at e v er y pl a n n e d a n d u n s c h e d ul e d vi sit.  
S e e S e cti o n 5. 1 1. 1. 1 .
I n t h e pr e s e n c e of n e wl y i d e ntifi e d or w or s e ni n g n e ur ol o gi c al s y m pt o m s at a n y gi v e n 
ti m e i n t h e stu d y ( b li n d e d tr e at m e nt p eri o d, s af et y foll o w -u p p eri o d, or O L E p h a s e) , a 
n e ur ol o gi c al e v al u ati o n s h o ul d b e s c h e d ul e d pr o m ptl y.  T h e Tr e ati n g I n v e sti g at or s h o ul d 
a s s e s s w h et h er t h e p arti ci p a nt i s e x p eri e n ci n g:
 
A r el a p s e of M S or M S w or s e ni n g.  I n t hi s c a s e, t h e Tr e ati n g I n v e sti g at or s h o ul d 
r e q u e st E D S S t o b e p erf or m e d b y t h e E x a mi ni n g I n v e sti g at or ( s e e S e cti o n 5. 1 1. 1 ).
 
A n ot h er n e ur ol o gi c al ( n o n -M S) di s or d er.  I n t hi s c a s e, a n a d v er s e e v e nt s h o ul d b e 
r e p ort e d.
St u d y in v e sti g at or s will s cr e e n p arti ci p a nt s f or si g n s a n d s y m pt o m s of P M L b y e v al u ati n g 
n e ur ol o gi c al d efi cit s l o c ali z e d t o t h e c er e br al c ort e x, s u c h a s c orti c al s y m pt o m s/ si g n s, 
b e h a vi or al a n d n e ur o p s y c h ol o gi c al alt er ati o n, r etr o c hi a s m al vi s u al d ef e ct s, h e mi p ar e si s, 
c er e b ell ar s y m pt o m s/ si g n s ( e. g., g ait a b n or m aliti e s, li m b i n c o or di n ati o n).
A br ai n M RI s c a n a n d C S F a n al y si s m a y b e w arr a nt e d t o a s si st i n t h e di a g n o si s of P M L.  
S e e S e cti o n 7. 3. 4. 1 f or g ui d a n c e o n t h e di a g n o si s of P M L.
P arti ci p a nt s wit h s u s p e ct e d P M L, d efi n e d a s a n e w or w or s e ni n g n e ur ol o gi c al s y m pt o m 
w h i c h n e c e s sit at e s M RI a n d or l u m b ar p u n ct ur e a n d C S F a n al y s e s t o r ule o ut P M L, 
s h o ul d b e wit h h el d fr o m st u d y tr e at m e nt u ntil P M L i s r ul e d o ut b y c o m pl et e cli ni c al 
e v al u ati o n a n d a p pr o pri at e di a g n o sti c t e sti n g ( s e e S e cti o n 7. 3. 4. 1 ).  T h e m e di c al 
r e s p o n si bl e a n d M e di c al M o nit or s h o ul d b e c o nt a ct e d b y e -m ail.  I n a d diti o n , t h e m e di c al 
r e s p o n si bl e s h o ul d b e i m m e di at el y c o nt a ct e d b y p h o n e.
A p arti ci p a nt wit h c o nfir m e d P M L s h o ul d b e wit h dr a w n fr o m t h e st u d y. P r o gr e s si v e 
m ultif o c al l e u k o e n c e p h al o p at h y
s h o ul d b e r e p ort e d a s a s eri o u s a d v er s e e v e nt ( wit h all 
a v ail a bl e i nf or m ati o n) wit h i m m e di at e n otifi c ati o n of t h e M e di c al M o nit or 
( s e e S e cti o n s 7. 2. 2 a n d 7. 2. 3 ).


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5. 1 2. 4. 1 
T el e p h o n e I nt er vi e w f or N e w/ W or s e ni n g N e ur ol o gi c al 
S y m pt o m s
T h e p ur p o s e of t hi s str u ct ur e d i nt er vi e w i s t o i d e ntif y a n d c oll e ct i nf or m ati o n o n a n y 
c h a n g e s i n t h e p arti ci p a nt’ s h e alt h st at u s (i n cl u di n g n e w or w or s e ni n g n e ur ol o gi c al 
s y m pt o m s ) t h at w arr a nt a n u n s c h e d ul e d vi sit.  T h e t el e p h o n e i nt er vi e w will b e c o n d u ct e d 
b y sit e p er s o n n el f a mili ar wit h t h e p arti ci p a nt ( s) e v er y 4 w e e k s b et w e e n t h e st u d y vi sit s 
d uri n g t h e bli n d e d tr e at m e nt p eri o d, O L E p h a s e, a n d t hr o u g h o ut t h e s af et y foll o w -u p 
p eri o d.
T h e sit e will r e c or d t h e d at e of t h e t el e p h o n e i nt er vi e w i n t h e e C R F a n d d o c u m e nt ati o n 
of  t h e i nt er vi e w will b e m ai nt ai n e d i n t h e p arti ci p a nt’ s S t u d y F il e.
S e e A p p e n di x 5 f or d et ail e d i nf or m ati o n.
5. 1 2. 4. 2 
A s s e s s m e nt of R el a p s e
Alt h o u g h r el a p s e s ar e a nti ci p at e d t o b e r ar e i n t h e P P M S p o p ul ati o n, p arti ci p a nt s will b e 
e v al u at e d f or r el a p s e s b y t h e Tr e ati n g I n v e sti g at or at e a c h vi sit t hr o u g h o ut t h e st u d y 
a n d, if n e c e s s ar y, at u n s c h e d ul e d vi sit s t o c o nfir m r el a p s e s o c c urri n g b et w e e n t h e vi sit s.
All n e w or w or s e ni n g n e ur ol o gi c al e v e nt s c o m p ati bl e wit h M S r e pr e s e nti n g a cli ni c al 
r el a p s e ar e t o b e r e p ort e d i n t h e e C R F.  P arti ci p a nt s wit h cli ni c al r el a p s e s s h o ul d b e 
r ef err e d t o t h e E x a mi ni n g I n v e sti g at or w h o will a s s e s s t h e F S S/ E D S S i n d e p e n d e ntl y t o 
all o w c o nfir m ati o n a s t o w h et h er or n ot t h e cli ni c al r el a p s e( s) m e et t h e crit eri a f or 
pr ot o c ol -d efi n e d r el a p s e( s).
T o m e et t h e crit eri a f or a pr ot o c ol -d ef i n e d r el a p s e, t h e r el a p s e i s d efi n e d a s t h e 
o c c urr e n c e of n e w or w or s e ni n g n e ur ol o gi c al s y m pt o m s attri b ut a bl e t o M S a n d 
i m m e di at el y pr e c e d e d b y a r el ati v el y st a bl e or i m pr o vi n g n e ur ol o gi c al st at e of l e a st 
3 0 d a y s.  S y m pt o m s m u st p er si st f or 2 4 h o ur s a n d s h o ul d n ot b e attri b ut a bl e t o
c o nf o u n di n g cli ni c al f a ct or s ( e. g. , f e v er, i nf e cti o n, i nj ur y, a d v er s e r e a cti o n s t o 
c o n c o mit a nt m e di c ati o n s).  T h e n e w or w or s e ni n g n e ur ol o gi c al s y m pt o m s m u st b e 
a c c o m p a ni e d b y o bj e cti v e n e ur ol o gi c al w or s e ni n g c o n si st e nt wit h a n i n cr e a s e of at l e a st 
h alf a st e p o n t h e E D S S, or 2 p oi nt s o n 1 of t h e a p pr o pri at e F S S, or 1 p oi nt o n 2 or m or e 
of  t h e a p pr o pri at e F S S.  T h e c h a n g e m u st aff e ct t h e s el e ct e d F S S 
(i. e., p yr a mi d al, a m b ul ati o n, c er e b ell ar, br ai n st e m, s e n s or y, or vi s u al).  E pi s o di c s p a s m s, 
s e x u al d y sf u n ct i o n, f ati g u e, m o o d c h a n g e or bl a d d er or b o w el ur g e n c y or i n c o nti n e n c e 
will n ot s uffi c e t o e st a bli s h a r el a p s e.  N ot e t h at t h e f oll o wi n g it e m s n e e d n ot b e s c or e d: 
S e x u al d y sf u n cti o n a n d F ati g u e.
It s h o ul d b e n ot e d t h at all p arti ci p a nt s wit h n e w n e ur ol o gi c al s y m pt o m s d efi n e d at a vi sit 
or o v er t h e p h o n e s h o ul d b e r ef err e d t o t h e E x a mi ni n g I n v e sti g at or u nl e s s t h e 
Tr e ati n g I n v e sti g at or c o n si d er s t h e s y m pt o m s c o n si st e nt wit h a n i nt e n sifi c ati o n of 
n e ur ol o gi c al s y m pt o m s fr o m a tr a n si e nt s y st e mi c i nf e cti o n.


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Cli ni c al r el a p s e s (i. e., r e g ar dl e s s of w h et h er t h e y m e et crit eri a f or a pr ot o c ol -d ef i n e d 
r el a p s e) will b e r e c or d e d o n a pr e-s p e cifi e d “M S r el a p s e” e C R F; t h e s e will al s o b e 
r e p ort e d a s a d v er s e e v e nt s ( s e e S e cti o n 7. 1. 1 ).
5. 1 3 
L A B O R A T O R Y A S S E S S M E N T S
5. 1 3. 1 
S p e cifi c S cr e e ni n g L a b or at or y  T e st s f or I n cl u si o n/ E x cl u si o n
T h e f oll o wi n g s cr e e ni n g l a b or at or y t e st s m u st b e p erf or m e d b ef or e i n cl u di n g t h e 
p arti ci p a nt i nt o t h e st u d y .  Te st s will b e p erf or m e d at a c e ntr al l a b or at or y.  All s cr e e ni n g 
l a b or at or y r e s ult s will b e a v ail a bl e t o b ot h sit e s a n d t h e S p o n s or.
5. 1 3. 1. 1 
H e p atiti s S cr e e ni n g a n d Li v er F u n cti o n M o nit ori n g 
P arti ci p a nt s wit h r e c urr e nt or c hr o ni c i nf e cti o n of h e p atiti s B or hi s t or y/ pr e s e n c e of 
h e p atiti s C m u st b e e x cl u d e d fr o m e nr oll m e nt i nt o t h e st u d y ( s e e S e cti o n 5. 3 ).
I n a d diti o n, h e p atiti s B a n d C s er ol og y will b e p erf or m e d at s cr e e ni n g.  A p o siti v e r e s ult 
t o eit h er H B s A g or t ot al H B c A b a s s o ci at e d wit h p o siti v e vir al D N A tit er s a s m e a s ur e d b y 
P C R, or a p o siti v e r e s ult f or H e p C A b s h o ul d r e s ult i n t h e p arti ci p a nt’ s e x cl u si o n.  
P arti ci p a nt s wit h e vi d e n c e of p a st r e s ol v e d h e p atiti s B i nf e cti o n (i. e. , p o siti v e t ot al 
H B c A b a s s o ci at e d wit h a n e g ati v e vir al D N A) c a n b e e nr oll e d, a n d will h a v e t h e h e p atiti s 
B vir u s ( H B V ) D N A c h e c k e d e v er y 1 2 w e e k s.  P arti ci p a nt s i n w h o m t h e vir al D N A 
b e c o m e s p o siti v e b ut i n w h o m t h e q u a ntit y i s at t h e l o w er li mit of d et e cti o n of t h e a s s a y 
s h o ul d h a v e t h e t e st r e p e at e d a s s o o n a s p o s si bl e.  P arti ci p a nt s f o u n d t o h a v e a 
c o nfir m e d vir al D N A p o siti v e t e st s h o ul d b e r ef err e d t o a h e p at ol o gi st f or a s s e s s m e nt 
i m m e di at el y.  T h e s e p arti ci p a n t s will n ot r e c ei v e f urt h er i nf u si o n s of o cr eli z u m a b a n d will 
e nt er t h e s af et y foll o w - up p eri o d.
Li v er f u n cti o n (i. e., A L T/ S G P T, A S T/ S G O T, g a m m a gl ut a m yl tr a n sf er a s e [G G T ], al k ali n e 
p h o s p h at a s e, t ot al bilir u bi n ) s h o ul d b e r e vi e w e d t hr o u g h o ut t h e st u d y.  
P a rti ci p a nt s d e v el o pi n g e vi d e n c e of li v er d y sf u n cti o n s h o ul d b e a s s e s s e d f or vir al 
h e p atiti s a n d, if n e c e s s ar y, r ef err e d t o a h e p at ol o gi st or ot h er a p pr o pri at el y q u alifi e d 
e x p ert.  St u d y dr u g s h o ul d b e wit h h el d u ntil t h e di a g n o si s of vir al h e p atiti s h a s b e e n
e x cl u d e d.  P arti ci p a nt s d e v el o pi n g h e p atiti s B or C s h o ul d b e wit h dr a w n fr o m t h e st u d y 
a n d s h o ul d e nt er t h e s af et y foll o w -u p p eri o d.  S h o ul d tr e at m e nt b e pr e s cri b e d, t hi s will 
b e r e c or d e d i n t h e e C R F.  P arti ci p a nt s wit h vir al h e p atiti s d u e t o ot h er a g e nt s , s u c h a s 
h e p atiti s A, m a y r e s u m e tr e at m e nt aft er t h e p arti ci p a nt’ s r e c o v er y.
I nf or m ati o n r el ati n g t o t h e ri s k of r e c urr e n c e of h e p atiti s B is pr o vi d e d i n S e cti o n 7. 3. 1
a n d i nf or m ati o n r el ati n g t o h e p atiti s B i m m u ni z ati o n i s pr o vi d e d i n S e cti o n 5. 5. 3 .
5. 1 3. 1. 2 
Ot h er S p e cifi c S cr e e ni n g T e st s
F urt h er s p e cifi c l a b or at or y s cr e e ni n g t e st s, li st e d b el o w will b e p erf or m e d, a n d 
p arti ci p a nt s m a y b e e x cl u d e d b a s e d o n t h e r e s ult s of t h e s e t e st s, i n a c c or d a n c e wit h t h e 
i n cl u si o n/ e x cl u si o n crit eri a:
 
P o siti v e R P R f or s y p hili s, wit h M H A -T P or F T A -A B S c o nfir m ati o n if p o siti v e


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
8 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
C D 4 c o u nt 3 0 0/ L
 
A N C 1. 5 1 0 3 /L
 
L e v el s of s er u m I g G 1 8 % b el o w t h e L L N (f or c e ntr al l a b or at or y I g G 4. 6 g/ L)
 
L e v el s of s er u m I g M 8 % b el o w t h e L L N (f or c e ntr al l a b or at or y I g M 0. 3 7 g/ L)
 
F or G er m a n y o nl y:
– 
P o siti v e a nti -HI V I at s cr e e ni n g
– 
P o siti v e a nti -HI V II at s cr e e ni n g
– 
P o siti v e Q u a nti F E R O N -T B G ol d t e st at s cr e e ni n g 
– 
P arti ci p a nt s wit h a n i n d et er mi n at e r e s ult ar e n ot eli gi bl e f or t h e st u d y u nl e s s 
a d diti o n al t e sti n g d e m o n str ati n g a n e g ati v e r e s ult i s pr o vi d e d.
T h u s, t h e s e 
p arti ci p a nt s s h o ul d h a v e eit h er a t u b er c uli n s ki n t e st or h a v e t h e 
Q u a nti F E R O N T B G ol d t e st r e p e at e d pri or t o e nr oll m e nt i nt o t h e st u d y.
If a 
t u b er c uli n s ki n t e st i s p erf or m e d, a n i n d ur ati o n of 6 m m i s “ p o siti v e” f or a 
p arti ci p a nt wit h hi st or y of B C G v a c ci n e, w hil e a n i n d ur ati o n of 1 0 m m i s 
“ p o siti v e” f or a p arti ci p a nt wit h o ut hi st or y of B C G v a c ci n e.
– 
If n e c e s s ar y a Q u a nti F E R O NT B G ol d t e st mi g ht b e c o m pl e m e nt e d b y 
a d diti o n al s p e cifi c di a g n o sti c t e st s a s p er st a n d ar d pr o c e d ur e s i n t h e c o u ntr y
 
F or ot h er r o uti n e s af et y s cr e e ni n g p ar a m et er s pl e a s e s e e “E x cl u si o n r el at e d t o 
L a b or at or y Fi n di n g s ” i n S e cti o n 5. 3 .
5. 1 3. 2  
St a n d ar d L a b or at or y  As s e s s m e nt s
T h e f oll o wi n g l a b or at or y t e st s will b e p erf or m e d a c c or di n g t o t h e s c h e d ul e of a cti viti e s .  
A c e ntr al l a b or at or y will b e u s e d f or all a s s e s s m e nt s, wit h t h e f oll o wi n g e x c e pti o n s:
 
Uri n al y si s a n d uri n e mi cr o s c o pi c e x a mi n ati o n will b e p erf or m e d at t h e sit e 
(l o c al l a b or at or y)
 
I n w o m e n of c hil d b e ari n g p ot e nti al, t h e uri n e pre g n a n c y t e st will b e p erf or m e d o n 
sit e
 
H A H A will b e a n al y z e d at G e n e nt e c h , I n c. a m e m b er of t h e R o c h e gr o u p, or a n 
alt er n at e l a b or at or y
F ull d et ail s of t h e c e ntr al l a b or at or y s a m pl e h a n dli n g, s hi p m e nt a n d r e p orti n g of r e s ult s
will b e d e s cri b e d i n t h e L a b or at or y M a n u al.
Ot h er l a b or at or y t e st s ar e di s c u s s e d i n S e cti o n s 5. 1 4 , 5. 1 5 a n d 5. 1 8 .
 
H e m at ol o g y : h e m o gl o bi n, h e m at o crit, R B C s , W B C s ( a b s ol ut e a n d diff er e nti al), 
A N C, a n d q u a ntit ati v e pl at el et c o u nt
 
Bl o o d c h e mi str y : A S T/ S G O T, A L T/ S G P T, G G T, al k ali n e p h o s p h at a s e, a m yl a s e, 
li p a s e, t ot al pr ot ei n, al b u mi n, c h ol e st er ol, t ot al bilir u bi n, ur e a, uri c a ci d, cr e ati ni n e, 
r an d o m gl u c o s e, p ot a s si u m, s o di u m, c al ci u m, p h o s p h or u s, l a cti c d e h y dr o g e n a s e, 
cr e ati n e p h o s p h o ki n a s e, a n d tri gl y c eri d e s


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8 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
T h yr oi d f u n cti o n t e st : se n siti v e T S H a n d t h yr oi d a ut o a nti b o di e s will b e a s s e s s e d 
at s cr e e ni n g
F A C S will i n cl u d e ( b ut i s n ot li mit e d t o) t h e f oll o wi n g c ell s:
 
T ot al B c ell s ( C D 1 9 p o s )
 
T ot al T c ell s ( C D 3p o s )
 
T h el p er c ell s ( C D 3 p o s , C D 4p o s )
 
T C T L ( C D 3p o s , C D 8p o s )
 
N at ur al kill er c ell s ( C D 3 n e g , C D 1 6/ 5 6p o s )
 
B c ell s u b s et s (e. g. , m e m or y B c ell s, n aï v e B c ell s, pl a s m a c ell s )
 
Q u a ntit ati v e I m m u n o gl o b uli n: I g l e v el s (i n cl u di n g T ot al I g, I g G, I g M, a n d I g A 
i s ot y p e s)
 
A n ti b o d y tit er s: m e a s ur e m e nt of a nti b o d y tit er s t o c o m m o n a nti g e n s 
( m u mp s, r u b ell a, v ari c ell a, a n d S. p n e u m o ni a e ) will b e p erf or m e d.  T hi s i nf or m ati o n 
i s u s e d t o a s s e s s t h e eff e ct of o cr eli z u m a b o n s p e cifi c h u m or al i m m u nit y t o b a ct eri al 
a n d vir al a nti g e n s.
 
H A H A : s er u m s a m pl e s will b e c oll e ct e d f or d et er mi n ati o n of a nti b o di e s a g ai n st 
o cr eli z u m a b ( H A H A).  S a m pl e s will b e s cr e e n e d wit h u s e of a n i m m u n o a s s a y a n d 
p o s si bl y g o t hr o u g h ot h er c h ar a ct eri z ati o n a s s a y s.  T h e H A H A a n al y si s will b e 
c arri e d o ut at G e n e nt e c h, I n c. a m e m b er of t h e R o c h e gr o u p, or a n alt er n at e 
l a b or at or y.  Si n c e o cr eli z u m a b c o n c e ntr ati o n s aff e ct t h e H A H A a s s a y, t h e 
c o n c e ntr ati o n of o cr eli z u m a b i n t h e s a m pl e s will b e m e a s ur e d t o e n a bl e 
i nt er pr et ati o n of t h e r e s ult s.  T h er ef or e, 2 s e p ar at e s a m pl e s ar e n e e d e d; 1 s a m pl e
f or t h e H A H A a s s a y a n d 1 s a m pl e f or o cr eli z u m a b c o n c e ntr ati o n m e a s ur e m e nt 
( P K s a m pl e) .
A s of pr ot o c ol v er si o n I ( v 9), H A H A a n d c o n c urr e nt P K a n al y s e s will b e di s c o nti n u e d 
o n t h e b a si s t h at i m m u n o g e ni cit y i n ci d e n c e wit h o cr eli z u m a b i s v er y l o w ( 1 %) wit h 
n o s af et y ri s k s i d e ntifi e d , s o c o nti n u o u s m o nit ori n g of H A H A s i n t hi s p o p ul ati o n i s 
u n n e c e s s ar y.   H o w e v er, i n a n y c a s e of a n a p h yl a xi s, a n a p h yl a ct oi d r e a cti o n, or 
s eri o u s or s e v er e h y p er s e n siti vit y r e a cti o n, H A H A a n d o cr eli z u m a b c o n c e ntr ati o n
s a m pl e s s h o ul d b e c oll e ct e d a s cl o s e a s p o s si bl e t o t h e e v e nt a n d t h e n at 4 a n d 
1 6 w e e k s p o st d o s e.
 
Uri n al y si s: a uri n e di p sti c k f or bl o o d, pr ot ei n, nitrit e a n d gl u c o s e ( wit h u s e of t h e 
di p sti c k s pr o vi d e d) a n d a mi cr o s c o pi c e x a mi n ati o n if a b n or m al a n d a p pli c a bl e will b e 
p erf or m e d o n sit e (l o c al l a b or at or y)
 
Pr e g n a n c y  T e st: a ll w o m e n of c hil d b e ari n g p ot e nti al m u st h a v e r e g ul ar pr e g n a n c y
t e st s.  At s cr e e ni n g, a s er u m pr e g n a n c y t e st will b e p erf or m e d t hr o u g h t h e c e ntr al 
l a b.  D uri n g t h e stu d y tr e at m e nt a n d s af et y foll o w -u p p eri o d s, a uri n e pr e g n a n c y t e st 
( s e n siti vit y of at l e a st 2 5 mI U/ m L -h C G) will b e p erf or m e d l o c all y at t h e ti m e p oi nt s 
s h o w n i n T a bl e 1 a n d T a bl e 2 .  O n i nf u si o n vi sit s, t h e uri n e pr e g n a n c y t e st s h o ul d 
b e p erf or m e d pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n.  A p o siti v e uri n e pr e g n a n c y 


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8 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
t e st s h o ul d b e c o nfir m e d wit h a s er u m t e st t hr o u g h t h e c e ntr al l a bor at or y pri or t o 
a n y f u rt h er d o si n g wit h o cr eli z u m a b.
5. 1 4 
P H A R M A C O KI N E TI C A S S E S S M E N T S
Bl o o d s a m pl e s will b e c oll e ct e d t o e v al u at e t h e P K of o cr eli z u m a b.
5. 1 4. 1 
Bli n d e d T r e at m e nt P eri o d
S er u m s a m pl e s will b e c oll e ct e d f or d et er mi n ati o n of o cr eli z u m a b c o n c e ntr ati o n s 
5 3 0 mi n ut e s pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n
at t h e ti m e p oi nt s d et ail e d i n t h e 
s c h e d ul e of a cti viti e s ( s e e T a bl e 1 ).  D uri n g i nf u si o n D a y s 1, 1 5, a n d 5 0 5, p arti ci p a nt s
will al s o h a v e s a m pl e s c oll e ct e d f o r P K a s s e s s m e nt 3 0 mi n ut e s ( 1 0 mi n ut e s) f oll o wi n g 
t h e c o m pl eti o n of t h e i nf u si o n of o cr eli z u m a b/ pl a c e b o, a s s p e cifi e d i n t h e s c h e d ul e of 
a cti viti e s .
5. 1 4. 2 
O p e n -L a b el E xt e n si o n P h a s e
S er u m s a m pl e s will b e c oll e ct e d f or d et er mi n ati o n of o cr eli z u m a b c o n c e ntr ati o n s a s 
s p e cifi e d i n t h e s c h e d ul e of a cti viti e s ( s e e T a bl e 4 ). O n t h e i nf u si o n d a y s i n C y cl e 1, 2
bl o o d s a m pl e s s h o ul d b e c oll e ct e d, 1 s a m pl e pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n
a n d t h e s e c o n d s a m pl e 3 0 mi n ut e s ( 1 0 mi n ut e s) f oll o wi n g t h e c o m pl eti o n of t h e 
o cr eli z u m a b i nf u si o n.  O n n o n -i nfu si o n vi sit s ( C y cl e 1, W e e k  1 2 a n d t h e Wit h dr a w al fr o m 
Tr e at m e nt Vi sit ), s a m pl e s m a y b e t a k e n at a n y ti m e d uri n g t h e vi sit.  F or all s u b s e q u e nt 
c y cl e s aft er C y cl e 1, o nl y 1 P K s a m pl e s h all b e t a k e n o n D a y 1 pri or t o t h e 
m et h yl pr e d ni s ol o n e i nf u si o n.
A s of pr ot o c ol v er si o n I ( v 9), H A H A a n d c o n c urr e nt P K a n al y s e s will b e di s c o nti n u e d o n 
t h e b a si s t h at i m m u n o g e ni cit y i n ci d e n c e wit h o cr eli z u m a b i s v er y l o w (1 %) wit h n o 
s af et y ri s k s i d e ntifi e d, s o c o nti n u o u s m o nit ori n g of H A H A s i n t hi s p o p ul ati o n i s 
u n n e c e s s ar y.  H o w e v er, i n a n y c a s e of a n a p h yl a xi s, a n a p h yl a ct oi d r e a cti o n, or s eri o u s 
or s e v er e h y p er s e n siti vit y r e a cti o n, H A H A a n d o cr eli z u m a b c o n c e ntr ati o n s a m pl e s 
s h o ul d b e c oll e ct e d a s cl o s e a s p o s si bl e t o t h e e v e nt a n d t h e n at 4 a n d 1 6 w e e k s 
p o st d o s e.
T h e t ot al bl o o d v ol u m e c oll e ct e d f or e a c h P K a s s e s s m e nt will b e a p pr o xi m at el y 3. 5 m L.  
T h e s e s a m pl e s will b e a s s a y e d f or o cr eli z u m a b c o n c e ntr ati o n wit h u s e of a n 
e n z y m e -li n k e d i m m u n o s or b e nt a ss a y at G e n e nt e c h, I n c. or at a n alt er n at e l a b or at or y .
F or s a m pli n g pr o c e d ur e s, st or a g e c o n diti o n s, a n d s hi p m e nt i n str u cti o n s, s e e t h e 
S a m pl e H a n dli n g a n d L o gi sti c s M a n u al, w hi c h will b e pr o vi d e d t o e a c h sit e.
5. 1 5 
R O C H E C LI NI C A L R E P O S I T O R Y
S p e ci m e n s f or d y n a mi c ( n o n -i n h erit e d) bi o m ar k er di s c o v er y a n d v ali d ati o n will b e 
c oll e ct e d fr o m c o n s e nti n g p arti ci p a nt s .


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8 5 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T h e s e s p e ci m e n s will b e u s e d f or r e s e ar c h p ur p o s e s t o i d e ntif y d y n a mi c bi o m ar k er s t h at 
ar e pr e di cti v e of r e s p o n s e t o o cr eli z u m a b tr e at m e nt (i n t er m s of d o s e, s af et y a n d 
t ol er a bilit y) a n d will h el p t o b ett er u n d er st a n d t h e p at h o g e n e si s, c o ur s e, a n d o ut c o m e of 
P P M S a n d r el at e d di s e a s e s.  S p e ci m e n s f or d y n a mi c bi o m ar k er di s c o v er y will b e si n gl e 
c o d e d li k e a n y ot h er cli ni c al s a m pl e (l a b el e d a n d tr a c k e d wit h u s e of t h e p arti ci p a nt’ s
st u d y i d e ntifi c ati o n n u m b er ( s e e S e cti o n 1 7 ).
S p e ci m e n s f or g e n eti c bi o m ar k er (i n h erit e d) di s c o v er y a n d v ali d ati o n will al s o b e 
c oll e ct e d fr o m c o n s e nti n g p arti ci p a nt s .
T h e p h a r m a c o g e n eti c i nf or m ati o n g at h er e d t hr o u g h t h e a n al y si s of s p e ci m e n s i n t h e 
R C R i s h o p e d t o i m pr o v e p arti ci p a nt o ut c o m e s b y pr e di cti n g w hi c h p arti ci p a nt s ar e m or e 
li k el y t o r e s p o n d t o s p e cifi c dr u g t h er a pi e s, pr e di cti n g w hi c h p arti ci p a nt s ar e s u s c e pti bl e 
t o d e v el o pi n g a d v er s e si d e eff e ct s a n d/ or pr e di cti n g w hi c h p arti ci p a nt s ar e li k el y t o 
pr o gr e s s t o m or e s e v er e di s e a s e st at e s.  S u c h g e n eti c s a m pl e s c oll e ct e d f or a n al y si s of 
h erit a bl e D N A v ari ati o n s will b e d o u bl e c o d e d: a n e w i n d e p e n d e nt c o d e will b e a d d e d t o 
t h e fir st c o d e t o i n cr e a s e c o nfi d e nti alit y a n d d at a pr ot e cti o n ( s e e S e cti o n 1 7 ).
T h e r e s ult s of s p e ci m e n a n al y si s fr o m t h e R C R wil l f a cilit at e t h e r ati o n al d e si g n of n e w 
p h ar m a c e uti c al a g e nt s a n d t h e d e v el o p m e nt of di a g n o sti c t e st s, w hi c h m a y all o w f or 
i n di vi d u ali z e d dr u g t h er a p y f or p arti ci p a nt s i n t h e f ut ur e.
All R C R s p e ci m e n s will b e d e str o y e d n o l at er t h a n 1 5 y e ar s aft er t h e fi n a l fr e e z e of t h e 
r e s p e cti v e cli ni c al d at a b a s e u nl e s s r e g ul at or y a ut h oriti e s r e q uir e t h at s p e ci m e n s b e 
m ai nt ai n e d f or a l o n g er p eri o d.  T h e s p e ci m e n s i n t h e R C R will b e m a d e a v ail a bl e f or 
f ut ur e bi o m ar k er r e s e ar c h t o w ar d s f urt h er u n d er st a n di n g of tr e at m e nt wit h o cr eli z u m a b 
of  P P M S, r el at e d di s e a s e s a n d a d v er s e e v e nt s a n d f or t h e d e v el o p m e nt of p ot e nti al 
a s s o ci at e d di a g n o sti c a s s a y s.  T h e i m pl e m e nt ati o n a n d u s e of t h e R C R s p e ci m e n s i s 
g o v er n e d b y t h e R C R p oli c y t o e n s ur e t h e a p pr o pri at e u s e of t h e R C R s p e ci m e n s.
5. 1 5. 1 
S p e ci m e n T y p e s
5. 1 5. 1. 1 
Bl o o d f or R N A  E x pr e s si o n Pr ofili n g
Bl o o d ( 2 a p pr o xi m at el y 2. 5 m L c oll e ct e d i n P A X g e n e v a c ut ai n er s) f or R N A i s ol ati o n will 
b e o bt ai n e d at v ari o u s ti m e p oi nt s a s s h o w n i n T a bl e 1 .  T h e s a m pl e s m a y b e t e st e d wit h 
u s e of t e c h ni q u e s s u c h a s a mi cr o arr a y pr ofili n g s y st e m a n d/or r e v er s e tr a n s cri pt a s e
P C R t o st u d y t h e e x pr e s si o n pr ofil e of g e n e s k n o w n t o b e i n v ol v e d wit h P P M S, a n d a n y 
ot h er diff er e nti all y e x pr e s s e d g e n e s r el ati v e t o tr e at m e nt r e s p o n s e, d o s e r e s p o n s e or 
r e-tr e at m e nt.  F or s a m pli n g pr o c e d ur e s, st or a g e c o n diti o n s, a n d s hi p m e nt i n str u cti o n s 
s e e st u d y S a m pl e H a n dli n g a n d L o gi sti c s M a n u al.
N ot e: in t h e O L E p h a s e, t hi s s a m pl e will n o l o n g er b e c oll e ct e d.


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8 6 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
5. 1 5. 1. 2 
Bl o o d S a m pl e f or G e n eti c A n al y si s
Bl o o d ( a p pr o xi m at el y 6 m L i n K 3 E D T A) f or D N A i s ol ati o n will b e c oll e ct e d a s s h o w n i n
T a bl e 1 .  If, h o w e v er, t h e R C R g e n eti c bl o o d s a m pl e i s n ot c oll e ct e d duri n g t h e 
s c h e d ul e d vi sit, it m a y b e c oll e ct e d at a n y ti m e ( aft er r a n d o mi z ati o n) d uri n g t h e c o n d u ct 
of  t h e cli ni c al st u d y.  S e e st u d y S a m pl e H a n dli n g a n d L o gi sti c s M a n u al f or m or e d et ail s.
F or all s a m pl e s, d at e s of c o n s e nt a n d s p e ci m e n c oll e cti o n s h o ul d b e r e c or d e d o n t h e 
a s s o ci at e d R C R p a g e of t h e el e ctr o ni c C a s e R e p ort F or m ( e C R F) a n d/ or i n t h e cli ni c al 
d at a b a s e.
5. 1 5. 1. 3 
Bl o o d f or Pl a s m a A s s a y s
Bl o o d ( 1 a p pr o xi m at el y 6 m L s a m pl e i n E D T A) f or pl a s m a i s ol ati o n will b e  o bt ai n e d at 
v ari o u s ti m e p oi nt s a s s h o w n i n T a bl e 1 , T a bl e 2 , T a bl e 3 , a n d T a bl e 4 .  T h e s e s a m pl e s 
will b e u s e d f or bi o m ar k er a s s a y s w hi c h m a y i n cl u d e n e ur ofil a m e nt s a n d ot h er c a n di d at e 
P P M S bi o m ar k er s.  F or s a m pli n g pr o c e d ur e s, st or a g e c o n diti o n s a n d s hi p m e nt 
i n str u cti on s s e e st u d y S a m pl e H a n dli n g a n d L o gi sti c s M a n u al.
5. 1 6 
O P TI O N A L S A M P L E S F O R
R E S E A R C H BI O S A M P L E 
R E P O SI T O R Y
If t h e p arti ci p a nt pr o vi d e s c o n s e nt ( s e e S e cti o n 5. 1 6. 5 ), a c oll e cti o n of bi o s a m pl e s f or 
t h e R B R will b e p erf or m e d at a si n gl e ti m e p oi nt d uri n g t h e O L E p h a s e of t h e st u d y.  
T h e s e s a m pl e s will b e u s e d f or r e s e ar c h i nt o M S di s e a s e pr o gr e s si o n m e c h a n i s m s, 
i d e ntifi c ati o n of n e w M S di s e a s e pr o gr e s si o n bi o m ar k er s, a n d d e v el o pm e nt of n e w 
t h er a p e uti c a g e nt s.
5. 1 6. 1 
O v er vi e w  of t h e R o c h e R e s e ar c h Bi o s a m pl e R e p o sit or y
T h e R B R i s a c e ntr all y a d mi ni st er e d gr o u p of f a ciliti e s u s e d f or t h e l o n g -t er m st or a g e of 
h u m a n bi ol o gi c al s p e ci m e n s, i n cl u di n g b o d y fl ui d s, s oli d ti s s u e s, a n d d eri v ati v e s t h er e of 
( e. g., D N A, R N A, pr ot ei n s, p e pti d e s).  T h e c oll e cti o n, st or a g e, a n d a n al y si s of R B R 
s a m pl e s will f a cilit at e t h e d e si g n of n e w p h ar m a c e uti c al a g e nt s a n d t h e d e v el o p m e nt of 
di a g n o sti c t e st s, w hi c h m a y all o w f or i n di vi d u ali z e d dr u g t h er a p y f or p arti ci p a nt s i n t h e 
f ut ur e.
S a m pl e s f or t h e R B R will b e c oll e ct e d fr o m p arti ci p a nt s w h o gi v e s p e cifi c c o n s e nt t o 
p arti ci p at e i n t hi s o pti o n al r e s e ar c h.  R e s e ar c h Bi o s a m pl e R e p o sit or y s a m pl e s m a y b e 
u s e d t o a c hi e v e t h e f oll o wi n g o bj e cti v e s:
 
T o st u d y t h e a s s o ci ati o n of bi o m ar k er s wit h effi c a c y or M S di s e a s e pr o gr e s si o n
 
T o i d e ntif y s af et y bi o m ar k er s t h at ar e a s s o ci at e d wit h s u s c e pti bilit y t o d e v el o pi n g 
a d v er s e e v e nt s or c a n l e a d t o i m pr o v e d a d v er s e e v e nt m o nit ori n g or i n v e sti g ati o n
 
T o i n cr e a s e k n o wl e d g e a n d u n d er st a n di n g of M S di s e a s e bi ol o g y a n d dr u g s af et y
 
T o st u d y dr u g r e s p o n s e, i n cl u di n g dr u g ef f e ct s a n d t h e pr o c e s s e s of dr u g a b s or pti o n 
a n d di s p o siti o n


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
8 7 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
T o d e v el o p bi o m ar k er or di a g n o sti c a s s a y s a n d e st a bli s h t h e p erf or m a n c e 
c h ar a ct eri sti c s of t h e s e a s s a y s
5. 1 6. 2 
A p pr o v al b y t h e I n stit uti o n al R e vi e w  B o ar d or Et hi c s 
C o m mitt e e
C oll e cti o n, st or a g e, a n d a n al y si s of R B R s a m pl e s i s c o nti n g e nt u p o n t h e r e vi e w a n d 
a p pr o v al of t h e e x pl or at or y r e s e ar c h a n d t h e R B R p orti o n of t h e I C F b y e a c h sit e' s I R B
or E C a n d, if a p pli c a bl e, a n a p pr o pri at e r e g ul at or y b o d y.  If a sit e h a s n ot b e e n gr a nt e d 
a p pr o v al f or R B R s a m pli n g , t hi s s e cti o n of t h e pr ot o c ol (S e cti o n 5. 1 6 ) will n ot b e 
a p pli c a bl e at t h at sit e.
5. 1 6. 3 
S a m pl e C oll e cti o n
T h e f oll o wi n g s a m pl e s will b e st or e d i n t h e R B R a n d u s e d f or r e s e ar c h p ur p o s e s, 
i n cl u di n g, b ut n ot li mit e d t o, r e s e ar c h o n bi o m ar k er s r el at e d t o o cr eli z u m a b a n d M S 
di s e a s e pr o gr e s si o n or dr u g s af et y .  T h e s e s a m pl e s s h o ul d b e c oll e ct e d aft er t h e 
p arti ci p a nt’ s c o n s e nt a n d at t h e n e xt p o s si bl e vi sit d uri n g O L E p h a s e .
 
C S F
 
P air e d pl a s m a s a m pl e s f or t h e C S F
 
Bl o o d s a m ples i ncl u di n g left o ver s a m ples c ollecte d d uri n g t he tri al
D at a g e n er at e d fr o m R B R s a m pl e s will b e a n al y z e d i n t h e c o nt e xt of t hi s st u d y b ut m a y 
al s o b e e x pl or e d i n a g gr e g at e wit h d at a fr o m ot h er st u di e s.  T h e a v ail a bilit y of a l ar g er 
d at a s et will a s si st i n i d e ntifi c ati o n a n d c h ar a ct eri z ati o n of i m p ort a nt bi o m ar k er s a n d 
p at h w a y s t o s u p p ort f ut ur e dr u g d e v el o p m e nt.
F or s a m pli n g pr o c e d ur e s, st or a g e c o n diti o n s, a n d s hi p m e nt i n str u cti o n s, s e e t h e 
L a b or at or y M a n u al.
R e s e ar c h Bi o s a m pl e R e p o sit or y s a m pl e s ar e t o b e st or e d u ntil t h e y ar e n o l o n g er 
n e e d e d or u ntil t h e y ar e e x h a u st e d.  H o w e v er, t h e R B R st or a g e p eri o d will b e i n 
a c c or d a n c e wit h t h e I R B/ E C a p pr o v e d I C F a n d a p pli c a bl e l a w s ( e. g., h e alt h a ut h orit y 
r e q uir e m e nt s).
5. 1 6. 4 
C o nfi d e nti alit y
R e s e ar c h Bi o s a m pl e R e p o sit or y s a m pl e s a n d a s s o ci at e d d at a will b e l a b el e d wit h a 
u ni q u e p arti ci p a nt i d e ntifi c ati o n n u m b er.
P arti ci p a nt m e di c al i nf or m ati o n a s s o ci at e d wit h R B R s a m pl e s i s c o nfi d e nti al a n d m a y b e 
di s cl o s e d t o t hir d p arti e s o nl y a s p er mitt e d b y t h e I C F ( or s e p ar at e a ut h ori z ati o n f or u s e 
a n d di s cl o s ur e of p er s o n al h e alt h i nf or m ati o n) si g n e d b y t h e p arti ci p a nt , u nl e s s p er mitt e d 
or r e q uir e d b y l a w.
Gi v e n t h e c o m pl e xit y a n d e x pl or at or y n at ur e of t h e a n al y s e s of R B R s a m pl e s, d at a 
d eri v e d fr o m t h e s e a n al y s e s will g e n er all y n ot b e pr o vi d e d t o st u d y i n v e sti g at or s or 


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p arti ci p a nt s u nl e s s r e q uir e d b y l a w.  T h e a g gr e g at e r e s ult s of a n y c o n d u ct e d r e s e ar c h 
will b e a v ail a bl e i n a c c or d a n c e wit h t h e eff e cti v e S p o n s or p oli c y o n st u d y d at a 
p u bli c ati o n.
D at a g e n er at e d fr o m R B R s a m pl e s m u st b e a v ail a bl e f or i n s p e cti o n u p o n r e q u e st b y 
r e pr e s e nt ati v e s of n ati o n al a n d l o c al h e alt h a ut h oriti e s, a n d S p o n s or m o nit or s, 
r e pr e s e nt ati v e s, a n d c oll a b or at or s, a s a p pr o pri at e.
5. 1 6. 5 
C o n s e nt t o P arti ci p at e i n t h e R e s e ar c h Bi o s a m pl e R e p o sit or y
T h e I C F will c o nt ai n a s e p ar at e s e cti o n t h at a d dr e s s e s p arti ci p ati o n i n t h e R B R.  
T h e i n v e sti g at or or a ut h ori z e d d e si g n e e will e x pl ai n t o e a c h p arti ci p a nt t h e o bj e cti v e s, 
m et h o d s, a n d p ot e nti al h a z ar d s of p arti ci p ati o n i n t h e R B R.  P arti ci p a nt s will b e t ol d t h at 
t h e y ar e fr e e t o r ef u s e t o p arti ci p at e a n d m a y wit h dr a w t h eir c o n s e nt at a n y ti m e a n d f or 
a n y r e a s o n d uri n g t h e st or a g e p eri o d.  A s e p ar at e, s p e cif i c si g n at ur e will b e r e q uir e d t o 
d o c u m e nt a p arti ci p a nt’ s a gr e e m e nt t o pr o vi d e o pti o n al R B R s a m pl e s.  P arti ci p a nt s w h o 
d e cli n e t o p arti ci p at e will n ot pr o vi d e a s e p ar at e si g n at ur e.
T h e i n v e sti g at or s h o ul d d o c u m e nt w h et h er or n ot t h e p arti ci p a nt h a s gi v e n c o n s e nt t o 
p arti ci p at e a n d (if a p pli c a bl e) t h e d at e( s) of c o n s e nt, b y c o m pl eti n g t h e R B R R e s e ar c h 
S a m pl e I nf or m e d C o n s e nt e C R F.
I n t h e e v e nt of a n R B R p arti ci p a nt' s d e at h or l o s s of c o m p et e n c e, t h e p arti ci p a nt' s 
s a m pl e s a n d d at a will c o nti n u e t o b e u s e d a s p art of t h e R B R r e s e ar c h.
5. 1 6. 6 
Wit h dr a w al fr o m t h e R e s e ar c h Bi o s a m pl e R e p o sit or y
P arti ci p a nt s w h o gi v e c o n s e nt t o pr o vi d e R B R s a m pl e s h a v e t h e ri g ht t o wit h dr a w t h eir 
c o n s e nt at a n y ti m e f or a n y r e a s o n.  Aft er wit h dr a w al of c o n s e nt, a n y r e m ai ni n g s a m pl e s 
will b e d e str o y e d or will n o l o n g er b e li n k e d t o t h e p arti ci p a nt .  H o w e v er, if R B R s a m pl e s 
h a v e b e e n t e st e d pri or t o wit h dr a w al of c o n s e nt, r e s ult s fr o m t h o s e t e st s will r e m ai n a s 
p art of t h e o v er all r e s e ar c h d at a.  If a p arti ci p a nt wi s h e s t o wit h dr a w c o n s e nt t o t h e 
t e sti n g of hi s or h er R B R s a m pl e s d uri n g t h e st u d y, t h e i n v e sti g at or m u st i nf or m t h e 
M e di c al M o nit or i n writi n g of t h e p arti ci p a nt’ s wi s h e s t hr o u g h u s e of t h e a p pr o pri at e R B R 
P arti ci p a nt Wi t h dr a w al F or m a n d m u st e nt er t h e d at e of wit h dr a w al o n t h e R B R 
R e s e ar c h S a m pl e W it h dr a w al of I nf or m e d C o n s e nt e C R F.  If a p arti ci p a nt wi s h e s t o 
wit h dr a w c o n s e nt t o t h e t e sti n g of hi s or h er R B R s a m pl e s aft er cl o s ur e of t h e sit e, t h e 
i n v e sti g at or m u st i nf or m t h e S p o n s or b y e-m aili n g t h e st u d y n u m b er a n d p a rti ci p a nt
n u m b er t o t h e f oll o wi n g e -m ail a d dr e s s:
gl o b al _r cr -wit h dr a w al @r o c h e. c o m
A p arti ci p a nt’ s wit h dr a w al fr o m t hi s st u d y d o e s n ot, b y it s elf, c o n stit ut e wit h dr a w al of 
c o n s e nt f or t e sti n g of R B R s a m pl e s.  Li k e wi s e, a p arti ci p a nt’ s wit h dr a w al of c o n s e nt f or 
t e sti n g of R B R s a m pl e s d o e s n ot c o n stit ut e wit h dr a w al fr o m t hi s st u d y.


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5. 1 6. 7 
M o nit ori n g a n d O v er si g ht
R e s e ar c h Bi o s a m pl e R e p o sit or y s a m pl e s will b e tr a c k e d i n a m a n n er c o n si st e nt wit h 
G o o d Cli ni c al Pr a c ti c e b y a q u alit y-c o ntr oll e d, a u dit a bl e, a n d a p pr o pri at el y v ali d at e d 
l a b or at or y i nf or m ati o n m a n a g e m e nt s y st e m, t o e n s ur e c o m pli a n c e wit h d at a 
c o nfi d e nti alit y a s w ell a s a d h er e n c e t o a ut h ori z e d u s e of s a m pl e s a s s p e cifi e d i n t hi s 
pr ot o c ol a n d i n t h e I C F.  Sp o n s or m o nit or s a n d a u dit or s will h a v e dir e ct a c c e s s t o 
a p pr o pri at e p art s of r e c or d s r el ati n g t o p arti ci p a nt p arti ci p ati o n i n t h e R B R f or t h e 
p ur p o s e s of v erif yi n g t h e d at a pr o vi d e d t o t h e S p o n s or.  T h e sit e will p er mit m o nit ori n g, 
a u dit s, I R B/ E C r e vi e w, a n d h e alt h a ut h orit y i n s p e cti o n s b y pr o vi di n g dir e ct a c c e s s t o 
s o ur c e d at a a n d d o c u m e nt s r el at e d t o t h e R B R s a m pl e s.
5. 1 7 
P R O T EI N BI O M A R K E R S A M P L E
S p e ci m e n s f or pr ot ei n bi o m ar k er di s c o v er y a n d v ali d ati o n will b e c oll e ct e d fr o m all 
p arti ci p a nt s .  T h e s e s p e ci m e n s will b e u s e d f or r e s e ar c h p ur p o s e s t o i d e ntif y a n d/ or 
v erif y pr ot ei n bi o m ar k er s t h at ar e pr e di cti v e of r e s p o n s e t o o cr eli z u m a b tr e at m e nt 
(i n t er m s of d o s e, s af et y a n d t ol er a bilit y) a n d will h el p t o u n d er st a n d t h e p at h o g e n e si s, 
c o ur s e a n d o ut c o m e of P P M S a n d r el at e d di s e a s e s.  I d e ntifi c ati o n of p arti ci p a nt
s u b gr o u p s wit h i n cr e a s e d r e s p o n s e t o t h er a p y or i n cr e a s e d pr o gr e s si o n r at e s w o ul d 
pr o vi d e i nf or m ati o n of si g nifi c a nt cli ni c al v al u e t o g ui d e tr e at m e nt d e ci si o n s a n d ai d i n 
t h e a p pr o pri at e u s e of t h e t h er a py .  A n al y s e s m a y i n cl u d e , b ut ar e n ot li mit e d t o ,
i nt erl e u ki n-6 (I n gr a m et al. 2 0 1 0) .  F or s a m pli n g pr o c e d ur e s, st or a g e c o n diti o n s a n d 
s hi p m e nt i n str u cti o n s s e e st u d y S a m pl e H a n dli n g a n d L o gi sti c s M a n u al, w hi c h will b e 
pr o vi d e d t o e a c h st u d y sit e.
At Vi sit 2, bl o o d s p e ci m e n s ( a p pr o xi m at el y 6 m L bl o o d s a m pl e i n a pl ai n t u b e wit h o ut 
E D T A f or s er u m i s ol ati o n) f or pr ot ei n bi o m ar k er di s c o v er y a n d v ali d ati o n will b e c oll e ct e d 
fr o m all p arti ci p a nt s .
Bl o o d s p e ci m e n s f or pr ot ei n bi o m ar k er di s c o v er y a n d v ali d ati o n wi ll b e c oll e ct e d fr o m all 
p arti ci p a nt s a s p er t h e s c h e d ul e of a cti viti e s. T h e s e s p e ci m e n s will b e st or e d f or 5 y e ar s 
af t er t h e e n d of t h e st u d y a n d t h e n d e str o y e d, u nl e s s a diff er e nt r e g ul ati o n f or st or a g e 
ti m e i s i n pl a c e at a gi v e n sit e.
5. 1 8 
C LI NI C A L G E N O T Y P I N G
S p e cifi c i n h erit e d D N A p ol y m or p hi s m s k n o w n or h y p ot h e si z e d t o b e a s s o ci at e d wit h M S 
or o cr eli z u m a b a cti vit y will b e i n v e sti g at e d i n all p arti ci p a nt s .  At Vi sit 2, a w h ol e bl o o d 
s a m pl e ( a p pr o xi m at el y 3 m L) will b e t a k e n f or D N A e xtr a cti o n fr o m e v er y p ar ti ci p a nt.  
T h e D N A will b e u s e d t o d et er mi n e if all el e s at h u m a n l e u k o c yt e a nti g e n ( H L A) cl a s s II, 
F c r e c e pt or II a a n d F c r e c e pt or III a aff e ct t h e P K , P D , effi c a c y or s af et y of 
o cr eli z u m a b.  D at a ari si n g fr o m t hi s st u d y will b e s u bj e ct t o t h e s a m e c o nfi d e nti alit y a s 
t h e r e st of t h e st u d y.  G e n eti c c o u n s eli n g will b e pr o vi d e d t o p arti ci p a nt s wi s hi n g t o 
u n d er st a n d t h e cli ni c al r el e v a n c e of st u d y r e s ult s if i n di c at e d.


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P ol y m or p hi s m s i n t h e F c r e c e pt or III a h a v e b e e n s h o w n t o i nfl u e n c e t h e d e gr e e of 
B c ell d e pl eti o n b y rit u xi m a b i n t h e tr e at m e nt of p arti ci p a nt s wit h s y st e mi c 
er yt hr o m at o s u s ( A n oli k et al. 2 0 0 3).  T h er ef or e, t h e F c r e c e pt or RIII A p ol y m or p hi s m at 
p o siti o n 1 5 8 ( V al/ P h e) a n d t h e F c r e c e pt or RII A p ol y m or p hi s m at p o siti o n 1 3 1 ( Ar g/ Hi s) 
wil l b e i n v e sti g at e d.
G e n e s of t h e m aj or h i st o c o m p ati bilit y c o m pl e x ( M H C) h a v e b e e n a s s o ci at e d wit h M S.  
T h e g e n e s h a v e b e e n m a p p e d t o t h e H L A cl a s s II r e gi o n a n d a c c o u nt f or 1 0 % 6 0 % of 
t h e g e n eti c ri s k of M S ( R a m a g op al a n a et al. 2 0 0 9) .  T h u s, h a pl ot y p e s of H L A -D R a n d 
H L A -D Q will b e a n al y z e d.
T h e pr o c e d ur e s f or t h e c oll e cti o n, h a n dli n g a n d s hi p pi n g of cli ni c al g e n ot y pi n g s a m pl e s 
ar e s p e cifi e d i n t h e st u d y S a m pl e H a n dli n g a n d L o gi sti c s M a n u al.
I n t h e O L E p h a s e , f or p arti ci p a nt s t h at di d n ot h a v e a cli ni c al g e n ot y pi n g s a m pl e 
c oll e ct e d i n t h e b li n d e d tr e at m e nt p eri o d , a n o p e n-l a b el cli ni c al g e n ot y pi n g s a m pl e 
s h o ul d b e c oll e ct e d.  A w h ol e bl o o d s a m pl e ( a p pr o xi m at el y 3 m L) will b e t a k e n f or D N A 
e xtr a cti o n fr o m e a c h p arti ci p a nt t h at di d n ot h a v e a D N A s a m pl e a s se s s e d fr o m t h e 
b li n d e d tr e at m e nt p eri o d .  T hi s s a m pl e i s pr ef err e d t o b e c oll e ct e d at Vi sit 1 of t h e 
O L E p h a s e, b ut if n ot c oll e ct e d at Vi sit 1, it m a y b e c oll e ct e d at a n y vi sit d uri n g t h e 
O L E p h a s e.
F or p arti ci p a nt s w h er e a s a m pl e w a s alr e a d y c oll e ct e d, n o a d diti o n al 
s a m pl e will b e c oll e ct e d.
5. 1 9 
P L A S M A  AN D U RI N E B A N KI N G F O R J O H N C U N NI N G H A M
VI R U S
L o n g -t er m st or a g e of pl a s m a s a m pl e s a n d uri n e i s pl a n n e d f or J o h n C u n ni n g h a m vir u s 
( J CV) D N A a n d/ or ot h er r el e v a nt t e st s f or J C V , i n d e p e n d e nt of a n o c c urr e n c e of 
s u s p e ct e d P M L .  Pl a s m a s a m pl e s ( 5 m L) a n d uri n e s a m pl e s ( 1 0 m L ) will b e c oll e ct e d a s 
p er t h e s c h e d ul e of a cti viti e s.  A s t h e a s s a y of t h e D N A vir u s h a s n ot b e e n st a n d ar di z e d, 
a n d a c orr el ati o n b et w e e n vir e mi a a n d o n s et of P M L h a s n ot b e e n e st a bli s h e d, t h e 
J C V a s s e s s m e nt s i n pl a s m a a n d uri n e will b e p erf or m e d if d e e m e d n e c e s s ar y i n t h e 
f ut ur e a n d n ot o n a n o n g oi n g b a si s.  All s a m pl e s c oll e ct e d f or J C V t e sti n g will b e st or e d 
f or 1 y e ar aft er t h e l a st p arti ci p a nt’ s l a st vi sit i n t h e st u d y.
A s of pr ot o c ol v er si o n I ( v 9) , c oll e cti o n of pl a s m a a n d uri n e s a m pl e s pl a n n e d f or J C V
D N A will b e di s c o nti n u e d . In t h e e v e nt t h at P M L i s s u s p e ct e d, a n a d diti o n al pl a s m a, 
uri n e, a n d C S F s a m pl e s h o ul d b e o bt ai n e d f or J C V a n al y si s ( s e e S e cti o n 7. 3. 4. 1 ).  
F or d et ail s, pl e a s e r ef er t o t h e m o st u p -t o-d at e L a b or at or y M a n u al pr o vi di n g st or a g e 
c o n diti o n s a n d s hi p m e nt i n str u cti o n s.
5. 2 0 
P A R TI CI P A N T -R E P O R T E D O U T C O M E S
P arti ci p a nt -r e p ort e d o ut c o m e s a s s e s s m e nt s f or p ur p o s e s of a s s e s si n g tr e at m e nt b e n efit 
(i. e., S F-3 6 v 2 , MFI S) s h o ul d b e p erf or m e d b ef or e ot h er effi c a c y or s af et y a s s e s s m e nt s 
a n d b ef or e a d mi ni str ati o n of st u d y dr u g i n or d er t o mi n i mi z e bi a s.


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T h e S F -3 6 ( v er si o n 2) will b e m e a s ur e d t o a s s e s s h e alt h -r el at e d q u alit y of lif e.  
C h a n g e s fr o m b a s eli n e will b e a s s e s s e d f or t h e t ot al s c or e, P C S a n d M C S , a s w ell a s all 
ot h er s u b s c al e s t h at c o m pri s e t h e S F -3 6.
T h e M FI S will a s s e s s c h a n g e i n t h e l e v el of f ati g u e.  T h e M FI S i s a 2 1 -it e m i n str u m e nt 
t h at a s k s p arti ci p a nt s t o r at e t h eir f ati g u e o v er t h e p a st 4 w e e k s o n a 5 -p oi nt Li k ert s c al e, 
i n di c ati n g “ N e v er” t o “ Al m o st al w a y s.”  F o ur s c or e s c a n b e d eri v e d fr o m t h e M FI S, 
i n cl u di n g a t ot al s c or e a s w ell a s s c or e s f or 3 s u b s c al e s: p h y si c al, c o g niti v e, a n d 
p s y c h o s o ci al f u n cti o ni n g.  C h a n g e s fr o m b a s eli n e will b e c al c ul at e d f or t h e t ot al s c al e 
s c or e s a s w e ll a s f or t h e s u b s c al e s c or e s.
P arti ci p a nt -r e p ort e d o ut c o m e s d at a will b e c oll e ct e d a c c or di n g t o t h e pr ot o c ol s c h e d ul e 
of  a cti viti e s a n d t h e d at a will b e e nt er e d i nt o t h e cli ni c al d at a b a s e.   F or all P R O s, 
p arti ci p a nt s will c o m pl et e t h e a s s e s s m e nt s i n c o u ntri e s w h er e tr a n sl ati o n s of t h e 
i n str u m e nt s ar e c urr e ntl y a v ail a bl e.
P arti ci p a nt s w h o ar e u n a bl e t o c o m pl et e e x pl or at or y a s s e s s m e nt s ( e. g., e l e ctr o ni c 
p arti ci p a nt -r e p ort e d o ut c o m e s) b e c a u s e of p h y si c al/ di s e a s e li mit ati o n s will n ot b e 
e x cl u d e d fr o m t h e st u d y.
5. 2 1 
P H A R M A C O E C O N O MI C A S S E S S M E N T S
P h ar m a c o e c o n o mi c a s s e s s m e nt s will b e i n cl u d e d f or p ur p o s e s of d eri vi n g h e alt h utiliti e s 
f or e c o n o mi c m o d eli n g.  T h e E Q-5 D will b e u s e d t o d eri v e utiliti e s f or h e alt h st at e s 
i n cl u d e d i n M S e c o n o mi c m o d el s.  D uri n g t h e b li n d e d tr e at m e nt p eri o d, it will b e 
a d mi ni st er e d at b a s eli n e a n d W e e k s 4 8 a n d 1 2 0.  T h e E Q -5 D i s a P R O a n d s h o ul d b e 
p erf or m e d b ef or e a n y ot h er st u d y a s s e s s m e nt s a n d b ef or e a d mi ni str ati o n of st u d y dr u g 
i n or d er t o mi ni mi z e bi a s.
N ot e: in t h e O L E p h a s e , t h e E Q-5 D will n ot b e p erf or m e d.
5. 2 2 
O P TI O N A L E X P L O R A T O R Y S U B S T U DI E S
P arti ci p a nt s w h o ar e r a n d o mi z e d t o t h e m ai n St u d y W A 2 5 0 4 6 pr ot o c ol h a v e t h e o pti o n 
t o p arti ci p at e i n e x pl or at or y s u b st u di e s u n d er s e p ar at e pr ot o c ol s a n d u p o n c o n s e nt a n d 
f ulfill m e nt of a d diti o n al e x pl or at or y s u b st u d y pr ot o c ol crit eri a.  T h e O C T E x pl or at or y 
S u b st u d y i s i n cl u d e d i n t h e m ai n st u d y pr ot o c ol ( s e e S e cti o n 5. 2 2. 1 a n d A p p e n di x 6 ).
Ot h e r e x pl or at or y s u b st u di e s ar e r u n u n d er s e p ar at e st u d y pr ot o c ol s:
 
B c ell a n d T c ell r e p ert oir e s i n o cr eli z u m a b -tr e at e d p arti ci p a nt s wit h M S 
(St u d y B E 2 9 3 5 3)
 
Br ai n m y eli n m a p pi n g t o q u a ntif y d e m y eli n ati o n a n d r e p air i n M S i n a P h a s e III tri al 
of  o cr eli z u m a b (St u d y B E 2 9 3 4 0)


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9 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
A s s e s s m e nt of o cr eli z u m a b tr e at m e nt eff e ct s o n di s a bilit y of p arti ci p a nt s wit h M S 
e nr oll e d i n t h e P h a s e III Or c h e str a pr o gr a m wit h u s e of m ulti m o d al e v o k e d 
p ot e nti al s ( m E P) a n d hi g h -r e s ol uti o n el e ctr o e n c e p h al o gr a m ( E E G; St u d y B E 2 9 3 5 4)
 
S u b st u d y of br ai n a n d s pi n al c or d M RI i n p arti ci p a nt s wit h M S p arti ci p ati n g i n t h e
St u d y B E 2 9 3 5 2 ( O P E R A ) cli ni c al tri al
S u b st u di e s will b e r u n o n l y at t h e s p e cifi c a s si g n e d sit e s t h at ar e r ef err e d t o i n t h e 
s u b st u d y pr ot o c ol s.
5. 2 2. 1 
O pti c al C o h er e n c e T o m o gr a p h y  E x pl or at or y S u b st u d y
A R o c h e -s p o n s or e d, m ulti c e nt er , O C T E x pl or at or y S u b st u d y i s b ei n g c o n d u ct e d.  
O pti c al c o h er e n c e t o m o gr a p h y i s a n o ni n v a si v e i m a gi n g t o ol c a p a bl e of m e a s uri n g 
c h a n g e s i n str u ct ur al ar c hit e ct ur e of t h e r eti n a a n d r eti n al n er v e fi b er s e n siti v el y a n d 
r a pi dl y (Fr o h m a n et al. 2 0 0 8) .  Opti c al c o h er e n c e t o m o gr a p h y c a n b e of p arti c ul ar 
i nt er e st i n M S, b e c a u s e o pti c n e uriti s i s oft e n t h e pi v ot al e v e nt i n e st a bli s hi n g t h e 
di a g n o si s of M S.  O pti c n er v e d y sf u n cti o n i s c h ar a ct eri z e d b y o pti c di s c p all or, l o s s of 
c o ntr a st s e n siti vit y, a n d vi s u al fi el d d ef e ct s a n d m a y o c c ur s u b cli ni c all y i n m a n y ot h er 
p arti ci p a nt s .  It i s e stim at e d t h at n e arl y 2 0 % of all p arti ci p a nt s wit h M S pr e s e nt i niti all y 
wit h o pti c al n e uriti s, a n d a n a d diti o n al 3 0 % – 1 0 0 % will h a v e o pti c al n e uriti s at s o m e p oi nt 
i n t h eir di s e a s e c o ur s e ( S er g ott et al. 2 0 0 7).  Opti c al c o h er e n c e t o m o gr a p h y o ut c o m e 
m e a s ur e s, s u c h a s R N F L t hi c k n e s s a n d m a c ul ar v ol u m e s , h a v e b e e n s h o w n t o c orr el at e 
wit h cli ni c al m e a s ur e s of vi si o n l o s s a n d m a y f a cilit at e vi s u ali z ati o n of a n y pr o c e s s of 
n e ur o d e g e n er ati o n or r e p air a s p art of n at ur al hi st or y of M S or a s a c o n s e q u e n c e of 
n e ur o pr ot e ct i v e i nt er v e nti o n s ( C o st ell o et al. 2 0 0 8).
T h e pr o c e d ur e s a n d s c h e d ul e of a cti viti e s ar e s p e cifi e d i n t h e s u b st u d y pr ot o c ol 
(A p p e n di x 6 ) a n d I n d e p e n d e nt R e vi e w C o m mitt e e C h art er.
I n J ul y 2 0 1 7, R o c h e d et er mi n e d t h at s uffi ci e nt d at a h a d b e e n o bt ai n e d fr o m t h e 
O C T s u b st u d y.  D uri n g 2 0 1 7 a n d 2 0 1 8, p arti ci p ati n g p arti ci p a nt s will b e di s c o nti n u e d 
fr o m t h e O C T s u b st u d y b ut m a y c o nti n u e i n t h e O L E.
5. 2 3 
O P E N -L A B E L E X T E N SI O N P H A S E
T h e fir st t r e at m e nt c y cl e of t h e O L E p h a s e will c o n si st of t w o 3 0 0 m g I V i nf u si o n s of 
o cr eli z u m a b s e p ar at e d b y 1 4 d a y s . S u b s e q u e nt c y cl e s of t h e O L E p h a s e will c o n si st of 
si n gl e 6 0 0 m g o cr eli z u m a b I V i nf u si o n s at a s c h e d ul e d i n t er v al of e v er y 2 4 w e e k s.   
F or p arti ci p a nt s r a n d o mi z e d t o t h e pl a c e b o gr o u p i n t h e b li n d e d tr e at m e nt p eri o d, t h e 
fir st i nf u si o n of o cr eli z u m a b i n t h e O L E p h a s e c a n o c c ur o n c e a p arti ci p a nt m e et s t h e r e -
tr e at m e nt crit eri a ( s e e S e cti o n 5. 4 ) at a s c h e d ul e d vi sit f oll o wi n g c o m m u ni c ati o n wit h t h e
S p o n s or.   F or p arti ci p a nt s w h o w er e i n t h e o cr eli z u m a b tr e at m e nt ar m d uri n g t h e b li n d e d 
tr e at m e nt p eri o d, a mi ni m u m of 2 0 w e e k s m u st b e m ai nt ai n e d b et w e e n t h e l a st i nf u si o n 
i n t h e b li n d e d tr e at m e nt p eri o d a n d t h e fir st i nf u si o n i n t h e O L E p h a s e .


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P arti ci p a nt s w h o di s c o nti n u e d fr o m t h e b li n d e d tr e at m e nt p eri o d will b e gi v e n a n 
o p p ort u nit y t o e nt er a n O L E s u b st u d y .  S e e A p p e n di x 8 f or d et ail s.
P arti ci p a nt s w h o ar e pr e g n a nt a n d br e a stf e e di n g s h o ul d c o nti n u e t o f oll o w t h e s c h e d ul e 
of  a cti viti e s f or t h e O L E; h o w e v er, n o i nf u si o n s will o c c ur.  If t h er e i s a c o n c er n wit h t h e 
a bilit y of a pr e g n a nt or br e a stf e e di n g p arti ci p a nt t o c o m pl et e all s c h e d ul e d a s s e s s m e nt s, 
or if a s s e s s m e nt s ar e c o ntr ai n di c at e d wit h pr e g n a n c y, t h e in v e sti g at or m u st c o nt a ct t h e 
M e di c al M o nit or f or f urt h er di s c u s si o n.
5. 2 3. 1 
O v er vi e w  of S c h e d ul e of A c ti viti e s i n t h e O p e n-L a b el E xt e n si o n 
P h a s e
P arti ci p a nt s p arti ci p ati n g i n t h e O L E p h a s e will b e a s s e s s e d at cli ni c al vi s it s a s p er t h e 
s c h e d ul e of a cti viti e s (T a bl e 4 ).  F or t h e d e s cri pti o n of t h e a s s e s s m e nt s, s e e
S e cti o n 5. 1 1 .
T h e m e c h a ni s m s n e c e s s ar y t o g u ar a nt e e t h at t h e bli n di n g of t h e a s s e s s or i s m ai nt ai n e d 
ar e n ot n e c e s s ar y d uri n g t h e O L E p h a s e.  All r e q uir e d a s s e s s m e nt s d uri n g t h e 
O L E p h a s e s h o ul d o c c ur a s d e s cri b e d i n S e cti o n 5. 1 1 .  It i s r e c o m m e n d e d t h at t h e s a m e 
E x a mi ni n g In v e sti g at or p erf or m t h e a s s e s s m e nt s t hr o u g h o ut t h e O L E p h a s e.
Vi sit s s h o ul d b e s c h e d ul e d wit h r e s p e ct t o t h e d at e of fir st i nf u si o n d uri n g t h e 
O L E p h a s e .  T h e vi sit f or t h e s e c o n d i nf u si o n s h o ul d b e s c h e d ul e d 1 4 d a y s aft er t h e fir st 
i nf u si o n of O L E C y cl e 1.  A mi ni m u m i nt er v al of 2 0 w e e k s s h o ul d b e k e pt b et w e e n t h e 
o cr eli z u m a b s e c o n d i nf u si o n of O L E C y cl e 1 a n d t h e n e xt i nf u si o n at O L E C y cl e 2 .  
A mi ni m u m of 2 2 w e e k s s h o ul d o c c ur b et w e e n o cr eli z u m a b si n gl e i nf u si o n s 
a d mi ni st er e d fr o m O L E C y cl e 2 o n w a r ds.
I n t h e e v e nt t h at a n i nf u si o n i s d el a y e d, a d diti o n al t e st s or a s s e s s m e nt s, s u c h a s r o uti n e 
s af et y l a b or at or y t e st s, m a y b e p erf or m e d w h e n t h e I n v e sti g at or j u d g e s t h at t h e y ar e 
w arr a nt e d.  At i nf u si o n vi sit s, p arti ci p a nt s s h o ul d r e m ai n i n o b s er v ati o n f or at l e a st 1 h o ur 
af t er t h e c o m pl eti o n of t h e i nf u si o n.
A d diti o n al u n s c h e d ul e d vi sit s f or t h e a s s e s s m e nt of p ot e nti al M S r el a p s e s, n e w 
n e ur ol o gi c al s y m pt o m s, or s af et y e v e nt s m a y o c c ur at a n y ti m e.  
A s s e s s m e nt s p erf or m e d at u n s c h e d ul e d ( n o n -d o si n g) vi sit s will d e p e n d o n t h e cli ni c al 
n e e d s of t h e p arti ci p a nt .
P arti ci p a nt s wit h n e w n e ur ol o gi c al s y m pt o m s s u g g e sti v e of M S r el a p s e or M S w or s e ni n g 
s h o ul d h a v e a n E D S S p erf or m e d b y t h e E x a mi ni n g I n v e sti g at or.  
Ot h er t e st s/ a s s e s s m e nt s m a y b e d o n e a s a p pr o pri at e.
S e e S e cti o n 7. 3. 4. 1 f or g ui d a n c e o n t h e di a g n o si s of P M L.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
9 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
5. 2 3. 2 
D el a y e d D o si n g Vi sit i n t h e O p e n -L a b el E xt e n si o n P h a s e
D el a y e d d o si n g vi sit s m a y b e s c h e d ul e d if t h e i nf u si o n c a n n ot b e a d mi ni st er e d at t h e 
ti m e p oi nt s d efi n e d i n t h e s c h e d ul e of a cti viti e s (T a bl e 4 ).  A p arti ci p a nt w h o h a s all 
a s s e s s m e nt s of a d o si n g vi sit p erf or m e d b ut c a n n ot r e c ei v e hi s/ h er i nf u si o n s h o ul d b e 
r e-s c h e d ul e d f or t h e i nf u si o n.
At t h e d el a y e d d o si n g vi sit, a d diti o n al t e st s or a s s e s s m e nt s, s u c h a s r o uti n e s af et y 
l a b or at or y t e st s, m a y b e p erf or m e d w h e n t h e in v e sti g at or j u d g e s t h at t h e s e ar e 
w arr a nt e d.
I n u nf or e s e e n sit u ati o n s, if t h e i nf u si o n of t h e fir st tr e at m e nt c y cl e ( D a y 1) i s d el a y e d, 
t h e n t h e vi sit f or t h e s e c o n d i nf u sio n s h o ul d b e s c h e d ul e d 1 4 d a y s aft e r t h e d el a y e d fir st 
i nf u si o n (5 d a y s).  I n t h e e v e nt a n y s u b s e q u e nt i nf u si o n n e e d s t o b e d el a y e d, a 
mi ni m u m i nt er v al of 2 0 w e e k s b et w e e n t h e s e c o n d i nf u si o n of C y cl e 1 ( W e e k 2) a n d t h e 
n e xt i nf u si o n o n C y cl e 2 ( W e e k 2 4) i s r e q uir e d; a mi ni m u m of 2 2 w e e k s m u st o c c ur 
b et w e e n s u b s e q u e nt i nf u si o n s.
5. 2 3. 3 
U n s c h e d ul e d Vi sit s i n t h e O p e n -L a b el E xt e n si o n P h a s e
P arti ci p a nt s w h o d e v el o p n e w or w or s e ni n g n e ur ol o gi c al s y m pt o m s s h o ul d b e s e e n at 
t h e i n v e sti g ati o n al sit e a s s o o n a s p o s si bl e, r e g ar dl e s s of t h e d at e s of t h eir pr e pl a n n e d, 
s c h e d ul e d st u d y vi sit s.  A s s e s s m e nt s p erf or m e d at u n s c h e d ul e d ( n o n -d o si n g) vi sit s will 
d e p e n d o n t h e cli ni c al n e e d s of t h e p arti ci p a nt a s j u d g e d b y t h e i n v e sti g at or.
P arti ci p a nt s wit h n e w n e ur ol o gi c al s y m pt o m s s u g g e sti v e of r el a p s e or w or s e ni n g of 
M S
s y m pt o m s s h o ul d h a v e a n E D S S p erf or m e d b y t h e E x a mi ni n g I n v e sti g at or.  
Ot h er t e st s/ a s s e s s m e nt s m a y b e p erf or m e d a s a p pr o pri at e.
S e e S e cti o n 7. 3. 4. 1 f or g ui d a n c e o n t h e di a g n o si s of P M L.
5. 2 3. 4 
Wit h dr a w al Vi sit s i n t h e O p e n -L a b el E xt e n si o n P h a s e
W h e n a p arti ci p a nt m e et s 1 or m or e of t h e wit h dr a w al crit eri a ( S e cti o n 5. 6 ), t hi s 
p arti ci p a nt i s r e g ar d e d a s wit h dr a w n fr o m tr e at m e nt.  P arti ci p a nt s w h o wit h dr a w fr o m 
o cr eli z u m a b tr e at m e nt will n e e d t o c o m pl et e all a s s e s s m e nt s a s s h o w n i n T a bl e 4 a n d 
s h o ul d e nt e r t h e s af et y foll o w - up p eri o d.
F or p arti ci p a nt s w h o h a v e wit h dr a w n fr o m t h e O L E p h a s e or w h o ar e n o l o n g er eli gi bl e 
f or tr e at m e nt wit h o cr eli z u m a b, it i s at t h e di s cr eti o n of t he in v e sti g at or t o d e ci d e o n 
f urt h er tr e atm e nt of t h e u n d erl yi n g di s e a s e.
S i n c e s uffi ci e nt d at a ar e n ot a v ail a bl e t o i nf or m t h e ri s k s a s s o ci at e d wit h s wit c hi n g t o 
ot h er pr o d u ct s, c ert ai n tr e at m e nt s f or M S , s u c h a s l y m p h o c yt e -d e pl eti n g a g e nt s or 
l y m p h o c yt e-tr affi c ki n g bl o c k er s (e. g. , al e mt u z u m a b, n at ali z u m a b, fi n g oli m o d, di m et h yl 
f u m ar at e, c y cl o p h o s p h a mi d e, a z at hi o pri n e, et c.) ar e str o n gl y di s c o ur a g e d f or a s l o n g a s 
t h e p arti ci p a nt r e m ai n s B c ell d e pl et e d b e c a u s e of u n k n o w n eff e ct s o n t h e i m m u n e 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
9 5 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
s y st e m ( e.g. , i n cr e a s e d ri s k, i n ci d e n c e, or s e v erit y of i nf e cti o n ; s e e S e cti o n 5. 5. 2 f or 
r e c o m m e n d ati o n s o n alt er n ati v e tr e at m e nt s f or M S).
P arti c i p a nt s w h o st art tr e at m e nt wit h c o m m er ci al o cr eli z u m a b ( O C R E V U S) or a n ot her 
D M T will di s c o nti n u e fr o m t h e st u d y c o m pl et el y a n d will n ot e nt er or c o nti n u e i n t h e 
s af et y foll o w -u p p eri o d .
5. 2 3. 5 
C o nti n u e d A c c e s s t o St u d y Tr e at m e nt Aft er t h e E n d of t h e 
St u d y
T he S p o ns or will offer c o nti n ue d access t o R oc he i n vesti g ati o n al me dici n al pr o d uct
(I M P; ocreli z u m a b) free of c h ar ge t o eli gi ble p artici p a nts i n acc or d a nce wit h t he R oc he 
Gl o b al P olic y o n C o nti n ue d Access t o I n vesti g ati o n al Me dici n al Pr o d uct , as o utli ne d 
bel o w.
A p artici p a nt will be eli gi ble t o recei ve R oc he I M P ( ocreli z u m a b) after c o m pleti n g t he 
st u d y if he/s he deci des n ot t o r oll o ver t o t he ne w e xte nsi o n st u d y ( M N 4 3 9 6 4) a n d if all
of t he f oll o wi n g c o n diti o ns are met:
 
T he p artici p a nt h as a life -t hre ate ni n g or severe me dic al c o n diti o n a n d re q uires 
c o nti n ue d R oc he I M P tre at me nt f or his or her well -bei n g
 
T here are n o a p pr o pri ate alter n ati ve tre at me nts a v ail a ble t o t he p artici p a nt
 
T he p artici p a nt a n d his or her d oct or c o m pl y wit h a n d s atisf y a n y le g al or 
re g ul at or y re q uire me nts t h at a p pl y t o t he m
A p arti ci p a nt will n ot be eli gi ble t o recei ve R oc he I M P ( ocreli z u m a b) after c o m pleti n g 
t he st u d y if a n y of t he f oll o wi n g c o n diti o ns are met:
 
T he R oc he I M P is c o m merci all y m ar kete d i n t he p artici p a nt's c o u ntr y a n d is 
re as o n abl y accessi ble t o t he p artici p a nt (e. g., is c o vere d b y t he p artici p a nt's 
i ns ur a nce or w o ul d n't ot her wise cre ate a fi n a nci al h ar ds hi p f or t he p artici p a nt)
 
T he S p o ns or h as disc o nti n ue d de vel o p me nt of t he I M P or d at a s u g gest t h at t he 
I M P is n ot effecti ve f or R M S or P P M S
 
T he S p o ns or h as re as o n a ble s afet y c o ncer ns re g ar di n g t he I M P as a tre at me nt f or 
R M S or P P M S
 
Pr o visi o n of t he R oc he I M P is n ot per mitte d u n der t he l a ws a n d re g ul ati o ns of t he 
p artici p a nt's c o u ntr y
T he R oc he Gl o b al P olic y o n C o nti n ue d Access t o I n vesti g ati o n al Me dici n al Pr o d uct is 
a v ail a ble at t he f oll o wi n g we bsite:
htt ps:// w w w.r oc he.c o m/ p olic y _c o nti n ue d _ access _t o _i n vesti g ati o n al _ me dici nes. p df


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
9 6 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
6.
I N V E S TI G ATI O N A L M E DI CI N A L P R O D U C T
6. 1 
D O S E A N D S C H E D U L E O F O C R E LI Z U M A B
D uri n g t h e b li n d e d tr e at m e nt p eri o d, p arti ci p a nt s will b e r a n d o ml y a s si g n e d t o eit h er 
o cr eli z u m a b 3 0 0 m g 2 or pl a c e b o.  T h e fir st I V i nfu si o n of o cr eli z u m a b or pl a c e b o will 
b e a d mi ni st er e d o n st u d y D a y 1.
T a bl e 6 
Tr e at m e nt Gr o u p s a n d S c h e d ul e of St u d y  M e di c ati o n d uri n g t h e 
Bli n d e d Tr e at m e nt P eri o d
Tr e at m e nt Gr o u p
A s si g n e d 
Tr e at m e nt
R e gi m e n
Gr o u p A
O cr eli z u m a b 6 0 0 m g  
2 I V i nf u si o n s of o cr eli z u m a b 3 0 0 m g s e p ar at e d 
b y  1 4 d a y s
Gr o u p B
Pl a c e b o
2 I V i nf u si o n s of pl a c e b o s e p ar at e d b y 1 4 d a y s 
D uri n g t h e O L E p h a s e, all p arti ci p a nt s will r e c ei v e 2 I V i nfu si o n s of 3 0 0 m g o cr eli z u m a b 
s e p ar at e d b y 1 4 d a y s f or t h e fir st c y cl e. F or t h e s u b s e q u e nt c y cl e s, p arti ci p a nt s will 
c o nti n u e o p e n -l a b el tr e at m e nt wit h a si n gl e i nf u si o n of 6 0 0 m g o cr eli z u m a b 
e v er y 2 4 w e e k s.
T o r e d u c e p ot e nti al I R R s, all p arti ci p a nt s will r e c ei v e pr o p h yl a cti c tr e at m e nt wit h 1 0 0 m g 
m et h yl pr e d ni s ol o n e, a d mi ni st er e d
b y sl o w I V i nf u si o n, a n d a n or al or I V a nti hi st a mi n e 
( s u c h a s di p h e n h y dr a mi n e 5 0 m g or e q ui v al e nt d o s e of alt er n ati v e).
T h e m et h yl pr e d ni s ol o n e a d mi ni str ati o n i s t o b e c o m pl et e d a p pr o xi m at el y 3 0 mi n ut e s 
b ef or e t h e st art of e a c h o cr eli z u m a b i nf u si o n; a nti hi st a mi n e s s h o ul d b e a d mi ni st er e d 
3 0 6 0 mi n ut e s pri or t o t h e st art of a n i nf u si o n. 
I n p arti ci p a nt s w h er e m et h yl pr e d ni s ol o n e 
i s c o ntr ai n di c at e d, c orr e s p o n di n g d o s e s of ot h er I V st er oi d s ( e. g., d e x a m et h a s o n e) 
s h o ul d b e u s e d a s pr e m e di c ati o n ( s e e d et ail s i n S e cti o n 6. 4 ).
6. 2 
P R E P A R A TI O N A N D A D MI NI S T R A TI O N O F O C R E LI Z U M A B 
I N F U SI O N S
D et ail e d i n str u cti o n s f or t h e pr e p ar ati o n of t h e i nf u si o n b a g s c o nt ai ni n g t h e st u d y dr u g or 
pl a c e b o will b e pr o vi d e d s e p ar at el y.
6. 2. 1 
A d mi ni str ati o n of t h e I V I nf u si o n s
Alt h o u g h o cr eli z u m a b m a y b e a d mi ni st er e d o n a n o ut p ati e nt b a si s, p arti ci p a nt s m a y b e 
h o s pit ali z e d f or o b s er v ati o n at t h e di s cr eti o n of t h e in v e sti g at or (i n s o m e c o u ntri e s t hi s i s 
t h e st a n d ar d pr o c e d ur e).  T h e st u d y dr u g i nf u si o n s s h o ul d al w a y s b e a d mi ni st er e d i n a 
h o s pit al or cli ni c e n vir o n m e nt u n d er cl o s e s u p er vi si o n of t h e in v e sti g at or or a m e di c all y 
q u alifi e d st aff m e m b er wit h i m m e di at e a v ail a bilit y of f ull r e s u s cit ati o n f a ciliti e s.
O cr eli z u m a b i nf u si o n s s h o ul d b e gi v e n a s a sl o w I V i nf u si o n.  It m u st n ot b e 
a d mi ni st er e d a s a n I V p u s h or b ol u s.  W e ll-a dj u st e d i nf u si o n p u m p s s h o ul d b e u s e d t o 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
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c o ntr ol t h e i nf u si o n r at e a n d t h e st u d y dr u g s h o ul d b e i nf u s e d t hr o u g h a d e di c at e d li n e.  
It i s i m p ort a nt n ot t o u s e e v a c u at e d gl a s s c o nt ai n er s (t o pr e p ar e t h e i nf u si o n), w hi c h 
r e q uir e ve nt e d a d mi ni str ati o n s et s b e c a u s e t hi s c a u s e s f o a mi n g a s air b u b b l e s p a s s 
t hr o u g h t h e s ol uti o n.
6. 2. 1. 1 
Pr e p ar ati o n of I nf u si o n
O cr eli z u m a b dr u g pr o d u ct m u st b e dil ut e d b ef or e a d mi ni str ati o n.  S ol uti o n s of 
o cr eli z u m a b f or I V a d mi ni str ati o n ar e pr e p ar e d b y dil uti o n of  t h e dr u g pr o d u ct i nt o a n 
i nf u si o n b a g c o nt ai ni n g 0. 9 % s o di u m c hl ori d e, t o a fi n al dr u g c o n c e ntr ati o n of
a p pr o xi m at el y 1. 1 6 m g/ m L.
S p e cifi c i n str u cti o n s f or t h e pr e p ar ati o n of o cr eli z u m a b ar e 
pr o vi d e d s e p ar at el y i n t h e D o s e Pr e p ar ati o n G ui d eli n e s.
6. 2. 1. 2 
I nf u si o n Pr o c e d ur e s
All p arti ci p a nt s s h o ul d r e c ei v e pr e tr e at m e nt b ef or e t h e i nf u si o n ( s e e S e cti o n 6. 4 ).
6. 2. 1. 3 
D u al I nf u si o n Cy c l e (Bli n d e d Tr e at m e nt P eri o d a n d F ir st C y c l e 
of O p e n L a b el E xt e n si o n P h a s e )
All tr e at m e nt c y cl e s of t h e b li n d e d tr e at m e nt p eri o d a n d t h e fir st c y cl e of t h e O L E p h a s e 
will c o n si st of 2 I V i nfu si o n s of 3 0 0 m g o cr eli z u m a b a d mi ni st er e d 1 4
d a y s a p art.  
F or e a c h i nf u si o n, it i s o nl y n e c e s s ar y t o pr e p ar e a si n gl e i nf u si o n b a g 
( c o nt ai ni n g 3 0 0 m g of o cr eli z u m a b).  S p e cifi c i n str u cti o n s ar e pr o vi d e d s e p ar at el y i n t h e 
D o s e Pr e p ar ati o n G ui d eli n e s a n d m u st b e f oll o w e d e x a ctl y.
Pri or t o t h e st art of t h e i nf u si o n, pl e a s e b e s ur e t h at t h e c o nt e nt of t h e b a g s i s at r o o m 
t e m p er at ur e t o a v oi d a n i nf u si o n r e a cti o n d u e t o t h e a d mi ni str ati o n of t h e s ol uti o n at l o w 
t e m p er at ur e s.  I nf u si o n s h o ul d b e st art e d at a r at e of 3 2 m L/ h r.  T hi s s h o ul d b e 
e s c al at e d at t h e r at e s s h o w n i n T a bl e 7 .
T a bl e 7 
I nf u si o n s of O cr eli z u m a b/ Pl a c e b o 3 0 0 m g
Ti m e
( Mi n ut e s)
I nf u si o n R at e
( m L/ hr)
M a xi m u m D o s e p er 
I nt er v al ( m g)
C u m ul ati v e D o s e
( m g)
0 3 0
3 2
1 8. 7 5
1 8. 7 5
3 1 6 0
6 5
3 7. 5
5 6. 2 5
6 1 9 0
9 7
5 6. 2 5
1 1 2. 5
9 1 1 2 0
1 2 9
7 5
1 8 7. 5
1 2 1 1 5 0 a
1 9 4
1 1 2. 5
3 0 0 a
a
I nf u si o n of 3 0 0 m g o cr eli z u m a b s h o ul d b e c o m pl et e d at a p pr o xi m at el y 1 5 0 mi n ut e s 
( a p pr o xi m at el y 2. 5 h o ur s).
6. 2. 1. 4 
Si n gl e Inf u si o n C y c l e (O p e n -L a b el E xt e n si o n C y cl e 2 O n w ar d s)
C y cl e 2 a n d o n w ar d s of t h e O L E p h a s e will c o n si st of 1 I V i nfu si o n of 6 0 0 m g 
o cr eli z u m a b a d mi ni st er e d o n D a y 1 of e a c h c y cl e. F or e a c h c y cl e , it i s n e c e s s ar y t o 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
9 8 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
pr e p ar e a si n gl e i nf u si o n b a g c o nt ai ni n g a t ot al of 6 0 0 m g o cr eli z u m a b. 
S p e cifi c i n str u cti o n s f or t h e pr e p ar ati o n of o cr eli z u m a b ar e pr o vi d e d s e p ar at el y i n t h e 
D o s e Pr e p ar ati o n G ui d eli n e s a n d m u st b e f oll o w e d e x a ctl y. Inf u si o n s h o ul d b e gi n at a 
r at e of 4 0 m L/ h r a n d s h o ul d b e e s c al at e d at t h e r at e s s h o w n i n T a bl e 8 .
T a bl e 8 
I nf u si o n R at e s f or Si n gl e I nf u si o n of O cr eli z u m a b 6 0 0 m g
Ti m e
( Mi n ut e s)
I nf u si o n R at e
( m L/ hr)
M a xi m u m D o s e p er 
I nt er v al ( m g)
C u m ul ati v e D o s e
( m g)
0 3 0
4 0
2 3. 1 8
2 3. 1 8
3 1 6 0
8 5
4 9. 2 7
7 2. 4 5
6 1 9 0
1 3 0
7 5. 3 6
1 4 7. 8 1
9 1 1 2 0
1 6 9
9 8. 0 5
2 4 5. 8 6
1 2 1 2 1 5 a
2 0 0
3 5 4. 1 4 b
6 0 0. 0 0
a
I nf u si o n of 6 0 0 m g o cr eli z u m a b s h o ul d b e c o m pl et e d at a p pr o xi m at el y 2 1 5 mi n ut e s 
( a p pr o xi m at el y 3. 6 h o ur s).
b
T hi s l a st i nt er v al i s a p pr o xi m at el y 9 5 mi n ut e s, d eli v eri n g a m a xi m u m d o s e of 1 1 5. 9 4 m g  p er 
0. 5 h o ur.
6. 2. 1. 5 
Al t er n ati v e S h ort er Inf u si o n of S u b s e q u e nt 6 0 0 m g 
O cr eli z u m a b D o s e s
If p arti ci p a nt s di d n ot e x p eri e n c e a s eri o u s I R R wit h a n y pr e vi o u s o cr eli z u m a b i nf u si o n, a 
s h ort er ( 2 -h o ur) i nf u si o n of 6 0 0 m g c a n b e a d mi ni st er e d f or s u b s e q u e nt d o s e s.  
T h e s h ort er i nf u si o n s h o ul d b e st art e d at a r at e of 1 0 0 m L/ hr.  T hi s s h o ul d b e e s c al at e d 
at t h e r at e s s h o w n i n T a bl e 9 .
T a bl e 9 
Al t er n ati v e S h ort er I nf u si o n s of O cr eli z u m a b 6 0 0 m g
Ti m e
( Mi n ut e s)
I nf u si o n R at e
( m L/ hr)
M a xi m u m D o s e p er 
I nt er v al ( m g) a
C u m ul ati v e D o s e
( m g)
0 1 5
1 0 0
3 0
3 0
1 5 3 0
2 0 0
6 0
9 0
3 0 6 0
2 5 0
1 5 0
2 4 0
6 0 1 2 0 b
3 0 0
3 6 0
6 0 0
a
A s s u m e s t h at t h e i nf u si o n b a g c o nt ai n s 6 0 0 m g  o cr eli z u m a b i n 5 0 0 m L  0. 9 % s o di u m 
c hl ori d e.  R ef er t o D o s e Pr e p ar ati o n G ui d eli n e s f or m or e i nf or m ati o n.
b
T h e s h ort er i nf u si o n of 6 0 0 m g o cr eli z u m a b s h o ul d b e c o m pl et e d i n a p pr o xi m at el y 
1 2 0 mi n ut e s ( 2 h o ur s).
S e e S e cti o n 7. 3. 1. 1 a n d t h e c urr e nt v er si o n of t h e O cr eli z u m a b I B f or f urt h er d et ail s o n 
t h e alt er n ati v e s h ort er i nf u si o n o pti o n, i n cl u di n g s af et y i nf or m ati o n.
B e c a u s e of t h e p o s si bl e n e e d t o v ar y i nf u si o n r at e s d e p e n di n g o n t ol er a n c e of t h e 
i nf u si o n, t h e t ot al i nf u si o n ti m e m a y e x c e e d t h e ti m e st at e d.  Unl e s s a n i nf u si o n r e a cti o n 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
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o c c ur s n e c e s sit ati n g di s c o nti n u ati o n, t h e e ntir e c o nt e nt of i nf u si o n b a g s m u st b e 
a d mi ni st er e d t o t h e p arti ci p a nt .
Aft er c o m pl eti o n of t h e i nf u si o n, t h e I V c a n n ul a s h o ul d r e m ai n i n sit u f or at l e a st 1 h o ur 
t o all o w f or a d mi ni str ati o n of dr u g s I V, if n e c e s s ar y, i n t h e e v e nt of a d el a y e d r e a cti o n.  
If n o a d v er s e e v e nt s o c c ur d uri n g t hi s p eri o d of ti m e, t h e I V c a n n ul a m a y b e r e m o v e d 
a n d t h e p arti ci p a nt
m a y b e di s c h ar g e d.
T h e pr e p ar e d i nf u si o n s ol uti o n of o cr eli z u m a b i s p h y si c all y a n d c h e mi c all y st a bl e f or 
2 4 h o ur s at 2 – 8 C a n d s u b s e q u e ntl y 8 h o ur s at r o o m t e m p er at ur e. T h e pr e p ar e d 
i nf u si o n s ol uti o n s h o ul d b e u s e d i m m e di at el y. If n ot u s e d i mm e di at el y, it c a n b e st or e d 
u p t o 2 4 h o ur s at 2 – 8 C.
I nf u si o n s ol uti o n m u st b e c o m pl et el y a d mi ni st er e d t o t h e 
p arti ci p a nt wit hi n 3 2 h o ur s of pr e p ar ati o n ( n ot e x c e e di n g 2 4 h o u r s at 2– 8 C a n d 8 h o ur s 
at r o o m t e m p er at ur e).  I n t h e e v e nt a n I V i nf u si o n c a n n ot b e c o m pl et e d t h e s a m e d a y, 
t h e r e m ai ni n g s ol uti o n s h o ul d b e di s c ar d e d. T h e i nf u si o n s ol uti o n m u st b e a d mi ni st er e d 
wit h u s e of a n i nf u si o n s et wit h a n i n -li n e, st eril e, n o n-p yr o g e ni c, l o w -pr ot ei n -bi n di n g filt er 
( p or e si z e of u p t o 0. 2 M ). A s n ot e d a b o v e, t h e dil ut e d i nf u si o n b a g s s h o ul d b e at r o o m 
t e m p er at ur e pri or t o a d mi ni str ati o n t o t h e p arti ci p a nt .
F or f urt h er i nf or m ati o n, pl e a s e r ef er t o t h e D o s e P r e p ar ati o n G ui d eli n e s.
6. 2. 2 
O cr eli z u m a b D o s e M o difi c ati o n s, I nt err u pti o n s , a n d D el a y s
N o d o s e m o d ifi c ati o n s ar e f or e s e e n.
Sl o wi n g of t h e i nf u si o n r at e or i nt err u pti o n of t h e i nf u si o n, m a y b e n e c e s s ar y i n t h e e v e nt 
of  a n i nf u si o n r e a cti o n.  I n r ar e c a s e s, o cr eli z u m a b tr e at m e nt m a y n e e d t o b e 
di s c o nti n u e d.  G ui d a n c e i s pr o vi d e d b el o w.
6. 2. 2. 1 
H a n dli n g I nf u si o n-R el at e d R e a cti o n s
H a n dli n g of I R R s will d e p e n d o n t h e i nt e n sit y of s y m pt o m s ( s e e S e cti o n 7. 1. 1. 1 f or 
gr a di n g of i nt e n sit y of I R R s).
I n t h e e v e nt t h at a p arti ci p a nt e x p eri e n c e s a mil d t o m o d er at e ( C T C A E Gr a d e 1 or 2; 
A p p e n di x 4 ) n o n-all er gi c i nf u si o n r el at e d e v e nt, t h e i nf u si o n r at e s h o ul d b e r e d u c e d t o 
h alf t h e r at e b ei n g gi v e n at t h e ti m e of o n s et of t h e e v e nt ( e. g. , fr o m 5 0 m L/ hr t o 
2 5 m L/ hr or fr o m 1 0 0 m L/ hr t o 5 0 m L/ hr).  O n c e t h e e v e nt h a s r e s ol v e d, t h e in v e sti g at or 
s h o ul d w ait f or 3 0 mi n ut e s w hil e d eli v eri n g t h e i nf u si o n at t h e r e d u c e d r at e.  If t ol er at e d, 
t h e i nf u si o n r at e m a y t h e n b e i n cr e a s e d t o t h e n e xt cl o s e st r at e o n t h e p arti ci p a nt’ s
i nf u si o n s c h e d ul e an d t h e r at e i n cr e m e nt s r e s u m e d.
P arti ci p a nt s w h o e x p eri e n c e a s e v er e i nf u si o n -r el at e d e v e nt ( C T C A E Gr a d e 3) or a 
c o m pl e x of fl u s hi n g, f e v er , a n d t hr o at p ai n s y m pt o m s, s h o ul d h a v e t h eir i nf u si o n 
i nt err u pt e d i m m e di at el y a n d s h o ul d r e c ei v e a g gr e s si v e s y m pt o m ati c tr e at m e nt.  
T h e i nfu si o n s h o ul d b e r e -st art e d o nl y aft er all t h e s y m pt o m s h a v e di s a p p e ar e d.  


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
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T h e i niti al i nf u si o n r at e at r e st art s h o ul d b e h alf of t h e i nf u si o n r at e t h at w a s i n pr o gr e s s 
at t h e ti m e of o n s et of t h e r e a cti o n.
P arti ci p a nt s w h o e x p eri e n c e a life- t hr e at e ni n g i nf u si o n-r el at e d e v e nt ( C T C A E Gr a d e 4)
d uri n g a n i nf u si o n s h o ul d h a v e t h eir i nf u si o n i m m e di at el y st o p p e d a n d s h o ul d r e c ei v e 
a p pr o pri at e tr e at m e nt (i n cl u di n g u s e of r e s u s cit ati o n m e di c ati o n s a n d e q ui p m e nt t h at 
m u st b e a v ail a bl e a n d u s e d a s cli ni c all y i n di c at e d).  T h e s e p arti ci p a nt s will b e wit h dr a w n 
fr o m tr e at m e nt a n d s h o ul d e nt er t h e s af et y foll o w -u p p eri o d ( s e e S e cti o n 5. 1 0. 1. 4 ).
6. 2. 3 
Crit eri a f or R e -tr e at m e nt wit h O cr eli z u m a b
Pri or t o r e -tr e at m e nt wit h o cr eli z u m a b, p arti ci p a nt s will b e e v al u at e d f or t h e f oll o wi n g 
c o n diti o n s a n d l a b or at or y a b n or m aliti e s.  If a n y of t h e s e c o n diti o n s ar e pr e s e nt pri or t o 
r e-d o si n g, f urt h er a d mi ni str ati o n of o cr eli z u m a b s h o ul d b e s u s p e n d e d u ntil r e s ol v e d or 
h el d i n d efi nit el y:
 
Lif e -t hr e at e ni n g ( C T C A E Gr a d e 4) i nf u si o n-r el at e d e v e nt t h at o c c urr e d d uri n g a 
pr e vi o u s o cr eli z u m a b i nf u si o n
 
A n y si g nifi c a nt or u n c o ntr oll e d m e di c al c o n diti o n or tr e at m e nt -e m er g e nt, cli ni c all y 
si g nifi c a nt l a b or at or y a b n or m alit y
 
A cti v e i nf e cti o n (i n cl u di n g a cti v e T B i nf e cti o n, eit h er n e w o n s et or r e a cti v ati o n)
P arti ci p a nt s wit h a cti v e T B i nf e cti o n, eit h er n e w o n s et or r e a cti v ati o n, m u st s u s p e n d 
o cr eli z u m a b tr e at m e nt f or a s l o n g a s n e e d e d t o e n s ur e f ull r e s ol uti o n of t h e 
T B i nf e cti o n.  T h e s e p arti ci p a nt s s h o ul d r e c ei v e m e di c al c ar e i n a d h er e n c e wit h 
l o c al/ n ati o n al r e q uir e m e nt s u ntil c o m pl et e r e s ol uti o n of t h e T B i nf e cti o n a n d s h o ul d 
b e m o nit or e d s u b s e q u e ntl y a s p er l o c al m e di c al pl a n s.  U p o n r e s ol uti o n of t h e 
T B i nf e cti o n a n d b a s e d o n i n di vi d u al b e n efitri s k a s s e s s m e nt s, t h e s e p arti ci p a nt s
will h a v e t h e o p p ort u nit y t o r e st art o cr eli z u m a b tr e at m e nt if it i s c o n si d er e d 
b e n efi ci al f or t h e m.  Ot h er wi s e , t h e T r e ati n g I n v e sti g at or c a n d e ci d e t o p er m a n e ntl y 
st o p o cr eli z u m a b.
 
A N C 1. 5 1 0 3 /L
 
C D 4 c ell c o u nt 2 5 0/ L
 
H y p o g a m m a gl o b uli n e mi a I g G 3. 3 g/ L
 
O n g oi n g pr e g n a n c y or br e a stf e e di n g (f or f e m al e p arti ci p a nt s )
I n t h e e v e nt of pr e g n a n c y, t h e i n v e sti g at or m u st c o u n s el t h e p arti ci p a nt a s t o t h e 
ri s k s of c o nti n ui n g wit h t h e pr e g n a n c y a n d t h e p o s si bl e eff e ct s o n t h e f et u s.  
Gi v e n t h at t h er e ar e i n s uffi ci e nt, w ell-c o ntr oll e d d at a fr o m st u di e s t e sti n g t h e u s e of 
o cr eli z u m a b i n pr e g n a nt or br e a stf e e di n g w o m e n, all i nf u si o n s of o cr eli z u m a b m u st 
b e s u s p e n d e d u ntil t h e c o m pl eti o n of pr e g n a n c y a n d br e a stf e e di n g.  Pr e g n a nt a n d 
br e a stf e e di n g p arti ci p a nt s s h o ul d c o nti n u e t o f oll o w t h e s c h e d ul e of a cti viti e s f or t h e 
O L E; h o w e v er , n o i nf u si o n s of o cr eli z u m a b will o c c ur.  If t h er e i s a c o n c er n wit h t h e 
a bilit y of a pr e g n a nt or br e a stf e e di n g p arti ci p a nt t o p erf or m all s c h e d ul e d 
a s s e s s m e nt s, t h e i n v e sti g at or m u st c o nt a ct t h e M e di c al M o nit or f or f urt h er 
di s c u s si o n.  I n t h e O L E p eri o d of t h e st u d y, r e st art of o cr eli z u m a b tr e at m e nt 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 0 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
f oll o wi n g pr e g n a n c y a n d br e a stf e e di n g will b e d e ci d e d a s a r e s ult of a t h or o u g h 
b e n efit/ri s k di s c u s si o n b et w e e n t h e p arti ci p a nt a n d i n v e sti g at or.
A n y criti c al bli n d e d l a b or at or y v al u e s f or I g G, a b s ol ut e n e utr o p hil c o u nt a n d C D 4 will b e 
pr o vi d e d t o t h e Tr e ati n g I n v e sti g at or a n d t h e M e di c al M o nit or.  I n v e sti g at or s n otifi e d of 
t h eir p arti ci p a nt ’ s criti c al l a b or at or y t e st r e s ult will b e i n str u ct e d t o s u s p e n d f urt h er 
tr e at m e nt wit h st u d y dr u g u ntil t h e p arti ci p a nt c a n b e f urt h er e v al u at e d.  A r e p e at 
l a b or at or y t e st m a y b e n e c e s s ar y t o c o nfir m t h e r e s ult s.  P arti ci p a nt s wit h v al u e s b el o w 
t h e s e criti c al v al u e s s h o ul d n ot b e r e-tr e at e d u ntil t h e r e -tr e at m e nt crit eri a ar e m et a n d 
t h e s e l a b or at or y v al u e s h a v e n or m ali z e d.
I n a d diti o n, pri or t o t h e s e c o n d i nf u si o n of e a c h tr e at m e nt c y cl e p arti ci p a nt s will b e 
e v al u at e d f or t h e f oll o wi n g c o n diti o n s.  If a n y of t h e s e ar e pr e s e nt pri or t o r e -d o si n g, 
f urt h er a d mi ni str ati o n of o cr eli z u m a b s h o ul d b e s u s p e n d e d u ntil r e s ol v e d or h eld 
i n d efi nit el y: 
 
Lif e -t hr e at e ni n g ( C T C A E Gr a d e 4) i nf u si o n-r el at e d e v e nt t h at o c c urr e d d uri n g a 
pr e vi o u s o cr eli z u m a b i nf u si o n
 
A n y si g nifi c a nt or u n c o ntr oll e d m e di c al c o n diti o n or tr e at m e nt -e m er g e nt, cli ni c all y 
si g nifi c a nt l a b or at or y a b n or m alit y
 
A cti v e i nf e cti o n
6. 3 
F O R M U L A T I O N, P AC K A GI N G , A N D L A B E LI N G
T h e h o s pit al u nit s/ p h ar m a c y will r e c ei v e a st u d y m e di c ati o n kit f or e a c h p arti ci p a nt .
 
B li n d e d tr e at m e nt p eri o d: t h e st u d y m e di c ati o n kit will c o nt ai n 2 si n gl e-u s e li q ui d 
vi a l s wit h o cr eli z u m a b or pl a c e b o
 
O L E p h a s e:
e a c h st u d y m e di c ati o n kit will c o nt ai n 1 si n gl e -u s e vi al c o nt ai ni n g 
3 0 0 m g of o cr eli z u m a b.
F or O L E C y cl e 1 , c o n si sti n g of t w o 3 0 0 m g I V i nfu si o n s , th e
m e di c ati o n kit s will b e di s p e n s e d 1 4 d a y s a p art. F or O L E C y cl e 2 a n d s u b s e q u e nt 
c y cl e s , c o n si st in g of o n e 6 0 0 m g V i nfu si o n, 2 m e di c ati o n kit s ( of 3 0 0
m g 
o cr eli z u m a b e a c h) will b e di s p e n s e d.
R e -s u p pl y of st u d y m e di c ati o n p a c k a g e will b e r e q u e st e d vi a t h e I x R S.
O cr eli z u m a b i s m a n uf a ct ur e d a s a st eril e, cl e ar, c ol orl e s s, pr e s er v ati v e-fr ee li q ui d 
i nt e n d e d f or dil uti o n f or I V a d mi ni str ati o n.
O cr eli z u m a b i s s u p pli e d a s a li q ui d f or m ul ati o n c o nt ai ni n g 3 0 m g/ m L o cr eli z u m a b i n 
2 0 m M s o di u m a c et at e at p H 5. 3, wit h 4 %
( 1 0 6 m M) tr e h al o s e d e h y dr at e a n d 
0. 0 2 % p ol y s or b at e 2 0.  T h e dr u g pr o d u ct i s pr o vi d e d a s a si n gl e -u s e li q ui d f or m ul ati o n i n 
a 1 5 c c T y p e I U S P gl a s s vi al, fitt e d wit h a 2 0 m m fl u or o -r e si n l a mi n at e d st o p p er a n d a n 
al u mi n u m s e al wit h a fli p -off pl a sti c c a p a n d c o nt ai n s n o mi n al 3 0 0 m g o cr eli z u m a b .  
N o pr e s er v ati v e i s u s e d a s e a c h vi al i s d e si g n e d f or si n gl e u s e.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 0 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
O cr eli z u m a b m a y c o nt ai n fi n e tr a n sl u c e nt a n d/ or r efl e cti v e p arti cl e s a s s o ci at e d wit h 
e n h a n c e d o p al e s c e n c e.  D o n ot u s e t h e s ol uti o n if di s c ol or e d or if t h e s ol uti o n c o nt ai n s 
di s cr et e f or ei g n p arti c ul at e m att er.
O cr eli z u m a b -m at c hi n g pl a c e b o i s al s o s u p pli e d i n 1 5 c c si n gl e -u s e vi al s.  Pl a c e b o h a s 
t h e s a m e c o m p o siti o n a n d c o nfi g ur ati o n a s t h e dr u g pr o d u ct, b ut d o e s n ot c o nt ai n 
o cr eli z u m a b.  O cr eli z u m a b pl a c e b o s ol uti o n s f or I V a d mi ni str ati o n ar e pr e p ar e d b y 
dil uti o n of t h e o cr eli z u m a b pl a c e b o i nt o i nf u si o n b a g s c o nt ai ni n g 0. 9 % s o di u m c hl ori d e, 
u si n g a n i d e nti c al pr o c e d ur e a s f or t h e dr u g pr o d u ct.
F or r e c o n stit uti o n a n d a d mi ni str ati o n of m et h yl pr e d ni s ol o n e, pl e a s e r ef er t o t h e l o c al 
Pr e s cri bi n g I nf or m ati o n .
6. 3. 1  
St or a g e of O cr eli z u m a b a n d Pl a c e b o Vi al s f or I nf u si o n
O cr eli z u m a b a n d pl a c e b o vi al s ar e st a bl e at 2 8° C (r efri g er at e d st or a g e).  T h e y s h o ul d 
n ot b e u s e d b e y o n d t h e e x pir ati o n d at e st a m p e d o n t h e c art o n.  E x pir ati o n d ati n g m a y 
b e e xt e n d e d d uri n g t h e tri al; t h e S p o n s or will pr o vi d e d o c u m e nt ati o n.  O cr eli z u m a b vi al s 
s h o ul d n ot b e fr o z e n or s h a k e n a n d s h o ul d b e pr ot e ct e d fr o m dir e ct s u nli g ht.
T h e st u d y m e di c ati o n l a b el s will b e pr o d u c e d i n a c c or d a n c e wit h t h e l o c al r e q uir e m e nt s.  
T h e l a b el s will c o nt ai n t h e st u d y n u m b er, t h e m e di c ati o n n u m b er, t h e r e t e st d at e, e x pir y 
d at e, u s e b y d at e, d o si n g a n d st or a g e i n str u cti o n s.
6. 4 
P R E V E N TI O N A N D T R E A T M E N T O F I N F U SI O N -R E L A T E D 
R E A C TI O N S
M et h yl pr e d ni s ol o n e h a s b e e n s h o w n t o d e cr e a s e t h e i n ci d e n c e a n d t h e s e v erit y of 
i nf u si o n r e a cti o n s.  I n p arti ci p a nt s wit h R A tr e at e d wit h a si mil ar a g e nt, rit u xi m a b, t h e 
r at e a n d s e v erit y of i nfu si o n r e a cti o n s m ar k e dl y d e cr e a s e d wit h I V c orti c o st er oi d 
pr e -m e di c ati o n
( E m er y et al. 2 0 0 6).  A r e c e nt i nt e gr at e d a n al y si s of p arti ci p a nt s wit h M S 
tr e at e d wit h o cr eli z u m a b r e v e al e d t h at t h e a d diti o n of a nti hi st a mi n e s t o t h e pr etr e at m e nt
wit h m et h yl pr e d ni s ol o n e d e cr e a s e d t h e i n ci d e n c e of I R R s b y 2 f ol d.
T o r e d u c e p ot e nti al i nf u si o n r e a cti o n s, all p arti ci p a nt s will r e c ei v e pr o p h yl a cti c tr e at m e nt 
wit h 1 0 0 m g of m et h yl pr e d ni s ol o n e, a d mi ni st er e d b y sl o w I V i nf u si o n, a n d a n or al or 
I V a nti hi st a mi n e , s u c h a s di p h e n h y dr a mi n e 5 0
m g or e q ui v al e nt d o s e of a n alt er n ati v e.
T h e m et h yl pr e d ni s ol o n e a d mi ni str ati o n i s t o b e c o m pl et e d a p pr o xi m at el y 3 0 mi n ut e s 
b ef or e t h e st art of e a c h o cr eli z u m a b i nf u si o n ; a nti hi st a mi n e s s h o ul d b e a d mi ni st er e d 
3 0 6 0 mi n ut e s pri or t o t h e st art of a n i nf u si o n .  I n t h e r ar e c a s e w h e n t h e u s e of 
m et h yl pr e d ni s ol o n e i s c o ntr ai n di c at e d f or t h e p arti ci p a nt , u s e of a n e q ui v al e nt d o s e of 
alt er n ati v e st er oi d i s all o w e d a s pr e m e di c ati o n pri or t o t h e i nf u si o n.
It i s al s o r e c o m m e n d e d t h at t h e i nf u si o n b e a c c o m p a ni e d b y pr o p h yl a cti c tr e at m e nt wit h 
a n a n al g e si c/ a nti p yr eti c , s u c h a s a c et a mi n o p h e n/ p ar a c et a m ol ( 1 g) , 3 0 6 0 mi n ut e s pri or 
t o t h e st art of a n i nf u si o n t o r e d u c e p ot e nti al i nf u si o n r e a cti o n s.  


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 0 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
P arti ci p a nt s a d mi ni st er e d a s e d ati n g a nti hi st a mi n e f or t h e tr e at m e nt or pr e v e nti o n of 
i nf u si o n r e a cti o n s s h o ul d b e gi v e n a p pro pri at e w ar ni n g s c o n c er ni n g dr o w si n e s s a n d 
p ot e nti al i m p air m e nt of a bilit y t o dri v e or o p er at e m a c hi n er y.
Si n c e tr a n si e nt h y p ot e n si o n m a y o c c ur d uri n g o cr eli z u m a b i nf u si o n, t h e in v e sti g at or m a y 
wi s h t o wit h h ol d a nti h y p ert e n si v e m e di c ati o n s 1 2 h o ur s pri or t o o cr eli z u m a b i nf u si o n.
I nf u si o n-r el at e d r e a cti o n s s h o ul d b e tr e at e d s y m pt o m ati c all y wit h or al 
a c et a mi n o p h e n/ p ar a c et a m ol ( 1 g), a n d I M or sl o w I V a nti hi st a mi n e a d mi ni str ati o n, s u c h 
a s di p h e n h y dr a mi n e ( 2 5 m g t o 1 0 0 m g).  A c et a mi n o p h e n/ p ar a c et a m ol a n d 
di p h e n h y dr a mi n e d o si n g s h o ul d b e r e p e at e d a s cli ni c all y i n di c at e d .  N o n -all er gi c e v e nt s 
s h o ul d b e tr e at e d s y m pt o m ati c all y a s j u d g e d cli ni c all y r el e v a nt b y t h e in v e sti g at or.
I n p arti ci p a nt s wit h C T C A E Gr a d e 3 or hi g h er ( s e v er e) i nf u si o n r e a cti o n s wit h a s s o ci at e d 
r e s pir at or y s y m pt o m s ( stri d or, w h e e z e or br o n c h o s p a s m), a d diti o n al tr e at m e nt wit h 
br o n c h o dil at or s m a y b e i n di c at e d.
S e cti o n 6. 2. 2 d et ail s t h e r e d u cti o n, i nt err u pti o n or di s c o nti n u ati o n of t h e i nf u si o n i n t h e 
e v e nt of a n i nf u si o n r e a cti o n.
6. 5 
B LI N DI N G A N D U N B LI N D I N G ( F O R T H E B LI N D E D T R EA T M E N T 
P E RI O D)
T h e R a n d o mi z ati o n Li st will n ot b e a v ail a bl e t o t h e st u d y c e nt er s, m o nit or s, pr oj e ct 
s t ati sti ci a n s, or t o t h e pr oj e ct t e a m at R o c h e.  All i n di vi d u al s dir e ctl y i n v ol v e d i n t hi s 
st u d y will r e m ai n bli n d e d t o t h e tr e at m e nt a s si g n m e nt of o cr eli z u m a b or pl a c e b o o nl y 
u ntil t h e a n al y si s of t h e pri m ar y p ar a m et er at W e e k 1 2 0 or, i n t h e e v e nt a d diti o n al 
tr e at m e nt c y cl e s ar e r e q uir e d, w h e n a p pr o xi m at el y 2 5 3 c o nfir m e d di s a bilit y pr o gr e s si o n 
e v e nt s h a v e o c c urr e d.  U n bli n di n g of t h e tr e at m e nt a s si g n m e nt s h o ul d n ot o c c ur e x c e pt 
i n t h e c a s e of e mer g e n c y sit u ati o n s w h er e t h e i d e ntit y of t h e st u d y m e di c ati o n i s 
n e c e s s ar y f or p arti ci p a nt m a n a g e m e nt i n t h e c a s e of a s eri o u s a d v er s e e v e nt.  I n s u c h 
cir c u m st a n c e s, t h e sit e n e e d s t o c o nt a ct t h e I x R S f or u n bli n di n g.
E m er g e n c y c o d e s s h o ul d o nl y b e br o k e n w h e n k n o wl e d g e of t h e tr e at m e nt i s e s s e nti al 
f or t h e f urt h er e m er g e n c y m a n a g e m e nt of t h e p arti ci p a nt .  T h e P ri n ci p al I n v e sti g at or 
s h o ul d m a k e e v er y att e m pt t o c o nt a ct t h e S p o n s or b ef or e u n bli n di n g a n y p arti ci p a nt’ s
tr e at m e nt a s si g n m e nt, b ut m u st c o nt a ct t h e S p o n s or wit hi n o n e w or ki n g d a y aft er t h e 
e v e nt.
A n y r e q u e st fr o m t h e in v e sti g at or f or i nf or m ati o n a b o ut t h e o cr eli z u m a b d o s e 
a d mi ni st er e d t o st u d y p arti ci p a nt s f or a n ot h er p ur p o s e m u st b e di s c u s s e d wit h t h e 
S p o n s or.
A s p er r e g ul at or y r e p orti n g r e q uir e m e nt s, t h e S p o n s or will u n bli n d t h e i d e ntit y of t h e 
o cr eli z u m a b d o s e f or all u n e x p e ct e d s eri o u s a d v er s e e v e nt s t h at ar e c o n si d er e d b y t h e 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 0 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
in v e sti g at or t o b e r el at e d t o st u d y dr u g a s p er t h e r el e v a nt s af et y r ef er e n c e d o c u m e nt( s) 
(e. g., t h e O cr eli z u m a b I n v e sti g at or’ s Br o c h ur e).  D et ail s of o cr eli z u m a b-tr e at e d 
p arti ci p a nt s w h o ar e u n bli n d e d d uri n g t h e st u d y will b e i n cl u d e d i n t h e Cli ni c al St u d y 
R e p ort.
U n bli n di n g of t h e tr e at m e nt a s si g n m e nt f or o n g oi n g s af et y m o nit ori n g b y a n i n d e p e n d e nt
D at a M o nit ori n g C o m mitt e e ( iD M C) will b e p erf or m e d a c c or di n g t o pr o c e d ur e s i n pl a c e 
t o e n s ur e i nt e grit y of t h e d at a.  F urt h er d et ail s ar e d e s cri b e d i n t h e D M C C h art er 
( s e e S e cti o n 1 0 ).
I n or d er t o f a cilit at e a n al y si s of t h e bi ol o gi c al s a m pl e s c oll e ct e d i n t hi s st u d y, t h e 
tr e at m e nt c o d e will b e r el e a s e d t o t h e r e s p o n si bl e a n al yti c al p er s o n w h e n t h e s a m pl e s 
h a v e b e e n r e c ei v e d at t h e a n al yti c al sit e a n d ar e r e a d y f or a s s a y.  T h e r e s ult of t h e 
a n al y si s m u st n ot b e r el e a s e d wit h i n di vi d u al i d e ntifi c ati o n of t h e p arti ci p a nt u ntil aft er 
t h e i nt eri m u n bli n di n g f or t h e pri m ar y a n al y si s.
A n i n d e p e n d e nt I x R S pr o vi d er will c o n d u ct t h e p arti ci p a nt ra n d o mi z ati o n a n d h ol d t h e 
tr e at m e nt a s si g n m e nt c o d e s.
6. 6 
A S S E S S M E N T O F C O M P LI A N C E
A c c o u nt a bilit y a n d c o m pli a n c e will b e a s s e s s e d b y m ai nt ai ni n g a d e q u at e dr u g 
di s p e n si n g a n d r et ur n r e c or d s.  T h e p h ar m a ci st s s h o ul d k e e p all dr u g vi al s t o m e a s ur e 
c o m pli a n c e.
A D r u g Di s p e n si n g L o g m u st b e k e pt c urr e nt a n d s h o ul d c o nt ai n t h e f oll o wi n g 
i nf or m ati o n:
 
T h e i d e ntifi c ati o n of t h e p arti ci p a nt t o w h o m t h e st u d y m e di c ati o n w a s di s p e n s e d
 
T h e d at e( s) , q u a ntit y of t h e st u d y m e di c ati o n di s p e n s e d
T hi s i n v e nt or y m u st b e a v ail a bl e f or i n s p e cti o n b y t h e M o nit or.  All s u p pli e s, i n cl u di n g 
p arti all y u s e d or e m pt y vi al s a n d t h e di s p e n si n g l o g s, m u st b e a v ail a bl e f or t h e M o nit or 
t o c o n d u ct dr u g a c c o u nt a bilit y.
6. 7 
D E S T R U C TI O N O F T H E I N V E S TI G A TI O N A L M E DI C I N AL 
P R O D U C T
L o c al or i n stit uti o n al r e g ul ati o n s m a y r e q uir e i m m e di at e d e str u cti o n of u s e d I MP f or 
s af et y r e a s o n s.  I n t h e s e c a s e s, it m a y b e a c c e pt a bl e f or i n v e sti g ati o n al sit e st aff t o 
d e str o y di s p e n s e d I M P b ef or e a m o nit ori n g i n s p e cti o n pr o vi d e d t h at s o ur c e d o c u m e nt 
v erifi c ati o n i s p erf or m e d o n t h e r e m ai ni n g i n v e nt or y a n d r e c o n cil e d a g ai n st t h e 
d o c u m e nt ati o n of q u a ntit y s hi p p e d, di s p e n s e d, r et ur n e d a n d d e str o y e d.  Writt e n 
a ut h ori z ati o n m u st b e o bt ai n e d fr o m t h e S p o n s or at st u d y st art -u p b ef or e d e str u cti o n.


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Wr itt e n d o c u m e nt ati o n of d e str u cti o n m u st c o nt ai n t h e f oll o wi n g:
 
I d e ntit y ( b at c h n u m b er s or m e di c ati o n n u m b er s) of I M P a n d c o m p ar at or s d e str o y e d
 
Q u a ntit y of I M P d e str o y e d
 
D at e of d e str u cti o n
 
M et h o d of d e str u cti o n
 
N a m e a n d si g n at ur e of r e s p o n si bl e p er s o n w h o d e str o y e d t h e I M P.
W h er e v er p o s si bl e, dr u g s h o ul d b e d e str o y e d l o c all y o n sit e a c c or di n g t o t h eir l o c al 
p oli ci e s a n d pr o c e d ur e s o n c e dr u g a c c o u nt a bilit y h a s b e e n c o m pl et e d.
7.
S A F E T Y I N S T R U C TI O N S A N D G UI D A N C E
7. 1 
A D V E R S E E V E N T S A N D L A B O R A T O R Y A B N O R M A LI TI E S
7. 1. 1 
Cli ni c al A d v er s e E v e nt s
A c c or di n g t o t h e I nt er n ati o n al C o nf er e n c e of H ar m o ni s ati o n (I C H), a n a d v er s e e v e nt i s 
a n y u nt o w ar d m e di c al o c c urr e n c e i n a p arti ci p a nt or cli ni c al i n v e sti g ati o n p arti ci p a nt
a d mi ni st er e d a p h ar m a c e uti c al pr o d u ct a n d w hi c h d o e s n ot n e c e s s aril y h a v e a c a u s al 
r el ati o n s hi p wit h t hi s tr e at m e nt.  A n a d v er s e e v e nt c a n , t h er ef or e, b e a n y u nf a v or a bl e 
a n d u ni nt e n d e d si g n, i n cl u di n g a n a b n or m al l a b or at or y fi n di n g, s y m pt o m, or di s e a s e 
t em p or all y a s s o ci at e d wit h t h e u s e of a (i n v e sti g ati o n al) m e di ci n al pr o d u ct, w h et h er or 
n ot c o n si d er e d r el at e d t o t h e m e di ci n al (i n v e sti g ati o n al) pr o d u ct.  Pr e e xi sti n g c o n diti o n s 
w h i c h w or s e n d uri n g a st u d y ar e t o b e r e p ort e d a s a d v er s e e v e nt s .
I n t h e e C R F, a d v er s e e v e nt s w ill b e r e p ort e d at e a c h vi sit.
Cli ni c al r el a p s e s will b e r e c or d e d o nl y o n a pr e -s p e cifi e d “M S R el a p s e” e C R F.
I nf u si o n-r el at e d r e a cti o n s will b e r e c or d e d o nl y o n a pr e -s p e cifi e d “I nf u si o n -R el at e d 
R e a cti o n” e C R F .
B c ell d e pl eti o n i s t h e e x p e c t e d o ut c o m e of o cr eli z u m a b tr e at m e nt a n d i s n ot a n a d v er s e 
e v e nt.  H o w e v er, p arti ci p a nt s m a y b e at ri s k f or i nf e cti o n s a n d p arti c ul ar att e nti o n s h o ul d 
b e dir e ct e d t o w ar d e arl y i d e ntifi c ati o n a n d tr e at m e nt of i nf e cti o n s .  D uri n g t h e st u d y, 
in v e sti g at or s ar e r e q u e st e d t o pr o m ptl y i n v e sti g at e p arti ci p a nt s r e p orti n g si g n s or 
s y m pt o m s of i nf e cti o n, t o t a k e a p pr o pri at e s p e ci m e n s f or i d e ntifi c ati o n of t h e p at h o g e n 
a n d t o tr e at i nf e cti o n s a g gr e s si v el y ( s e e S e cti o n 7. 3. 1 ).  Pri or t o e nr oll m e nt i nt o t h e 
st u d y, it i s r e c o m m e n d e d t h at t h e I n v e sti g at or r e vi e w a n d, if w arr a nt e d, u p d at e e a c h 
p arti ci p a nt’ s i m m u ni z ati o n s i n a c c or d a n c e wit h c o u ntr y m e di c al i m m u ni z ati o n g ui d eli n e s 
( s e e S e cti o n 5. 5. 3 ).


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7. 1. 1. 1 
I nt e n sit y
A d v er s e e v e nt s will b e gr a d e d a c c or di n g t o N ati o n al C a n c er I n stit ut e C T C A E v 4 a n d i s 
pr o vi d e d t o t h e i n v e sti g at or i n a s e p ar at e h a n d o ut e ntitl e d “ C o m m o n T er mi n ol o g y 
Crit eri a f or A d v er s e E v e nt s v 4. 0” ( A p p e n di x 4 ).
A d v er s e e v e nt s n ot li st e d b y t h e C T C A E will b e gr a d e d wit h u s e of t h e f oll o wi n g crit eri a:
 
Gr a d e 1: d i s c o mf ort n oti c e d b ut n o di sr u pti o n of n or m al d ail y a cti vit y
 
Gr a d e 2: d i s c o mf ort s uffi ci e nt t o r e d u c e or aff e ct n or m al d ail y a cti vit y
 
Gr a d e 3:
in a bilit y t o w or k or p erf or m n or m al d ail y a cti vit y
 
Gr a d e 4: re pr e s e nt s a n i m m e di at e t hr e at t o lif e
A n y Gr a d e 4 a d v er s e e v e nt , eit h er b y C T C A E crit eri a or t h e a d diti o n al crit eri a li st e d 
a b o v e, s h o ul d b e r e p ort e d a s a n s eri o u s a d v er s e e v e nt ( S e cti o n 7. 2. 2 ).
7. 1. 1. 2 
Dr u g A d v er s e E v e nt R el ati o n s hi p
R el ati o n s hi p of t h e a d v er s e e v e nt t o t h e tr e at m e nt s h o ul d al w a y s b e a s s e s s e d b y t h e 
in v e sti g a t or.  D e s cri pti o n of s c al e s c a n b e f o u n d i n A p p e n di x 2 .
7. 1. 1. 3 
S eri o u s A d v er s e E v e nt s (I m m e di at el y  R e p ort a bl e t o S p o n s or)
A s eri o u s a d v er s e e v e nt i s a n y e x p eri e n c e t h at s u g g e st s a si g nifi c a nt h a z ar d, 
c o ntr ai n di c ati o n, si d e eff e ct or pr e c a uti o n.  It i s a n y a d v er s e e v e nt t h at, at a n y d o s e, 
f ulfil s at l e a st 1 of t h e f oll o wi n g crit eri a:
 
I s f at al (r e s ult s i n d e at h; N O T E: d e at h i s a n o ut c o m e, n ot a n e v e nt )
T h e t er m “s u d d e n d e at h ” s h o ul d o nl y b e u s e d w h e n t h e c a u s e i s of a c ar di a c ori gi n 
a s p er st a n d ar d d efi niti o n.  T h e t er m s “d e at h ” a n d “s u d d e n d e at h ” ar e cl e arl y di sti n ct 
a n d m u st n ot b e u s e d i nt er c h a n g e a bl y.
 
I s life-t hr e at e ni n g (N O T E:
t h e t er m “life-t hr e at e ni n g” r ef er s t o a n e v e nt i n w hi c h t h e 
p arti ci p a nt w a s at i m m e di at e ri s k of d e at h at t h e ti m e of t h e e v e nt; it d o e s n ot r ef er 
t o a n e v e nt w hi c h c o ul d h y p ot h eti c all y h a v e c a u s e d a d e at h h a d it b e e n m or e 
s e v er e )
 
R e q uir e d i n -p arti ci p a nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n
 
R e s ult s i n p er si st e nt or si g nifi c a nt di s a bilit y/i n c a p a cit y
 
I s a c o n g e nit al a n o m al y/ birt h d ef e ct
 
I s m e di c all y si g nifi c a nt or r e q uir e s i nt er v e nti o n t o pr e v e nt o n e or ot h er of t h e 
o ut c o m e s li st e d a b o v e
D e at h s h o ul d b e c o n si d er e d a n o ut c o m e a n d n ot a di sti n ct e v e nt.  T h e e v e nt or 
c o n diti o n t h at c a u s e d or c o ntri b ut e d t o t h e f at al o ut c o m e s h o ul d b e r e c or d e d a s t h e 
si n gl e m e di c al c o n c e pt o n t h e A d v er s e E v e nt e C R F.  G e n er all y, o nl y 1 s u c h e v e nt 
s h o ul d b e r e p ort e d.  If t h e c a u s e of d e at h i s u n k n o w n a n d c a n n ot b e a s c ert ai n e d at 
t h e ti m e of r e p orti n g, " u n e x pl ai n e d d e at h " s h o ul d b e r e c or d e d o n t h e 
A d v er s e E v e nt e C R F.  If t h e c a u s e of d e at h l at er b e c o m e s a v ail a bl e 
( e. g., aft er a ut o p s y), " u n e x pl ai n e d d e at h" s h o ul d b e r e pl a c e d b y t h e e st a bli s h e d 


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c a u s e of d e at h.  T h e t er m " s u d d e n d e at h " s h o ul d n ot b e u s e d u nl e s s c o m bi n e d 
wit h t h e pr e s u m e d c a u s e of d e at h ( e. g., " s u d d e n c ar di a c d e at h").
F or a li st of s eri o u s a d v er s e dr u g r e a cti o n s t h at ar e c o n si d er e d e x p e ct e d, r ef er t o t h e 
c urr e nt O cr el i z um a b
I n v e sti g at or’ s Br o c h ur e.
T h e st u d y will c o m pl y wit h all l o c al r e g ul at or y r e q uir e m e nt s a n d will a d h er e t o t h e f ull 
r e q uir e m e nt s of t h e I C H G ui d eli n e f or Cli ni c al S af et y D at a M a n a g e m e nt, D efi niti o n s a n d 
St a n d ar d s f or E x p e dit e d R e p orti n g, T o pi c E 2 ( s e e A p p e n di x 3 ).
7. 1. 1. 4 
A d v er s e E v e nt s of S p e ci al I nt er e st (I m m e di at el y  R e p ort a bl e t o 
S p o n s or)
A d v er s e e v e nt s of s p e ci al i nt er e st ar e r e q uir e d t o b e r e p ort e d b y t h e in v e sti g at or t o t h e 
S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4 h o ur s aft er l e ar ni n g of t h e e v e nt; 
s e e S e cti o n 7. 2. 2 f or r e p orti n g i n str u cti o n s).  C o m p a n y m a n d at e d a d v er s e e v e nt s of 
s p e ci al i nt er e st i n cl u d e t h e f oll o wi n g:
 
C a s e s of p ot e nti al dr u g -i n d u c e d li v er i nj ur y t h at i n cl u d e a n el e v at e d A L T or A S T i n 
c o m bi n ati o n wit h eit h er a n el e v at e d bilir u bi n or cli ni c al j a u n di c e, a s d efi n e d b y 
H y’ s l a w ( s e e S e cti o n 7. 1. 3. 1 )
 
S u s p e ct e d tr a n s mi s si o n of  a n i nf e cti o u s a g e nt b y t h e st u d y dr u g, a s d efi n e d b el o w
A n y or g a ni s m, vir u s, or i nf e cti o u s p arti cl e ( e. g., pri o n pr ot ei n -tr a n s mitti n g 
tr a n s mi s si bl e s p o n gif or m e n c e p h al o p at h y), p at h o g e ni c or n o n-p at h o g e ni c, i s 
c o n si d er e d a n i nf e cti o u s a g e nt.
Tr a n s mi s si o n of a n i nf e cti o u s a g e nt m a y b e s u s p e ct e d fr o m cli ni c al s y m pt o m s or 
l a b or at or y fi n di n g s t h at i n di c at e a n i nf e cti o n i n a p arti ci p a nt e x p o s e d t o a m e di ci n al 
pr o d u ct.  T hi s t er m a p pli e s o nl y w h e n a c o nt a mi n ati o n of t h e st u d y dr u g i s s u s p e ct e d.
7. 1. 2 
Tr e at m e nt a n d F oll o w -U p of A d v er s e E v e nt s
A d v er s e e v e nt s s h o ul d b e f oll o w e d u p u ntil t h e y h a v e st a bili z e d or h a v e r et ur n e d t o 
b a s eli n e st at u s (i n t h e e v e nt of a n e x a c er b ati o n of a pr e e xi sti n g c o n diti o n).  T hi s i s 
e s p e ci all y i m p ort a nt f or t h o s e e v e nt s w h er e t h e r e p ort e d c a u s al r el ati o n s hi p t o st u d y 
m e di c ati o n( s) i s
“r el at e d”.  If a cl e ar e x pl a n ati o n i s e st a bli s h e d, it s h o ul d b e r e c or d e d o n 
t h e e C R F.
If aft er st u d y c o m pl eti o n or wit h dr a w al, r et ur n t o b a s eli n e st at u s or st a bili z ati o n c a n n ot 
b e e st a bli s h e d a n e x pl a n ati o n s h o ul d b e r e c or d e d o n t h e e C R F.
7. 1. 3 
L a b or at or y  T e st A b n or m aliti e s
L a b or at or y t e st r e s ult s will b e r e c or d e d o n t h e l a b or at or y r e s ult s s e cti o n of t h e e C R F, or 
a p p e ar o n el e ctr o ni c all y pr o d u c e d l a b or at or y r e p ort s s u b mitt e d dir e ctl y fr o m t h e c e ntr al 
l a b or at or y, if a p plic a bl e.


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A n y tr e at m e nt -e m er g e nt a b n or m al l a b or at or y r e s ult w hi c h i s cli ni c all y si g nifi c a nt, 
i. e., m e eti n g 1 or m or e of t h e f oll o wi n g c o n diti o n s, s h o ul d b e r e c or d e d a s a si n gl e 
di a g n o si s o n t h e A d v er s e E v e nt e C R F:
 
A c c o m p a ni e d b y cli ni c al s y m pt o m s
 
L e a di n g t o a c h a n g e i n st u d y m e di c ati o n ( e. g., d o s e m o difi c ati o n, i nt err u pti o n or 
p er m a n e nt di s c o nti n u ati o n)
 
R e q uiri n g a c h a n g e i n c o n c o mit a nt t h er a p y ( e. g. , a d diti o n of, i nt err u pti o n of , 
di s c o nti n u ati o n of, or a n y ot h er c h a n g e i n a c o n c o mit a nt m e di c ati o n, t h er a p y or 
tr e at m e nt)
A n y l a b or at or y r e s ult a b n or m alit y f ulfilli n g t h e crit eri a f or a s eri o u s a d v er s e e v e nt s h o ul d 
b e r e p ort e d a s s u c h, i n a d diti o n t o b ei n g r e c or d e d a s a n a d v er s e e v e n t i n t h e e C R F.
7. 1. 3. 1 
A b n or m al Li v er F u n cti o n T e st s
T h e fi n d i n g of a n el e v at e d A L T or A S T (3 U L N) i n c o m bi n ati o n wit h eit h e r a n el e v at e d 
t ot al bilir u bi n (2 U L N) or cli ni c al j a u n di c e i n t h e a b s e n c e of c h ol e st a si s or ot h er 
c a u s e s of h y p er bilir u bi n e mi a i s c o n si d er e d t o b e a n i n di c at or of s e v er e li v er i nj ur y.  
T h er ef or e, in v e sti g at or s m u st r e p ort a s a n a d v er s e e v e nt t h e o c c urr e n c e of eit h er of t h e 
f oll o wi n g:
 
Tr e a t m e nt-e m er g e nt A L T or A S T 3 U L N i n c o m bi n ati o n wit h t ot al bilir u bi n 
2 U L N
 
Tr e at m e nt -e m er g e nt A L T or A S T 3 U L N i n c o m b i n ati o n wit h cli ni c al j a u n di c e
T h e m o st a p pr o pri at e di a g n o si s or (if a di a g n o si s c a n n ot b e e st a bli s h e d) t h e a b n or m al 
l a b or at or y v al u e s s h o ul d b e r e c or d e d o n t h e A d v er s e E v e nt e C R F ( s e e S e cti o n 7. 1. 1 ) 
a n d r e p ort e d t o t h e S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4
h o ur s aft er l e ar ni n g of 
t h e e v e nt), eit h er a s a s eri o u s a d v er s e e v e nt or a n o n-s eri o u s a d v er s e e v e nt of s p e ci al 
i nt er e st ( s e e S e cti o n 7. 1. 1. 3 a n d S e cti o n 7. 1. 1. 4 ).
7. 1. 3. 2 
F oll o w - Up of A b n or m al L a b or at or y  T e st V al u e s
I n t h e e v e nt of m e di c all y si g nifi c a nt u n e x pl ai n e d a b n or m al l a b or at or y t e st v al u e s, t h e 
t e st s s h o ul d b e r e p e at e d a n d f oll o w e d u p u ntil t h e y h a v e r et ur n e d t o t h e n or m al r a n g e 
a n d/ or a n a d e q u at e e x pl a n ati o n of t h e a b n or m alit y i s f o u n d.  If a cl e ar e x pl a n ati o n i s 
e st a bli s h e d it s h o ul d b e r e c or d e d o n t h e e C R F.
B c ell d e pl eti o n i s a P D eff e c t a n d i s n ot a n a d v er s e e v e nt.
D uri n g t h e b li n d e d tr e at m e nt p eri o d , bli n d e d l a b or at or y v al u e s f or I g G, A N C a n d C D 4 ,
w h i c h ar e criti c al will b e pr o vi d e d t o t h e in v e sti g at or a n d t h e M e di c al M o nit or.  
I n v e sti g at or s n otifi e d of t h eir p arti ci p a nt’ s criti c al l a b or at or y t e st r e s ult will b e i n str u ct e d 
t o s u s p e n d f urt h er tr e at m e nt wit h st u d y dr u g u ntil t h e p arti ci p a nt c a n b e f urt h er 
e v al u at e d.  A r e p e at l a b or at or y t e st m a y b e n e c e s s ar y t o c o nfir m t h e r e s ult s.  
P arti ci p a nt s wit h v al u e s b el o w t h e s e criti c al v al u e s s h o ul d n ot b e r e -tr e at e d u ntil t h e 


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r e-tr e at m e nt crit eri a ar e m et ( S e cti o n 6. 2. 3 ) a n d t h e s e l a b or at or y v al u e s h a v e 
n or m ali z e d.   D uri n g t h e O L E p h a s e, t h e s e l a b or at or y v al u e s will n ot b e bli n d e d.
7. 2 
H A N D LI N G O F S A F E T Y P A R A M E T E R S
7. 2. 1 
R e p orti n g of A d v er s e E v e nt s
All a d v er s e e v e nt s will b e d o c u m e nt e d i n t h e e C R F.
N e w or w or s e ni n g n e ur ol o gi c al s y m pt o m s n ot c o n si d er e d M S r el at e d s h o ul d b e 
r e c or d e d o n a n A d v er s e E v e nt e C R F a n d t h e m o nit or s h o ul d b e i nf or m e d.
7. 2. 2 
R e p orti n g of S eri o u s A d v er s e E v e nt s
7. 2. 2. 1 
I m m e di at e R e p orti n g R e q uir e m e nt s t o t h e S p o n s or
A n y cli ni c al a d v er s e e v e nt or a b n or m al l a b or at or y t e st v al u e t h at i s s eri o u s (a s d efi n e d i n 
S e cti o n 7. 1. 1. 3 ) a n d w hi c h o c c ur s d uri n g t h e c o ur s e of t h e st u d y, r e g ar dl e s s of t h e 
tr e at m e nt gr o u p, m u st b e r e p ort e d t o t h e S p o n s or wit hi n 2 4 h o ur s of t h e in v e sti g at or 
b e c o mi n g a w ar e of t h e e v e nt ( e x p e dit e d r e p orti n g).  I n a d diti o n, f or f at al a n d 
lif e-t hr e at e ni n g e v e nt s, t h e R o c h e M e di c al M o nit or s h o ul d b e c o nt a ct e d i m m e di at el y.  
C o nt a ct n u m b er s f or t h e R o c h e M e di c al M o nit or (i n cl u di n g aft er h o ur s c o v er) will b e 
pr o vi d e d t o t h e sit e b ef or e a n y p arti ci p a nt s ar e s cr e e n e d.
N ot e:  a ft er i nf or m e d c o n s e nt, b ut pri or t o i niti ati o n of st u d y m e di c ati o n s, o nl y s eri o u s 
a d v er s e e v e nt s c a u s e d b y a pr ot o c ol -m a n d at e d i nt er v e nti o n will b e c oll e ct e d 
( e. g., s eri o u s a d v er s e e v e nt s r el at e d t o i n v a si v e pr o c e d ur e s s u c h a s bi o p si e s, 
m e di c ati o n w a s h o ut, or n o tr e at m e nt r u n -i n).
T h e in v e sti g at or m u st c o m pl et e t h e S eri o u s A d v er s e E v e nt R e p orti n g F or m i n t h e e C R F.  
R el e v a nt f oll o w -u p i nf or m ati o n s h o ul d b e s u b mitt e d a s s o o n a s it b e c o m e s a v ail a bl e.  
O nl y if a t e c h ni c al f ail ur e pr e v e nt s t h e a bilit y t o r e p ort a n s eri o u s a d v er s e e v e nt i n t h e 
e C R F, t h e n t h e p a p er S eri o u s A d v er s e E v e nt R e p orti n g F or m pr o vi d e d b y t h e S p o n s or 
m u st b e c o m pl et e d a n d
f a x e d t o t h e n u m b er pr o vi d e d.
R el at e d s eri o u s a d v er s e e v e nt s M U S T
b e c oll e ct e d a n d r e p ort e d r e g ar dl e s s of t h e ti m e 
el a p s e d fr o m t h e l a st st u d y dr u g a d mi ni str ati o n, e v e n if t h e st u d y h a s b e e n cl o s e d.
U nr el at e d s eri o u s a d v er s e e v e nt s m u st b e c oll e ct e d a n d r e p ort e d d uri n g t h e st u d y 
t hr o u g h t h e e n d of t h e s af et y foll o w - up p eri o d, w hi c h i s u p t o 4 8 w e e k s aft er t h e l a st 
i nf u si o n.
N o n -s eri o u s a d v er s e e v e nt s m u st b e r e p ort e d u ntil t h e e n d of t h e s af et y foll o w -u p
p eri o d .
A d e at h o c c urri n g d uri n g t h e st u d y or i nf or m ati o n r el at e d t o s u c h o c c urr e n c e w hi c h 
c o m e s t o t h e att e nti o n of t h e in v e sti g at or d uri n g t h e st u d y m u st b e r e p ort e d, w h et h er 




O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 1 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
7. 2. 2. 3 
E x p e dit e d R e p orti n g t o H e alt h A ut h oriti e s, I n v e sti g at or s, 
I n stit uti o n al R e vi e w B o ar d s, a n d Et hi c s C o m mitt e e s
T h e S p o n s or will pr o m ptl y e v al u at e all r e p ort e d s eri o u s a d v er s e e v e nt s a g ai n st 
c u m ul ati v e pr o d u ct e x p eri e n c e t o i d e ntif y a n d e x p e diti o u sl y c o m m u ni c at e p o s si bl e n e w 
s af et y fi n di n g s t o in v e sti g at or s, I R B s, E C s, a n d r el e v a nt h e alt h a ut h oriti e s b a s e d o n 
a p pli c a bl e l e gi sl ati o n.
R e p orti n g r e q uir e m e nt s will b e b a s e d o n t h e in v e sti g at or’ s a s s e s s m e nt of c a u s alit y a n d 
s eri o u s n e s s, wit h all o w a n c e f or u p gr a di n g b y t h e S p o n s or a s n e e d e d.  T o d et er mi n e 
r e p orti n g r e q uir e m e nt s f or si n gl e a d v er s e e v e nt c a s e s, t h e S p o n s or will al s o a s s e s s t h e 
e x p e ct e d n e s s of t h e e v e nt o n t h e b a si s of t h e c urr e nt O cr eli z u m a b
I n v e sti g at or’ s Br o c h ur e.
I n pri n ci pl e, a d v er s e e v e nt s t h at ar e s eri o u s, r el at e d, a n d u n e x p e ct e d will b e r e p ort e d i n 
a n e x p e dit e d m a n n er wit hi n 1 5 d a y s ( n o n -f at al/ n o n-lif e-t hr e at e ni n g) or 7 d a y s (f at al or 
lif e-t hr e at e ni n g).
O nl y t h o s e a d v er s e e v e nt s q u alif yi n g f or e x p e dit e d r e p orti n g o c c urri n g i n p arti ci p a nt s o n 
a cti v e tr e at m e nt will b e s e nt i n a n e x p e dit e d ti m efr a m e t o h e alt h a ut h oriti e s, 
in v e sti g at or s, I R B s, a n d E C s.  T hi s r e q uir e s u n bli n di n g of p arti ci p a nt tr e at m e nt 
all o c ati o n.  I n v e sti g at or s, I R B s, a n d E C s will r e c ei v e r e p ort s u nl e s s l o c al r e g ul ati o n s 
r e q uir e t h at u n bli n d e d e x p e dit e d r e p ort s ar e s e nt.
T h e D M C will r e vi e w a d v er s e e v e nt s at e a c h q u art erl y m e eti n g a n d a s s e s s t h eir r el ati o n 
t o st u d y m e di c ati o n b a s e d o n r e vi e w of a g gr e g at e u n bli n d e d s af et y i nf orm ati o n
u ntil t h e 
pri m ar y a n al y si s i s p erf or m e d . F oll o wi n g u n bli n di n g, i D M C i n v ol v e m e nt i n s af et y 
m o nit ori n g t hr o u g h o ut t h e O L E p h a s e i s n o l o n g er n e e d e d.
7. 2. 3 
Pr e g n a n c y  a n d L a ct ati o n
I n t h e O L E p h a s e of t h e st u d y , f em al e p arti ci p a nt s s h o ul d t a k e all a p pr o pri at e 
pr e c a uti o n s t o a v oi d b e c o mi n g pr e g n a nt . 
Wo m e n of c hil d b e ari n g p ot e nti al m u st u s e t h e 
m et h o d
of c o ntr a c e pti o n d ef i n e d b y t h e pr ot o c ol ( s e e S e cti o n 5. 4 ) f or t h e d ur ati o n of t h e 
tri al a n d f or 6 m o nt h s aft er r e c ei vi n g t h eir l a st i nf u si o n of o cr eli z u m a b .  
R e g ul ar pr e g n a n c y t e st s will b e p erf or m e d d uri n g t h e st u d y.
R e pr o d u cti v e t o xi c ol o g y st u di e s of o cr eli z u m a b c o n d u ct e d i n c y n o m ol g u s m o n k e y s ar e 
d e s cri b e d i n t h e O cr eli z u m a b I n v e sti g at or’ s Br o c h ur e .  St u di e s of t h e eff e ct of 
o cr eli z u m a b o n h u m a n r e pr o d u cti o n h a v e n ot b e e n p erf or m e d.  It i s n ot k n o w n w h et h er 
o cr eli z u m a b c a n c a u s e f et al h ar m w h e n a d mi ni st er e d t o pr e g n a nt w o m e n or w h et h er it 
c a n aff e ct r e pr o d u cti v e c a p a cit y.  H o w e v er, si n c e I g G m ol e c ul e s s u c h a s o cr eli z u m a b 
ar e k n o w n t o cr o s s t h e pl a c e nt a, o cr eli z u m a b m a y c a u s e f et al C D 2 0 B c ell d e pl eti o n.
B e c a u s e pr e g n a n c y i n d u c e s a n at ur al st at e of i m m u n o s u p pr e s si o n, it i s u n k n o w n 
w h et h er pr e g n a n c y i n c o m bi n ati o n wit h o cr eli z u m a b e x p o s ur e m a y c a u s e a m or e 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 1 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
pr of o u n d st at e of i m m u n o s u p pr e s si o n ( Br a n c h 1 9 9 2). It i s al s o u n k n o w n w h et h er 
o cr eli z u m a b i s e x cr et e d i n br e a st mil k, a n d w h at eff e ct t hi s mi g ht h a v e o n t h e 
br e a stf e e di n g i nf a nt.  H o w e v er, it s h o ul d b e n ot e d t h at I g s ar e f o u n d i n br e a st mil k .
R e g ar dl e s s of t h e tr e at m e nt s h e i s r e c ei vi n g, a f e m al e p arti ci p a nt m u st b e i n str u ct e d t o 
i m m e di at el y i nf or m t h e i nv e sti g at or if s h e b e c o m e s pr e g n a nt d uri n g t h e st u d y 
(i n cl u di n g t h e s af et y foll o w -u p p eri o d).  I n t h e e v e nt of pr e g n a n c y, t h e in v e sti g at or m u st 
c o u n s el t h e p arti ci p a nt a s t o t h e ri s k s of c o nti n ui n g wit h t h e pr e g n a n c y a n d t o t h e 
p o s si bl e eff e ct s o n t h e f et u s. Gi v e n t h er e ar e i n s uffi ci e nt, w ell -c o ntr oll e d d at a fr o m 
st u di e s t e sti n g t h e u s e of o cr eli z u m a b i n pr e g n a nt or br e a stf e e di n g w o m e n, all i nf u si o n s 
of  o cr eli z u m a b m u st b e s u s p e n d e d u ntil t h e e n d of pr e g n a n c y a n d br e a stf e e di n g.
Pr e g n a nt a n d br e a stf e e di n g p arti ci p a nt s s h o ul d c o nti n u e t o f oll o w t h e s c h e d ul e of 
a cti viti e s f or t h e O L E p h a s e; h o w e v er , n o i nf u si o n s will o c c ur. If t h er e i s a c o n c er n wit h 
t h e a bilit y of a pr e g n a nt or br e a stf e e di n g p arti ci p a nt t o p erf or m all s c h e d ul e d 
a s s e s s m e nt s , or if a n a s s e s s m e nt i s c o ntr ai n di c at e d d uri n g pr e g n a n c y, t h e in v e sti g at or 
m u st c o nt a ct t h e M e di c al M o nit or f or f urt h er di s c u s si o n. 
R e st art of o cr eli z u m a b 
tr e at m e nt f oll o wi n g pr e g n a n c y a n d br e a stf e e di n g will b e d e ci d e d a s a r e s ult of a 
t h or o u g h b e n efit ri s k di s c u s si o n b et w e e n t h e p arti ci p a nt a n d in v e sti g at or.
T h e in v e sti g at or s h o ul d r e p ort all pr e g n a n ci e s wit hi n 2 4 h o ur s t o t h e S p o n s or b y m e a n s 
of  a n e C R F Pr e g n a n c y R e p orti n g F or m.  T h e sit e s h o ul d c o nti n u e t o m o nit or t h e 
p arti ci p a nt’ s pr e g n a n c y a n d e nt er t h e f oll o wi n g i nf or m ati o n i n t h e e C R F P r e g n a n c y 
R e p orti n g F or m:
t h e o ut c o m e of t h e pr e g n a n c y (i n cl u di n g s p o nt a n e o u s or v ol u nt ar y 
a b orti o n s), t h e d et ail s of t h e birt h, t h e pr e s e n c e or a b s e n c e of birt h d ef e ct s or c o n g e nit al 
a b n or m aliti e s, a n d a n y ot h er m at er n al or n e w b or n c o m pli c ati o n s.
B a bi e s b or n t o 
m ot h er s p arti ci p ati n g i n t hi s st u d y s h o ul d h a v e a n a s s e s s m e nt of t h eir l y m p h o c yt e 
c o u nt s a n d b e c ar ef ull y f oll o w e d u ntil t h e s e ar e wit hi n t h e n or m al r a n g e f or t h e a g e of 
t h e i nf a nt.
A s p o n t a n e o u s a b orti o n s h o ul d b e cl a s sifi e d a s a s eri o u s a d v er s e e v e nt ( a s t h e S p o n s or 
c o n si d er s a b orti o n s t o b e m e di c all y si g nifi c a nt), r e c or d e d o n t h e A d v er s e E v e nt e C R F, 
a n d r e p ort e d t o t h e S p o n s or i m m e di at el y (i. e., n o m or e t h a n 2 4 h o ur s aft er l e ar ni n g of 
t he e v e nt; s e e S e cti o n 7. 2. 2 ).
If a t h er a p e uti c or el e cti v e a b orti o n w a s p erf or m e d b e c a u s e of a n u n d erl yi n g m at er n al or 
e m br y of et al t o xi c it y, t h e t o xi cit y s h o ul d b e cl a s sifi e d a s a s eri o u s a d v er s e e v e nt, 
r e c or d e d o n t h e A d v er s e E v e nt e C R F, a n d r e p ort e d t o t h e S p o n s or i m m e di at el y 
(i. e., n o m or e t h a n 2 4 h o ur s aft er l e ar ni n g of t h e e v e nt; s e e S e cti o n 7. 2. 2 ).  A t h er a p e uti c 
or el e cti v e a b orti o n p erf or m e d f or r e a s o n s ot h er t h a n a n u n d erl yi n g m at er n al or 
e m br y of et al t o xi cit y i s n ot c o n si d er e d a n a d v er s e e v e nt.
F or pr e g n a n ci e s o c c urri n g i n f e m al e p arti ci p a nt s w h o h a v e b e e n e x p o s e d t o o cr eli z u m a b 
at a n y ti m e d uri n g pr e g n a n c y or wit hi n 6 m o nt h s pri or t o c o n c e pti o n , a d diti o n al 


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1 1 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
pr e g n a n c y o ut c o m e i nf or m ati o n a n d t h e h e alt h st at u s of t h e c hil d will b e f oll o w e d u ntil 
t h e c hil d i s 1 y e ar of a g e.  D at a c oll e cti o n i s v ol u nt ar y o nl y; it d o e s n ot i n cl u d e a n y 
i nt er v e nti o n s or i n v a si v e pr o c e d ur e s.  T h e d at a will b e c oll e ct e d o n a p a p er Pr e g n a n c y 
O ut c o m e a n d I nf a nt H e al t h I nf or m ati o n o n Fir st Y e ar of Lif e q u e sti o n n air e t h at will b e 
s u b mitt e d t o h e alt h a ut h oriti e s a n d I R B/ E C s f or t h eir a p pr o v al, al o n g wit h t h e i nf a nt d at a 
r el e a s e c o n s e nt f or m.
F or m or e i nf or m ati o n o n t h e I nf a nt H e alt h Q u e sti o n n air e, pl e a s e r ef er t o t h e l a t e st 
v er si o n of t h e I nf a nt H e alt h Q u e sti o n n air e G ui d a n c e d o c u m e nt.
7. 3 
W A R NI N G S A N D P R E C A U T I O N S
7. 3. 1 
O cr eli z u m a b
P arti ci p a nt s s h o ul d b e i nf or m e d of t h e ri s k s a s s o ci at e d wit h t a ki n g o cr eli z u m a b.  
B el o w ar e li st e d s p e cifi c m aj or ri s k s of w hi c h t h e p arti ci p a nt s s h o ul d b e m a d e a w ar e.  
F or t h e m o st r e c e nt i nf or m ati o n r e g ar di n g i d e ntifi e d a n d p ot e nti al ri s k s a s s o ci at e d wit h 
o cr eli z u m a b, pl e a s e r ef er t o t h e c urr e nt v er si o n of t h e O cr eli z u m a b 
I n v e sti g at or’ s Br o c h ur e .
7. 3. 1. 1 
I d e ntifi e d Ri s k s a n d Ad v er s e Dr u g R e a cti o n s A s s o ci at e d w it h 
O cr eli z u m a b U s e
I nf u si o n-R el at e d R e a cti o n s
All C D 2 0 -d e pl eti n g a g e nt s a d mi ni st er e d vi a t h e I V r o ut e, i n cl u di n g o cr eli z u m a b, h a v e 
b e e n a s s o ci at e d wit h a c ut e I R R s . F oll o wi n g t h e a p pr o v e d a d mi ni str ati o n r e gi m e n 
( w hi c h i n cl u d e s t h e u s e of pr e m e di c ati o n pri or t o tr e at m e nt wit h o cr eli z u m a b i n or d er t o 
r e d u c e fr e q u e n c y a n d s e v erit y of I R R s), s y m pt o m s of I R R s m a y o c c ur d uri n g a n y 
o cr eli z u m a b i nf u si o n b ut h a v e b e e n m or e fr e q u e ntl y r e p ort e d d uri n g t h e fir st i nf u si o n. 
P h y si ci a n s s h o ul d al ert p arti ci p a nt s t h at IR R s c a n o c c ur wit hi n 2 4 h o ur s of t h e i nf u si o n.  
A cr o s s t h e R M S a n d P P M S tri al s, s y m pt o m s a s s o ci at e d wit h I R R s i n cl u d e d, b ut w er e 
n ot li mit e d t o, pr urit u s, r a s h, urti c ari a, er yt h e m a, t hr o at irrit ati o n, or o p h ar y n g e al p ai n, 
d y s p n e a, p h ar y n g e al or l ar y n g e al e d e m a, fl u s hi n g, h y p ot e n si o n, p yr e xi a, f ati g u e, 
h e a d a c h e, di z zi n e s s, n a u s e a , a n d t a c h y c ar di a .
P arti ci p a nt s s h o ul d b e o b s er v e d f or at l e a st 1 h o ur aft er t h e c o m pl eti o n of t h e i nf u si o n 
f or a n y s y m pt o m of I R R a n d s h o ul d b e i nf or m e d a b o ut t h e p o s si bilit y of d el a y e d 
p o st -i nfu si o n s y m pt o m s a n d i n str u ct e d t o c o nt a ct t h eir st u d y p h y si ci a n if t h e y d e v el o p 
s u c h s y m pt o m s .
H y p ot e n si o n, a s a s y m pt o m of I R R, m a y o c c ur d uri n g o cr eli z u m a b i nf u si o n .  
T h er ef or e, wit h h ol di n g of a nti h y p ert e n si v e tr e at m e n ts s h o ul d b e c o n si d er e d f or 1 2 h o ur s 
pri or t o a n d t hr o u g h o ut e a c h o cr eli z u m a b i nf u si o n.
Al t er n ati v e S h ort er I nf u si o n of S u b s e q u e nt D o s e s
I n a st u d y ( M A 3 0 1 4 3, E N S E M B L E Pl u s) d e si g n e d t o c h ar a ct eri z e t h e s af et y pr ofil e of 
s h ort er o cr eli z u m a b i nf u si o n s i n p arti ci p a nt s wit h R R M S, n o diff er e n c e s w er e f o u n d i n 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 1 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
t h e fr e q u e n c y a n d s e v erit y of I R R s a s s o ci at e d wit h s h ort er ( 2-h o ur) i nf u si o n s c o m p ar e d 
wit h l o n g er ( 3. 5 -h o ur) c o n v e nti o n al i nf u si o n s.  F or f urt h er d et ail s, r ef er t o t h e c urr e nt 
v er si o n of t h e O cr eli z u m a b I B.
I nf e cti o n s
I nf e cti o n i s a n i d e ntifi e d ri s k a s s o ci at e d wit h o cr eli z u m a b tr e at m e nt, pr e d o mi n a ntl y 
i n v ol vi n g mil d t o m o d er at e r e s pir at or y tr a ct i nf e cti o n s.  N o n -di s s e mi n at e d h er p e s 
vir u s a s s o ci at e d i nf e cti o n s, m o stl y mil d t o m o d er at e, w er e al s o r e p ort e d m or e fr e q u e ntl y 
wit h o cr eli z u m a b ( a p pr o xi m at el y 5 % 6 %, si m pl e x a n d z o st er) t h a n wit h c o m p ar at or s 
( a p pr o xi m at el y 3 %).
D uri n g t h e c o nt r oll e d p eri o d of t h e pi v ot al tri al s, t h e pr o p orti o n of p arti ci p a nt s wit h 
s eri o u s i nf e cti o n s i n R M S w a s l o w er i n t h e o cr eli z u m a b gr o u p ( 1. 3 %) t h a n i n t h e 
I F N - 1-a gr o u p ( 2. 9 %); i n P P M S, t h e pr o p orti o n of p arti ci p a nt s wit h s eri o u s i nf e cti o n s 
w a s si mil ar i n b ot h gr o u p s: 6. 7 % i n t h e pl a c e b o gr o u p c o m p ar e d wit h 6. 2 % i n t h e 
o cr eli z u m a b gr o u p.
S eri o u s, o p p ort u ni sti c , a n d f at al i nf e cti o n s h a v e o c c urr e d i n p arti ci p a nt s wit h l u p u s a n d 
R A tr e at e d wit h o cr eli z u m a b i n P h a s e III cli ni c al tri al s.  D at a fr o m c o m pl et e d st u di e s 
r e g ar di n g i nf e cti o n ri s k s wit h o cr eli z u m a b tr e at m e nt i n t h e s e p arti ci p a nt p o p ul ati o n s ar e 
pr o vi d e d i n t h e O cr eli z u m a b I n v e sti g at or’ s Br o c h ur e .
N o o p p ort u ni sti c i nf e cti o n s h a v e b e e n r e p ort e d b y a n y p arti ci p a nt wit h M S  tr e at e d wit h 
o cr eli z u m a b d uri n g t h e c o ntr oll e d p eri o d of t h e pi v ot al tri al s .
I n i nt er v e nti o n al cli ni c al st u di e s, t h er e ar e n o r e p ort s of h e p atiti s B r e a cti v ati o n i n
p arti ci p a nt s wit h M S tr e at e d wit h o cr eli z u m a b, b ut it h a d b e e n r e p ort e d i n 1 p arti ci p a nt 
wit h R A tr e at e d wit h o cr eli z u m a b.  H e p atiti s B vir u s s cr e e ni n g s h o ul d b e p erf or m e d i n all 
p arti ci p a nt s b ef or e i niti ati o n of tr e at m e nt wit h o cr eli z u m a b a s p er l o c al g ui d eli n e s.  
P arti ci p a nt s wit h a cti v e H B V i nf e cti o n s h o ul d n ot b e tr e at e d wit h o cr eli z u m a b .  
P arti ci p a nt s wit h p o siti v e s er ol o g y s h o ul d c o n s ult li v er di s e a s e e x p ert s b ef or e st art of 
tr e at m e nt a n d s h o ul d b e m o nit or e d a n d m a n a g e d f oll o wi n g l o c al m e di c al st a n d ar d s t o 
pr e v e nt h e p atiti s B r e a cti v ati o n .  O cr eli z u m a b a d mi ni str ati o n s h o ul d b e d el a y e d f or 
p arti ci p a nt s wit h a cti v e i nf e cti o n u ntil t h e i nf e cti o n i s r e s ol v e d.
F or P M L, s e e t h e “ P ot e nti al Ri s k s A s s o ci at e d wit h O cr eli z u m a b U s e” s e cti o n b el o w.
D e cr e a s e i n I m m u n o gl o b uli n s
Tr e at m e nt wit h o cr eli z u m a b r e s ult e d i n a d e cr e a s e i n t ot al I g s o v er t h e c o ntr oll e d p eri o d 
of  t h e st u di e s, m ai nl y dri v e n b y r e d u cti o n i n I g M.  T h e pr o p orti o n of p arti ci p a nt s wit h 
d e cr e a s e i n I g s b el o w L L N i n cr e a s e d o v er ti m e a n d wit h s u c c e s si v e d o si n g.  B a s e d o n 
a d diti o n al p arti ci p a nt e x p o s ur e, i n c a s e s of c o nti n u o u s d e cr e a s e o v er ti m e, a hi g h er ri s k 
of  s eri o u s i nf e cti o n c a n n ot b e r ul e d o ut ( s e e b el o w ).


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S eri o u s I nf e cti o n s R el at e d t o D e cr e a s e i n I m m u n o gl o b uli n s ( P arti c ul arl y  i n 
P arti ci p a nt s Pr e vi o u sl y  E x p o s e d t o I m m u n o s u p pr e s si v e or 
I m m u n o m o d ul ar y Dr u g s or wit h Pr e e xi sti ng H y p o g a m m a gl o b uli n e mi a)
B a s e d o n a d diti o n al p arti ci p a nt e x p o s ur e, a n a p p ar e nt a s s o ci ati o n b et w e e n s u st ai n e d 
d e cr e a s e i n I g s a n d s eri o u s i nf e cti o n s wit h o cr eli z u m a b w a s o b s er v e d a n d w a s m o st 
a p p ar e nt f or I g G. T h er e w a s n o diff er e n c e i n t h e p att er n (t y p e, l at e n c y, d ur ati o n, 
o ut c o m e) of t h e s eri o u s i nf e cti o n s r e p ort e d i n t hi s s u b s et of p arti ci p a nt s c o m p ar e d wit h
t h e o v er all s eri o u s i nf e cti o n s pr ofil e. I n a d diti o n, ri s k f a ct or s f or a s u b s et of p arti ci p a nt s
at hi g h er ri s k of s eri o u s i nf e cti o n s c o ul d n ot b e i d e ntifi e d.
D el a y e d R et ur n of P eri p h er al B C ell s
Tr e at m e nt wit h o cr eli z u m a b l e a d s t o r a pi d d e pl eti o n of C D 1 9 B c ell s i n bl o o d b y 
1 4 d a y s p o s t-tr e at m e nt (fir st ti m e p oi nt of a s s e s s m e nt) a n d i s a n e x p e ct e d 
p h ar m a c ol o gi c eff e ct.  T hi s w a s s u st ai n e d t hr o u g h o ut t h e tr e at m e nt p eri o d.  T h e l o n g e st 
f oll o w-u p ti m e aft er t h e l a st o cr eli z u m a b i nf u si o n i s fr om
5 1 p arti ci p a nt s i n 
St u d y W A 2 1 4 9 3 a n d i n di c at e s t h at t h e m e di a n ti m e t o B c ell r e pl eti o n (r et ur n e d t o 
b a s eli n e or L L N, w hi c h e v er o c c urr e d fir st) of B c ell s w a s 7 2 w e e k s 
(r a n g e:  2 7 1 7 5 w e e k s ).
I m p air e d R e s p o n s e t o V a c ci n ati o n
Aft er tr e at m e nt wit h o cr eli z u m a b o v er 2 y e ar s i n pi v ot al cli ni c al tri al s, t h e pr o p orti o n of 
p arti ci p a nt s wit h M S wit h p o siti v e a nti b o d y tit er s a g ai n st S. p n e u m o ni a e , m u m p s, 
r u b ell a, a n d v ari c ell a w er e g e n er all y si mil ar t o t h e pr o p orti o n s at b a s eli n e.
P h y si ci a n s s h o ul d r e vi e w t h e i m m u ni z ati o n st at u s of p arti ci p a nt s b ei n g c o n si d er e d f or 
tr e at m e nt wit h o cr eli z u m a b.  P arti ci p a nt s w h o r e q uir e v a c ci n ati o n s h o ul d c o m pl et e it at 
l e a st 6 w e e k s pri or t o i niti ati o n of o cr eli z u m a b.
I n t h e r a n d o mi z e d o p e n-l a b el S t u d y B N 2 9 7 3 9, t h e h u m or al r e s p o n s e s t o t et a n u s t o x oi d 
( T T), 2 3-v al e nt p n e u m o c o c c al p ol y s a c c h ari d e ( 2 3 -P P V), k e y h ol e l i m p et h e m o c y a ni n 
( K L H) n e o a nti g e n, a n d s e a s o n al i nfl u e n z a v a c ci n e s w er e d e cr e a s e d i n p arti ci p a nt s wit h
R M S tr e at e d wit h o cr eli z u m a b ( c o m p ar e d wit h t h o s e p arti ci p a nt s n ot tr e at e d wit h 
o cr eli z u m a b) at all ti m e p oi nt s m e a s ur e d.  N e v ert h el e s s, p arti ci p a nt s wit h R M S w h o 
r e c ei v e d o cr eli z u m a b a n d w er e p eri p h er all y B c ell d e pl et e d w er e a bl e t o m o u nt h u m or al 
r e s p o n s e s, al b eit d e cr e a s e d, t o cli ni c all y r el e v a nt v a c ci n e s ( T T, 2 3-P P V, i nfl u e n z a) a n d 
t h e n e o a nti g e n K L H.  T h e r e s ult s of t h e st u d y c o nfir m t h e c urr e nt r e c o m me n d ati o n t h at 
p arti ci p a nt s s h o ul d c o m pl et e l o c al v a c ci n ati o n r e q uir e m e nt s 6 w e e k s pri or t o i niti ati o n of 
o cr eli z u m a b t o o bt ai n f ull eff e cti v e n e s s of t h e v a c ci n e s.  I n a d diti o n, f or s e a s o n al 
i nfl u e n z a v a c ci n e s, it i s still r e c o m m e n d e d t o v a c ci n at e p arti ci p a nt s r e c ei vi n g 
o cr eli z u m a b, a s a h u m or al r e s p o n s e t o t h e v a c ci n e, e v e n if att e n u at e d, c a n b e e x p e ct e d.
D u e t o t h e p ot e nti al d e pl eti o n of B c ell s i n n e o n at e s a n d i nf a nt s of m ot h er s w h o h a v e 
b e e n e x p o s e d t o o cr eli z u m a b d uri n g pr e g n a n c y, it i s r e c o m m e n d e d t h at v a c ci n ati o n of 
n e o n at e s a n d i nf a nt s wit h li v e or li v e -att e n u at e d v a c ci n e s s h o ul d b e d el a y e d u ntil B c ell 


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l e v el s h a v e r e c o v er e d.  T h er ef or e, m e a s uri n g C D 1 9B c ell l e v el s i n n e o n at e s a n d 
i nf a nt s pri or t o v a c ci n ati o n i s r e c o m m e n d e d.
T h e s af et y of i m m u ni z at i o n wit h li v e or li v e-att e n u at e d vir al v a c ci n e s, f oll o wi n g 
o cr eli z u m a b t h er a p y h a s n ot b e e n st u di e d, a n d v a c ci n ati o n wit h li v e -att e n u at e d or li v e 
v a c ci n e s i s n ot r e c o m m e n d e d w hil e B c ell s ar e d e pl et e d.
7. 3. 1. 2 
P ot e nti al Ri s k s A s s o ci at e d wit h O cr eli z u m a b U s e
M ali g n a n ci e s, I n cl u di n g Br e a st C a n c er
A n i n cr e a s e d ri s k of m ali g n a n c y wit h o cr eli z u m a b m a y e xi st.  P arti ci p a nt s s h o ul d f oll o w 
st a n d ar d br e a st c a n c er s cr e e ni n g g ui d eli n e s.
Pr o gr e s si v e M ultif o c al L e u k o e n c e p h al o p at h y
Pr o gr e s si v e m ultif o c al l e u k o e n c e p h al o p at h y i s a n i m p ort a nt p ot e nti al ri s k f or 
o cr eli z u m a b. It h a s b e e n r e p ort e d i n p arti ci p a nt s r e c ei vi n g o cr eli z u m a b b ut o nl y i n 
p arti ci p a nt s w h er e ot h er c o ntri b ut or y f a ct or s w er e pr e s e nt, s u c h a s pri or 
i m m u n o s u p pr e s si v e tr e at m e nt (e. g., n at ali z u m a b or fi n g oli m o d) . P h y si ci a n s s h o ul d b e 
vi gil a nt f or e arl y si g n s a n d s y m pt o m s of P M L, w hi c h c a n i n cl u d e a n y n e w o n s et or 
w or s e ni n g of n e ur ol o gi c al si g n s or s y m pt o m s, a s t h e s e c a n b e si mil ar t o a n M S r el a p s e.  
If P M L i s s u s p e ct e d, d o si n g wit h o cr eli z u m a b m u st b e wit h h el d. E v al u ati o n of P M L, 
i n cl u di n g M RI, c o nfir m at or y C S F t e sti n g f or J C V D N A, a n d r e p e at n e ur ol o gi c al 
a s s e s s m e nt s, s h o ul d b e c o n si d er e d.  If P M L i s c o nfir m e d, o cr eli z u m a b m u st b e 
di s c o nti n u e d p er m a n e ntl y.   M or e i nf or m ati o n o n P M L c a n b e f o u n d i n
S e cti o n 7. 3. 4 .  
Pl e a s e s e e t h e m o st r e c e nt O cr eli z u m a b I n v e sti g at or’ s Br o c h ur e f or m or e d et ail s 
r e g ar di n g P M L ri s k a n d s e e S e cti o n 7. 3. 4. 1 f or g ui d a n c e o n di a g n o si n g P M L.
N e utr o p e ni a
I n t h e c o ntr oll e d tr e at m e nt p eri o d, d e cr e a s e d n e utr o p hil s w er e o b s er v e d i n 1 2 % a n d 
1 5 % of p arti ci p a nt s wit h M S tr e at e d wit h o cr eli z u m a b, i n P P M S a n d R M S, r e s p e cti v el y .  
M o st e v e nt s w er e mil d t o m o d er at e i n s e v erit y.  A p pr o xi m at el y 1 % of t h e p arti ci p a nt s
h a d Gr a d e 3 or 4 n e utr o p e ni a, a n d n o t e m p or al a s s o ci ati o n wit h i nf e cti o n s w a s 
i d e ntifie d.
H y p er s e n siti vit y  R e a cti o n s
N o h y p er s e n siti vit y r e a cti o n s t o o cr eli z u m a b w er e r e p ort e d i n t h e c o ntr oll e d cli ni c al tri al s .  
H y p er s e n siti vit y m a y b e diffi c ult t o di sti n g ui s h fr o m I R R s i n t er m s of s y m pt o m s.  
A h y p er s e n siti vit y r e a cti o n m a y pr e s e nt d uri n g a n y i nf u si o n, alt h o u g h n ot t y pi c all y d uri n g 
t h e fir st i nf u si o n.  F or s u b s e q u e nt i nf u si o n s, m or e s e v er e s y m pt o m s t h a n pr e vi o u sl y 
e x p eri e n c e d, or n e w s e v er e s y m pt o m s, s h o ul d pr o m pt c o n si d er ati o n of a p ot e nti al 
h y p er s e n siti vit y r e a cti o n .  If a h y p er s e n siti vit y r e a cti o n i s s u s p e ct e d d uri n g a n i nf u si o n, 
t h e i nf u si o n m u st b e st o p p e d i m m e di at el y a n d p er m a n e ntl y.  P arti ci p a nt s wit h k n o w n 
I g Em e di at e d h y p er s e n siti vit y t o o cr eli z u m a b m u st n ot b e tr e at e d.


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7. 3. 2 
C orti c o st er oi d s
T h e a d v er s e r e a cti o n s of c orti c o st er oi d s m a y r e s ult fr o m u n w a nt e d gl u c o c orti c oi d 
a cti o n s or fr o m i n hi biti o n of t h e h y p ot h al a mi c -a dr e n al a xi s.  Pl e a s e r ef er t o t h e l o c al 
P r e s cri bi n g Inf or m ati o n.
7. 3. 3 
A n ti hi st a mi n e s
T h e a d v er s e r e a cti o n s d e p e n d o n t h e s e d ati n g pr o p erti e s of t h e a nti hi st a mi n e a n d 
i n cl u d e, b ut ar e n ot li mit e d t o, n a u s e a, dr o w si n e s s, h e a d a c h e s, dr y m o ut h, a n d all er gi c 
r e a cti o n s s u c h a s r a s h.  Pl e a s e r ef er t o l o c al Pr e s cri bi n g I nf or m ati o n ( O C R E V U S U S PI).
7. 3. 4 
Pr o gr e s si v e M ultif o c al L e u k o e n c e p h al o p at h y
P r o gr e s si v e m ultif o c al l e u k o e n c e p h al o p at h y i s a p ot enti all y f at al n e ur ol o gi c al c o n diti o n 
li n k e d t o r e a cti v ati o n of a p ol y o m a vir u s ( JC V ) a n d a cti v e vir al r e pli c ati o n i n t h e br ai n.  
P ol y o m a vir u s i nf e cti o n i s a c q uir e d i n c hil d h o o d a n d u p t o 8 0 % of a d ult s d e m o n str at e 
s er ol o gi c al e vi d e n c e of p a st i nf e cti o n.  R e a cti v ati o n of J C V r e pli c ati o n wit h tr a n si e nt 
vir e mi a or viri uri a u n a s s o ci at e d wit h cli ni c al s y m pt o m s m a y o c c ur s p o nt a n e o u sl y i n 
h e alt h y p er s o n s.  L e s s fr e q u e ntl y, C N S s y m pt o m s a s s o ci at e d wit h a cti v e vir al r e pli c ati o n 
i n br ai n ti s s u e i s o b s er v e d.  T h e cli ni c al s y n dr o m e i s si g nifi c a ntl y m or e fr e q u e nt a m on g 
i m m u n e s u p pr e s s e d p arti ci p a nt s .
P h y si ci a n s s h o ul d c o n si d er t h e di a g n o si s of P M L i n a n y p arti ci p a nt pr e s e nti n g wit h n e w 
n e ur ol o gi c al d efi cit s l o c ali z e d t o t h e c er e br al c ort e x, s u c h a s c orti c al s y m pt o m s/ si g n s, 
b e h a vi or al a n d n e ur o p s y c h ol o gi c al alt er ati o n, r etr o c hi a s m al vi s u al d ef e ct s, h e mi p ar e si s, 
c er e b ell ar s y m pt o m s/ si g n s ( e. g., g ait a b n or m aliti e s, li m b i n c o or di n ati o n), at e a c h vi sit.
If P M L i s c o n si d er e d, a n e ur ol o gi c al c o n s ult ati o n s h oul d b e o bt ai n e d a n d tr e at m e nt 
s u s p e n d e d u ntil P M L h a s b e e n r ul e d o ut.  If P M L i s c o nfir m e d i n a p arti ci p a nt r e c ei vi n g 
o cr eli z u m a b, n o f urt h er i nf u si o n s s h o ul d b e a d mi ni st er e d a n d t h e p arti ci p a nt will b e 
wit h dr a w n fr o m tr e at m e nt ( s e e S e cti o n 5. 6 ).  N o k n o w n i nt er v e nti o n s c a n r eli a bl y 
pr e v e nt P M L or a d e q u at el y tr e at P M L, if it o c c ur s.
It i s n ot k n o w n w h et h er t h e ri s k of P M L i s alt er e d b y anti -C D 2 0 tr e at m e nt gi v e n a s 
m o n ot h er a p y.  S e e S e cti o n 7. 3. 4. 1 f or g ui d a n c e o n t h e di a g n o si s of P M L.
P r o gr e s si v e m ultif o c al l e u k o e n c e p h al o p at h y s h o ul d b e r e p ort e d a s a s eri o u s a d v er s e 
e v e nt ( wit h all a v ail a bl e i nf or m ati o n) wit h i m m e di at e n otifi c ati o n of t h e M e di c al M o nit or.  
St u d y dr u g s h o ul d b e wit h h el d a n d p arti ci p a nt s wit h c o nfir m e d P M L s h o ul d b e wit h dr a w n 
fr o m t h e st u d y.
T h er e i s n o k n o w n tr e at m e nt or c ur e f or P M L .  Tr e at m e nt c o n si d er ati o n s ar e di s c u s s e d 
i n t h e m e di c al lit er at ur e ( C al a br e s e et al. 2 0 07) .
D et ail e d i nf or m ati o n r e g ar di n g P M L ri s k wit h o cr eli z u m a b tr e at m e nt c a n b e f o u n d i n t h e 
c urr e nt O cr eli z u m a b In v e sti g at or’ s B r o c h ur e.


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7. 3. 4. 1 
G ui d a n c e f or Di a g n o si s of P M L
T h e f oll o wi n g di a g n o sti c al g orit h m fr a m e w or k ( s e e Fi g ur e 1 ) will b e i m pl e m e nt e d i n t hi s 
st u d y.
C o m pr e h e n si v e n e ur ol o gi c al a s s e s s m e nt s will b e p erf or m e d e v er y 1 2 w e e k s at t h e 
r e g ul ar st u d y vi sit s.  P arti ci p a nt s will b e r e q uir e d t o u n d er g o a n e ur ol o gi c al e x a m i n ati o n
f or c al c ul ati o n of a n E D S S s c or e e v er y 1 2 w e e k s.  T hi s r e q uir e s t h at F S S al s o b e 
d et er mi n e d.  T h e e x a mi n ati o n t o c al c ul at e t h e F S S i n cl u d e s c o g niti v e, vi s u al a n d m ot or 
a s s e s s m e nt s, t h e n e ur ol o gi c al s y st e m s m o st oft e n aff e ct e d b y P M L, a s w ell a s 
a s s e s s m e nt s of ot h er n e ur ol o gi c al s y st e m s.
I n t h e e C R F, t h e in v e sti g at or will r e c or d t h e pr e s e n c e or a b s e n c e of n e ur ol o gi c al d efi cit s 
l o c ali z e d t o t h e c er e br al c ort e x ( e. g., c orti c al s y m pt o m s/ si g n s, b e h a vi or al a n d 
n e ur o p s y c h ol o gi c al alt er ati o n, r etr o c hi a s m al vi s u al d ef e ct s, h e mi p ar e si s), c er e b ell ar 
s y m pt o m s/ si g n s ( e. g., g ait a b n or m aliti e s, li m b i n c o or di n ati o n), at e a c h vi sit.  Pr e s e n c e of 
s u c h n e ur ol o gi c al fi n di n g s wil l b e r e c or d e d a s a d v er s e e v e nt s.
If a di a g n o si s f or t h e d efi cit s i s i d e ntifi e d, t h e s y m pt o m s s h o ul d b e r e pl a c e d b y t h e 
di a g n o si s i n t h e a d v er s e e v e nt e C R F.
I n a d diti o n t o t h e n e ur ol o gi c al e v al u ati o n at r e g ul ar vi sit s, p arti ci p a nt s will u n d er g o a 
t el e p h o n e i nt er vi e w b et w e e n t h e st u d y vi sit s b y sit e p er s o n n el f a mili ar wit h t h e 
p arti ci p a nt ( s).  T h e p ur p o s e of t hi s i nt er vi e w i s t o i d e ntif y n e w or w or s e ni n g n e ur ol o gi c al 
s y m pt o m s t h at w arr a nt a n u n s c h e d ul e d vi sit ( A p p e n di x 5 ).  P art n er s or c ar e gi v er s of
st u d y p arti ci p a nt s , if a p pli c a bl e, will b e i nf or m e d o n s y m pt o m s a nd si g n s t h at m a y b e 
s u g g e sti v e of  P M L a n d s h o ul d b e i n str u ct e d t o c o nt a ct t h e sit e, s h o ul d a n y su c h si g n s or 
s y m pt o m s a p p e ar.
I n t h e e v e nt t h at n e w or w or s e ni n g n e ur ol o gi c al s y m pt o m s ar e c o n si d er e d d uri n g t h e 
t el e p h o n e i nt er vi e w, a n e ur ol o gi c al e v al u ati o n will b e c o n d u ct e d.  S h o ul d a n o n-M S 
eti ol o g y, s u c h a s P M L, b e c o n si d er e d, f urt h er a s s e s s m e nt s s h o ul d b e d o n e
( s e e Fi g ur e 1 ).
T h e f oll o wi n g cli ni c al g ui d a n c e i s pr o vi d e d .
Tr e at m e nt of R el a p s e a n d Ot h er N e ur ol o gi c al S y m pt o m s
 
A s i n all M S st u di e s, n e w or r e c urr e nt n e ur ol o gi c al s y m pt o m s o c c urri n g i n st u d y 
p arti ci p a nt s s h o ul d pr o m pt c ar ef ul cli ni c al e v al u ati o n
 
Gi v e n t h e o c c urr e n c e of P M L i n i m m u n o c o m pr o mi s e d p arti ci p a nt s wit h ot h er 
a nti C D 2 0 a n d M S D M T s , P M L s h o ul d b e c o n si d er e d i n p arti ci p a nt s w h o d e v el o p 
w or s e ni n g n e ur ol o gi c al si g n s or s y m pt o m s
 
T h er e ar e n o p at h o g n o m o ni c si g n s or s y m pt o m s t h at di sti n g ui s h M S fr o m P M L, b ut 
t h er e ar e c ert ai n cli ni c al f e at ur e s t h at m a y h el p diff er e nti at e b et w e e n t h e 
2 c o n diti o n s ( s e e T a bl e 1 0 )


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 1 9 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
I n a d diti o n t o P M L a n d M S, ot h er C N S c o n diti o n s ( e. g., str o k e, mi gr ai n e, et c.) 
s h o ul d b e c o n si d er e d w h e n e v al u ati n g a p arti ci p a nt wit h n e w n e ur ol o gi c al c h a n g e s
 
R el a p s e s s h o ul d b e m a n a g e d a c c or di n g t o t h e st u d y pr ot o c ol
 
C orti c o st er oi d tr e at m e nt s h o ul d o nl y b e c o n si d er e d f or c a s e s i n w hi c h P M L i s 
u nli k el y o n cli ni c al gr o u n d s a n d w h e n t h e s e v erit y of t h e r el a p s e w arr a nt s s u c h 
tr e at m e nt.  L a c k of r e s p o n s e t o c orti c o st er oi d s s h o ul d tri g g er f urt h er i n v e sti g ati o n.
A c ti o n St e p s if P M L i s S u s pe ct e d
If t h e cli ni c al pr e s e nt ati o n i s s u g g e sti v e of P M L, f urt h er i n v e sti g ati o n s s h o ul d i n cl u d e 
br ai n M RI e v al u ati o n a s s o o n a s p o s si bl e.  If M RI e v al u ati o n r e v e al s l e si o n s s u s pi ci o u s 
f or P M L ( s e e Fi g ur e 1 ), a l u m b ar p u n ct ur e wit h e v al u ati o n of t h e C S F f or t h e d et e cti o n of 
J C V D N A s h o ul d b e u n d ert a k e n.  A di a g n o si s of P M L c a n p ot e nti all y b e m a d e b y 
e v al u ati n g cli ni c al a n d M RI fi n di n g s pl u s t h e i d e ntifi c ati o n of J C V i n t h e C S F.
Pl e a s e n ot e :  in t h e e v e nt t h at P M L i s s u s p e ct e d, a d diti o n al pl a s m a, uri n e, a s w ell a s 
C S F s a m pl e s s h o ul d b e o bt ai n e d f or J C V a n al y si s .  C er e br o s pi n al fl ui d s a m pl e s will b e 
a n al y z e d , wit h u s e of a hi g h -s e n siti vit y t e st, u p o n r e c ei pt a n d t h e r e s ult s will b e pr o vi d e d 
dir e ctl y t o t h e i n v e sti g ati o n al sit e a n d t o t h e S p o n s or.  T h e a d diti o n al pl a s m a a n d uri n e 
s a m pl e s will b e st or e d t o g et h er wit h t h e r o uti n e J C V s a m pl e s. T h e J C V s a m pl e s will b e 
st or e d f or 1 y e ar aft er l a st p arti ci p a nt, l a st vi sit. F or d et ail s, r ef er t o t h e m o st u p -t o-d at e 
L a b or at or y M a n u al pr o vi di n g st or a g e c o n diti o n s a n d s hi p m e nt i n str u cti o n s .
M RI A s s e s s m e nt
 
Alt h o u g h t h er e ar e n o p at h o g n o m o ni c fi n di n g s t h at diff er e nti at e P M L fr o m M S, a 
br ai n M RI s c a n t h at i n cl u d e s fl ui d-att e n u at e d i n v er si o n r e c o v er y ( F L AI R) a n d 
T 2 -w ei g ht e d a n d T 1 -w ei g ht e d s e q u e n c e s, wit h a n d wit h o ut g a d oli ni u m, s h o ul d b e 
p erf or m e d t o a s s e s s p arti ci p a nt s wit h n e ur ol o gi c al c h a n g e s s u g g e sti v e of P M L 
( s e e Fi g ur e 1 )
 
C o m p ari s o n wit h a b a s eli n e s c a n m a y a s si st wit h i nt er pr et ati o n of t h e fi n di n g s o n 
t h e n e wl y a c q uir e d M RI ( s e e T a bl e 1 1 f or diff er e n c e s i n l e si o n c h ar a ct eri sti c s t h at 
m a y h el p diff er e nti at e b et w e e n P M L a n d M S)
C S F A s s e s s m e nt
 
T h e d et e cti o n of J C V D N A i n t h e C S F of a p arti ci p a nt wit h cli ni c al a n d M RI f e at ur e s 
s u g g e sti v e of P M L e st a bli s h e s t h e di a g n o si s of P M L
 
If J C V D N A i s n ot d et e ct e d i n C S F a n d if cli ni c al s u s pi ci o n of P M L r e m ai n s hi g h, a 
r e p e at l u m b ar p u n ct ur e s h o ul d b e p erf or m e d
 
If di a g n o si s r e m ai n s u n c ert ai n a n d s u s pi ci o n of P M L r e m ai n s hi g h, a br ai n bi o p s y 
m a y b e c o n si d er e d t o e st a bli s h a d efi niti v e di a g n o si s


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 0 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
Fi g ur e 1 
Di a g n o sti c A l g orit h m Fr a m e w or k f or P M L
S o ur c e:  B er g er et al. 2 0 1 3
C S F c er e br o s pi n al fl ui d; F L AI R fl ui d-att e n u at e d i n v er si o n r e c o v e r y; J C VJ o h n C u n ni n g h a m 
vir u s; M RI m a g n eti c r e s o n a n c e i m a gi n g; P C R p ol y m e r a s e c h ai n r e a cti o n; P M Lpr o gr e s si v e 
m u ltif o c al l e u k o e n c e p h al o p at h y; P R E Sp o st eri or r e v er si bl e e n c e p h al o p at h y s y n dr o m e; 
V Z V v ari c ell a z o st er vir u s.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T a bl e 1 0
Cli ni c al Si g n s a n d S y m pt o m s T y pi c al of M S a n d P M L
M S  R el a p s e
P M L
O n s et
A c ut e
S u b a c ut e
E v ol uti o n
 
O v er h o ur s t o d a y s
 
N or m all y st a bili z e s
 
R e s ol v e s s p o nt a n e o u sl y or 
wit h tr e at m e nt
 
O v er w e e k s
 
Pr o gr e s si v e
Cli ni c al pr e s e nt ati o n 
 
Di pl o pi a
 
P ar e st h e si a
 
P ar a p ar e si s
 
O pti c n e uriti s
 
M y el o p at h y
 
C orti c al si g n s a n d s y m p t o m s
 
B e h a vi or al a n d 
n e ur o p s y c h ol o gi c al alt er ati o n s 
 
R etr o c hi a s m al vi s u al d efi cit s
 
H e mi p ar e si s
 
C er e b ell ar s y m p t o m s/ si g n s 
( e. g., g ait a b n or m aliti e s, li m b 
i n c o or di n ati o n)
S o ur c e:  K a p p o s et al. 2 0 0 7.
M S m u lti pl e s cl er o si s; P M L pr o gr e s si v e m ultif o c al l e u k o e n c e p h al o p at h y .
T a bl e 1 1
M RI L e si o n C h ar a ct eri sti c s T y pi c al of M S a n d P M L
F e at ur e
M S  (r el a p s e)
P M L
L o c ati o n of n e w l e si o n s 
M o stl y f o c al; aff e ct e ntir e 
br ai n a n d s pi n al c or d, i n 
w hit e a n d p o s si bl y gr e y 
m a tt er
Diff u s e l e si o n s, m ai nl y s u b c orti c al 
a n d r ar el y p eri v e ntri c ul ar, l o c at e d 
al m o st e x cl u si v el y i n w hit e m att er, 
alt h o u g h o c c a si o n al e xt e n si o n t o 
gr e y m att er h a s b e e n s e e n; 
p o st eri or f o s s a fr e q u e ntl y i n v ol v e d 
( c er eb ell u m)
B or d er s
S h ar p e d g e s; m o stl y r o u n d 
or fi n g er -li k e i n s h a p e 
( e s p e ci all y p eri v e ntri c ul ar 
l e si o n s), c o nfl u e nt wit h ot h er 
l e si o n s; U-fi b er s m a y b e 
i n v ol v e d
Ill-d efi n e d e d g e s; irr e g ul ar i n s h a p e; 
c o nfi n e d t o w hit e m att er; s p ari n g 
gr e y m att er; p u s hi n g a g ai n st t h e 
c er e br al c ort e x; U -fi b er s d e str o y e d
M o d e of e xt e n si o n
I niti all y f o c al; l e si o n s e nl ar g e 
wit hi n d a y s or w e e k s a n d 
l at er d e cr e a s e i n si z e wit hi n 
m o nt h s
L e si o n s ar e diff u s e a n d 
a s y m m e tri c, e xt e n di n g 
h o m o g e n e o u sl y; n o c o nfl u e n c e wit h 
ot h er l e si o n s; c o nfi n e d t o w hit e 
m a tt er tr a c k s, s p ari n g t h e c ort e x; 
c o nti n u o u s pr o gr e s si o n
M a s s eff e ct
A c ut e l e si o n s s h o w s o m e 
m a s s eff e ct
N o m a s s eff e ct e v e n i n l ar g e 
l e si o n s ( b ut l e si o n sli g htl y a b ut s 
c er e br al c ort e x)


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
T a bl e 1 1
M RI L e si o n C h ar a ct eri sti c s T y pi c al of M S a n d P M L ( c o nt.)
F e at ur e
M S  (r el a p s e)
P M L
O n T 2 -w ei g ht e d s e q u e n c e 
A c ut e l e si o n s:  
h y p eri nt e n s e c e nt er, 
i s oi nt e n s e ri n g, di s cr et e 
h y p eri nt e n sit y o ut si d e t h e 
ri n g str u ct ur e
S u b a c ut e a n d c hr o ni c 
l e si o n s:  h y p eri nt e n s e wit h 
n o ri n g str u ct ur e
Diff u s e h y p eri nt e n sit y, sli g htl y 
i n cr e a s e d i nt e n sit y of n e wl y 
i n v ol v e d ar e a s c o m p ar e d wit h ol d 
ar e a s, littl e irr e g ul ar si g n al i nt e n sit y 
of l e si o n s
O n T 1 -w ei g ht e d s e q u e n c e 
A c ut e l e si o n s: 
d e n s el y h y p oi nt e n s e 
(l ar g e l e si o n s) or i s oi nt e n s e 
( s m all l e si o n s); i n cr e a si n g 
si g n al i nt e n sit y o v er ti m e i n 
8 0 %; d e cr e a si n g si g n al 
i nt e n sit y ( a x o n al l o s s) i n 
a b o ut 2 0 % 
Sli g htl y h y p oi nt e n s e at o n s et, wit h 
si g n al i nt e n sit y d e cr e a si n g o v er 
ti me a n d al o n g t h e aff e ct e d ar e a; 
n o r e v er si o n of si g n al i nt e n sit y
O n F L AI R s e q u e n c e 
H y p eri nt e n s e, s h ar pl y 
d eli n e at e d
H y p eri nt e n sit y m or e o b vi o u s; tr u e 
e xt e n si o n of a b n or m alit y m or e 
cl e arl y vi si bl e t h a n i n T 2 -w ei g ht e d 
i ma g e s
Wi t h e n h a n c e m e nt 
A c ut e l e si o n s:  
d e n s e h o m o g e n e o u s 
e n h a n c e m e nt, s h ar p 
e d g e s
S u b a c ut e l e si o n s:  
ri n g e n h a n c e m e nt
C hr o ni c l e si o n s:  
n o e n h a n c e m e nt
U s u all y n o e n h a n c e m e nt, e v e n i n 
l ar g e l e si o n s; i n p arti ci p a nt s wit h 
HI V, s o m e p eri p h er al e n h a n c e m e nt 
i s p o s si bl e, e s p e ci all y u n d er 
t h er a p y.
Atr o p h y
F o c al atr o p h y p o s si bl e d u e 
t o f o c al w hit e m att er 
d e g e n er ati o n; n o 
pr o gr e s si o n
N o f o c al atr o p h y
S o ur c e:  Y o u sr y  et al. 2 0 0 6.
M S m u lti pl e s cl er o si s; P M L pr o gr e s si v e m ultif o c al l e u k o e n c e p h al o p at h y .
8.
S T A TI S TI C A L C O N SI D E R A T I O N S A N D A N A L Y T I C AL P L A N
F ull d et ail s of all st ati sti c al i s s u e s a n d pl a n n e d st ati sti c al a n al y s e s w er e s p e cifi e d i n a 
s e p ar at e S A P , w hi c h w a s fi n ali z e d pri or t o t h e pri m ar y d at a b a s e l o c k a n d u n bli n di n g of 
t h e st u d y d at a b a s e.  T h e e xi sti n g S A P m a y b e u p d at e d t o d e s cri b e t h e a n al y s e s of t h e 
O L E p h a s e or a s e p ar at e S A P will b e pr e p ar e d, pri or t o t h e fi n al st u d y d at a b a s e l o c k.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
8. 1 
S T U D Y E N D P OI N T S
8. 1. 1 
Pri m ar y  Effi c a c y E n d p oi nt
T h e pri m ar y effi c a c y e n d p oi nt i s t h e ti m e t o o n s et of c o nfir m e d di s a bilit y pr o gr e s si o n 
d uri n g t h e bli n d e d tr e at m e nt p eri o d.  Di s a bilit y pr o gr e s si o n i s d efi n e d a s a n i n cr e a s e of 
1. 0 p oi nt fr o m b a s eli n e E D S S, if t h e b a s eli n e E D S S i s 5. 5 p oi nt s, or a n i n cr e a s e of 
0. 5 p oi nt s, if t h e b a s eli n e E D S S i s 5. 5 p oi nt s, f or w hi c h c h a n g e i s n ot attri b ut a bl e t o 
a n ot h er eti ol o g y ( e. g., f e v er, c o n c urr e nt ill n e s s, M S r el a p s e or e x a c er b ati o n, or 
c o n c o mit a nt m e di c ati o n).  C o nfir m ati o n of di s a bilit y pr o gr e s si o n m u st o c c ur at a 
r e g ul arl y s c h e d ul e d vi sit t h at i s at l e a st 1 2 w e e k s aft er t h e i niti al di s e a s e pr o gr e s si o n.  
T h e n o n -c o nfir m at or y E D S S a s s e s s m e nt s (if a n y) b et w e e n t h e i niti al a n d c o nfir m ati o n of 
di s a bilit y pr o gr e s si o n s h o ul d b e at l e a st a s hi g h a s t h e mi ni m u m c h a n g e r e q uir e d f or 
pr o gr e s si o n.
8. 1. 2 
S e c o n d ar y  Effi c a c y E n d p oi nt s
T h e s e c o n d ar y effi c a c y e n d p oi nt s ar e:
 
T h e ti m e t o o n s et of c o nfir m e d di s a bilit y pr o gr e s si o n o v er t h e tr e at m e nt p eri o d, 
d ef i n e d a s a n i n cr e a s e of 1. 0 p oi nt fr o m b a s eli n e E D S S, if t h e b a s eli n e E D S S i s 
5. 5 p oi nt s, or a n i n cr e a s e of 0. 5 p oi nt s, if t h e b a s eli n e E D S S i s 5. 5 p oi nt s, t h at 
i s s u st ai n e d f or at l e a st 2 4 w e e k s
 
T h e c h a n g e i n T 2 5 F W T
fr o m b a s eli n e t o We e k 1 2 0
 
T h e c h a n g e i n t ot al v ol u m e of T 2 l e si o n s o n M RI s c a n s of t h e br ai n fr o m b a s eli n e t o 
W e e k 1 2 0
 
T h e p er c e nt a g e c h a n g e i n t ot al br ai n v ol u m e a s d et e ct e d b y br a i n M RI fr o m 
W e e k 2 4 1 2 0
 
T h e c h a n g e i n S F -3 6 P C S s c or e fr o m b a s eli n e t o W e e k 1 2 0
 
T o e v al u at e t h e s af et y a n d t ol er a bilit y of o cr eli z u m a b 3 0 0 m g 2 
( o v er 2 4 -w e e k tr e at m e nt c y cl e s) c o m p ar e d wit h pl a c e b o i n p arti ci p a nt s wit h P P M S
8. 1. 3 
E x pl or at or y  Effi c a c y E n d p oi nt s
T h e e x pl or at or y effi c a c y e n d p oi nt s i n t hi s st u d y will i n cl u d e, b ut m a y n ot b e li mit e d t o:
Cli ni c al :
 
T h e pr o p orti o n of p arti ci p a nt s wit h c o nfir m e d 1 2 -w e e k di s a bilit y pr o gr e s si o n at 
W e e k 1 2 0
 
T h e c h a n g e i n E D S S s c or e ( m e a n c h a n g e a n d A U C) fr o m b a s eli n e t o W e e k s 4 8, 
9 6, a n d 1 2 0
 
T h e c h a n g e i n M S F C S s c or e fr o m b a s eli n e t o W e e k s 4 8, 9 6, a n d 1 2 0
 
T h e ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n o v er t h e tr e at m e nt p eri o d, d efi n e d a s a n 
i n cr e a s e i n E D S S t h at i s s u st ai n e d f or at l e a st 1 2 w e e k s ( 0. 5 or 1 p oi nt s, s a m e 
crit eri a a s f or t h e p ri m ar y e n d p oi nt ti m e t o 1 2-w e e k C D P) or a 2 0 % i n cr e a s e i n 
T 2 5 F W T
t h at i s s u st ai n e d f or at l e a st 1 2 w e e k s, or a 2 0 % i n cr e a s e i n t h e 9- H P T t h at 
i s s u st ai n e d f or at l e a st 1 2 w e e k s


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
T h e ti m e t o s u st ai n e d 2 0 % i n cr e a s e i n T 2 5 F W T
a n d 9 -H P T
 
T h e p r o p orti o n of p arti c i p a nt s wit h a 2 0 % i n cr e a s e i n T 2 5 F W T
 
T h e pr o p orti o n of p arti ci p a nt s wit h a 2 0 % i n cr e a s e i n 9- H P T
 
T h e c h a n g e i n P A S A T fr o m b a s eli n e t o W e e k 1 2 0
I m a gi n g:
 
T h e n u m b er of G d -e n h a n ci n g T 1 l e si o n s a n d n u m b er of n e w or e nl ar gi n g T 2 l e si o n s 
a s d et e ct e d b y br ai n M R I
 
T h e p er c e nt a g e c h a n g e i n c orti c al gr e y m att er v ol u m e fr o m b a s eli n e t o W e e k 1 2 0
 
T h e p er c e nt a g e c h a n g e i n w hit e -m att er v ol u m e fr o m b a s eli n e t o W e e k 1 2 0
 
T h e c h a n g e fr o m b a s eli n e i n t ot al n o n -e n h a n ci n g T 1 l e si o n v ol u m e o n M RI s c a n of 
t h e br ai n
P arti ci p a nt -R e p ort e d O ut c o m e s:
 
T h e c h a n g e i n f ati g u e, a s m e a s ur e d b y t h e M FI S t ot al s c or e a n d s u b s c al e s c or e s 
(P h y si c al I m p a ct, C o g niti v e I m p a ct, a n d P s y c h ol o gi c al I m p a ct) fr o m b a s eli n e t o 
W e e k 1 2 0
 
T h e c h a n g e i n q u alit y of lif e, a s m e a s ur e d b y t h e S F -3 6 M C S s c or e fr o m b a s eli n e t o 
W e e k 1 2 0
Bi o m ar k er s :
 
T o i n v e sti g at e t h e P K a n d ot h er P D st u d y e n d p oi nt s of o cr eli z u m a b
 
T o e x pl or e t h e i m p a ct of o cr eli z u m a b t h er a p y o n bi o m ar k er s a s s o ci at e d wit h t h e 
pr o p o s e d i nfl a m m at or y or n e ur o d e g e n er ati v e pr o c e s s i n P P M S
O L E :
 
T o e v al u at e t h e l o n g-t er m s af et y of o cr eli z u m a b tr e at m e nt d uri n g t h e O L E p h a s e of 
t h e st u d y
 
T o e v al u at e t h e l o n g -t er m eff e ct s of o cr eli z u m a b o n cli ni c al a n d M RI p ar a m et er s of 
di s e a s e a cti vit y a n d pr o gr e s si o n d uri n g t h e O L E p h a s e of t h e st u d y
8. 1. 4 
S af et y
S af et y will b e a s s e s s e d t hr o u g h r e g ul ar n e ur ol o gi c a n d p h y si c al e x a mi n ati o n s, vit al 
si g n s, E C G a n d t h e o c c urr e n c e of a d v er s e e v e nt s , a s p er t h e s c h e d ul e of a cti viti e s .  
I n a d diti o n, t h e f oll o wi n g will b e e x a mi n e d:
 
N o n -M S p at h ol o g y i n all a v ail a bl e M RI s c a n s
 
C o m pl et e r o uti n e h e m at ol o g y, c h e mi str y a n d uri n al y s e s
 
Cir c ul ati n g B c ell t ot al a n d s u b s et s, T c ell s, n at ur al kill er c ell s a n d ot h er l e u k o c yt e s
 
Pl a s m a I g s


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 5 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
H A H A :  in a n y c a s e of a n a p h yl a xi s, a n a p h yl a ct oi d r e a cti o n, or s eri o u s or s e v er e 
h y p er s e n siti vit y r e a cti o n, H A H A a n d o cr eli z u m a b c o n c e ntr ati o n s a m pl e s s h o ul d b e 
c oll e ct e d a s cl o s e a s p o s si bl e t o t h e e v e nt a n d t h e n at 4 a n d 1 6 w e e k s p o st d o s e
 
A nti b o d y tit er s f or m u m p s, r u b ell a, v ari c ell a, a n d S. p n e u m o ni a e
 
S eri al pr e g n a n c y t e st s [ s er u m/ uri n e -h C G) will b e p erf or m e d i n w o m e n of 
c hil d b e ari n g p ot e nti al
 
J C V pl a s m a/ uri n e a s s e s s m e nt o nl y if d e e m e d n e c e s s ar y
8. 2 
S T A TI S TI C A L A N D A N A L Y TI C A L M E T H O D S
Pri or t o u n bli n di n g t h e tr e at m e nt gr o u p s, a S A P will b e pr o d u c e d t h at will c o nt ai n f ull 
d et ail s of all pl a n n e d a n al y s e s.  A n o utli n e of t h e pl a n n e d a n al y s e s i s d e s cri b e d b el o w.
T h e pri m ar y a n al y si s will b e c o n d u ct e d w h e n t h e b li n d e d tr e at m e nt p eri o d e n d s.  
A pri m ar y d at a b a s e l o c k will o c c ur w h e n t h e l a st p arti ci p a nt h a s c o m pl et e d t h eir 
W e e k 1 2 0 a s s e s s m e nt.  I n t h e e v e nt a n a d diti o n al tr e at m e nt c y cl e i s i n stit ut e d f or all 
p arti ci p a nt s b e c a u s e of l o w er t h a n a nti ci p at e d di s a bilit y pr o gr e s si o n r at e s at 1 2 0 w e e k s, 
t h e n t h e pri m ar y d at a b a s e l o c k will o c c ur w h e n a p pr o xi m at el y 2 5 3 c o nfir m e d di s a bilit y 
pr o gr e s si o n e v e nt s h a v e o c c urr e d.  T h e tr e at m e n t a s si g n m e nt s will b e u n bli n d e d t o t h e 
S p o n s or at t hi s ti m e f or t h e p ur p o s e s of d at a a n al y si s.  A n a d diti o n al a n al y si s c o m pri si n g 
of  b ot h s af et y a n d effi c a c y e n d p oi nt s will b e c o n d u ct e d at t h e e n d of t h e f oll o w-u p p eri o d 
t o i n v e sti g at e t h e m ai nt e n a n c e of th e tr e at m e nt eff e ct a n d/ or t h e p ot e nti al f or a 
wit h dr a w al eff e ct.
T h e pri m ar y a n d s e c o n d ar y e n d p oi nt r el at e d t o c o nfir m e d di s a bilit y pr o gr e s si o n will u s e 
all a v ail a bl e d at a i n t h e d at a b a s e at t h e ti m e of t h e a n al y si s.  All ot h er e n d p oi nt s 
c o n c er ni n g a s p e cifi c ti m e p oi nt, e. g. , c h a n g e fr o m b a s eli n e t o W e e k  1 2 0, will o nl y u s e 
d at a c oll e ct e d f or e a c h p arti ci p a nt u p t o a n d i n cl u di n g t h at ti m e p oi nt.  A n y d at a c oll e ct e d 
f or p arti ci p a nt s b e y o n d t h at ti m e p oi nt will n ot b e i n cl u d e d i n t h e e n d p oi nt d eri v ati o n o r 
a n al y si s.
All a n al y s e s, s u m m ari e s a n d li sti n g s will b e p erf or m e d u si n g S A S ® s oft w ar e ( v 8. 2 or 
hi g h er i n a U NI X e n vir o n m e nt).
8. 2. 1 
Pri m ar y  Effi c a c y An al y si s
T h e pri m ar y effi c a c y a n al y si s f or t hi s tri al will c o m p ar e t h e ti m e t o c o nfir m e d di s a bilit y 
pr o gr e s si o n ( 1 2-w e e k c o nfir m ati o n) b et w e e n o cr eli z u m a b a n d pl a c e b o.
Ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n ( 1 2 -w e e k c o nfir m ati o n) i s d efi n e d a s t h e ti m e 
fr o m ba s eli n e t o t h e fir st di s a bilit y pr o gr e s si o n, w hi c h i s c o nfir m e d at t h e n e xt r e g ul arl y 
s c h e d ul e d vi sit 1 2 w e e k s aft er t h e i niti al di s a bilit y pr o gr e s si o n.  D i s a bilit y pr o gr e s si o n i s 
d ef i n e d a s a n i n cr e a s e of 1. 0 p oi nt fr o m b a s eli n e E D S S, if t h e b a s eli n e E D S S i s 
b et w e e n 3. 0 5. 5 p oi nt s (i n cl u si v e), or a n i n cr e a s e of 0. 5 p oi nt s, if t h e b a s eli n e E D S S i s 
5. 5 p oi nt s.  T h e a s s e s s m e nt s wit hi n 3 0 d a y s aft er a pr ot o c ol -d ef i n e d r el a p s e will n ot b e 


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 6 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
u s e d f or c o nfir m ati o n of c o nfir m e d di s a bilit y pr o gr e s si o n.  T h e n o n- c o nfir m at or y E D S S 
a s s e s s m e nt s (if a n y) b et w e e n t h e i niti al a n d c o nfir m ati o n of di s a bilit y pr o gr e s si o n s h o ul d 
b e at l e a st a s hi g h a s t h e mi ni m u m c h a n g e r e q uir e d f or pr o gr e s si o n.
P arti ci p a nt s w h o di d n ot h a v e i niti al di s a bilit y pr o gr e s si o n at ti m e of pri m ar y d at a b a s e 
l o c k, ti m e of e arl y di s c o nti n u ati o n, or l o st t o f oll o w-u p will b e c e n s or e d at t h e d at e of t h eir 
l a st E D S S a s s e s s m e nt o c c urri n g d uri n g t h e tr e at m e nt p eri o d.  P arti ci p a nt s w h o h a d 
i niti al di s a bilit y pr o gr e s si o n wit h n o c o nfir m at or y E D S S a s s e s s m e nt a n d w h o ar e o n 
tr e at m e nt at ti m e of pri m ar y d at a b a s e l o c k will b e c e n s or e d at t h e d at e of t h eir l a st 
E D S S a s s e s s m e nt.  P arti ci p a nt s w h o h a d i niti al di s a bilit y pr o gr e s si o n a n d t h e n 
di s c o nti n u e t h e tr e at m e nt e arl y wit h n o c o nfir m at or y E D S S a s s e s s m e nt s will b e 
c o n si d er e d a s h a vi n g c o nfir m e d di s a bilit y pr o gr e s si o n.
Ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n f or t h e o cr eli z u m a b ar m a n d t h e pl a c e b o ar m 
will b e c o m p ar e d wit h u s e of a 2- si d e d l o g -r a n k t e st str atif yi n g b y g e o gr a p hi c r e gi o n 
( U. S. v s. R O W ) a n d a g e (4 5 v s. 4 5) .  T h e pr o p orti o n of p arti ci p a nt s wit h c o nfir m e d 
di s a bilit y pr o gr e s si o n will b e e sti m at e d wit h u s e of K a pl a n -M ei er m et h o d ol o g y.  
T h e o v er all h a z ar d r ati o will b e e sti m at e d wit h u s e of a str atifi e d C o x r e gr e s si o n m o d el 
wit h t h e s a m e str atifi c ati o n f a ct or s u s e d i n t h e str atifi e d l o g -r a n k te st a b o v e.
Ot h er s e n siti vit y a n al y s e s m a y al s o b e p erf or m e d f or t h e pri m ar y effi c a c y e n d p oi nt 
( a n d d o c u m e nt e d i n t h e S A P ).
8. 2. 2 
S e c o n d ar y  Effi c a c y A n al ys e s
E a c h s e c o n d ar y effi c a c y e n d p oi nt will b e t e st e d i n t h e hi er ar c hi c al or d er li st e d h er e, if 
t h e pri m ar y e n dp oi nt a n d e a c h pr e c e di n g e n d p oi nt h a v e r e a c h e d t h e si g nifi c a n c e l e v el of 
0. 0 5.
8. 2. 2. 1 
Ti m e t o O n s et of C o nfir m e d Di s a bilit y  Pr o gr e s si o n C o nfir m e d 
f or 2 4 W e e k s
Ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n o v er t h e tr e at m e nt p eri o d, d efi n e d a s a n 
i n cr e a s e of 1. 0 p oi nt fr o m b a s eli n e E D S S if t h e b a s eli n e E D S S i s 5. 5 p oi nt s, or a n 
i n cr e a s e of 0. 5 p oi nt s if t h e b a s eli n e E D S S i s 5. 5 p oi nt s, t h at i s s u st ai n e d f or 
2 4 w e e k s .
A s e c o n d ar y effi c a c y a n al y si s f or E D S S -b a s e d di s a bilit y pr o gr e s si o n i n t hi s tri al will 
c o m p ar e t h e ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n b et w e e n o cr eli z u m a b a n d pl a c e b o 
u si n g a 2 4 -w e e k c o nfir m ati o n wi n d o w f or di s a bilit y pr o gr e s si o n.  T h e a n al y si s of E D S S 
pr o gr e s si o n will b e c o n d u ct e d a s d e s cri b e d f or t h e pri m ar y a n al y si s wit h t h e e x c e pti o n
t h at t h e ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n ( 2 4 -w e e k c o nfir m ati o n) i s d efi n e d a s t h e 
ti m e fr o m b a s eli n e t o t h e fir st di s a bilit y pr o gr e s si o n, w hi c h i s c o nfir m e d at t h e n e xt 
r e g ul arl y s c h e d ul e d vi sit 2 4 w e e k s (1 6 1 d a y s) aft er t h e i niti al di s a bilit y pr o gr e s si o n.   
T h e s a m e a n al y si s pri n ci pl e s a s d e s cri b e d i n S e cti o n 8. 2. 1 will b e a p pli e d t o t h e 
2 4 w e e k c o nfir m e d di s a bili t y e n d p oi nt.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 7 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
8. 2. 2. 2 
C h a n g e i n Ti m e d 2 5 -F o ot W al k T e st fr o m B a s eli n e t o W e e k 1 2 0
F or t h e a s s e s s m e nt of diff er e n c e s i n t h e m e a n c h a n g e i n t h e T 2 5 F W T  fr o m b a s eli n e u p 
t o W e e k  1 2 0, a Mi x e d-Eff e ct M o d el R e p e at e d M e a s ur e s ( M M R M) a n al y si s will b e 
p erf or m e d.
8. 2. 2. 3 
C h a n g e i n T o t al V ol u m e of T 2 L e si o n s o n M RI S c a n s of t h e 
Br ai n fr o m B a s eli n e t o W e e k 1 2 0
F or t h e a s s e s s m e nt of diff er e n c e s i n t h e m e a n c h a n g e i n t ot al v ol u m e of T 2 l e si o n s fr o m 
b a s eli n e u p t o W e e k 1 2 0, a n M M R M a n al y si s will b e p erf or m e d.
8. 2. 2. 4 
P er c e nt C h a n g e o n M RI fr o m W e e k 2 4 t o W e e k 1 2 0 i n T ot al 
Br ai n V ol u m e
F or t h e a s s e s s m e nt of diff er e n c e s i n t h e p er c e nt c h a n g e i n t ot al v ol u m e of T 2 l e si o n s 
fr o m b a s eli n e u p t o We e k 1 2 0, a n M M R M a n al y si s will b e p erf or m e d.
8. 2. 2. 5 
C h a n g e fr o m B a s eli n e i n Q u alit y  of Lif e a s M e a s ur e d b y t h e 
S F -3 6 ( P h y si c al C o m p o n e nt S u m m ar y )
F or t h e a s s e s s m e nt of diff er e n c e s i n t h e m e a n c h a n g e i n P C S s c or e fr o m b a s eli n e t o 
W e e k 1 2 0, a n M M R M  a n al y si s will b e p erf or m e d.
8. 2. 3 
E x pl or at or y  An al y s e s
T h e e x pl or at or y e n d p oi nt s will b e s u m m ari z e d wit h u s e of t a bl e s, li sti n g s a n d gr a p h s, 
w h er e a p pr o pri at e.  F ull d et ail s of t h e d eri v ati o n s a n d a n al y s e s of e x pl or at or y e n d p oi nt s 
will b e pr o vi d e d i n t h e S A P .
8. 2. 4 
S a m pl e Si z e
T h e s a m pl e si z e w a s e sti m at e d o n t h e b a si s of d at a fr o m a rit u xi m a b P h a s e II/III tri al i n 
a d ult s wit h P P M S ( St u d y U 2 7 8 6 g).  F or t h e c urr e nt st u d y, t h e 2- y e ar pr o gr e s si o n r at e 
a m o n g p arti ci p a nt s r e c ei vi n g o cr eli z u m a b i s pr e di ct e d t o b e 3 0 %, a s c o m p ar e d wit h 4 3 % 
a m o n g p arti ci p a nt s r e c ei vi n g pl a c e b o.  A 2- gr o u p t e st of e q u al e x p o n e nti al s ur vi v al wit h 
e x p o n e nti al dr o p o ut i s u s e d t o d et er mi n e t h e s a m pl e si z e f or t h e ti m e t o c o nfir m e d 
di s a bilit y pr o gr e s si o n.  Wit h a 2: 1 r a n d o mi z ati o n r ati o b et w e e n t h e o cr eli z u m a b a n d 
pl a c e b o ar m s a n d t h e a s s u m pti o n of a 1- y e ar a c cr u al p eri o d wit h a 3. 5 -y e ar m a xi m u m 
tr e at m e nt p eri o d, t h e t ot al s a m pl e si z e of 6 3 0 p arti ci p a nt s pr o vi d e s a p pr o xi m at el y 8 0 %
p o w er, m ai nt ai ni n g t h e t y p e I err or r at e of 0. 0 1 ( or a p pr o xi m at el y 9 2 % p o w er f or 
T y p e I err or r at e of 0. 0 5) , a n d a s s u mi n g a dr o po ut r at e of 2 0%
o v er 2 y e ar s.
8. 2. 5 
H y p ot h e si s T e sti n g
T h e n ul l h y p ot h e si s will b e t e st e d at 0. 0 5 l e v el ( 2- si d e d t e st).  T h e h y p ot h e s e s t o b e 
t e st e d ar e a s f oll o w s :
 
H 0 ( n ull h y p ot h e si s): th er e i s n o diff er e n c e i n t h e ti m e t o c o nfir m e d di s a bilit y 
pr o gr e s si o n b et w e e n t h e o cr eli z u m a b a n d pl a c e b o gr o u p s
 
H 1 ( alt er n ati v e h y p ot h e si s): th er e i s a diff er e n c e i n t h e ti m e t o c o nfir m e d di s a bilit y 
pr o gr e s si o n b et w e e n t h e o cr eli z u m a b a n d pl a c e b o gr o u p s


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 2 8 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
Ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n f or t h e o cr eli z u m a b gr o u p a n d t h e pl a c e b o 
gr o u p will b e c o m p ar e d wit h u s e of a 2- si d e d l o g -r a n k t e st str atif yi n g b y g e o gr a p hi c 
r e gi o n ( U. S. v s. R O W)  a n d a g e (4 5 v s. 4 5).  If t h e t e st r e s ult i s st ati sti c all y si g nifi c a nt 
at 0. 0 5 l e v el ( 2- si d e d t e st), w e will c o n cl u d e t h at t h e o cr eli z u m a b ar m d e m o n str at e d a 
s u p eri or eff e ct of i n cr e a si n g ti m e t o c o nfir m e d di s a bilit y pr o gr e s si o n of p arti ci p a nt s, 
w h e n c o m p ar e d wit h t h e pl a c e b o ar m.
Si mil ar h y p ot h e s e s will al s o b e t e st e d f or t h e s e c o n d ar y effi c a c y p ar a m et er s. 
M et h o d s
f or h a n dli n g m ulti pli cit y i s s u e s r el at e d t o s e c o n d ar y e n d p oi nt s will b e d e s cri b e d 
i n t h e SA P .
8. 2. 6 
A n al y si s P o p ul ati o n s
O n e p arti ci p a nt p o p ul ati o n will b e d efi n e d f or t h e p ur p o s e of t h e s af et y a n al y si s a n d t w o 
f or t h e effi c a c y a n al y si s.  All effi c a c y an al y s e s will b e p erf or m e d wit h u s e of t h e 
i nt e nt-t o-tr e at (I T T) p o p ul ati o n.  T h e p er pr ot o c ol ( P P) p o p ul ati o n will b e u s e d f or t h e
pri m ar y a n d s o m e s e c o n d ar y effi c a c y a n al y s e s i n or d er t o e v al u at e t h e i nfl u e n c e of 
m aj or pr ot o c ol vi ol at or s a n d a s a s e n siti v it y c h e c k t o t h e I T T a n al y si s.
8. 2. 6. 1 
S af et y  P o p ul ati o n
T hi s p o p ul ati o n will b e u s e d f or all s u m m ari e s of s af et y d at a.  T h e s af et y p o p ul ati o n will 
i n cl u d e all p arti ci p a nt s w h o r e c ei v e d a n y st u d y dr u g.  R a n d o mi z e d p arti ci p a nt s t h at 
r e c ei v e i n c orr e ct t h er a p y fr o m t h at i nt e n d e d will b e s u m m ari z e d i n t h e gr o u p a c c or di n g 
t o t h e t h er a p y a ct u all y r e c ei v e d.  P arti ci p a nt s w h o ar e n ot r a n d o mi z e d, b ut w h o r e c ei v e 
st u d y dr u g will b e i n cl u d e d i n t h e s af et y p o p ul ati o n a n d s u m m ari z e d a c c or di n g t o t h e 
t h er a p y a ct u all y r e c ei v e d.
8. 2. 6. 2 
I nt e nt-t o-Tr e at P o p ul ati o n
All r a n d o mi z e d p arti ci p a nt s will b e i n cl u d e d i n t h e i nt e nt – t o-tr e at p o p ul ati o n.  
P arti ci p a nt s w h o pr e m at ur el y wit h dr a w fr o m t h e st u d y f or a n y r e a s o n a n d f or w h o m a n 
a s s e s s m e nt i s n ot p erf or m e d f or w h at e v er r e a s o n will still b e i n cl u d e d i n t h e 
I T T a n al y si s.  P arti ci p a nt s w h o r e c ei v e a n i n c orr e ct t h er a p y fr o m t h at w hi c h i s i nt e n d e d 
will b e s u m m ari z e d a c c or di n g t o t h eir r a n d o mi z e d tr e at m e nt.
8. 2. 6. 3 
P er Pr ot o c ol P o p ul ati o n
T h e P P p o p ul ati o n will i n cl u d e all p arti ci p a nt s i n t h e I T T p o p ul ati o n a d h eri n g t o t h e 
pr ot o c ol.  P arti ci p a nt s m a y b e e x cl u d e d if t h e y si g nifi c a ntl y vi ol at e t h e 
i n cl u si o n/ e x cl u si o n crit eri a or d e vi at e fr o m t h e st u d y pl a n.  S p e cifi c r e a s o n s f or 
w arr a nti n g e x cl u si o n will b e a gr e e d a n d d o c u m e nt e d i n t h e S A P pri or t o u n bli n di n g of 
t h e tr e at m e nt gr o u p s.  O nl y t h o s e p arti ci p a nt s wit h vi ol ati o n s t h at ar e d e e m e d t o 
p ot e nti all y aff e ct t h e effi c a c y of st u d y tr e at m e nt will b e e x cl u d e d fr o m t h e P P p o p ul ati o n.  
P arti ci p a nt s w h o r e c ei v e a n i n c orr e ct t h er a p y fr o m t h at i nt e n d e d will b e e x cl u d e d fr o m 
t h e P P p o p ul ati o n.


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8. 2. 7 
I nt eri m An al y si s
N o f or m al effi c a c y i nt eri m a n al y s e s ar e pl a n n e d.
8. 2. 8 
S af et y  D at a A n al y si s
All s af et y p ar a m et er s will b e s u m m ari z e d a n d pr e s e nt e d i n t a bl e s b a s e d o n t h e s af et y 
p o p ul ati o n.  R a n d o mi z e d p arti ci p a nt s t h at r e c ei v e i n c orr e ct t h er a p y fr o m t h at i nt e n d e d 
will b e s u m m ari z e d i n t h e gr o u p a c c or di n g t o t h e t h er a p y a ct u all y r e c ei v e d.  
P arti ci p a nt s w h o ar e n ot r a n d o mi z e d, b ut w h o r e c ei v e st u d y dr u g will b e i n cl u d e d i n t h e 
s af et y p o p ul ati o n a n d s u m m ari z e d a c c or di n g t o t h e t h er a p y a ct u all y r e c ei v e d.
T h e s af et y d at a will b e li st e d a n d s u m m ari z e d at d et er mi n e d c u t off p oi nt s, e. g., at t h e 
ti m e of t h e pri m ar y a n al y si s wit h u s e of all s af et y d at a a v ail a bl e, aft er t h e 1 2 0 -w e e k vi sit 
f or e a c h p arti ci p a nt , a n d at t h e e n d of f oll o w-u p p eri o d wit h u s e of all s af et y d at a 
a v ail a bl e.
All a d v er s e e v e nt s will b e c o d e d a n d t a b ul at e d b y S y st e m Or g a n Cl a s s a n d 
Pr ef err e d T er m f or i n di vi d u al e v e nt s wit hi n e a c h b o d y s y st e m, a n d will b e pr e s e nt e d i n 
d e s c e n di n g fr e q u e n c y.  A d v er s e e v e nt s will al s o b e t a b ul at e d b y s e v erit y a n d 
r el ati o n s hi p t o t h e st u d y m e di c ati o n.  S eri o u s a d v er s e e v e nt s will b e s u m m ari z e d 
s e p ar at el y.
A s s o ci at e d l a b or at or y p ar a m et er s s u c h a s h e p ati c f u n cti o n, r e n al f u n cti o n a n d 
h e m at ol o g y v al u e s will b e gr o u p e d a n d pr e s e nt e d t o g et h er.  M ar k e d a b n or m aliti e s will 
al s o b e fl a g g e d.  M ar k e d a b n or m aliti e s will b e t a b ul at e d f or e a c h l a b or at or y t e st b y 
tr e at m e nt gr o u p.
A n al y si s of H A H A t o o cr eli z u m a b will b e s u m m ari z e d gr a p hi c all y a n d d e s cri pti v el y.  
C or r el ati o n b et w e e n pr e s e n c e of H A H A a n d I R R/ a n a p h yl a cti c r e a cti o n s/ B c ell d e pl eti o n 
will b e pr e s e nt e d d e s cri pti v el y.
T h e c h a n g e fr o m b a s eli n e f or e a c h of t h e vit al si g n v ari a bl e s will b e c o m p ut e d a n d 
i n cl u d e d i n i n di vi d u al p arti ci p a nt li sti n g s a n d s u m m ari z e d wit h u s e of d e s cri pti v e 
st ati sti c s.
P h y si c al e x a mi n ati o n a n d E C G d at a will b e s u m m ari z e d d e s cri pti v el y a n d pr e s e nt e d i n 
i n di vi d u al p arti ci p a nt li sti n g s.
A n e xt er n al, iD M C will r e vi e w s af et y d at a t hr o u g h o ut t h e st u d y a n d will c o n v e n e at l e a st 
3 p er y e ar.  Aft er t h e pri m ar y u n bli n di n g , i D M C i n v ol v e m e nt i n s af et y m o nit ori n g 
t hr o u g h o ut t h e O L E p h a s e i s n o l o n g er n e e d e d.  A n al y s e s r e q uir e d f or t h e D M C d at a 
r e vi e w will b e p erf or m e d a s d e s cri b e d i n t h e D M C C h art er a n d D M C d at a h a n dli n g pl a n.


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8. 2. 9 
S af et y  F oll o w-U p P eri o d
D at a fr o m t hi s p eri o d will b e a n al y z e d t o pr o vi d e i nf or m ati o n o n t h e m ai nt e n a n c e eff e ct 
a n d t h e p ot e nti al wit h dr a w al eff e ct of o cr eli z u m a b.  I n a d diti o n, d at a will b e a n al y z e d t o 
pr o vi d e i nf or m ati o n c o n c er ni n g t h e l o n g -t er m s af et y of o cr eli z u m a b.  D at a will b e 
s u m m ari z e d a n d t a bl e s a n d li sti n g s will b e pr o d u c e d.
8. 2. 1 0 
O p e n -L a b el E xt e n si o n P h a s e
D at a fr o m t hi s p eri o d of t h e st u d y will b e a n al y z e d i n or d er t o c h ar a ct eri z e t h e l o n g -t er m 
s af et y a n d effi c a c y of o cr eli z u m a b b e y o n d t h e b li n d e d tr e at m e nt p eri o d of t h e st u d y.  
T h e d at a will b e s u m m ari z e d a c c or di n g t o t h e r a n d o mi z e d tr e at m e nt gr o u p s of t h e 
b li n d e d tr e at m e nt p eri o d of t h e st u d y.  D et ail s of t h e st ati sti c al a n al y s e s will b e pr o vi d e d 
i n t h e S A P.
8. 2. 1 1 
Ot h er A n al y s e s
8. 2. 1 1. 1 
P h ar m a c o ki n eti c A n al y si s
P h a r m a c o ki n eti c P ar a m et er s
O cr eli z u m a b s er u m c o n c e ntr ati o n -ti m e d at a will b e m o d el e d wit h u s e of a p o p ul ati o n 
a p pr o a c h.  T h e pri m ar y p o p ul ati o n P K p ar a m et er s ( c l e ar a n c e s a n d v ol u m e s) f or 
o cr eli z u m a b will b e e sti m at e d b y m e a n s of n o n li n e ar mi x e d -eff e ct s m o d eli n g ( N O N M E M )
a n al y si s of t h e s p ar s e P K d at a.  Cl e ar a n c e s wit h a s s o ci at e d i nt er -p arti ci p a nt v ari a bilit y 
m a y b e c h ar a ct eri z e d b y a s at ur a bl e a n d n o n -s at ur a bl e cl e ar a n c e a s w ell a s a n 
i nt er c o m p art m e nt al cl e ar a n c e d e p e n di n g o n t h e fi n al str u ct ur al m o d el.  V ol u me s wit h 
a s s o ci at e d i nt er -p arti ci p a nt v ari a bilit y m a y b e c h ar a ct eri z e d b y c e ntr al a n d p eri p h er al 
v ol u m e s d e p e n di n g o n t h e fi n al str u ct ur al m o d el.  E x p o s ur e ( A U C) t o o cr eli z u m a b will b e 
e sti m at e d.  T h e s el e cti o n of ot h er p ar a m et er s will d e p e n d o n t h e fi n al P K m o d el u s e d f or 
t hi s a n al y si s.
P h ar m a c o ki n eti c A n al y si s
N o nli n e ar mi x e d -eff e ct s m o d eli n g ( wit h s oft w ar e N O N M E M [ B e al et al. 1 9 9 2 ]) will b e 
u s e d t o a n al y z e t h e s p ar s e s a m pli n g d o s e -c o n c e ntr ati o n -ti m e d at a of o cr eli z u m a b.  
P arti ci p a nt s w h o h a v e m e a s ur a bl e c o n c e ntr ati o n s of o cr eli z u m a b will b e i n cl u d e d i n t h e 
P K a n al y si s u nl e s s m aj or pr ot o c ol d e vi ati o n s or u n a v a il a bilit y of i nf or m ati o n 
( e. g., e x a ct bl o o d s a m pli n g ti m e) o c c urr e d w hi c h m a y i nt erf er e wit h P K e v al u ati o n.  T h e 
P K d at a of t hi s st u d y m a y b e p o ol e d w it h m or e e xt e n si v e d at a fr o m ot h er st u di e s.  
P o p ul ati o n P K p ar a m et er s ( c l e ar a n c e s a n d v ol u m e s) will b e e sti m at e d a n d t h e i nfl u e n c e 
of  c o v ari at e s, s u c h a s a g e, s e x , w ei g ht, H A H A, a n d b a s eli n e C D 1 9 l y m p h o c yt e s, o n 
t h e s e p ar a m et er s will b e i n v e sti g at e d.
D et ail s of t h e mi x e d -eff e ct s m o d eli n g a n al y s e s will b e d e s cri b e d i n a M o d eli n g a n d 
Si m ul ati o n A n al y si s Pl a n a n d r e s ult s will b e r e p ort e d s e p ar at el y.
8. 2. 1 1. 2 
P h ar m a c o d y n a mi c A n al y si s
If p o s si bl e, n o nli n e ar mi x e d-eff e ct s m o d eli n g ( wit h s oft w ar e N O N M E M [ B e al et al. 1 9 9 2 ]) 
will b e u s e d t o i n v e sti g at e t h e r el ati o n s hi p b et w e e n o cr eli z u m a b e x p o s ur e a n d t h e s af et y 


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a n d effi c a c y p ar a m et er s, w hi c h m a y , i n cl u d e b ut ar e n ot li mit e d t o, t h e pr o p orti o n of 
p arti ci p a nt s wit h c o nfir m e d di s a bilit y pr o gr e s si o n, n u m b er of G d -e n h a n ci n g T 1 l e si o n s 
o n br ai n M RI s c a n s, a n d v ol u m e a n d n u m b er of T 2 l e si o n s o n br ai n M RI s c a n s.  
Cl a s si c al hi er ar c hi c al P K -P D m o d el s li k e li n e ar, E m a x or si g m oi d al E m a x m o d el s will b e 
u s e d.  T h e p o s si bilit y of a d el a y b et w e e n t h e ti m e -c o ur s e of eff e ct s a n d e x p o s ur e will b e 
i n v e sti g at e d wit h u s e of i n dir e ct P D m o d el s.  Ti m e t o e v e nt a n d l o gi sti c r e gr e s si o n 
a n al y s e s will al s o b e c o n d u ct e d w h e n a p pr o pri at e.
E x pl or at or y a n al y s e s m a y b e p erf or m e d t o a s s e s s t h e p o s si bl e r el ati o n s hi p b et w e e n 
P D m ar k er s, P K a n d cli ni c al r e s p o n s e.
8. 2. 1 1. 3 
Bi o m ar k er S a m pl e R e p o sit or y / Bi o m ar k er R e s e ar c h S a m pl e s
A d diti o n al bl o o d s a m pl e s f or s er u m a n d/ or pl a s m a a n al y s e s a n d C S F ( C S F f or R B R 
o nl y) will b e t a k e n f or r e s e ar c h p ur p o s e s s u bj e ct t o di s cr eti o n ar y a p pr o v al fr o m e a c h 
c e nt er’ s I R B/ E C a n d t h e p arti ci p a nt ’ s s p e cifi c writt e n c o n s e nt.  T h e s e s a m pl e s will b e 
u s e d t o i d e ntif y d y n a mi c bi o m ar k er s t o h el p u s b ett er u n d er st a n d t h e p at h o g e n e si s of 
P P M S a n d r e s p o n s e t o tr e at m e nt wit h o cr eli z u m a b.  S u c h f ut ur e bi o m ar k er s h a v e y et t o 
b e d et er mi n e d b ut m a y i n cl u d e cir c ul ati n g bi o c h e mi c al m ar k er s i n bl o o d , i n cl u di n g 
c yt o ki n e s a s w ell a s p eri p h er al bl o o d g e n e e x pr e s si o n p att er n s.  E x pl or at or y st ati sti c al 
d at a a n al y s e s m a y i n cl u d e a s s e s s m e nt s f or p o s si bl e r el ati o n s hi p s b et w e e n t h e s e 
bi o m ar k er l e v el s, P K a n d cli ni c al r e s p o n s e.
8. 2. 1 1. 4 
Cli ni c al G e n ot y pi n g
D N A a n al y si s will b e p erf or m e d o nl y o n b a s eli n e s a m pl e s ( c oll e ct e d d uri n g t h e b li n d e d 
tr e at m e nt p eri o d a n d t h e O L E p h a s e ) cl e arl y d e si g n at e d f or t hi s p ur p o s e.  
T h e s e s a m pl e s will o nl y b e u s e d f or i n v e sti g ati o n i n v ol vi n g P P M S a n d o cr eli z u m a b 
r e s p o n s e, a n d will n ot b e u s e d t o d et er mi n e g e n eti c s u s c e pti bilit y t o di s e a s e s t h at 
p arti ci p a nt s d o n ot c urr e ntl y h a v e.
9.
D A T A  C O L L E C TI O N, M AN A G E M E N T , A N D Q U A LI T Y 
A S S U R A N C E
T h e o v er all pr o c e d ur e s f or q u alit y a s s ur a n c e of cli ni c al st u d y d at a ar e d e s cri b e d i n t h e 
S p o n s or’ s ( or d e si g n e e) St a n d ar d O p er ati o n al Pr o c e d ur e s.
D at a f or t hi s st u d y will b e r e c or d e d vi a a n El e ctr o ni c D at a C a pt ur e ( E D C) s y st e m wit h 
u s e of el e ctr o ni c C a s e R e p ort F or m s.  It will b e tr a n s cri b e d b y t h e sit e fr o m t h e p a p er 
s o ur c e d o c u m e nt s o nt o t h e e C R F (i n n o c a s e i s t h e e C R F t o b e c o n si d er e d a s s o ur c e 
d at a f or t hi s tri al) .  I n a d diti o n, E D S S, M S F C S, a n d P R O s will b e c oll e ct e d a c c or di n g t o 
t h e pr ot o c ol s c h e d ul e of a cti viti e s , a n d t h e d at a will b e e nt er e d i nt o t h e cli ni c al d at a b a s e . 
A c c ur at e a n d r eli a bl e d at a c oll e cti o n will b e a s s ur e d b y v erifi c ati o n a n d cr o s s -c h e c k of 
t h e e C R F s a g ai n st t h e in v e sti g at or’ s r e c or d s b y t h e st u d y m o nit or ( s o ur c e d o c u m e nt 
v erifi c ati o n), a n d t h e m ai nt e n a n c e of a dr u g di s p e n si n g l o g b y t h e in v e sti g at o r.


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A c o m pr e h e n si v e v ali d ati o n c h e c k pr o gr a m utili zi n g fr o nt -e n d c h e c k s i n t h e e C R F a n d 
b a c k -e n d c h e c k s i n t h e d at a b a s e will v erif y t h e d at a a n d di s cr e p a n ci e s will b e 
g e n er at e d a c c or di n gl y.  T h e s e ar e tr a n sf err e d el e ctr o ni c all y t o t h e e C R F at t h e sit e f or 
r e sol uti o n b y t h e in v e sti g at or.
T hr o u g h o ut t h e st u d y t h e St u d y M a n a g e m e nt T e a m will r e vi e w d at a a c c or di n g t o t h e 
D at a V ali d ati o n M a n u al.
I n or d er f or t h e S p o n s or t o m a k e r e c o m m e n d ati o n s or d e ci si o n s r e g ar di n g f urt h er 
d e v el o p m e nt of t h e dr u g, it m a y o p e n t h e b li n di n g c o d e a s s o o n a s t h e a d v er s e e v e nt
a n d pri m ar y d at a f or a gr o u p h a v e b e e n tr a n s cri b e d o nt o t h e e C R F a n d t h e cli ni c al 
s ci e nti st a n d in v e sti g at or h a v e r e vi e w e d t h e d at a.
I n or d er t o f a cilit at e a n al y si s of t h e bi ol o gi c al s a m pl e s c oll e ct e d i n t hi s st u d y, t h e 
tr e at m e nt c o d e will b e r el e a s e d t o t h e r e s p o n si bl e a n al yti c al p er s o n w h e n t h e s a m pl e s 
h a v e b e e n r e c ei v e d at t h e a n al yti c al sit e a n d ar e r e a d y f or a s s a y.  T h e r e s ult of t h e 
a n al y si s m u st n ot b e r el e a s e d wit h i n di vi d u al i d e ntifi c ati o n of t h e s u bj e ct u ntil t h e 
d at a b a s e i s cl o s e d.
9. 1 
A S SI G N M E N T O F P R E F E R R E D T E R M S A N D O RI GI N A L  
T E R MI N O L O G Y
F or cl a s sifi c ati o n p ur p o s e s, pr ef err e d t er m s will b e a s si g n e d b y t h e S p o n s or t o t h e 
ori gi n al t er m s e nt er e d o n t h e e C R F, wit h u s e of t h e m o st u p-t o-d at e v er si o n of t h e 
M e d D R A t er mi n ol o g y f or a d v er s e e v e nt s, di s e a s e s a n d m e di c al hi st or y a n d t h e 
I nt er n ati o n al N o n-pr o pri et ar y N a m e Dr u g T er m s a n d Pr o c e d ur e s Di cti o n ar y f or 
tr e at m e nt s a n d s ur gi c al a n d m e di c al pr o c e d ur e s.
1 0. 
S T U D Y C O M MI T T E E S
1 0. 1 
S T E E RI N G C O M MI T T E E
A n e xt er n al St e eri n g C o m mitt e e will pr o vi d e g e n er al g ui d a n c e, a s si st wit h li ai s o n t o 
i n v e sti g at or s a n d o v er s e e a n y e xt er n al c o m m u ni c ati o n of t h e r e s ult s of t h e st u d y.
1 0. 2 
D A T A  M O NI T O RI N G C O M MI T T E E
A n e xt er n al iD M C will b e c h art er e d t o r e vi e w s af et y d at a a n d m a k e r e c o m m e n d ati o n s 
r eg ar di n g c o nti n u ati o n, t er mi n ati o n, or m o difi c ati o n of t h e st u d y.  R e g ul arl y s c h e d ul e d 
s af et y d at a r e vi e w s will o c c ur a p pr o xi m at el y o n a q u art erl y b a si s aft er t h e fir st p arti ci p a nt
i s e nr oll e d.  A f ull r e vi e w f or s af et y will b e p erf or m e d aft er all p arti ci p a nt s h a v e 
c o m pl et e d t h e fir st tr e at m e nt c y cl e.  Aft er t h e pri m ar y u n bli n di n g, i D M C i n v ol v e m e nt i n 
s af et y m o nit ori n g t hr o u g h o ut t h e O L E p h a s e i s n o l o n g er n e e d e d.
A n y s af et y e v e nt t h at r e q uir e s u n bli n di n g will b e i m m e di at el y r e p ort e d t o t h e D M C a n d t o 
t h e h ealt h a ut h oriti e s i n a n e x p e dit e d s af et y r e p ort.  T h e D M C m a y r e q u e st a n d r e vi e w 
a n y a d diti o n al r e p ort s o ut si d e of t h e pl a n n e d a n al y s e s at a n y ti m e if d e e m e d n e c e s s ar y 


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1 3 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
t o e n s ur e t h e s af et y of p arti ci p a nt s.  T h e s af et y e v al u ati o n s will b e c o n d u ct e d o n 
p ar a m e t er s s p e cifi e d wit hi n t h e D M C C h art er a n d m a y v ar y d e p e n di n g o n t h e 
r e q uir e m e nt s a n d r e q u e st s of t h e D M C.  B e si d e s t h e c o n v e nti o n al s af et y v ari a bl e s, s u c h 
a s s eri o u s a d v er s e e v e nt s, l a b or at or y t e st s, a n d vit al si g n c h a n g e s, r e s ult s of B c ell 
c o u nt s, I R R s, t hr o m b o s e s, i nf e cti o n s, a n d H A H A r at e s, will b e c ar ef ull y e x a mi n e d.  
I n a d diti o n, o n e M RI m e a s ur e m e nt (t h e t ot al n u m b er of g a d oli ni u m -e n h a n ci n g T 1 
l e si o n s) will b e e v al u at e d t o m o nit or f or a n y w or s e ni n g ( s af et y M RI p ar a m et er).
T h e d et ail s of t h e D M C r ol e s a n d r e s p o n si biliti e s a n d t h e l o gi sti c s of t h e D M C a cti viti e s 
will b e o utli n e d i n a D M C C h art er.  T h e p ur p o s e of t h e D M C i nt eri m a n al y s e s i s pri m aril y 
s af et y e v al u ati o n, a n d t h e st u d y m a y b e st o p p e d or a m e n d e d b e c a u s e of si g nifi c a nt 
s af et y c o n c er n s .


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 3 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
1 1. 
R E F E R E N C E S
Al oi si F a n d P uj ol -B orr ell R. L y m p h oi d n e o g e n e si s i n c hr o ni c i nfl a m m at or y di s e a s e s. 
N at R e v I m m u n ol 2 0 0 6; 6: 2 0 5 1 7.
A n d er s s o n P B, W a u b a nt E, G e e L, et al. M ulti pl e s cl er o si s t h at i s pr o gr e s si v e fr o m t h e 
ti m e of o n s et: cli ni c al c h ar a ct eri sti c s a n d pr o gr e s si o n of di s a bilit y. Ar c h N e ur ol 
1 9 9 9; 5 6: 1 1 3 8 4 2.
A n d er s s o n M, Y u M, S ö d er str ö m M, et al. M ulti pl e M A G p e pti d e s ar e r e c o g ni z e d b y 
cir c ul ati n g T a n d B l y m p h o c yt e s i n p ol y n e ur o p at h y a n d m ulti pl e s cl er o si s. E ur J 
N e ur ol 2 0 0 2; 9: 2 4 3 5 1.
A n oli k J H, C a m p b ell D, F el g ar R E, et al . T h e r el ati o n s hi p of F c g a m m a RIII a g e n ot y p e t o 
d e gr e e of B c ell d e pl eti o n b y rit u xi m a b i n t h e tr e at m e nt of s y st e mi c l u p u s 
er yt h e m at o s u s. Art hriti s R h e u m 2 0 0 3; 4 8: 4 5 5 9.
B a n c h er e a u J a n d R o u s s et F. H u m a n B l y m p h o c yt e s: p h e n ot y p e, pr olif er ati o n, a n d 
diff er e nti ati o n. A d v I m m u n ol 1 9 9 2; 5 2: 1 2 5 2 6 2.
B ar a n zi ni S E, J e o n g M C, B ut u n oi C, et al. B c ell r e p ert oir e di v er sit y a n d cl o n al
e x p a n si o n i n m ulti pl e s cl er o si s br ai n l e si o n s. J I m m u n ol 1 9 9 9; 1 6 3: 5 1 3 3 4 4.
B ar -Or A, C al a br e si P A, Ar n ol d D, et al. Rit u xi m a b i n r el a p si n g -r e mitti n g m ulti pl e 
s cl er o si s: a 7 2 -w e e k, o p e n -l a b el, p h a s e I tri al. A n n N e ur ol 2 0 0 8; 6 3: 3 9 5 4 0 0.
B e al S L, B o e c k m a n A J, S h ei n er L B.  N O N M E M U s er’ s G ui d e, P art s I VIII 
S a n Fr a n ci s c o: Di vi si o n of Cli ni c al P h ar m a c ol o g y - U ni v er sit y of C alif or ni a, 1 9 9 2.
B er g er J R, A k s a mit h A J, Cliff or d D B, et al. P M L di a g n o sti c crit eri a: c o n s e n s u s st at e m e nt
fr o m t h e A A N N e ur oi nf e cti o u s Di s e a s e S e cti o n. N e ur ol o g y 2 0 1 3; 8 0: 1 4 3 0 8.
Br a n c h D W.  P hy si ol o gi c a d a pt ati o n s of pr e g n a n c y. A m J R e pr o d I m m u n ol 
1 9 9 2; 2 8: 1 2 0 2.
C al a br e s e L H, M oll o y E S, H u a n g D, et al. Pr o gr e s si v e m ultif o c al l e u k o e n c e p h al o p at h y i n 
r h e u m ati c di s e a s e s: e v ol vi n g cli ni c al a n d p at h ol o gi c p att er n s of di s e a s e. Art hriti s 
R h e u m 2 0 0 7; 5 6: 2 1 1 6 – 2 8.
C o h e n J A, Fi s c h er J S, B oli br u s h D M, et al. I ntr ar at er a n d i nt err at er r eli a bilit y of t h e M S 
f u n cti o n al c o m p o sit e o ut c o m e m e a s ur e. N e ur ol o g y 2 0 0 0; 5 4: 8 0 2– 6.
C ol o m b o M, D o n o M, G a z z ol a P, et al. A c c u m ul ati o n of cl o n all y r el at e d B l y m p h o c yt e s i n 
t h e c er e br o s pi n al fl ui d of m ulti pl e s cl er o si s p ati e nt s. J I m m u n ol 2 0 0 0; 1 6 4: 2 7 8 29.
C o st ell o F, H o d g e W , P a n YI, et al. Tr a c ki n g r eti n al n er v e fi b er l a y er l o s s aft er o pti c 
n e uriti s: a pr o s p e cti v e st u d y u si n g o pti c al c o h er e n c e t o m o gr a p h y. M ult
S cl er 
2 0 0 8; 1 4: 8 9 3 – 9 0 5.
C ottr ell D A, Kr e m e n c h ut z k y M, Ri c e G P, et al. T h e n at ur al hi st or y of m ulti pl e s cl er o si s: a 
g e o gr a p hi c all y b a s e d st u d y. 5. T h e cli ni c al f e at ur e s a n d n at ur al hi st or y of pri m ar y 
pr o gr e s si v e m ulti pl e s cl er o si s. Br ai n 1 9 9 9; 1 2 2: 6 2 5 3 9.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
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E b er s G C. N at ur al hi st or y of pri m ar y pr o gr e s si v e m ulti pl e s cl er o si s. M ult S cl er 
2 0 0 4; 1 0: S 8 1 3.
E g g R, R ei n dl M, D ei s e n h a m m er F, et al. A nti -M O G a n d a nti -M B P a nti b o d y s u b cl a s s e s 
i n m ulti pl e s cl er o si s. M ult S cl er 2 0 0 1; 7: 2 8 59.
E m er y P, Fl ei s c h m a n n R, Fili p o w i c z-S o s n o w s k a A, et al. T h e effi c a c y a n d s af et y of 
rit u xi m a b i n p ati e nt s wit h a cti v e r h e u m at oi d art hriti s d e s pit e m et h otr e x at e 
tr e at m e nt: r e s ult s of a p h a s e II B r a n d o mi z e d, d o u bl e-bli n d, pl a c e b o -c o ntr oll e d, 
d o s e -r a n gi n g tri al. Art hriti s R h e u m 2 0 0 6; 5 4: 1 3 9 0 – 4 0 0.
Fi s c h er J S, R u di c k R A, C utt er G R, et al. N ati o n al M S S o ci et y Cli ni c al O ut c o m e s 
A s s e s s m e nt T a s k F or c e. T h e M ulti pl e S cl er o si s F u n cti o n al C o m p o sit e M e a s ur e 
( M S F C): a n i nt e gr at e d a p pr o a c h t o M S cli ni c al o ut c o m e a s s e s s m e nt. M ult S cl er 
1 9 9 9; 5: 2 4 4 5 0.
Fr a n c i ott a D, S al v etti M, L olli F, et al. B c ell s a n d m ulti pl e s cl er o si s. L a n c et N e ur ol 
2 0 0 8; 7: 8 5 2 8.
Fr o h m a n E M, F uji m ot o J G, Fr o h m a n T C, et al. O pti c al c o h er e n c e t o m o gr a p h y: a wi n d o w 
i nt o t h e m e c h a ni s m s of m ulti pl e s cl er o si s. N at ur e Cli n Pr a ct 2 0 0 8; 4: 6 6 4 7 5.
G e n ai n C P, C a n n ell a B, H a u s er S L, et al. I d e ntifi c ati o n of a ut o a nti b o di e s a s s o ci at e d wit h 
m y eli n d a m a g e i n m ulti pl e s cl er o si s. N at M e d 1 9 9 9; 5: 1 7 0 5.
G e n o v e s e M C, K ai n e J L, L o w e n st ei n M B, et al . O cr eli z u m a b, a h u m a ni z e d a nti -C D 2 0 
m o n o cl o n al a nti b o d y, i n t h e tr e at m e nt of p ati e nt s wit h r h e u m at oi d art hriti s: a p h a s e 
I/II r a n d o mi z e d, bli n d e d, pl a c e b o-c o ntr oll e d, d o s e -r a n gi n g st u d y. Art hriti s R h e u m 
2 0 0 8; 5 8: 2 6 5 2 6 1.
H a u s er S L, W a u b a nt E, Ar n ol d D L, et a l. H E R M E S Tri al Gr o u p. B -c ell d e pl eti o n wit h
rit u xi m a b i n r el a p si n g-r e mitti n g m ulti pl e s cl er o si s. N E n gl J M e d 2 0 0 8; 3 5 8: 6 7 68 8.
H a w k er K, O’ C o n n or P, Fr e e d m a n M, et al. Rit u xi m a b i n p ati e nt s wit h pri m ar y 
pr o gr e s si v e m ulti pl e s cl er o si s: r e s ult s of a r a n d o mi z e d d o u bl e -bli n d 
pl a c e b o -c o ntr oll e d m ulti c e nt er tri al. A n n N e ur ol 2 0 0 9; 6 6: 4 6 0 7 1.
H o w ell O W , R e e v e s C, M a gli o z zi R, et al. T h e i n ci d e n c e of m e ni n g e al B-c ell f olli cl e s i n 
s e c o n d ar y pr o gr e s si v e m ulti pl e s cl er o si s: a n e ur o p at h ol o gi c al st u d y of 9 6 c a s e s 
( a b stra ct). M ult S cl er 2 0 0 9; 1 5: S 5.
I n gr a m G, H a k o b y a n S, Hir st C L, et al. C o m pl e m e nt r e g ul at or f a ct or H a s a s er u m 
bi o m ar k er of m ulti pl e s cl er o si s di s e a s e st at e. Br ai n 2 0 1 0; 1 3 3: 1 6 0 2 1 1.
K a p p o s L, Li D, C al a br e si P A, et al. O cr eli z u m a b i n r el a p si n g -r e mitti n g m ulti pl e
s cl er o si s: a p h a s e 2, r a n d o mi s e d, pl a c e b o -c o ntr oll e d, m ulti c e ntr e tri al. 
L a n c et 2 0 1 1; 3 7 8: 1 7 7 9 8 7.
Kit a M, C o h e n J, F o x R. A p h a s e II tri al of mit o x a ntr o n e i n p arti ci p a nt s wit h pri m ar y 
pr o gr e s si v e m ulti pl e s cl er o si s ( a b str a ct). N e ur ol 2 0 0 4; 6 2: A 9 9.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 3 6 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
K ut z el ni g g A, F a b er -R o d J C, B a u er J, et al. Wi d e s pr e a d d e m y eli n ati o n i n t h e c er e b ell ar 
c ort e x i n m ulti pl e s cl er o si s. Br ai n P at h ol 2 0 0 7; 1 7: 3 8 4 4.
L a m br a c ht -W a s hi n gt o n D, O' C o n n or K C, C a m er o n E M, et al. A nti g e n s p e cifi cit y of 
cl o n all y e x p a n d e d a n d r e c e pt or e dit e d c er e br o s pi n al fl ui d B c ell s fr o m p ati e nt s wit h 
r el a p si n g-r e mitti n g M S. J N e ur oi m m u n ol 2 0 0 7; 1 8 6: 1 6 4 7 6.
L e ar y S M, Mill er D H, St e v e n s o n V L, et al. I nt erf er o n b et a-1 a i n pri m ar y pr o gr e s si v e M S: 
a n e x pl or at or y, r a n d o mi z e d, c o ntr oll e d tri al. N e ur ol o g y 2 0 0 3; 6 0: 4 4 5 1.
L u bli n F D, R ei n g ol d S C, C o h e n J A, et al. D ef i ni n g t h e cli ni c al c o ur s e of m ulti pl e 
s cl er o si s: t h e 2 0 1 3 r e vi si o n s. N e ur ol o g y 2 0 1 4; 8 3: 2 7 8 8 6.
M a gli o z zi R, H o w ell O, V or a A, et al. M e ni n g e al B -c ell f olli cl e s i n s e c o n d ar y pr o gr e s si v e 
m ulti pl e s cl er o si s a s s o ci at e d wit h e arl y o n s et of di s e a s e a n d s e v er e c orti c al 
p at h ol o g y. Br ai n 2 0 0 7; 1 3 0: 1 0 8 9 1 0 4.
M c D o n al d W I, C o m p st o n A, E d a n G, et al. R e c o m m e n d e d di a g n o sti c crit eri a f or m ulti pl e
s cl er o si s: g ui d eli n e s fr o m t h e I nt er n ati o n al P a n el o n t h e Di a g n o si s o f Multi pl e 
S cl er o si s. A n n N e ur ol 2 0 0 1; 5 0: 1 2 1 7.
M c F arl a n d H F. T h e B c ell — ol d pl a y er, n e w p o siti o n o n t h e t e a m. N E n gl J M e d 
2 0 0 8; 3 5 8: 6 6 4 5.
M e i nl E, Kr u m b h ol z M, H o hlf el d R. B li n e a g e c ell s i n t h e i nfl a m m at or y c e ntr al n er v o u s 
s y st e m e n vir o n m e nt: mi gr ati o n, m ai nt e n a n c e, l o c al a nti b o d y pr o d u cti o n, a n d 
t h er a p e uti c m o d ul ati o n. A n n N e ur ol 2 0 0 6; 5 9: 8 8 0 9 2.
Mill er D H, L e ar y S M. Pri m ar y pr o gr e s si v e m ulti pl e s cl er o si s. L a n c et N e ur ol
2 0 0 7; 6: 9 0 3 1 2.
M o n s o n N L, Br e zi n s c h e k H P, Br e zi n s c h e k RI, et al. R e c e pt or r e vi si o n a n d at y pi c al
m ut ati o n al c h ar a ct eri sti c s i n cl o n all y e x p a n d e d B c ell s fr o m t h e c er e br o s pi n al fl ui d 
of  r e c e ntl y di a g n o s e d m ulti pl e s cl er o si s p ati e nt s. J N e ur oi m m u n ol 
2 0 0 5; 1 5 8: 1 7 0 8 1.
M o nt al b a n X. O v er vi e w of E ur o p e a n pil ot st u d y of i nt erf er o n b et a -I b i n pri m ar y 
pr o gr e s si v e m ulti pl e s cl er o si s. M ult S cl er 2 0 0 4; 1 0: S 6 2.
O b er m ei er B, M e nt el e R, M al ot k a J, et al. M at c hi n g of oli g o cl o n al i m m u n o gl o b uli n 
tr a n s cri pt o m e s a n d pr ot e o m e s of c ere br o s pi n al fl ui d i n m ulti pl e s cl er o si s. N at M e d 
2 0 0 8; 1 4: 6 8 8 9 3.
O C R E V U S ( o cr eli z u m a b) I nj e cti o n, G e n e nt e c h. M ar c h 2 0 1 7 [ cit e d 7 S e pt e m b er 2 0 1 7]. 
A v ail a bl e fr o m:
htt p s:// w w w. g e n e. c o m/ d o w nl o a d/ p df/ o cr e v u s _ pr e s cri bi n g. p df.
O w e n s G P, Kr a u s H, B ur g o o n M P, et al. R e stri ct e d u s e of V H 4 g er mli n e s e g m e nt s i n a n 
a c ut e m ulti pl e s cl er o si s br ai n. A n n N e ur ol 1 9 9 8; 4 3: 2 3 6 4 3.
O w e n s G P, W i n ge s K M, Rit c hi e A M, et al. V H 4 g e n e s e g m e nt s d o mi n at e t h e i ntr at h e c al 
h u m or al i m m u n e r e s p o n s e i n m ul ti pl e s cl er o si s. J I m m u n ol 2 0 0 7; 1 7 9: 6 3 4 35 1.


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P ol m a n C H, R ei n g ol d S C, B ar k h of F, et al. Et hi c s of pl a c e b o -c o ntr oll e d cli ni c al tri al s i n 
m ulti pl e s cl er o si s: a r e a s s e s s m e nt. N e ur ol o g y 2 0 0 8; 7 0: 1 1 3 4 4 0.
P ol m a n C H, R ei n g ol d S C, E d a n G, et al. Di a g n o sti c crit eri a f or m ulti pl e s cl er o si s: 2 0 0 5 
r e vi sio n s t o t h e " M c D o n al d Crit eri a". A n n N e ur ol 2 0 0 5; 5 8: 8 4 0 6.
Qi n Y, D u q u ett e P, Z h a n g Y, et al. Cl o n al e x p a n si o n a n d s o m ati c h y p er m ut ati o n of V( H) 
g e n e s of B c ell s fr o m c er e br o s pi n al fl ui d i n m ulti pl e s cl er o si s. J Cli n I n v e st 
1 9 9 8; 1 0 2: 1 0 4 5 5 0.
R a m a g o p al a n a S V, K ni g ht J C , E b er s G C . M ulti pl e s cl er o si s a n d t h e m aj or 
hi st o c o m p ati bilit y c o m pl e x. C urr O pi n N e ur ol 2 0 0 9; 2 2: 2 1 9 – 2 5.
R ei n dl M, Li ni n gt o n C, Br e h m U, et al. A nti b o di e s a g ai n st t h e m y eli n oli g o d e n dr o c yt e 
gl y c o pr ot ei n a n d t h e m y eli n b a si c pr ot ei n i n m ulti pl e s cl er o si s a n d ot h er 
n e ur ol o gi c al di s e a s e s: a c o m p ar ati v e st u d y. Br ai n 1 9 9 9; 1 2 2: 2 0 4 7 5 6.
Rit c hi e A M, Gil d e n D H, W illi a m s o n R A, et al. C o m p ar ati v e a n al y si s of t h e C D 1 9 a n d 
C D 1 3 8 c ell a nti b o d y r e p ert oir e s i n t h e c er e br o s pi n al fl ui d of p ati e nt s wit h m ulti pl e 
s cl er o si s. J I m m u n ol 2 0 0 4; 1 7 3: 6 4 9 5 6.
S er afi ni B, R o si c ar elli B, M a gli o z zi R, et al. D et e cti o n of e ct o pi c B -c ell f olli cl e s wit h 
g er mi n al c e nt er s i n t h e m e ni n g e s of p ati e nt s wit h s e c o n d ar y pr o gr e s si v e m ulti pl e 
s cl er o si s. Br ai n P at h ol 2 0 0 4; 1 4: 1 6 4 7 4.
S er g ott R C, Fr o h m a n E, Gl a n z m a n R, et al. T h e r ol e of o pti c al c o h er e n c e t o m o gr a p h y i n 
m ulti pl e s cl er o si s: e x p ert p a n el c o n s e n s u s. J N e ur ol S ci 2 0 0 7; 2 6 3: 3 – 1 4.
Si d é n A. I s o el e ctri c f o c u si n g a n d cr o s s e d i m m u n o el e ctr of o c u si n g of C S F 
i m m u n o gl o b uli n s i n M S. J N e ur ol 1 9 7 9; 2 2 1: 3 9 5 1.
W o li n s k y J S, N ar a y a n a P A, O' C o n n or P, et al. Gl atir a m er a c et at e i n pri m ar y pr o gr e s si v e 
m ulti pl e s cl er o si s: r e s ult s of a m ulti n ati o n al, m ulti c e nt er, d o u bl e -bl i n d, 
pl a c e b o -c o ntr oll e d tri al. A n n N e ur ol 2 0 0 7; 6 1: 1 4 2 4.
W o rl d M e di c al A s s o ci ati o n D e cl ar ati o n of H el si n ki Et hi c al Pri n ci pl e s f or M e di c al 
R e s e ar c h I n v ol vi n g H u m a n S u bj e ct s. O ct o b er 2 0 0 8. [ a c c e s s e d 5 F e br u ar y 2 0 1 0]. 
A v ail a bl e fr o m :
htt p s:// w w w .w m a .n et/ e n/ 3 0 p u b li c ati o n s/ 1 0 p oli ci e s/ b 3/i n d e x.ht ml.
Y o u sr y T A, M aj or E O, R y s c h k e wit s c h C, et al. E v al u ati o n of p ati e nt s tr e at e d wit h 
n at ali z u m a b f or pr o gr e s si v e m ultif o c al l e u k o e n c e p h al o p at h y . N E n gl J M e d 
2 0 0 6; 3 5 4: 9 2 4 – 3 3.


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P A R T II:
E T HI C S A N D G E N E R A L S T U D Y A D MI N I S T R ATI O N
1 2. 
E T HI C A L A S P E C T S
1 2. 1 
L O C A L R E G U L A TI O N S/ D E C L A R A TI O N O F H E L SI N K I
T h e in v e sti g at or will e n s ur e t h at t hi s st u d y i s c o n d u ct e d i n f ull c o nf or m a n c e wit h t h e 
pri n ci pl e s of t h e “ D e cl ar ati o n of H el si n ki” or wit h t h e l a w s a n d r e g ul ati o n s of t h e c o u ntr y 
i n w hi c h t h e r e s e ar c h i s c o n d u ct e d, w hi c h e v er aff or d s t h e gr e at er pr ot e cti o n t o t h e 
i n di vi d u al.  T h e st u d y m u st f ull y a d h er e t o t h e pri n ci pl e s o utli n e d i n “ G ui d eli n e f or G o o d 
Cli ni c al Pr a cti c e” I C H Tri p artit e G ui d eli n e or wit h l o c al l a w if it aff or d s gr e at er pr ot e cti o n 
t o t h e s u bj e ct.  F or st u di e s c o n d u ct e d i n t h e E. U./ E E A c o u ntri e s, t h e in v e sti g at or will 
e n s ur e c o m pli a n c e wit h t h e E . U. Cli ni c al Tri al Dir e cti v e [ 2 0 0 1/ 2 0/ E C].  F or st u di e s 
c o n d u ct e d i n t h e U. S. or u n d er U . S. I N D, t h e in v e sti g at or will a d dit i o n all y e n s ur e 
a d h er e n c e t o t h e b a si c pri n ci pl e s of “ G o o d Cli ni c al Pr a cti c e” a s o utli n e d i n t h e c urr e nt 
v er si o n of 2 1 C F R, S u b c h a pt er D, P art 3 1 2, “ R e s p o n si biliti e s of S p o n s or s a n d 
I n v e sti g at or s”, P art 5 0, “ Pr ot e cti o n of H u m a n S u bj e ct s”, a n d P art 5 6, 
“I n stit uti o n al R e vi e w B o ar d s”.
I n ot h er c o u ntri e s w h er e a “ G ui d eli n e f or G o o d Cli ni c al Pr a cti c e” e xi st s, R o c h e a n d t h e 
in v e sti g at or s will stri ctl y e n s ur e a d h er e n c e t o t h e st at e d pr o vi si o n s.
1 2. 2 
I N F O R M E D C O N S E N T
Wr itt e n inf or m e d c o n s e nt fr o m p arti ci p a nt s :
It i s t h e r e s p o n si bilit y of t h e in v e sti g at or, or a p er s o n d e si g n at e d b y t h e in v e sti g at or 
(if a c c e pt a bl e b y l o c al r e g ul ati o n s ), t o o bt ai n si g n e d i nf or m e d c o n s e nt fr o m e a c h 
p arti ci p a nt pri or t o p arti ci p ati n g i n t hi s st u d y aft er a d e q u at e e x pl a n ati o n of t h e ai m s, 
m et h o d s, a nti ci p at e d b e n efit s, a n d p ot e nti al h a z ar d s of t h e st u d y.  F or t h e p arti ci p a nt n ot 
q u alifi e d or i n c a p a bl e of gi vi n g l e g al c o n s e nt, writt e n c o n s e nt m u st b e o bt ai n e d fr o m t h e 
l e g all y a c c e pt a bl e r e pr e s e nt ati v e.  I n t h e c a s e w h er e b ot h t h e p arti ci p a nt a n d hi s/ h er 
l e g all y a c c e pt a bl e r e pr e s e nt ati v e ar e u n a bl e t o r e a d, a n i m p arti al wit n e s s s h o ul d b e 
pr e s e nt d uri n g t h e e ntir e i nf or m e d c o n s e nt di s c u s si o n.  Aft er t h e p arti ci p a nt a n d 
r e pr e s e nt ati v e h a v e or all y c o n s e nt e d t o p arti ci p ati o n i n t h e tri al, t h e wit n e s s’ si g n at ur e 
o n t h e f or m will att e st t h at t h e i nf or m ati o n i n t h e c o n s e nt f or m w a s a c c ur at el y e x pl ai n e d 
a n d u n d er st o o d.  T h e in v e sti g at or or d e si g n e e m u st al s o e x pl ai n t h at t h e p arti ci p a nt s ar e 
c o m pl et el y fr e e t o r ef u s e t o e nt er t h e st u d y or t o wit h dr a w fr o m it at a n y ti m e, f or a n y 
r e a s o n.  T h e e C R F s f or t hi s st u d y c o nt ai n a s e cti o n f or d o c u m e nti n g p arti ci p a nt i nfor m e d 
c o n s e nt, a n d t hi s m u st b e c o m pl et e d a p pr o pri at el y.  If n e w s af et y i nf or m ati o n r e s ult s i n 
si g nifi c a nt c h a n g e s i n t h e b e n efit ri s k a s s e s s m e nt, t h e c o n s e nt f or m s h o ul d b e r e vi e w e d 
a n d u p d at e d if n e c e s s ar y.  All p arti ci p a nt s (i n cl u di n g t h o s e alr e a d y b ei n g tr e at e d) s h o ul d 
b e i nf or m e d of t h e n e w i nf or m ati o n, gi v e n a c o p y of t h e r e vi s e d f or m a n d gi v e t h eir 
c o n s e nt t o c o nti n u e i n t h e st u d y.


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1 2. 3 
I N S TIT U TI O N A L R E VI E W B O A R D/ E T HI C S C O M MI T T E E
Et hi c s c o m mitt e e s [ n o n- U. S.] for E E A m e m b er st at e s, t h e S p o n s or or it s 
d e p ut y/r e pr e s e nt ati v e will s u b mit t o t h e C o m p et e nt A ut h orit y a n d E C s t h e pr ot o c ol a n d 
a n y a c c o m p a n yi n g m at eri al pr o vi d e d t o t h e p arti ci p a nt ( s u c h a s p arti ci p a nt i nfor m ati o n 
s h e et s or d e s cri pti o n s of t h e st u d y u s e d t o o bt ai n i nf or m e d c o n s e nt a s w ell a s a n y 
a d v erti si n g or c o m p e n s ati o n gi v e n t o t h e p arti ci p a nt ).
A p pr o v al fr o m t h e c o m mitt e e m u st b e o bt ai n e d b ef or e st arti n g t h e st u d y, a n d s h o ul d b e 
d o c u m e nt e d i n a l ett er t o t h e in v e sti g at or s p e cif yi n g t h e d at e o n w hi c h t h e c o m mitt e e 
m et a n d gr a nt e d t h e a p pr o v al.
A n y m o difi c ati o n s m a d e t o t h e pr ot o c ol aft er r e c ei pt of t h e E C’ s a p pr o v al m u st b e 
r e-s u b mitt e d b y t h e in v e sti g at or i n t h e U . S. a n d b y t h e S p o n s or i n t h e E E A m e m b er 
st at e s i n a c c or d a n c e wit h l o c al pr o c e d ur e s a n d r e g ul at or y r e q uir e m e nt s.
W h e n n o l o c al r e vi e w b o ar d e xi st s, t h e in v e sti g at or i s e x p e ct e d t o s u b mit t h e pr ot o c ol t o 
a r e gi o n al c o m mitt e e.  If n o r e gi o n al c o m mitt e e e xi st s, R o c h e will a s si st t h e in v e sti g at or 
i n s u b mitti n g t h e pr ot o c ol t o t h e E ur o p e a n Et hi c s R e vi e w C o m mitt e e.
I n stit uti o n al R e vi e w B o ar d [ U. S.]: it i s t h e un d er st a n di n g of t h e S p o n s or t h at t hi s 
pr ot o c ol (a n d a n y m o difi c ati o n s ) a s w ell a s a p pr o pri at e c o n s e nt pr o c e d ur e s a n d 
a d v erti s e m e nt s, will b e r e vi e w e d a n d a p pr o v e d b y a n I R B.  T hi s b o ar d m u st o p er at e i n 
a c c or d a n c e wit h t h e c urr e nt F e d er al R e g ul ati o n s.  T h e S p o n s or will r e c ei v e a l ett er or 
c ertifi c at e of a p pr o v al pri or t o i niti ati o n of t h e st u d y, a n d al s o w h e n e v er s u b s e q u e nt 
a m e n d m e nt s/ m o difi c ati o n s ar e m a d e t o t h e pr ot o c ol.
S a m pli n g f or t h e R C R a n d R B R i s c o nti n g e nt o n r e vi e w a n d a p pr o v al f or t h e e x pl or at or y
bi o m ar k er a s s e s s m e nt s a n d writt e n i nf or m e d c o n s e nt b y a n a p pr o pri at e r e g ul at or y b o d y 
( d e p e n di n g o n t h e c o u ntr y w h er e t h e st u d y i s p erf or m e d) a n d a sit e’ s I R B/E C.  If a 
r e g ul at or y or sit e’ s I R B/ E C d o e s n ot a p pr o v e t h e s a m pli n g f or t h e e x pl or at or y 
a s s e s s m e n t s t h e s e cti o n o n bi o m ar k er s a m pli n g will n ot b e a p pli c a bl e.
1 3. 
C O N DI TI O N S F O R M O DI F YI N G T H E P R O T O C O L
R e q u e st s fr o m in v e sti g at or s t o m o dif y t h e pr ot o c ol t o o n g oi n g st u di e s will b e c o n si d er e d 
o nl y b y c o n s ult ati o n b et w e e n a n a p pr o pri at e r e pr e s e nt ati v e of t h e S p o n s or a n d t h e 
in v e sti g at or (in v e sti g at or r e pr e s e nt ati v e[ s] i n t h e c a s e of a m ulti c e nt er tri al ).  
Pr ot o c ol m o difi c ati o n s m u st b e pr e p ar e d b y a r e pr e s e nt ati v e of t h e S p o n s or a n d i niti all y 
r e vi e w e d a n d a p pr o v e d b y t h e Cli ni c al S ci e n c e L e a d er/Cli ni c al P h ar m a c o l o gi st a n d 
Bi o st ati sti ci a n.
All pr ot o c ol m o difi c ati o n s m u st b e s u b mitt e d t o t h e a p pr o pri at e I R B or E C f or i nf or m ati o n 
a n d a p pr o v al i n a c c or d a n c e wit h l o c al r e q uir e m e nt s, a n d t o re g ul at or y a g e n ci e s if 
r e q uir e d.  A p pr o v al m u st b e o bt ai n e d b ef or e a n y c h a n g e s c a n b e i m pl e m e nt e d, e x c e pt 


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f or c h a n g e s n e c e s s ar y t o eli mi n at e a n i m m e di at e h a z ar d t o tri al p arti ci p a nt s, or w h e n t h e 
c h a n g e ( s) i n v ol v e s o nl y l o gi sti c al or a d mi ni str ati v e a s p e ct s of t h e tri al (e. g., c h a n g e i n 
m o nit or[ s], c h a n g e of t el e p h o n e n u m b er[ s] ).
1 4. 
C O N DI TI O N S F O R T E R MI N A TI N G T H E S T U D Y
B ot h t h e S p o n s or a n d t h e in v e sti g at or r e s er v e t h e ri g ht t o t er mi n at e t h e st u d y at a n y 
ti m e.  S h o ul d t hi s b e n e c e s s ar y, b ot h p arti e s will arr a n g e t h e pr o c e d ur e s o n a n i n di vi d u al 
st u d y b a si s aft er r e vi e w a n d c o n s ult ati o n.   I n t er mi n ati n g t h e st u d y, t h e S p o n s or a n d t h e 
in v e sti g at or will a s s ur e t h at a d e q u at e c o n si d er ati o n i s gi v e n t o t h e pr ot e cti o n of t h e 
p arti ci p a nt s’ i nt er e st s.
1 5. 
S T U D Y D O C U M E N T A TI O N, E L E C T R O NI C C R F S , AN D R E C O R D 
K E E PI N G
1 5. 1 
I N V E S TI G AT O R' S FI L E S / R E T E N TI O N O F D O C U ME N T S
T h e in v e sti g at or m u st m ai nt ai n a d e q u at e a n d a c c ur at e r e c or d s t o e n a bl e t h e c o n d u ct of 
t h e st u d y t o b e f ull y d o c u m e nt e d a n d t h e st u d y d at a t o b e s u b s e q u e ntl y v erifi e d.  
T h e s e d o c u m e nt s s h o ul d b e cl a s sifi e d i nt o 2 diff er e nt s e p ar at e c at e g ori e s 
( 1) I n v e sti g at or' s St u d y Fil e, a n d ( 2) p arti ci p a nt cli ni c al s o ur c e d o c u m e nt s.
T h e in v e sti g at or' s St u d y Fil e will c o nt ai n t h e pr ot o c ol/ a m e n d m e nt s a n d s c h e d ul e of 
a cti viti e s , I R B/E C a n d g o v er n m e nt al a p pr o v al wit h c orr e s p o n d e n c e, s a m pl e i nf or m e d 
c o n s e nt, dr u g r e c or d s, st aff c urri c ul u m vit a e a n d a ut h ori z ati o n f or m s a n d ot h er 
a p pr o pri at e d o c u m e nt s/ c orr e s p o n d e n c e, et c.  I n a d diti o n, at t h e e n d of t h e st u d y t h e 
in v e sti g at or will r e c ei v e t h e p arti ci p a nt d at a, w hi c h i n cl u d e s a n a u dit tr ail c o nt ai ni n g a 
c o m pl et e r e c or d o f all c h a n g e s t o d at a, q u er y r e s ol uti o n c orr e s p o n d e n c e a n d r e a s o n s 
f or c h a n g e s, i n h u m a n r e a d a bl e f or m at o n C D w hi c h al s o h a s t o b e k e pt wit h t h e 
in v e sti g at or’ s St u d y Fil e.
P arti ci p a nt cli ni c al s o ur c e d o c u m e nt s (u s u all y d efi n e d b y t h e pr oj e ct i n a d v a n c e t o
r e c or d k e y effi c a c y/ s af et y p ar a m et er s i n d e p e n d e nt of t h e e C R F s) w o ul d i n cl u d e 
p arti ci p a nt h o s pit al/ cli ni c r e c or d s, p h y si ci a n' s a n d n ur s e' s n ot e s, a p p oi nt m e nt b o o k, 
ori gi n al l a b or at or y r e p ort s, E C G, E E G, X -r a y, p at h ol o g y a n d s p e ci al a s s e s s m e nt r e p ort s, 
si g n e d I C F s, c o n s ult a nt l ett er s, a n d p arti ci p a nt s cr e e ni n g a n d e nr oll m e nt l o g s.
T h e in v e sti g at or m u st k e e p t h e s e 2 c at e g ori e s of d o c u m e nt s (i n cl u di n g t h e ar c hi v al C D) 
o n fil e f or at l e a st 1 5 y e ar s aft er c o m pl eti o n or di s c o nti n u ati o n of t h e st u d y.  Aft er t h at 
p eri o d of ti m e t h e d o c u m e nt s m a y b e d e str o y e d, s u bj e ct t o l o c al r e g ul ati o n s.
S h o ul d t h e in v e sti g at or wi s h t o a s si g n t h e st u d y r e c or d s t o a n ot h er p art y or m o v e t h e m 
t o a n ot h er l o c ati o n, R o c h e m u st b e n otifi e d i n a d v a n c e.
If t h e in v e sti g at or c a n n ot g u ar a nt e e t hi s ar c hi vi n g r e q uir e m e nt at t h e i n v e sti g ati o n al sit e 
f or a n y or all of t h e d o c u m e nt s, s p e ci al arr a n g e m e nt s m u st b e m a d e b et w e e n t h e 


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in v e sti g at or a n d R o c h e t o st or e t h e s e i n a s e al e d c o nt ai n er ( s) o ut si d e of t h e sit e s o t h at 
t h e y c a n b e r et ur n e d s e al e d t o t h e in v e sti g at or i n c a s e of a r e g ul at or y a u dit.  
W h er e s o ur c e d o c u m e nt s ar e r e q uir e d f or t h e c o nti n u e d c ar e of t h e p arti ci p a nt , 
a p pr o pri at e c o pi e s s h o ul d b e m a d e f or st ori n g o ut si d e of t h e sit e.
1 5. 2 
S O U R C E D O C U M E N T S A N D B A C K G R O U N D D A T A
T h e in v e sti g at or s h all s u p pl y t h e S p o n s or o n r e q u e st wit h a n y r e q uir e d b a c k gr o u n d d at a 
fr o m t h e st u d y d o c u m e nt ati o n or cli ni c r e c or d s.  T hi s i s p arti c ul arl y i m p ort a nt w h e n 
err or s i n d at a tr a n s cri pti o n ar e s u s p e ct e d.  I n c a s e of s p e ci al pr o bl e m s a n d/ or 
g o v er n m e nt al q u eri e s or r e q u e st s f or a u dit i n s p e cti o n s, it i s al s o n e c e s s ar y t o h a v e 
a c c e s s t o t h e c o m pl et e st u d y r e c or d s, pr o vi d e d t h at s u bj e ct c o nfi d e nti alit y i s pr ot e ct e d.
1 5. 3 
A U DI T S A N D I N S P E C TI O N S
T h e in v e sti g at or s h o ul d u n d er st a n d t h at s o ur c e d o c u m e nt s f or t hi s tri al s h o ul d b e m a d e 
a v ail a bl e t o a p pr o pri at el y q u alifi e d p er s o n n el fr o m t h e R o c h e P h ar m a D e v el o p m e nt 
Q u alit y A s s ur a n c e U nit or it s d e si g n e e s, or t o h e alt h a ut h orit y i n s p e ct or s aft er 
a p pr o pri at e n otifi c ati o n.  T h e v erifi c ati o n of t h e e C R F d at a m u st b e b y dir e ct i n s p e cti o n 
a n d a s p er t h e m o nit ori n g pl a n e st a bli s h e d i n t h e st u d y.
1 5. 4 
E L E C T R O NI C C A S E R E P O R T F O R M S
D at a f or t hi s st u d y will b e c a pt ur e d vi a a n E D C s y st e m, w hi c h will b e a c c e s s e d vi a t h e 
W e b.  A n a u dit tr ail will m ai nt ai n a r e c or d of i niti al e ntri e s a n d c h a n g e s m a d e; r e a s o n s 
f or c h a n g e; ti m e a n d d at e of e ntr y; a n d u s er n a m e of p er s o n a ut h ori zi n g e ntr y or 
c h a n g e.
F or e a c h p arti ci p a nt e nr oll e d, a n e C R F m u st b e c o m pl et e d a n d el e ctr o ni c all y si g n e d b y 
t h e P ri n ci p al I n v e sti g at or or a ut h ori z e d d el e g at e fr o m t h e st u d y st aff.  T hi s al s o a p pli e s 
t o r e c or d s f or t h o s e p arti ci p a nt s w h o f ail t o c o m pl et e t h e st u d y.  If a p arti ci p a nt
wit h dr a w s fr o m t h e st u d y, t h e r e a s o n m u st b e n ot e d o n t h e e C R F.  If a p arti ci p a nt i s 
wit h dr a w n fr o m t h e st u d y b e c a u s e of a tr e at m e nt -li miti n g a d v er s e e v e n t, t h or o u g h eff ort s 
s h o ul d b e m a d e t o cl e arl y d o c u m e nt t h e o ut c o m e.
T h e in v e sti g at or s h o ul d e n s ur e t h e a c c ur a c y, c o m pl et e n e s s a n d ti m eli n e s s of t h e d at a 
r e p ort e d t o t h e Sp o n s or i n t h e e C R F s a n d i n all r e q uir e d r e p ort s.
1 6. 
M O NI T O RI N G T H E S T U D Y
It i s u n d er st o o d t h at t h e r e s p o n si bl e R o c h e m o nit or (or d e si g n e e ) will c o nt a ct a n d vi sit 
t h e in v e sti g at or r e g ul arl y a n d will b e all o w e d, o n r e q u e st, t o i n s p e ct t h e v ari o u s r e c or d s 
of  t h e tri al (e C R F s a n d ot h er p erti n e nt d at a ) pr o vi d e d t h at p arti ci p a nt c o nfi d e nti alit y i s 
m ai nt ai n e d i n a c c or d wit h l o c al r e q uir e m e nt s.
It will b e t h e m o nit or' s r e s p o n si bilit y t o i n s p e ct t h e e C R F s at r e g ul ar i nt er v al s t hr o u g h o ut 
t h e st u d y, t o v erif y t h e a d h er e n c e t o t h e pr ot o c ol a n d t h e c o m pl et e n e s s, c o n si st e n c y a n d 


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a c c ur a c y of t h e d at a b ei n g e n t er e d o n t h e m.  T h e m o nit or m u st v erif y t h at t h e p arti ci p a nt
r e c ei v e d t h e st u d y dr u g a s si g n e d b y t h e r a n d o mi z ati o n c e nt er ( b y c o ntr olli n g t h e writt e n 
c o nfir m ati o n of t h e r a n d o mi z ati o n b y I x R S).  T h e m o nit or s h o ul d h a v e a c c e s s t o 
l a b or at or y t e st r e p ort s a n d ot h er p arti ci p a nt r e c or d s n e e d e d t o v erif y t h e e ntri e s o n t h e 
e C R F.  T h e in v e sti g at or (or d e p ut y ) a gr e e s t o c o o p er at e wit h t h e m o nit or t o e n s ur e t h at 
a n y pr o bl e m s d et e ct e d i n t h e c o ur s e of t h e s e m o nit ori n g vi sit s ar e r e s ol v e d.
R o c h e Cli ni c al R e p o sit or y s p e ci m e n s will at all ti m e s b e tr a c k e d i n a m a n n er c o n si st e nt 
wit h G o o d Cli ni c al Pr a cti c e, b y a q u alit y -c o ntr oll e d, a u dit a bl e a n d v ali d at e d 
L a b or at or y I nf or m ati o n M a n a g e m e nt S y st e m, t o e n s ur e c o m pli a n c e wit h d at a 
c o nfi d e nti alit y a s w ell a s a d h er e n c e t o a ut h o ri z e d u s e of s p e ci m e n s a s s p e cifi e d i n t h e 
st u d y pr ot o c ol a n d I C F, r e s p e cti v el y.  R o c h e m o nit or s a n d a u dit or s will h a v e dir e ct 
a c c e s s t o a p pr o pri at e p art s of r e c or d s r el ati n g t o p arti ci p a nt s p arti ci p ati n g i n t hi s st u d y 
f or t h e p ur p o s e s of v erif yi n g t h e d ata pr o vi d e d t o R o c h e.  T h e sit e will p er mit m o nit ori n g, 
a u dit s, I R B/ E C r e vi e w, a n d r e g ul at or y i n s p e cti o n s b y pr o vi di n g dir e ct a c c e s s t o s o ur c e 
d at a a n d d o c u m e nt s r el at e d t o t h e R C R R e s e ar c h Pr oj e ct .
1 7. 
C O N FI D E N TI A LI T Y O F T RI A L D O C U M E N T S A N D P A R TI CI P A N T
R E C O R D S
T h e in v e sti g at or m u st a s s ur e t h at p arti ci p a nt s’ a n o n y mit y will b e m ai nt ai n e d a n d t h at 
t h eir i d e ntiti e s ar e pr ot e ct e d fr o m u n a ut h ori z e d p arti e s.  O n e C R F s or ot h er d o c u m e nt s 
s u b mitt e d t o t h e S p o n s or, p arti ci p a nt s s h o ul d n ot b e i d e ntifi e d b y t h eir n a m e s, b ut b y a n 
i d e ntifi c ati o n c o d e.  T h e in v e sti g at or s h o ul d k e e p a P arti ci p a nt I d e ntifi c ati o n Lo g s h o wi n g 
c o d e s, n a m e s a n d a d dr e s s e s.  T h e in v e sti g at or s h o ul d m ai nt ai n d o c u m e nt s n ot f or 
s u b mi s si o n t o t h e S p o n s or, e. g. , p arti ci p a nt s’ writt e n c o n s e nt f or m s, i n stri ct c o nfi d e n c e.
R o c h e alr e a d y m ai nt ai n s ri g or o u s c o nfi d e nti alit y st a n d ar d s f or cli ni c al st u di e s b y 
“ c o di n g” (i. e., a s si g ni n g a u ni q u e p arti ci p a nt I D n u m b er at t h e in v e sti g at or sit e) all 
p arti ci p a nt s e nr oll e d i n R o c h e cli ni c al st u di e s.  T hi s m e a n s t h at p arti ci p a nt n a m e s ar e 
n ot i n cl u d e d i n d at a s et s t h at ar e tr a n s mitt e d t o a n y R o c h e l o c ati o n.  Gi v e n t h e s e n siti v e 
n at ur e of g e n eti c d at a, R o c h e h a s i m pl e m e nt e d a n u m b er of a d diti o n al pr o c e s s e s t o 
a s s ur e p arti ci p a nt c o nf i d e nti alit y.  All s p e ci m e n s t a k e n f or i n h erit e d g e n eti c r e s e ar c h t h at 
will b e st or e d i n t h e R C R ( s e e S e cti o n 5. 1 5 ) u n d er g o a s e c o n d l e v el of “ c o di n g”.  
At R o c h e, t h e s p e ci m e n i s tr a n sf err e d t o a n e w t u b e a n d l a b el e d wit h a n e w r a n d o m 
n u m b er.  T hi s i s r ef err e d t o a s “ D o u bl e C o di n g ( D e -I d e ntifi c ati o n)”.  D at a g e n er at e d 
f oll o wi n g t h e u s e of t h e s e s p e ci m e n s a n d all cli ni c al d at a tr a n sf erre d fr o m t h e cli ni c al 
st u d y d at a b a s e a n d c o n si d er e d r el e v a nt, will al s o b e l a b el e d wit h t hi s s a m e c o d e.  
T h e “li n ki n g k e y” b et w e e n t h e p arti ci p a nt’ s i d e ntifi c ati o n n u m b er a n d t hi s n e w 
i n d e p e n d e nt c o d e will b e st or e d i n a s e c ur e d at a b a s e s y st e m.  A c c e s s t o th e t a bl e 
li n ki n g t h e p arti ci p a nt i d e ntifi c ati o n n u m b er t o t h e s p e ci m e n c o d e will b e stri ctl y li mit e d 
a n d m o nit or e d b y a u dit tr ail.  L e giti m at e o p er ati o n al r e a s o n s f or a c c e s si n g t h e 
“li n ki n g k e y” will b e d o c u m e nt e d i n a st a n d ar d o p er ati n g pr o c e d ur e.  A c c e s s t o t h e 


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“li n ki n g k e y” f or a n y ot h er r e a s o n will r e q uir e writt e n a p pr o v al fr o m t h e G o v er n a n c e 
C o m mitt e e r e s p o n si bl e f or t h e s p e ci m e n( s).
1 8. 
P U B LI C A TI O N O F D A T A  AN D P R O T E C TI O N O F T R A D E 
S E C R E T S
R e g ar dl e s s of t h e o ut c o m e of a tri al, t h e S p o n s or i s d e di c at e d t o o p e nl y pr o vi di n g 
i nf or m ati o n o n t h e tri al t o h e alt h c ar e pr of e s si o n al s a n d t o t h e p u bli c, b ot h at s ci e ntifi c 
c o n gr e s s e s a n d i n p e er -r e vi e w e d j o ur n al s. T h e S p o n s or will c o m pl y wit h all 
r e q uir e m e nt s f or p u bli c ati o n of st u d y r e s ult s.  F or m or e i nf or m ati o n, r ef er t o t h e R o c h e 
Gl o b al P oli c y o n S h ari n g of Cli ni c al Tri al s D at a at t h e f oll o wi n g W e b sit e:
w w w.r o c h e. c o m/r o c h e _ gl o b al _ p oli c y _ o n _ s h ari n g _ of _ cli ni c al _ st u d y _i nf or m ati o n. p df
T h e r e s ult s of t hi s st u d y m a y b e p u bli s h e d or pr e s e nt e d at s ci e ntifi c c o n gr e s s e s .  F or all 
cli ni c al tri al s i n p arti ci p a nt s i n v ol vi n g a n I M P f or w hi c h a m ar k eti n g a ut h ori z ati o n 
a p pli c ati o n h a s b e e n fil e d or a p pr o v e d i n a n y c o u ntr y, t h e S p o n s or ai m s t o s u b mit a 
j o ur n al m a n u s cri pt r e p orti n g pri m ar y cli ni c al tri al r e s ult s wit hi n 6 m o nt h s aft er t h e 
a v ail a bilit y of t h e r e s p e cti v e Cli ni c al St u d y R e p ort.  I n a d diti o n, f or all cli ni c al tri al s i n 
p arti ci p a nt s i n v ol vi n g a n I M P f or w hi c h a m ar k eti n g a ut h ori z ati o n a p pli c ati o n h a s b e e n 
fil e d or a p pr o v e d i n a n y c o u ntr y, t h e S p o n s or ai m s t o p u bli s h r e s ult s fr o m a n al y s e s of 
a d diti o n al e n d p oi nt s a n d e x pl or at or y d at a t h at ar e cli ni c all y m e a ni n gf ul a n d st ati sti c all y 
s o u n d.
T h e i n v e sti g at or m u st a gr e e t o s u b mit all m a n u s cri pt s or a b str a ct s t o t h e S p o n s or pri or 
t o s u b mi s si o n f or p u bli c ati o n or pr e s e nt ati o n.  T hi s all o w s t h e S p o n s or t o pr ot e ct 
pr o pr i et ar y i nf or m ati o n a n d t o pr o vi d e c o m m e nt s b a s e d o n i nf or m ati o n fr o m ot h er 
st u di e s t h at m a y n ot y et b e a v ail a bl e t o t h e i n v e sti g at or.
I n a c c or d a n c e wit h st a n d ar d e dit ori al a n d et hi c al pr a cti c e, t h e S p o n s or will g e n er all y 
s u p p ort p u bli c ati o n of m ulti c e nt er tri al s o nl y i n t h eir e ntir et y a n d n ot a s i n di vi d u al c e nt er 
d at a.  I n t hi s c a s e, a c o or di n ati n g in v e sti g at or will b e d e si g n at e d b y m ut u al a gr e e m e nt.
A ut h or s hi p will b e d et er mi n e d b y m ut u al a gr e e m e nt a n d i n -li n e wit h I nt er n ati o n al 
C o m mitt e e of M e di c al J o ur n a l E dit or s (I C M J E) a ut h or s hi p r e q uir e m e nt s.  A n y f or m al 
p u bli c ati o n of t h e st u d y i n w hi c h i n p ut of t h e S p o n s or p er s o n n el e x c e e d e d t h at of
c o n v e nti o n al m o nit ori n g will b e c o n si d er e d a s a j oi nt p u bli c ati o n b y t h e in v e sti g at or a n d 
t h e a p pr o pri at e S p o n s or p er s on n el.
D at a d eri v e d fr o m R C R s p e ci m e n a n al y si s o n i n di vi d u al p arti ci p a nt s will n ot b e pr o vi d e d 
t o st u d y in v e sti g at or s, e x c e pt w h er e e x pli citl y sti p ul at e d i n a st u d y pr ot o c ol ( e .g. , if t h e 
r e s ult i s a n e nr oll m e nt crit eri o n).  E x c e pti o n s m a y b e gr a nt e d ( e. g., if bi o m ar k er d at a 
w o ul d b e li n k e d t o s af et y i s s u e s).  T h e a g gr e g at e r e s ult s of a n y r e s e ar c h c o n d u ct e d wit h 
u s e of R C R s p e ci m e n s will b e a v ail a bl e i n a c c or d a n c e wit h t h e eff e cti v e R o c h e p oli c y o n 
st u d y d at a p u bli c ati o n.


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A n y i n v e nti o n s a n d r e s ulti n g p at e nt s , i m pr o v e m e nt s a n d/ or k n o w-h o w ori gi n ati n g fr o m 
t h e u s e of d at a will b e c o m e a n d r e m ai n t h e e x cl u si v e a n d u n b ur d e n e d pr o p ert y of t h e 
S p o n s or , e x c e pt w h er e a gr e e d ot h er wi s e.


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A p p e n di x 1
R e vi s e d M c D o n al d Crit eri a 2 0 0 5
R E F E R E N C E
P ol m a n C H, R ei n g ol d S C, E d a n G, et al. Di a g n o sti c crit eri a f or m ulti pl e s cl er o si s: 2 0 0 5 
r e vi si o n s t o t h e " M c D o n al d Crit eri a". A n n N e ur ol 2 0 0 5; 5 8: 8 4 06.


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A p p e n di x 2
A d v er s e E v e nt C at e g ori e s f or D et er mi ni n g R el ati o n s hi p t o T e st 
Dr u g
T h e c a u s alit y r el ati o n s hi p of st u d y dr u g t o t h e a d v er s e e v e nt will b e a s s e s s e d b y t h e 
in v e sti g at or a s eit h er: Y e s or N o.
If t h er e i s a r e a s o n a bl e s u s p e ct e d c a u s al r el ati o n s hi p t o t h e st u d y m e di c ati o n, i. e., t h er e 
ar e f a ct s ( e vi d e n c e) or ar g u m e nt s t o s u g g e st a c a u s al r el ati o n s hi p, dr u g -e v e nt 
r el ati o n s hi p s h o ul d b e a s s e s s e d a s Y e s.
T h e f oll o wi n g crit eri a s h o ul d b e c o n si d er e d i n or d er t o a s s e s s t h e r el ati o n s hi p a s 
Y e s:
 
R e a s o n a bl e t e m p or al a s s o ci ati o n wit h d r u g a d mi ni str ati o n
 
It m a y
or m a y
n ot h a v e b e e n pr o d u c e d b y t h e p arti ci p a nt’ s cli ni c al st at e, 
e n vir o n m e nt al or t o xi c f a ct or s, or ot h er m o d e s of t h er a p y a d mi ni st er e d t o t h e 
p arti ci p a nt
 
K n o w n r e s p o n s e p att er n t o s u s p e ct e d dr u g
 
Di s a p p e ar s or d e cr e a s e s o n c e s s ati o n or r e d u cti o n i n d o s e
 
R e a p p e ar s o n r e c h all e n g e
T h e f oll o wi n g crit eri a s h o ul d b e c o n si d er e d i n or d er t o a s s e s s t h e r el ati o n s hi p a s 
N o:
 
It d o e s n ot f oll o w a r e a s o n a bl e t e m p or al s e q u e n c e fr o m a d mi ni str ati o n of t h e dr u g
 
It m a y r e a dily h a v e b e e n pr o d u c e d b y t h e p arti ci p a nt’ s cli ni c al st at e, e n vir o n m e nt al
or t o xi c f a ct or s, or ot h er m o d e s of t h er a p y a d mi ni st er e d t o t h e p arti ci p a nt
 
It d o e s n ot f oll o w a k n o w n p att er n of r e s p o n s e t o t h e s u s p e ct e d dr u g
 
It d o e s n ot r e a p p e ar or w or s e n w h e n t h e dr u g i s r e a d mi ni st er e d


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A p p e n di x 3
I C H G ui d eli n e s f or Cli ni c al S af et y D at a M a n a g e m e nt, D efi niti o n s 
a n d St a n d ar d s f or E x p e dit e d R e p orti n g, T o pi c E 2
A s eri o u s a d v er s e e v e nt i s a n y e x p eri e n c e t h at s u g g e st s a si g nifi c a nt h a z ar d, 
c o ntr ai n di c ati o n, si d e eff e ct or pr e c a uti o n.  It i s a n y a d v er s e e v e nt t h at at a n y d o s e f ulfill s 
at l e a st 1 of t h e f oll o wi n g crit eri a:
 
I s f at al (r e s ult s i n d e at h)
N O T E : d e at h i s a n o ut c o m e, n ot a n e v e nt .
 
I s life-t hr e at e ni n g
N O T E : t h e t er m "life-t hr e at e ni n g" r ef er s t o a n e v e nt i n w hi c h t h e p arti ci p a nt w a s at 
i m m e di at e ri s k of d e at h at t h e ti m e of t h e e v e nt; it d o e s n ot r ef er t o a n e v e nt w hi c h 
c o ul d h y p ot h eti c all y h a v e c a u s e d a d e at h h a d it b e e n m or e s e v er e.
 
R e q uir e s i n -p ati e nt h o s pit ali z ati o n or pr ol o n g ati o n of e xi sti n g h o s pit ali z ati o n
 
R e s ult s i n p er si st e nt or si g nifi c a nt di s a bilit y/i n c a p a cit y
 
I s a c o n g e nit al a n o m al y/ birt h d ef e ct
 
I s m e di c all y si g nifi c a nt or r e q uir e s i nt er v e nti o n t o pr e v e nt o n e or ot h er of t h e 
o ut c o m e s li st e d a b o v e
M e di c al a n d s ci e ntifi c j u d g m e nt s h o ul d b e e x er ci s e d i n d e ci di n g w h et h er e x p e dit e d 
r e p orti n g t o t h e Sp o n s or i s a p pr o pri at e i n ot h er sit u ati o n s, s u c h a s i m p ort a nt m e di c al 
e v e nt s t h at m a y n ot b e i m m e di at el y l ife- t hr e at e ni n g or r e s ult i n d e at h or h o s pit ali z ati o n 
b ut m a y j e o p ar di z e t h e p arti ci p a nt or m a y r e q uir e i nt er v e nti o n t o pr e v e nt o n e of t h e 
o ut c o m e s li st e d i n t h e d efi niti o n s a b o v e.  T h e s e sit u ati o n s s h o ul d al s o u s u all y b e 
c o n si d er e d s eri o u s.
E x a m pl e s of s u c h e v e nt s ar e i nt e n si v e tr e at m e nt i n a n e m er g e n c y r o o m or at h o m e f or 
all er gi c br o n c h o s p a s m; bl o o d d y s cr a si a s or c o n v ul si o n s t h at d o n ot r e s ult i n 
h o s pit ali z ati o n; or d e v el o p m e nt of dr u g d e p e n d e n c y or dr u g a b u s e.
A n u n e x p e ct e d a d v er s e e v e nt i s o n e i n w hi c h t h e n at ur e or s e v erit y i s n ot c o n si st e nt wit h 
t h e a p pli c a bl e pr o d u ct i nf or m ati o n.
C a u s alit y i s i niti all y a s s e s s e d b y t h e in v e sti g at or.  F or s eri o u s a d v er s e e v e nt s, p o s si bl e 
c a u s e s of t h e e v e nt ar e i n di c at e d b y s el e cti n g 1 or m or e o pti o n s (c h e c k all t h at a p pl y) :
 
Pr e e xi sti n g / U n d erl yi n g di s e a s e – s p e cif y
 
St u d y tr e at m e nt – s p e cif y t h e dr u g( s) r el at e d t o t h e e v e nt
 
Ot h er tr e at m e nt ( c o n c o mit a nt or pr e vi o u s) – s p e cif y
 
Pr ot o c ol -r el at e d pr o c e d ur e
 
Ot h er ( e. g., a c ci d e nt, n e w or i nt er c urr e nt ill n e s s) – s p e cif y


A p p e n di x 3 
I C H G ui d eli n e s f or Cli ni c al S af et y D at a M a n a g e m e nt, D efi niti o n s a n d 
St a n d ar d s f or E x p e dit e d R e p orti n g, T o pi c E 2 ( C o nt.)
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T h e t er m s e v er e i s a m e a s ur e of i nt e n sit y, t h u s a s e v er e a d v er s e e v e nt i s n ot 
n e c e s s aril y s eri o u s.  F or e x a m pl e, n a u s e a of s e v er al h o ur s' d ur ati o n m a y b e r at e d a s 
s e v er e, b ut m a y n ot b e cli ni c all y s eri o u s.
A s eri o u s a d v er s e e v e nt o c c urri n g d uri n g t h e st u d y or w hi c h c o m e s t o t h e att e nti o n of 
t h e in v e sti g at or wit hi n 1 5 d a y s aft er st o p pi n g t h e tr e at m e nt or d uri n g t h e pr ot o c ol -d ef i n e d 
f oll o w-u p p eri o d, if t hi s i s l o n g er, w h et h er c o n si d er e d tr e at m e nt -r el at e d or n ot, m u st b e 
r e p ort e d.  I n a d diti o n, a s eri o u s a d v er s e e v e nt t h at o c c ur s aft er t hi s ti m e, if c o n si d er e d 
r el at e d t o t e st “ dr u g”, s h o ul d b e r e p ort e d.
S u c h pr eli mi n ar y r e p ort s will b e f oll o w e d b y d et ail e d d e s cri pti o n s l at er w hi c h will i n cl u d e 
c o pi e s of h o s pit al c a s e r e p ort s, a ut o p s y r e p ort s a n d ot h er d o c u m e nt s w h e n r e q u e st e d 
a n d a p pli c a bl e.
F or s eri o u s a d v er s e e v e nt s, t h e f oll o wi n g m u st b e a s s e s s e d a n d r e c or d e d o n t h e 
A d v er s e E v e nt e C R F: i nt e n sit y, r el ati o n s hi p t o t e st s u b st a n c e, a cti o n t a k e n, a n d 
o ut c o m e t o d at e.
T h e in v e sti g at or m u st n otif y t h e I R B/ E C of a s eri o u s a d v er s e e v e nt i n writi n g a s s o o n a s 
i s pr a cti c al a n d i n a c c or d a n c e wit h i nt er n ati o n al a n d l o c al l a w s a n d r e g ul ati o n s.
2 4 - H O U R M E DI C A L C O V E R A G E
I d e ntifi c ati o n of a c o nt a ct f or 2 4-H o ur M e di c al C o v er a g e i s m a n d at or y t o b e c o m pli a nt 
wit h w orl d wi d e r e g ul at or y a g e n ci e s a n d t o e n s ur e t h e s af et y of st u d y p arti ci p a nt s.
A n E m er g e n c y M e di c al C all C e nt er H el p D e s k will a c c e s s t h e R o c h e M e di c al 
E m er g e n c y Li st, e s c al at e e m er g e n c y m e di c al c all s, pr o vi d e m e di c al tr a n sl ati o n s er vi c e 
(if n e c e s s ar y), c o n n e ct t h e in v e st i g at or wit h t h e R o c h e m e di c al c o nt a ct f or t hi s st u d y a n d 
tr a c k all c all s.  T h e E m er g e n c y M e di c al C all C e nt er H el p D e s k will b e m a n n e d 2 4 h o ur s 
7 d a y s a w e e k.  T oll -fr e e n u m b er s will b e di stri b ut e d t o all in v e sti g at or s r u n ni n g R o c h e 
P h ar m a D e v el o p m e nt cli ni c al tri al s.  T h e H el p D e s k will b e u s e d f or m e di c al 
e m er g e n ci e s o ut si d e r e g ul ar b u si n e s s h o ur s, or w h e n t h e r e g ul ar Cli ni c al S ci e n c e 
L e a d er c a n n ot b e r e a c h e d .


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 4 9 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A p p e n di x 4
C o m m o n T er mi n ol o g y  Crit eri a f or Ad v er s e E v e nt s
I n t h e pr e s e nt st u d y, t o xi citi e s will b e gr a d e d a c c or di n g t o t h e Co m m o n T er mi n ol o g y 
Crit eri a f or A d v er s e E v e nt s ( C T C A E) , V er si o n 4. 0.
T h e C T C A E v 4 c a n b e f o u n d i n t h e R o c h e h a n d o ut e ntitl e d: “C o m m o n T er mi n ol o g y 
Crit eri a f or A d v er s e E v e nt s v 4. 0” or o n t h e f oll o wi n g W e b sit e:   h tt ps: // ct e p.c a n c er .g o v .


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 0 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A p p e n di x 5
T el e p h o n e I nt er vi e w
T h e p ur p o s e of t hi s i nt er vi e w i s t o i d e ntif y a n d c oll e ct i nf or m ati o n o n a n y c h a n g e s i n t h e 
p arti ci p a nt ’ s h e alt h st at u s (i n cl u di n g n e w or w or s e ni n g n e ur ol o gi c al s y m pt o m s ) t h at 
w arr a nt a n u n s c h e d ul e d vi sit.
T h e t el e p h o n e i nt er vi e w will b e c o n d u ct e d b y sit e p er s o n n el f a mili ar wit h t h e 
p arti ci p a nt ( s) e v er y 4 w e e k s b et w e e n t h e st u d y vi sit s .
T h e d at e of t h e t el e p h o n e i nt er vi e w will b e r e c or d e d i n t h e e C R F.
T h e u s e of t hi s f or m i s o pti o n al, b ut if n ot u s e d, all i nf or m ati o n s h o ul d b e r e c or d e d i n t h e 
p arti ci p a nt ’ s m e di c al r e c or d s.  W h er e u s e d, t hi s f or m s h o ul d b e k e pt wit h t h e 
p arti ci p a nt ’ s r e c or d s.
Pl e a s e a s k t h e f oll o wi n g q u e sti o n s d uri n g t h e tel e p h o n e int er vi e w:
R e a d al o u d a n d r e c or d p arti ci p a nt ’ s a n s w er s t o t h e f oll o wi n g q u e sti o n s:
Q u e sti o n s
N o 
Y e s
1.  Si n c e y o ur l a st vi sit or t el e p h o n e i nt er vi e w, h a v e y o u h a d a n y n e w or 
w or s e ni n g m e di c al pr o bl e m s ( s u c h a s s u d d e n c h a n g e s i n y o ur t hi n ki n g, 
alt er ati o n s i n y o ur b e h a vi or, vi s u al di st ur b a n c e s, e xtr e mit y  w e a k n e s s, li m b 
c o or di n ati o n pr o bl e m s, or g ait a b n or m alit i e s) t h at h a v e p er si st e d m o r e t h a n 
1 d a y ?
2.  Si n c e y o ur l a st vi sit or t el e p h o n e i nt er vi e w, h a v e y o u h a d a n y si g n s of a n 
i nf e cti o n ?
3.  Si n c e y o ur l a st vi sit or t el e p h o n e i nt er vi e w, h a v e y o u h a d a n y ot h er n e w or 
w or s e ni n g m e di c al pr o bl e m s or c o n diti o n s (i n cl u di n g pr e g n a n c y or pr e g n a n c y 
of t h e p art n er of a m al e p arti ci p a nt ), s ur g er y, or h o s pit ali z ati o n?
4.  Si n c e y o ur l a st vi sit or t el e p h o n e i nt er vi e w, h a v e y o u t a k e n a n y n e w 
m e di ci n e s (i n cl u di n g m e di ci n e s t o tr e at c a n c er or M S, a n y ot h er n e w 
m e di ci n e s t h at w e a k e n y o ur i m m u n e s y st e m, or st er oi d m e di ci n e s ot h er t h a n 
f or t h e tr e at m e nt of a r e c e nt r el a p s e) ?
If t h e p arti ci p a nt a n s w er e d Y E S t o a n y q u e sti o n, c o nt a ct t h e in v e sti g at or a n d r e vi e w t h e 
p arti ci p a nt ’ s a n s w er s.  T h e in v e sti g at or c a n d et er mi n e if a n u n s c h e d ul e d vi sit i s r e q uir e d.


A p p e n di x 5 
T el e p h o n e I nt er vi e w ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
R e c or d a n y p erti n e nt c o m m e nt s m a d e b y t h e p arti ci p a nt d uri n g t h e i nt er vi e w:
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
N a m e a n d d at e of st aff c o m pl eti n g t h e t el e p h o n e i nt er vi e w:
N A M E: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ D at e: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
B el o w i s a s a m pl e li st of m e di c ati o n s t h at c a n w e a k e n t h e i m m u n e s y st e m:
E x a m pl e s of I m m u n o s u p pr e s s a nt s, A nti n e o pl a sti c s, a n d 
I m m u n o m o d ul at or s
A p pr o v e d M S T h er a pi e s ( a p pr o v e d i n at l e a st 1 c o u ntr y ):
 
Gl atir a m er a c et at e ( C o p a x o n e
)
 
I nt erf er o n b et a-1 a ( R e bif , A V O N E X)
 
I nt erf er o n b et a-1 b ( B et a s er o n )
 
Mit o x a ntr o n e ( N o v a ntr o n e
)
 
N at ali z u m a b ( T y s a bri )
 
Fi n g oli m o d ( Gil e n y a )
 
Al e mt u z u m a b ( L e mtr a d a )
 
T erifl u n o mi d e ( A u b a gi o )
 
Di m et h yl f u m ar at e ( T e cfi d er a )
I m m u n o s u p pr e s s a nt s/ Anti n e o pl a sti c s:
 
A z at hi o pri n e (I m ur a n , A z a s a n)
 
Cl a dri bi n e ( L e u st ati n )
 
C y cl o p h o s p h a mi d e ( C yt o x a n , N e o s ar® )
 
C y cl o s p ori n e ( S a n di m m u n e , N e or al)
 
Fl u d ar a bi n e p h o s p h at e ( Fl u d ar a )
 
L ef l u n o mi d e ( Ar a v a)
 
M er c a pt o p uri n e ( P uri n et h ol
)
 
M et h otr e x at e ( M et h otr e x
, R h e u m atr e x, Tr e x all)
 
M y c o p h e n ol at e m of etil ( C ell C e pt
)
 
P e m etr e x e d ( Ali mt a )


A p p e n di x 5 
T el e p h o n e I nt er vi e w ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A d diti o n al I m m u n o m o d ul at or s a n d I m m u n o s u p pr e s s a nt s:
 
Ot h er i nt erf er o n s ( A cti m m u n e
, I nf er g e n, I ntr o nA
 
P e g a s y s , P E G-I ntr o n, R e b etr o n, R of er o n-A)
 
A d ali m u m a b ( H u mir a )
 
Al ef a c e pt ( A m e vi v e )
 
Al e mt u z u m a b ( C a m p at h )
 
A n a ki nr a ( Ki n er et )
 
D a cli z u m a b ( Z e n a p a x )
 
Ef ali z u m a b ( R a pti v a )
 
Et a n er c e pt ( E n br el )
 
I nfli xi m a b ( R e mi c a d e)
 
I ntr a v e n o u s i m m u n o gl o b uli n (I VI G)
 
Of at u m u m a b ( Ar z err a )
 
Rit u xi m a b ( Rit u x a n/ M a b T h er a )
 
Tr a st u z u m a b ( H er c e pti n )
T hi s li st d o e s n ot i n cl u d e all dr u g s t h at c a n s u p pr e s s t h e i m m u n e s y st e m.
P arti ci p a nt s s h o ul d n otif y t h e st u d y t e a m of a n y n e w m e di c ati o n s t a k e n d uri n g t h e 
c o ur s e of t h e st u d y.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A p p e n di x 6
O pti c al C o h er e n c e T o m o gr a p h y  E x pl or at or y S u b st u d y
I N T R O D U C TI O N
O pti c al c o h er e n c e t o m o gr a p h y ( O C T) i s a n o ni n v a si v e i m a gi n g t o ol c a p a bl e of s e n siti v e, 
r e pr o d u ci bl e a n d r a pi d m e a s ur e m e nt s
of str u ct ur al ar c hit e ct ur e of t h e r eti n a a n d r eti n al 
n er v e fi b er l a y er ( R N F L; Fr o h m a n et al. 2 0 0 8).  Opti c al c o h er e n c e t o m o gr a p h y c a n b e of 
p arti c ul ar i nt er e st i n m ulti pl e s cl er o si s ( M S ), b e c a u s e o pti c n e uriti s oft e n t h e pi v ot al 
e v e nt i n e st a bli s hi n g t h e di a g n o si s of M S.  O pti c n er v e d y sf u n cti o n i s c h ar a ct eri z e d b y 
o pti c d i s c p all or a n d l o s s of c o ntr a st s e n siti vit y, a n d vi s u al fi el d d ef e ct s, w hi c h m a y o c c ur 
s u b cli ni c all y i n m a n y p arti ci p a nt s.  It i s e sti m at e d t h at n e arl y 2 0 % of all p arti ci p a nt s wit h 
M S pr e s e nt i niti all y wit h o pti c n e uriti s, a n d a n a d diti o n al 3 0 % 1 0 0 % will h a v e o pti c 
n e uriti s at s o m e p oi nt i n t h eir di s e a s e c o ur s e ( S er g ott et al. 2 0 0 7) .  O pti c al c o h er e n c e 
t o m o gr a p h y o ut c o m e m e a s ur e s s u c h a s R N F L t hi c k n e s s a n d m a c ul ar v ol u m e s h a v e 
b e e n s h o w n t o c orr el at e wit h cli ni c al m e a s ur e s of vi si o n l o s s a n d m a y f a cilit at e 
vi s u ali z ati o n of a n y pr o c e s s of n e ur o d e g e n er ati o n or r e p air a s p art of n at ur al hi st or y of 
M S or a s a c o n s e q u e n c e of n e ur o pr ot e cti v e i nt er v e nti o n s ( C o st ell o et al. 2 0 0 8) .
T hi s s u b st u d y i s p art of 3 o n g oi n g P h a s e III st u di e s t h at s er v e t o e v al u at e t h e 
n e ur o pr ot e cti v e eff e ct of o cr eli z u m a b i n M S a s m e a s ur e d b y R N F L t hi c k n e s s a n d 
m a c ul ar v ol u m e i n b ot h e y e s of p arti ci p a nt s w h o p arti ci p at e i n t h e c o nfir m at or y pi v ot al 
st u di e s i n p arti ci p a nt s wit h r el a p si n g m ulti pl e s cl er o si s ( R M S; St u di e s W A 2 1 0 9 2 a n d 
W A 2 1 0 9 3) or p arti ci p a nt s wit h pri m ar y pr o gr e s si v e M S
( P P M S; St u d y W A 2 5 0 4 6).
I n J ul y 2 0 1 7, R o c h e d et er mi n e d t h at s uffi ci e nt d at a h a d b e e n c oll e ct e d fr o m t h e 
O C T s u b st u d y.  D uri n g 2 0 1 7 a n d 2 0 1 8, p arti ci p ati n g p ati e nt s will b e di s c o nti n u e d fr o m 
t h e O C T s u b st u d y b ut m a y c o nti n u e i n t h e O L E.
O B J E C TI V E S
E F FI C A C Y O B J E C TI V E S
T h e pri m ar y effi c a c y o bj e cti v e s f or t hi s s u b st u d y ar e a s f oll o w s:
 
T o e v al u at e t h e n e ur o pr ot e cti v e eff e ct of o cr eli z u m a b t h er a p y a s m e a s ur e d b y 
m a c ul ar v ol u m e a n d R N F L o v er ti m e
 
T o c h ar a ct eri z e t h e ti m e -c o ur s e of c h a n g e s i n R N F L t h at i m pl y a x o n al l o s s i n 
p arti ci p a nt s wit h b ot h R M S a n d P P M S wit h or wit h o ut o cr eli z u m a b tr e at m e nt
T h e s e c o n d ar y effi c a c y o bj e cti v e s f or t hi s st u d y ar e a s f oll o w s:
 
I n t h e c a s e of R M S p arti ci p a nt s ( St u di e s W A 2 1 0 9 2 a n d W A 2 1 0 9 3), t h e st u d y will 
a s s e s s w h et h er o cr eli z u m a b 3 0 0 m g 2 h a s s u p eri or n e ur o pr ot e cti v e eff e ct 
c o m p ar e d wit h R e bif a s m e a s ur e d b y R N F L t hi c k n e s s


A p p e n di x 6 
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
I n t h e c a s e of P P M S p arti ci p a nt s ( St u d y W A 2 5 0 4 6), t h e st u d y will a s s e s s w h et h er 
o cr eli z u m a b 3 0 0 m g 2 h a s s u p eri or n e ur o pr ot e cti v e eff e ct c o m p ar e d wit h pl a c e b o 
a s m e a s ur e d b y R N F L t hi c k n e s s
S A F E T Y O B J E C TI V E S
T h e s af et y o bj e cti v e s f or t hi s st u d y ar e a s f oll o w s:
 
T o e v al u at e t h e o p ht h al m ol o gi c al s af et y of o cr eli z u m a b t h er a p y i n p arti ci p a nt s wit h 
M S, f o c u si n g o n s eri o u s a d v er s e e v e nt s
E X P L O R A T O R Y O B J E C TI V E S
T h e e x pl or at or y o bj e cti v e s f or t hi s st u d y ar e a s f oll o w s:
 
T o e v al u at e if O C T o ut c o m e s c a n s er v e a s a r eli a bl e a n d pr e di cti v e m e a s ur e of 
r e s p o n s e t o o cr eli z u m a b t h er a p y i n p arti ci p a nt s wit h M S or pr o gr e s si o n t o a m or e 
s e v er e di s e a s e st at e
 
T o e v al u at e t h e r el ati o n s hi p of O C T o ut c o m e s wit h o ut c o m e s fr o m o cr eli z u m a b 
P h a s e III pi v ot al st u di e s, s u c h a s
– 
C h a n g e i n br ai n v ol u m e a s m e a s ur e d b y br ai n m a g n eti c r e s o n a n c e i m a gi n g 
( M RI)
– 
C o nfir m e d di s a bilit y pr o gr e s si o n
– 
T 2 l e si o n v ol u m e
– 
N u m b er of T 1 g a d oli ni u m -e n h a n c e d l e si o n s
 
C h a n g e i n M ulti pl e S cl er o si s F u n cti o n al C o m p o sit e S c al e ( M S F C S) s c or e
S T U D Y D E SI G N
D E S C RI P TI O N O F S T U D Y
O v er vi e w
T h e c urr e nt s u b st u d y i s a n a d d -o n, m ulti c e nt er, l o n git u di n al st u d y t o t h e o n g oi n g 
P h a s e III o cr eli z u m a b St u di e s WA 2 1 0 9 2, W A 2 1 0 9 3, a n d W A 2 5 0 4 6 t o e v al u at e t h e 
n e ur o pr ot e cti v e eff e ct s of o cr eli z u m a b tr e at m e nt a s m e a s ur e d b y O C T.  
O pti c al c o h er e n c e t o m o gr a p h y will b e p erf or m e d i n p ar all el t o t h e o cr eli z u m a b pi v ot al 
P h a s e III st u di e s.  P arti ci p a nt s will h a v e O C T a s s e s s m e nt s a s l o n g a s t h e y ar e t a ki n g 
p art i n t h e m ai n st u d y f or at l e a st 1 y e ar.
P arti ci p a nt s c a n b e e nr oll e d at a n y ti m e d uri n g t h e fir st 4 8 w e e k s aft er e nr oll m e nt i n t h e 
m ai n pi v ot al st u di e s.  H o w e v er, all att e m pt s s h o ul d b e m a d e t o e nr oll t h e p arti ci p a nt at 
t h e ti m e of s cr e e ni n g of t h e m ai n pi v ot al st u d y.  P arti ci p a nt s will u n d er g o a n 
o p ht h al m ol o gi c al e x a mi n ati o n pri or t o fir st O C T s c a n a n d at t h e e n d of t h e st u d y.  
P arti ci p a nt s will al s o u n d er g o at l e a st 3 O C T s c a n s at 2 4 -w e e k i nt er v al s 
( s e e s c h e d ul e of a cti viti e s of t hi s s u b st u d y; A p p e n di x 7 ).


A p p e n di x 6 
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 5 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
F or p arti ci p a nt s p arti ci p ati n g i n St u d y W A 2 5 0 4 6:
 
T h e p arti ci p a nt s h o ul d u n d er g o O C T m e a s ur e m e nt s e v er y 2 4 w e e k s aft er t h e fir st 
O C T V i sit ( Vi sit 1 of t h e O C T s u b st u d y).  If t h e p arti ci p a nt is e nr oll e d i nt o t h e 
O C T s u b st u d y at b a s eli n e of t h e m ai n st u d y, t h e f oll o wi n g vi sit s s h o ul d o c c ur:  
Vi sit 1 ( b a s eli n e, o c c urri n g at t h e b a s eli n e vi sit of t h e m ai n st u d y), Vi sit 2 
( We e k 2 4 , o c c urri n g at Vi sit 5 of t h e m ai n st u d y), Vi sit 3 ( W e e k 4 8, o c c urri n g at 
Vi sit 8 of t h e m ai n st u d y), Vi sit 4 ( W e e k 7 2 , o c c urri n g at Vi sit 1 1 of t h e m ai n st u d y), 
Vi sit 5 ( W e e k 9 6, o c c urri n g at Vi sit 1 4 of t h e m ai n st u d y), a n d Vi sit 6 
( We e k 1 2 0, o c c urri n g at Vi sit 1 7 of t h e m ai n st u d y)..  If t h e p arti ci p a nt i s e nr oll e d 
af t er b a s eli n e of t h e m ai n st u d y, O C T vi sit s s h o ul d o c c ur e v er y 2 4 w e e k s aft er t h e 
fir st O C T V i sit ( Vi sit 1, b a s eli n e).
F or p arti ci p a nt s p arti ci p ati n g i n St u di e s W A 2 1 0 9 2 a n d W A 2 1 0 9 3:
 
T h e p arti ci p a nt s h o ul d u n d er g o O C T m e a s ur e m e nt s e v er y 2 4 w e e k s aft er t h e fir st 
O C T V i sit ( Vi sit 1 of t h e O C T s u b st u d y).  If t h e p arti ci p a nt i s e nr oll e d i nt o t h e 
O C T s u b st u d y at b a s eli n e of t h e m ai n st u d y, t h e f oll o wi n g vi sit s s h o ul d o c c ur:  
Vi sit 1 ( b a s eli n e, o c c urri n g a t t h e b a s eli n e vi sit of t h e m ai n st u d y), Vi sit 2 
( We e k 2 4, o c c urri n g at Vi sit 5 of t h e m ai n st u d y), Vi sit 3 ( W e e k 4 8, o c c urri n g at 
Vi sit 7 of t h e m ai n st u d y), Vi sit 4 ( W e e k 7 2, o c c urri n g at Vi sit 9 of t h e m ai n st u d y) 
a n d Vi sit 5 ( W e e k 9 6; o c c urri n g at Vi sit 1 1 of t h e m a i n st u d y).  If t h e p arti ci p a nt i s 
e nr oll e d aft er b a s eli n e of t h e m ai n st u d y, O C T vi sit s s h o ul d o c c ur e v er y 2 4 w e e k s 
af t er t h e fir st O C T V i sit ( Vi sit 1, b a s eli n e).
If t h e p arti ci p a nt i s wit h dr a w n fr o m st u d y tr e at m e nt i n t h e m ai n pr ot o c ol, a n O C T V i sit 
s h o ul d o c c ur if it h a s n ot b e e n p erf or m e d d uri n g t h e pr e vi o u s 4 w e e k s.  
P arti ci p a nt s s h o ul d t h e n h a v e a n O C T m e a s ur e m e nt at t h e e n d of t h e s af et y f oll o w -u p of 
t h e m ai n pr ot o c ol.
If a p art i ci p a nt d e ci d e s t o p arti ci p at e i n t h e O L E p h a s e of t h e m ai n pr ot o c ol, O C T 
m e a s ur e m e nt s s h o ul d c o nti n u e t o o c c ur e v er y 2 4 w e e k s d uri n g t h e O L E p h a s e.
A s c h e d ul e of a cti viti e s i s pr o vi d e d i n A p p e n di x 7 of t hi s s u b st u d y.
I M AG E R E VI E W
A m a s k e d, c e ntr al O C T r e a di n g c e nt er will r e vi e w a n d a n al y z e O C T i m a g e s.  
T h e pr o c e d ur e s will b e d et ail e d i n a n Im a gi n g R e vi e w C h art er.
E N D O F S T U D Y
I n J ul y 2 0 1 7, R o c h e d et er mi n e d t h at s uffi ci e nt d at a h a d b e e n c oll e ct e d fr o m t h e 
O C T s u b st u d y.  D uri n g 2 0 1 7 a n d 2 0 1 8, p arti ci p ati n g p arti ci p a nt s will b e di s c o nti n u e d 
fr o m t h e O C T s u b st u d y b ut m a y c o nti n u e i n t h e O L E.


A p p e n di x 6 
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 6 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
O U T C O M E M E A S U R E S
Effi c a c y  O ut c o m e M e a s ur e s
T h e effi c a c y o ut c o m e m e a s ur e s f or t hi s st u d y ar e a s f oll o w s:
 
O v er all a n d q u a dr a nt R N F L t hi c k n e s s m e a s ur e d b y O C T
 
M a c ul ar v ol u m e m a p s a s m e a s ur e d b y O C T
S af et y  O ut c o m e M e a s ur e s
T h e s af et y o ut c o m e m e a s ur e s f or t hi s st u d y ar e a s f oll o w s:
 
I n ci d e n c e, n at ur e, a n d s e v erit y of o p ht h al m ol o gi c al a d v er s e e v e nt s
M A T E RI A L S A N D M E T H O D S
P A R TI CI P A N T S
A d ult p arti ci p a nt s w h o f ulfill eli gi bilit y crit eri a f or o n e of t h e m ai n P h a s e III o cr eli z u m a b 
pi v ot al st u di e s (i. e., W A 2 1 0 9 2, W A 2 1 0 9 3, or W A 2 5 0 4 6) a n d t h e eli gi bilit y crit eri a 
o utli n e d i n t h e f oll o wi n g i n cl u si o n a n d e x cl u si o n s e cti o n s of t hi s s u b st u d y c a n b e e nr oll e d 
i nt o t h e st u d y.
I n cl u si o n Crit eri a
P arti ci p a nt s m u st m e et t h e f oll o wi n g crit eri a f or st u d y e ntr y:
 
A bl e a n d willi n g t o pr o vi d e writt e n i nf or m e d c o n s e nt a n d c o m pl y wit h t h e st u d y 
pr ot o c ol
 
B e a p arti ci p a nt i n 1 of t h e f oll o wi n g st u di e s: W A 2 1 0 9 2, W A 2 1 0 9 3, or W A 2 5 0 4 6
E x cl u si o n Crit eri a
P arti ci p a nt s w h o m e et a n y of t h e f oll o wi n g crit eri a will b e e x cl u d e d fr o m st u d y e ntr y:
 
M e di c al hi st or y of m a c ul ar d e g e n er ati o n, r eti n o p at h y, gl a u c o m a, a m bl y o pi a, 
di a b et e s, or a n y ot h er d o c u m e nt e d c a u s e of vi si o n l o s s
 
I n a bilit y t o u n d er g o r eli a bl e O C T t e sti n g
 
M or e t h a n 4 8 w e e k s h a v e l a p s e d si n c e r a n d o mi z ati o n
S T U D Y A S S E S S M E N T S 
S cr e e ni n g a n d B a s eli n e E x a mi n ati o n a n d Eli gi bilit y  S cr e e ni n g F or m
All p arti ci p a nt s m u st si g n a n d d at e t h e m o st c urr e nt I n stit uti o n al R e vi e w 
B o ar d/ Et hi c s C o m mitt e e’ s a p pr o v e d writt e n i nf or m e d c o n s e nt b ef or e a n y st u d y s p e cifi c 
a s s e s s m e nt s or pr o c e d ur e s ar e p erf or m e d.
C o n s e nti n g p arti ci p a nt s m u st al s o h a v e si g n e d t h e i nf or m e d c o n s e nt a n d b e eli gi bl e f or 
t h e m ai n pi v ot al P h a s e III st u d y.  P arti ci p a nt s will r e c ei v e a n o p ht h al m ol o gi c al a n d e y e 
e x a mi n ati o n t o b e e v al u at e d f or eli gi bilit y t o p arti ci p at e i n t hi s s u b st u d y.  If t h e p arti ci p a nt
i s eli gi bl e, t hi s o p ht h al m ol o gi c al e x a mi n ati o n will b e c o n si d er e d t h e b a s eli n e 
o p ht h al m ol o gi c al m e a s ur e ( O C T Vi sit 1).


A p p e n di x 6 
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 7 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
It s h o ul d b e st at e d i n t h e m e di c al r e c or d t h at t h e p arti ci p a nt i s p arti ci p ati n g i n t hi s cli ni c al 
st u d y.
O n c e a p arti ci p a nt h a s f ulfill e d all eli gi bilit y crit eri a, h e or s h e will u n d er g o O C T 
a c c or di n g t o s c h e d ul e of a cti viti e s (A p p e n di x 7 ).
Pr o c e d ur e i n C a s e of D el a y e d D o si n g Vi sit, R el a p s e or U n s c h e d ul e d Vi sit s, 
a n d Wit h dr a w al Vi sit s i n t h e M ai n P h a s e III O cr eli z u m a b Pi v ot al St u di e s
T h e m ai n o cr eli z u m a b pi v ot al st u di e s h a v e m e c h a ni s m s s et u p r e g ar di n g d el a y e d 
d o si n g vi sit s, u n s c h e d ul e d vi sit s d u e t o r el a p s e, a n d wit h dr a w al vi sit s.
O pti c al c o h er e n c e t o m o gr a p h y m e a s ur e m e nt s s h o ul d o c c ur at i ni ti all y s c h e d ul e d ti m e s 
a n d s h o ul d n ot b e r e s c h e d ul e d d u e t o d el a y e d d o si n g s c h e d ul e or u n s c h e d ul e d vi sit d u e 
t o r el a p s e.  I n c a s e t h er e i s a r el a p s e d uri n g a n O C T s c h e d ul e vi sit, t h e in v e sti g at or 
s h o ul d d o c u m e nt all o c ul ar s y m pt o m s, i n cl u di n g o c ul ar n e uriti s, i n t h e el e ctr o ni c C a s e 
R e p ort F or m a s w ell a s c o m m u ni c at e t h e m t o t h e Pri n ci p al I n v e sti g at or of t h e m ai n 
st u d y. If a p arti ci p a nt s uff er s a r el a p s e wit h s y m pt o m s a c ut e o pti c n e uriti s d uri n g t h e 
m o nt h b ef or e O C T st u d y, a s e c o n d O C T m u st b e p erf or m e d 1 m o nt h l at er t o a c c o u nt f or 
t h e eff e ct of p a pill e d e m a.
If t h e p arti ci p a nt i s wit h dr a w n fr o m st u d y tr e at m e nt i n t h e m ai n pr ot o c ol, a n O C T V i sit 
s h o ul d o c c ur if it h a s n ot b e e n p erf or m e d d uri n g t h e pr e vi o u s 4 w e e k s.  
P arti ci p a nt s s h o ul d t h e n h a v e a n O C T m e a s ur e m e nt e v er y 2 4 w e e k s u ntil t h e e n d of t h e 
s af et y f oll o w -u p of t h e m ai n pr ot o c ol.
D e s cri pti o n of St u d y  As s e s s m e nt s
M e di c al Hi st or y  a n d D e m o gr a p hi c D at a
M e di c al hi st or y a n d d e m o gr a p hi c d at a will b e c a pt ur e d i n m ai n st u d y i n w hi c h t h e 
p arti ci p a nt i s e nroll e d.  F urt h er m e di c al hi st or y i n cl u d e s cli ni c all y si g nifi c a nt di s e a s e s 
t h at m a y c a u s e vi si o n l o s s of t h e aff e ct e d e y e t h at h a v e b e e n d o c u m e nt e d b y t h e 
o p ht h al m ol o gi st.
O p ht h al m ol o gi c al a n d E y e E x a mi n ati o n
T h e pr e s e n c e of a n y vi s u al a b n or m aliti e s will b e e st a bli s h e d i n a f ull e y e e x a m i n ati o n.  
T hi s will i n cl u d e a n e x a mi n ati o n p erf or m e d b y a n o p ht h al m ol o gi st d uri n g s cr e e ni n g a n d 
at t h e e n d of t h e st u d y .  T hi s will i n cl u d e b e st c orr e ct e d vi s u al a c uit y e v al u ati o n 
( wit h E arl y Tr e at m e nt Di a b eti c R eti n o p at h y St u d y st a n d ar di z e d e y e c h art); c ol or vi si o n 
t e st ( H ar d y R a n d Rittl er p s e u d oi s o c hr o m ati c pl at e); vi s u al fi el d m e a s ur e m e nt; i ntr a o c ul ar 
pr e s s ur e; slitl a m p e x a mi n ati o n t o e x a mi n e t h e a nt eri or p art s ( c or n e a, l e n s, a n d s cl er a); 
a n d a dil at e d o p ht h al m o s c o pi c e x a mi n ati o n of r eti n a, o pti c n er v e, r eti n al bl o o d v e s s el s, 
a n d m a c ul a.  T h e e y e c h art c h o s e n f or a p arti ci p a nt m u st b e c o n si st e ntl y u s e d 
t hr o u g h o ut t h e st u d y a s w ell a s t h e u s e of c orr e cti v e l e n s e s d uri n g t h e o p ht h al m ol o gi c al 
e x a m.


A p p e n di x 6 
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 8 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
Vi s u al E v o k e d P ot e nti al
Vi s u al e v o k e d p ot e nti al ( V E P) i s a s e n siti v e t e st of vi s u al p at h w a y f u n cti o n a n d a m ar k er 
of  o pti c n er v e i n v ol v e m e nt i n M S, a n d it h a s b e e n u s e d a s a di a g n o sti c t o ol f or R M S a n d 
P P M S ( P ol m a n et al. 2 0 0 5).  It c a n b e u s e d t o s u p pl e m e nt i nf or m ati o n pr o vi d e d b y a 
cli ni c al e x a mi n ati o n t o pr o vi d e o bj e cti v e e vi d e n c e of a s e c o n d l e si o n pr o vi d e d t h at t h e 
o nl y cli ni c all y e x pr e s s e d l e si o n di d n ot aff e ct t h e vi s u al p at h w a y s.  T h e V E P
m e a s ur e m e nt s h o ul d o c c ur d uri n g O C T Vi sit 1.  If a v ail a bl e at t h e c e nt er, m ultif o c al V E P 
will b e p erf or m e d i n st e a d of f ull -fi el d V E P.
N ot e:  in t h e r ar e c a s e s t h at t h e s el e ct e d sit e c a n n ot d eli v er V E P d at a f or a n y r e a s o n, 
V E P m e a s ur e m e nt s will n ot b e n e c e s s ar y aft er di s c u s si o n wit h t h e S p o n s or.  
H o w e v er, all eff ort s s h o ul d b e m a d e t o c oll e ct V E P d at a d uri n g Vi sit 1 ( b a s eli n e ).
O pti c al C o h er e n c e T o m o gr a p h y
O pti c al c o h er e n c e t o m o gr a p h y i m a g e s will b e a c q uir e d i n all p arti ci p a nt s a s d et ail e d i n 
t h e s c h e d ul e of a cti viti e s (A p p e n di x 7 ).  I n a d diti o n, a n O C T s c a n will b e p erf or m e d i n 
p arti ci p a nt s wit h dr a w n fr o m t h e m ai n st u d y tr e at m e nt if it h a s n ot b e e n p erf or m e d wit hi n 
t h e pr e vi o u s 4 w e e k s.
All O C T i m a g e s will b e p erf or m e d b y c ertifi e d p er s o n n el.  T h e f oll o wi n g ti m e wi n d o w s 
a p pl y: 
 
O C T Vi sit 1 s h o ul d o c c ur pri or t o b a s eli n e vi sit of t h e pri m ar y st u d y a n d at 
W e e k s 2 4, 4 8, a n d 9 6
 
I n c a s e t h e p arti ci p a nt i s e nr oll e d aft er t h e b a s eli n e vi sit of m ai n st u d y, O C T Vi sit 1 
s h o ul d o c c ur at ti m e of e nr oll m e nt i nt o t h e s u b st u d y.  All f urt h er O C T s c a n s s h o ul d 
o c c ur e v er y 2 4 w e e k s t h er e aft er.
D uri n g O C T Vi sit 1, t h e O C T s c a n s h o ul d b e p erf or m e d t wi c e i n or d er t o c o ntr ol f or 
t e st-r et e st r eli a bilit y.
O pti c al c o h er e n c e t o m o gr a p h y i m a g e s will b e r e a d b y a c e ntr ali z e d r e a di n g c e nt er.  
T h e r e a di n g will b e p erf or m e d i n a m a s k e d f a s hi o n i n t h e a b s e n c e of cli ni c al i nf or m ati o n.  
F urt h er d et ail s o n t h e O C T pr ot o c ol s a n d st a n d ar di z ati o n of m a c hi n e s ar e d e s cri b e d i n a 
s e p ar at e I m a gi n g R e vi e w C h art er.
Pr o c e d ur e i n C a s e of O c ul ar N e uriti s or R el a p s e
If t h e p arti ci p a nt pr e s e nt s wit h o pti c n e uriti s, t h e aff e ct e d e y e s h o ul d b e d o c u m e nt e d.  
T h e p arti ci p a nt s h o ul d al s o b e r ef err e d t o t h e Pri n ci p al I n v e sti g at or of t h e m ai n st u d y f or 
e x a mi n ati o n.
If t h e p arti ci p a nt s uff er s a r el a p s e wit h s y m pt o m s of a c ut e o pti c n e uriti s 
d uri n g t h e m o nt h b ef or e a n O C T s c a n, a s e c o n d O C T s c a n m u st b e p erf or m e d 1 m o nt h 
l at er t o a c c o u nt f or t h e eff e ct of p a pill e d e m a.


A p p e n di x 6 
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 5 9 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A S S E S S M E N T O F S A F E T Y
S A F E T Y P L A N
A n y a d v er s e e v e nt r e g ar di n g o c ul ar fin di n g s s h o ul d b e r e p ort e d t o t h e 
Pri n ci p al I n v e sti g at or of t h e m ai n st u d y i n w hi c h t h e s u bj e ct i s p arti ci p ati n g, a s w ell a s 
t h e S p o n s or.  S e e m ai n pr ot o c ol S e cti o n 7 r e g ar di n g t h e pr o c e d ur e s r el at e d t o r e p orti n g 
of  a d v er s e e v e nt s a n d s eri o u s a d v er s e e v e nt s .
S T A TI S TI C A L C O N SI D E R A T I O N S A N D A N A L Y SI S P L A N
F ull d et ail s of all st ati sti c al i s s u e s a n d pl a n n e d st ati sti c al a n al y s e s will b e s p e cif i e d i n t h e 
I n d e p e n d e nt R e vi e w C h art er c h art er.
S A M P L E SI Z E
A t ot al of a p pr o xi m at el y 3 0 0 p arti ci p a nt s will b e e nr oll e d i n t hi s s u b st u d y, a n d t h e t ot al 
st u d y d ur ati o n will b e a p pr o xi m at el y 9 6 w e e k s, d e p e n di n g o n t h e ti m e of e nr oll m e nt.
E F FI C A C Y A N A L Y S E S
T h e p ur p o s e of t hi s st u d y i s t o e sti m at e t h e n e ur o pr ot e cti v e eff e ct of o cr eli z u m a b 
tr e at m e nt i n p arti ci p a nt s wit h M S r el ati v e t o R e bif i n t h e c a s e of St u di e s WA 2 1 0 9 2 a n d 
W A 2 1 0 9 3 a n d r el ati v e t o pl a c e b o i n t h e c a s e of St u d y W A 2 5 0 4 6.  P oi nt a n d i nt er v al 
e sti m at e s of t h e d e cr e a s e of R N F L t hi c k n e s s a n d m a c ul ar v ol u m e will b e o bt ai n e d.
P RI M A R Y E F FI C A C Y E N D P OI N T
T h e pri m ar y effi c a c y e n d p oi nt i s t h e d e cr e a s e i n R N F L t hi c k n e s s o v er ti m e d uri n g t h e 
d ur ati o n of t h e m ai n st u d y.
S E C O N D A R Y A N D E X P L O R A T O R Y E F FI C A C Y E N D P OI N T S
S e c o n d ar y a n d e x pl or at or y e n d p oi nt s ar e:
 
D et er mi n ati o n of m a c ul ar v ol u m e o v er ti m e d uri n g t h e d ur ati o n of t h e st u d y
 
E x pl or at or y c orr el ati o n a n al y s e s t o d et er mi n e t h e pr e di cti v e v al u e of O C T m e a s ur e s 
( R N F L t hi c k n e s s a n d m a c ul ar v ol u m e) wit h o ut c o m e s m e a s ur e d i n t h e m ai n st u d y, 
s u c h a s ( b ut n ot r e stri ct e d t o):
– 
C h a n g e i n br ai n v ol u m e a s m e a s ur e d b y br ai n M RI
– 
C o nfir m e d di s a bilit y pr o gr e s si o n
– 
T 2 l e si o n v ol u m e
– 
N u m b er of T 1 g a d oli ni u m -e n h a n c e d l e si o n s
 
C h a n g e i n M S F C S s c or e


A p p e n di x 6 
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 6 0 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
S A F E T Y A N A L Y S E S
N o s af et y a n al y s e s ar e pl a n n e d f or t hi s s u b st u d y.  A n y s af et y e v e nt n ot e d d uri n g t hi s 
s u b st u d y will b e f or w ar d t o t h e P ri n ci p al I n v e sti g at or of t h e m ai n st u d y.  S e e S e cti o n 7 of 
t h e m ai n pr ot o c ol.
R E F E R E N C E S
C o st ell o F, H o d g e W , P a n YI, et al. Tr a c ki n g r eti n al n er v e fi b er l a y er l o s s aft er o pti c 
n e uriti s: a pr o s p e cti v e st u d y u si n g o pti c al c o h er e n c e t o m o gr a p h y. M ult S cl er 
2 0 0 8; 1 4: 8 9 3 9 0 5.
Fr o h m a n, E M, F uji m ot o J G, Fr o h m a n T C, et al. O pti c al c o h er e n c e t o m o gr a p h y: a 
wi n d o w i nt o t h e m e c h a ni s m s of m ulti pl e s cl er o si s. N at Cli n Pr a c 2 0 0 8; 4: 6 6 4 7 5.
P ol m a n C H, R ei n g ol d S C, E d a n G, et al. Di a g n o sti c crit eri a f or m ulti pl e s cl er o si s: 
2 0 0 5 r e vi si o n s t o t h e " M cD o n al d Crit eri a". A n n N e ur ol 2 0 0 5; 5 8: 8 4 0 6.
S er g ott R C, Fr o h m a n E, Gl a n z m a n R, et al. T h e r ol e of o pti c al c o h er e n c e t o m o gr a p h y i n 
m ulti pl e s cl er o si s: e x p ert p a n el c o n s e n s u s. J N e ur ol S ci 2 0 0 7; 2 6 3: 3 1 4.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 6 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A p p e n di x 7
O pti c al C o h er e n c e T o m o gr a p h y E x pl or at or y S u b st u d y S c h e d ul e of A c ti viti e s
Bli n d e d Tr e at m e nt P eri o d
a
O p e n -L a b el 
E xt e n si o n 
P h a s e 
( W A2 5 0 4 6) c
(1 4)
C o m pl eti o n/
E arl y 
T er mi n ati o n 
Vi sit
S af et y 
F oll o w -U p
Wit h dr a w al 
V i sit
W e e k 
( wi n d o w i n d a y s) 
0
2 4 
(1 4)
4 8 
(1 4)
7 2 
(1 4)
9 6 
(1 4)
1 2 0 
(1 4)
A d diti o n al 
C y cl e s b
(1 4)
I nf or m e d c o n s e nt 
x
O p ht h al m ol o gi c al 
m e di c al hi st or y a n d 
b a s eli n e c o n diti o n s
x
O C T
d
x  
x  
x  
x  
x  
x  
x
x
x
x e
x
A d v er s e e v e nt s
f
x  
x  
x  
x  
x  
x  
x
x
x
x  
x
O C T o pti c al c o h er e n c e t o m o gr a p h y; O L E o p e n -l a b el e xt e n si o n.
a
Tr e at m e nt p eri o d i s v ari a bl e, a s it d e p e n d s o n t h e ti m e of e nr oll m e nt wit hi n t h e m ai n st u d y.
b
P arti ci p a nt s w h o c o nti n u e wit h a d diti o n al c y c l e s of t h e bli n d e d tr e at m e nt s h o ul d h a v e O C T a s s e s s m e nt s e v er y 2 4 w e e k s.
c
If a p arti ci p a nt e nr oll s i n t h e O L E p h a s e of t h e m ai n st u d y, O C T a s s e s s m e nt s s h o ul d o c c u r e v er y 2 4 w e e k s.
d
I n c a s e s w h er e t h e i niti all y s u b mitt e d O C T V i sit s c a n i s i n a d e q u at e/ n ot e v al u a bl e b y B er n P h ot o gr a p hi c R e a di n g C e nter , t h e sit e s h o ul d m a k e all 
eff ort s t o r e q u e st t h e p arti ci p a nt t o c o m e b a c k t o sit e t o p erf or m a n e w O C T s c a n.
e
S af et y f oll o w-u p: O C T a s s e s s m e nt s h o ul d c o nti n u e e v er y 2 4 w e e k s c o u nti n g aft er l a st O C T a s s e s s m e nt vi sit.
f
A n y a d v er s e e v e nt s s h o ul d b e r e p ort e d t o t h e P ri n ci p al In v e sti g at or of t h e st u d y.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 6 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A p p e n di x 8
O p e n -L a b el E xt e n si o n S u b st u d y  i n P arti ci p a nt s W h o 
D i s c o nti n u e d T r e at m e nt i n t h e B li n d e d P h a s e of St u d y W A 2 5 0 4 6
B A C K G R O U N D A N D R A T I O N AL E F O R T H E S U B S T U D Y
I n t h e a b s e n c e of pri or pr o of-of -c o n c e pt cli ni c al d at a wit h o cr eli z u m a b i n P P M S, 
St u d y W A 2 5 0 4 6 w a s d e si g n e d t o i ntr o d u c e t h e o p e n -l a b el e xt e n si o n ( O L E) p h a s e o nl y if 
a p o siti v e b e n efit ri s k of o cr eli z u m a b w a s d et er mi n e d b y t h e S p o n s or aft er t h e pri m ar y 
a n al y si s of t h e bli n d e d p eri o d.
T h e pri m ar y a n al y si s of t h e b li n d e d tr e at m e nt p eri o d i n Q 3 2 0 1 5 s h o w e d t h at t h e st u d y 
m et it s pri m ar y e n d p oi nt a n d k e y s e c o n d ar y e n d p oi nt s, a n d a d e ci si o n w a s m a d e b y t h e 
S p o n s or t o i niti at e t h e O L E p h a s e.
T h e m ai n pr ot o c ol e x cl u d e s p arti ci p a nt s fr o m t h e O L E if t h e y wit h dr e w e arl y fr o m t h e 
bli n d e d tr e at m e nt p eri o d.  T h e s u b st u d y d e s cri b e d h er e all o w s t h e s e p arti ci p a nt s t h e 
o p p ort u nit y of e nt eri n g t h e s u b st u d y O L E if t h e y m e et eli gi bilit y crit eri a f or t h e p ur p o s e s 
of  c oll e cti n g f urt h er s af et y d at a.
T h e s u b st u d y pr ot o c ol w a s d e si g n e d b e c a u s e t h e s e p arti ci p a nt s w h o w it h dr e w e arl y ar e
c o nf o u n d e d b y a ti m e g a p i n w hi c h t h e y di d n ot r e c ei v e a n y tr e at m e nt at all or r e c ei v e d 
tr e at m e nt wit h dr u g s ot h er t h a n o cr eli z u m a b. T h er ef or e, t h e d at a fr o m t h e s e p arti ci p a nt s 
will n e e d t o b e a n al y z e d s e p ar at el y fr o m t h o s e p arti ci p a nt s w h o tr a n siti o n e d dir e ctl y fr o m 
t h e bli n d e d tr e at m e nt p eri o d i nt o t h e O L E wit h o ut a g a p.  A s o p p o s e d t o p arti ci p a nt s w h o 
c o m pl et e d t h e b li n d e d tr e at m e nt p eri o d a n d w h o c a n tr a n siti o n i nt o O L E dir e ctl y, t h e 
p arti ci p a nt s w h o wit h dr e w fr o m b li n d e d tr e at m e nt e arl y will n e e d t o g o t hr o u g h a 
s cr e e ni n g st e p b ef or e t h e y ar e all o w e d t o e nt er O L E.
S U B S T U D Y O B J E C TI V E S
T h e s a m e o bj e cti v e s a p pl y t o t hi s O L E s u b st u d y a s f or t h e O L E p eri o d d e s cri b e d i n t h e 
m ai n pr ot o c ol ( S e cti o n 3 ).
S U B S T U D Y D E SI G N
D E S C RI P TI O N O F S T U D Y P E RI O D S
T hi s s u b st u d y c o n si st s of t h e f oll o wi n g st u d y p eri o d s:
a s cr e e ni n g p eri o d, a n O L E 
tr e at m e nt p eri o d, a n d a s af et y foll o w - up p eri o d.
 
S cr e e ni n g p eri o d: u p t o 4 w e e k s
 
O L E tr e at m e nt p eri o d: p arti ci p a nt s will b e r e c ei vi n g o p e n -l a b el o cr eli z u m a b. 
T h e s a m e c o n diti o n s a p pl y t o t h e d ur ati o n of t h e O L E p h a s e i n t hi s s u b st u d y a s f or 
t h e p arti ci p a nt s e nt eri n g O L E t hr o u g h t h e m ai n pr ot o c ol ( S e cti o n 4. 1 ).
 
S af et y foll o w -u p p eri o d: th e s af et y foll o w -u p p eri o d will b e gi n w h e n t h e p ar ti ci p a nt
c o m pl et e s or di s c o nti n u e s fr o m O L E p h a s e f or a n y r e a s o n.
T h e s a m e c o n diti o n s 


A p p e n di x 8 
O p e n -L a b el E xt e n si o n S u b st u d y i n P arti ci p a nt s W h o Di s c o nti n u e d 
Tr e at m e nt i n t h e Bli n d e d P h a s e of St u d y W A 2 5 0 4 6 ( c o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 6 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
a p pl y t o t h e d ur ati o n of t h e s af et y foll o w - up P eri o d i n t hi s s u b st u d y a s f or t h e 
p arti ci p a nt s e nt eri n g O L E t hr o u g h t h e m ai n pr ot o c ol ( S e cti o n 4. 1 ).
E N D O F S U B S T U D Y
T h e e n d of t h e s u b st u d y i s t h e s a m e a s t h e e n d of t h e m ai n St u d y W A 2 5 0 4 6 
( pr ot o c ol S e cti o n 4. 1. 9 ).
N U M B E R O F P A R TI CI P A N T S
P arti ci p a nt s w h o wit h dr e w e arl y fr o m t h e b li n d e d tr e at m e nt p eri o d of St u d y W A 2 5 0 4 6 f or 
a n y r e a s o n ar e gi v e n a n o pti o n t o e nt er s cr e e ni n g f or p arti ci p ati o n i n t hi s O L E s u b st u d y ,
e x c e pt t h o s e p arti ci p a nt s w h o di s c o nti n u e d d u e t o h y p er s e n siti vit y t o o cr eli z u m a b if it 
m a nif e st e d a s a Gr a d e 4 i nfu si o n -r el at e d r e a cti o n (I R R). P arti ci p a nt s will b e all o w e d t o 
e nr oll i n t hi s s u b st u d y u p t o 2 4 m o nt h s aft er c o m m u ni c ati o n fr o m S p o n s or.
S T U D Y P O P U L A TI O N
P arti ci p a nt s w h o f ulfill t h e eli gi bilit y crit eri a o utli n e d i n t h e f oll o wi n g i n cl u si o n a n d 
e x cl u si o n s e cti o n s of t hi s s u b st u d y pr ot o c ol c a n b e e nr oll e d i nt o t h e st u d y.
I N C L U SI O N C RI T E RI A
P arti ci p a nt s m u st m e et t h e f oll o wi n g crit eri a t o b e eli gi bl e f or s u b st u d y e ntr y:
 
H a vi n g r e c ei v e d at l e a st 1 d o s e ( 2 i nfu si o n s s e p ar at e d b y 2 w e e k s) of bli n d e d st u d y 
dr u g ( eit h er pl a c e b o or o cr eli z u m a b) i n t h e bli n d e d tr e at m e nt p eri o d of 
S t u d y W A 2 5 0 4 6
 
H a vi n g wit h dr a w n e arl y fr o m tr e at m e nt d uri n g t h e bli n d e d tr e at m e nt p eri o d of 
St u d y W A 2 5 0 4 6 f or a n y r e a s o n , wit h t h e e x c e pti o n of t h o s e p arti ci p a n ts w h o 
di s c o nti n u e d d u e t o h y p er s e n siti vit y t o o cr eli z u m a b if it m a nif e st e d a s a Gr a d e 4 
I R R; b ot h p arti ci p a nt s w h o e nt er e d t h e saf e t y foll o w - up a n d p arti ci p a nt s w h o 
wit h dr e w fr o m st u d y ar e eli gi bl e
 
P arti ci p a nt s w h o s e E D S S at s cr e e ni n g i s 6. 5 ar e eli gi bl e if i n t h e j u d g m e nt of t h e 
i n v e sti g at or a n d f oll o wi n g di s c u s si o n wit h t h e p arti ci p a nt , t h e b e n efitri s k of 
o cr eli z u m a b tr e at m e nt i s c o n si d er e d a c c e pt a bl e
 
Wi lli n g t o u s e a p pr o pri at e c o ntr a c e pti v e m et h o d s a s d e s cri b e d i n S e cti o n 5. 4 of t h e 
m ai n pr ot o c ol
 
A bilit y t o pr o vi d e writt e n i nf or m e d c o n s e nt a n d t o b e a bl e t o f oll o w t h e s c h e d ul e of 
a cti viti e s of  t h e s u b st u d y
E X C L U SI O N C RI T E RI A
P arti ci p a nt s w h o at t h e ti m e of s cr e e ni n g f or s u b st u d y e ntr y m e et a n y of t h e f oll o wi n g 
crit eri a will n ot b e all o w e d t o e nt er t h e s u b st u d y:
E x cl u si o n s I n h erit e d fr o m t h e Bli n d e d Tr e at m e nt P eri o d of W A 2 5 0 4 6
 
M e eti n g a n y of t h e g e n er al e x cl u si o n crit eri a of t h e bli n d e d tr e at m e nt p h a s e li st e d i n 
S e cti o n 5. 3 of t h e m ai n pr ot o c ol


A p p e n di x 8 
O p e n -L a b el E xt e n si o n S u b st u d y i n P arti ci p a nt s W h o Di s c o nti n u e d 
Tr e at m e nt i n t h e Bli n d e d P h a s e of St u d y W A 2 5 0 4 6 ( c o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 6 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
M e eti n g a n y of t h e ‘ e x cl u si o n crit eri a r el at e d t o g e n er al h e alt h ’ li st e d i n S e cti o n 5. 3. 1
of  t h e m ai n pr ot o c ol
 
M e eti n g a n y of t h e ‘ e x cl u si o n crit eri a r el at e d t o m e di c ati o n s’ li st e d i n S e cti o n 5. 3. 2
of  t h e m ai n pr ot o c ol
E x cl u si o n s R el at e d t o L a b or at or y  Fi n di n g s
 
P o siti v e s er u m h u m a n c h ori o ni c g o n a d otr o pi n ( -h C G ) m e a s ur e d at s cr e e ni n g
 
P o siti v e s cr e e ni n g t e st s f or h e p atiti s B (h e p atiti s B s urf a c e a nti g e n [H B s A g ] p o siti v e, 
or p o siti v e t ot al h e p atiti s B c or e a nti b o d y [H B c A b ] c o nfir m e d b y a p o siti v e vir al D N A 
p ol y m er a s e c h ai n r e a cti o n [P C R ]) or h e p atiti s C vir u s a nti b o d y
( H e p C A b; s e e S e cti o n 5. 1 3. 1. 1
 
P o siti v e r a pi d pl a s m a r e a gi n ( R P R) if c o nfir m e d b y mi cr o h e m a g gl uti n ati o n a s s a y 
( M H A-T P) or fl u or e s c e nt tr e p o n e m al a nti b o d y a b s or pti o n ( F T A -A B S) t e st
 
C D 4 c o u nt 2 5 0 /L
 
A N C 1. 5 1 0 3 /L
 
L e v el s of s er u m I g G 1 8 % b el o w t h e L L N (f or c e ntr al l a b or at or y I g G 3. 3 g/ L)
R e -t e sti n g b ef or e b a s eli n e: i n r ar e c a s e s i n w hi c h t h e s cr e e ni n g l a b or at or y s a m pl e s 
ar e r ej e ct e d b y t h e c e ntr al l a b or at or y ( e x a m pl e: h e m ol y z e d s a m pl e) or t h e r e s ult n ot 
a s s e s s a bl e ( e. g., i n d et er mi n at e) or a b n or m al, t h e t e st s n e e d t o b e r e p e at e d wit hi n 
4 w e e k s.  A n y a b n or m al s cr e e ni n g l a b or at or y v al u e t h at i s cli ni c all y r el e v a nt s h o ul d 
b e r et e st e d i n or d er t o r ul e o ut a n y pr o gr e s si v e or u n c o ntr oll e d u n d erl yi n g c o n diti o n.  
T h e l a st v al u e b ef or e e nr oll m e nt m u st m e et s u b st u d y crit eri a.  I n s u c h 
cir c u m st a n c e s, t h e s cr e e ni n g p eri o d m a y n e e d t o b e pr ol o n g e d b ut c a n n ot e x c e e d 
8 w e e k s.
E x cl u si o n s R el at e d t o M e di c ati o n s P ot e nti all y  U s e d f or t h e Tr e at m e nt of 
M ulti pl e S cl er o si s
 
A n y pr e vi o u s tr e at m e nt wit h t h e s e B c ell t ar g et e d t h er a pi e s: at a ci c e pt, b eli m u m a b, 
or of at u m u m a b
 
Tr e at m e nt wit h rit u xi m a b if t h e l a st i nf u si o n i s wit hi n 22 w e e k s pri or t o s cr e e ni n g
 
A n y pr e vi o u s tr e at m e nt wit h C a m p at h (al e mt u z u m a b ), a nti-C D 4, cl a dri bi n e, 
c y cl o p h o s p h a mi d e, mit o x a ntr o n e, a z at hi o pri n e, m y c o p h e n ol at e m of etil (M M F ), 
c y cl o s p ori n e, m et h otr e x at e, t ot al b o d y irr a di ati o n, or b o n e m arr o w tr a n s pl a nt ati o n
 
Tr e at m e nt wit h fi n g oli m o d or ot h er S 1 P r e c e pt or m o d ul at or ( e. g., si p o ni m o d ) wit hi n 
1 2 w e e k s pri or t o s cr e e ni n g
N B: o nl y p arti ci p a nt s wit h T l y m p h o c yt e c o u nt L L N will b e eli gi bl e f or t hi s st u d y.
 
Tr e at m e nt wit h n at ali z u m a b wit hi n 2 4 m o nt h s pri or t o i nf u si o n
N B: p arti ci p a nt s pr e vi o u sl y tr e at e d wit h n at ali z u m a b will b e eli gi bl e f or t hi s st u d y 
o nl y if d ur ati o n of tr e at m e nt wit h n at ali z u m a b w a s 1 y e ar .
 
Tr e at m e nt wit h t erifl u n o mi d e of di m et h yl f u m ar at e ( B G 1 2) wit h i n 1 2 w e e k s pri or t o 
s cr e e ni n g


A p p e n di x 8 
O p e n -L a b el E xt e n si o n S u b st u d y i n P arti ci p a nt s W h o Di s c o nti n u e d 
Tr e at m e nt i n t h e Bli n d e d P h a s e of St u d y W A 2 5 0 4 6 ( c o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 6 5 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
 
Tr e at m e nt wit h I V i m m u n o gl o b uli n, pl a s m a p h er e si s, or ot h er i m m u n o m o d ul at or y 
t h er a pi e s wit hi n 1 2 w e e k s pri or t o s cr e e ni n g; tr e at m e nt wit h I F N-or gl atir a m er 
a c et at e i s all o w e d u ntil s cr e e ni n g
P arti ci p a nt s s cr e e n e d f or t hi s s u b st u d y s h o ul d n ot b e wit h dr a w n fr o m t h er a pi e s f or 
t h e s ol e p ur p o s e of m e eti n g eli gi bilit y f or t h e s u b st u d y.
 
S y st e mi c c orti c o st er oi d t h er a p y wit hi n 4 w e e k s pri or t o s cr e e ni n g
T h e s cr e e ni n g p eri o d m a y b e e xt e n d e d ( b ut c a n n ot e x c e e d 8 w e e k s) f or p arti ci p a nt s 
w h o h a v e u s e d s y st e mi c c orti c o st er oi d s f or t h eir M S b ef or e s cr e e ni n g.  F or a 
p arti ci p a nt t o b e eli gi bl e, s y st e mi c c orti c o st er oi d s s h o ul d n ot h a v e b e e n 
a d mi ni st er e d al s o b et w e e n s cr e e ni n g a n d b a s eli n e.
S C H E D U L E O F A C TI VI TI E S A N D P R O C E D U R E S
S c h e d ul e of a c ti viti e s i n t hi s s u b st u d y will b e i d e nti c al t o t h at of p arti ci p a nt s e nt eri n g 
O L E t hr o u g h t h e m ai n pr ot o c ol ( T a bl e 4 of S e cti o n 1. 2 of m ai n pr ot o c ol), wit h t h e 
e x c e pti o n of s cr e e ni n g p eri o d t h at i s i n s ert e d s p e cifi c all y f or t hi s s u b st u d y b ef or e t h e 
O L E tr e at m e nt p h a s e.
S e e T a bl e 1 f or t h e s c h e d ul e of a cti viti e s f or s cr e e ni n g p eri o d, O L E tr e at m e nt p h a s e, 
d el a y e d d o si n g vi sit, U n s c h e d ul e d vi sit, a n d Wi t h dr a w al fr o m T r e at m e nt Vi sit.
F or t h e s af et y foll o w -u p p eri o d, t h e s a m e pr o vi si o n s a p pl y a s f or t h e p arti ci p a nt s 
e nt eri n g O L E t hr o u g h t h e m ai n pr ot o c ol. S e e T a bl e 3 of S e cti o n 1. 2 of t h e m ai n pr ot o c ol 
f or s c h e d ul e of a cti viti e s d uri n g s af et y foll o w - up p eri o d.




A p p e n di x 8 
O p e n -L a b el E xt e n si o n S u b st u d y i n P arti ci p a nt s W h o Di s c o nti n u e d Tr e at m e nt i n t h e Bli n d e d P h a s e of St u d y W A 2 5 0 4 6
( c o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 6 7 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1






A p p e n di x 8 
O p e n -L a b el E xt e n si o n S u b st u d y i n P arti ci p a nt s W h o Di s c o nti n u e d Tr e at m e nt i n t h e Bli n d e d P h a s e of St u d y W A 2 5 0 4 6
( c o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 7 0 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
e
U n s c h e d ul e d vi sit ( n o n-d o si n g):  a s s e s s m e nt s p erf or m e d at u n s c h e d ul e d ( n o n -d o si n g) vi sit s will d e p e n d o n t h e cli ni c al n e e d s of t h e p arti ci p a nt .  
All p arti ci p a nt s wit h n e w n e ur ol o gi c al s y m p t o m s s u g g e sti v e of M S w or s e ni n g or of a r el a p s e s h o ul d h a v e E D S S p erf or m e d b y t h e 
E x a mi ni n g I n v e sti g at or.  Ot h er t e st s/ a s s e s s m e nt s m a y b e d o n e a s a p pr o pri at e.
f
I nf or m e d c o n s e nt f or t hi s s u b st u d y will b e o bt ai n e d i n writt e n f or m fr o m all p arti ci p a nt s at s cr e e ni n g i n or d er t o m e et eli gi bilit y f or t h e s u b st u d y.
g
All r el e v a nt m e di c al hi st or y
fr o m t h e ti me of di s c o nti n u ati o n fr o m t h e m ai n st u d y u ntil s cr e e ni n g f or t h e s u b st u d y will b e r e p ort e d.
h
Vit al si g n s will b e o bt ai n e d w hil e t h e p arti ci p a nt i s i n t h e s e mi -s u pi n e p o siti o n ( aft er 5 mi n ut e s), i n cl u di n g p ul s e r at e, s y st oli c a n d di a st oli c bl o o d
pr e s s ur e, r e s pir ati o n r at e, a n d t e m p er at ur e.  At i nf u si o n vi sit s, t h e vit al si g n s f or all p arti ci p a nt s s h o ul d b e t a k e n wit hi n 4 5 mi n ut e s pri or t o t h e 
m e t h yl pr e d ni s ol o n e i nf u si o n.  I n a d diti o n, vit al si g n s s h o ul d b e o bt ai n e d pri or t o t h e st u d y dr u g or pla c e b o i nf u si o n, t h e n e v er y 1 5 mi n ut e s 
(5 mi n ut e s) f or t h e fir st h o ur; t h e n e v er y 3 0 mi n ut e s ( 1 0 mi n ut e s) u ntil 1 h o ur aft er t h e e n d of t h e i nf u si o n.  At n o n -i nf u si o n vi sit s, t h e vit al 
si g n s m a y  b e t a k e n at a n y ti m e d uri n g t h e vi sit.
i
E C G s ( pr e - a n d p o st d o s e):   E C G s s h o ul d b e p erf or m e d wit hi n 4 5 mi n ut e s pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n i n all p arti ci p a nt s a n d wit hi n 
6 0 mi n ut e s aft er c o m pl eti o n of t h e o cr eli z u m a b i nf u si o n.  Fr o m W e e k  7 2 o n w ar d s , E C G a s s e s s m e nt i s n ot m a n d at or y; it s h o ul d o nl y be 
p erf or m e d if cli ni c all y i n di c at e d.
j
A n y cli ni c al r el a p s e s fr o m t h e ti m e of di s c o nti n u ati o n fr o m t h e m ai n st u d y n e e d t o b e r e p ort e d.
k
A str u ct ur e d t el e p h o n e i nt er vi e w will b e c o n d u ct e d b y sit e p er s o n n el e v er y 4 w e e k s t o i d e ntif y a n d c oll e ct i nf or m ati o n o n a n y  c h a n g e s i n t h e 
p arti ci p a nt’ s h e alt h st at u s t h at w arr a nt a n u n s c h e d ul e d vi sit (i n cl u di n g n e w or w or s e ni n g n e ur ol o gi c al s y m p t o m s).
l
M RI s c a n s :  a br ai n M RI s c a n s h o ul d b e p erf or m e d at t h e st art of t h e s u b st u d y.  Br ai n M RI s s h o ul d b e d o n e o n c e a y e ar.  Br ai n M RI s c a n s 
s h o ul d o c c ur wit hi n a wi n d o w of 4 w e e k s of t h e s c h e d ul e d vi sit.  Al s o, br ai n M RI s c a n s will b e o bt ai n e d i n p arti ci p a nt s wit h dr a w n fr o m t h e 
s u b st u d y ( at a wit h dr a w al vi sit) if n ot p erf or m e d d uri n g t h e pr e vi o u s 4 w e e k s.
m
Uri n e -h C G ( s e n siti vity of at l e a st 2 5 mI U/ m L) will b e p erf or m e d.  O n i nf u si o n vi sit s, t h e uri n e pr e g n a n c y t e st s h o ul d b e p erf or m e d pri or t o 
m e t h yl pr e d ni s ol o n e i nf u si o n i n all w o m e n of c hil d b e ari n g p ot e nti al.  If p o siti v e, t h e p arti ci p a nt will n ot r e c ei v e t h e s c h e d u l e d d o s e, a n d f or 
c o nfir m ati o n, a s er u m pr e g n a n c y t e st will b e p erf or m e d.
n
A n ti b o d y tit er s:  m e a s ur e m e nt of  a nti b o d y tit er s a g ai n st c o m m o n a nti g e n s ( m u m p s, r u b ell a, v ari c ell a, a n d S. p n e u m o ni a e ) will b e p erf or m e d.
o
H A H A :  o n i nf u si o n vi sit s, s a m pl e s ar e c oll e ct e d pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n.
p
P K s a m pl e s :  o n i nf u si o n d a y s i n C ycl e 1, 2 bl o o d s a m pl e s s h o ul d b e c oll e ct e d, 1 s a m pl e pri or t o t h e m et h yl pr e d ni s ol o n e i nf u si o n, a n d t h e 
s e c o n d s a m pl e 3 0 mi n ut e s ( 1 0 mi n ut e s) f oll o wi n g t h e c o m pl eti o n of t h e o cr eli z u m a b i nf u si o n.  At ot h er ti m e s ( n o n -i nf u si o n vi sit s), s a m pl e s m a y 
b e t a k e n at a n y ti m e d uri n g t h e vi sit.  F or all s u b s e q u e nt c y cl e s aft er C y cl e 1, o nl y 1 P K s a m pl e will b e t a k e n o n D a y 1 pri o r t o t h e 
m e t h yl pr e d ni s ol o n e i nf u si o n.
q
H e p atiti s m o nit ori n g :  f or t h o s e p arti ci p a nt s e nr oll e d wit h n e g ati v e H B s A g a n d p o siti v e t ot al H B c A b, H B V D N A ( P C R) m u st c o nti n u e t o b e 
r e p e at e d e v er y 1 2 w e e k s d uri n g t h e s u b st u d y.
r
F A C S :  i n cl u di n g C D 1 9 a n d ot h er cir c ul ati n g B c ell s u b s et s, T c ell s, n at ur al kill er c ell s, a n d ot h er l e u k o c y t e s.  O n i nf u si o n d a y s, F A C S s a m pl e s 
s h o ul d b e c oll e ct e d pri or t o i nf u si o n.  S e e S e cti o n 5. 1 3. 2 f or s p e cifi c t e st s.


A p p e n di x 8 
O p e n -L a b el E xt e n si o n S u b st u d y i n P arti ci p a nt s W h o Di s c o nti n u e d Tr e at m e nt i n t h e Bli n d e d P h a s e of St u d y W A 2 5 0 4 6
( c o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 7 1 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
s
R o uti n e s af et y l a b or at or y t e st s :  h e m at ol o g y, c h e mi str y, a n d uri n al y si s:  o n i nf u si o n vi sit s, all uri n e a n d bl o o d s a m pl e s s h o ul d b e c oll e ct e d
pri or t o t h e i nf u si o n of m e t h yl pr e d ni s ol o n e.  At ot h er ti m e s, s a m pl e s m a y b e t a k e n at a n y ti m e d uri n g t h e vi sit.  S a m pl e s c oll e ct e d d uri n g 
u n s c h e d ul e d vi sit s s h o ul d pr ef er a bl y b e s e nt t o a n d a n al y z e d b y t h e c e ntr al l a b or at or y a n d n ot l o c al u nl e s s r e s ult s ar e r e q ui r e d ur g e ntl y.
t
R C R ( pr ot ei n) 6-m L  bl o o d s a m pl e s i n E D T A t u b e f or pl a s m a will b e t a k e n fr o m c o n s e nti n g p arti ci p a nt s f or a n al ysi s of pr ot ei n bi o m ar k er s.  
O n i nf u si o n vi sit s, s a m pl e s s h o ul d b e c oll e ct e d 53 0 mi n ut e s pri or t o m et h yl pr e d ni s ol o n e i nf u si o n.
u
Pl a s m a a n d uri n e s a m p l e s f or J C V will b e c oll e ct e d at s p e cifi e d ti me p oi nt s.
v
All p arti ci p a nt s will r e c ei v e pr o p h yl a cti c tr e at m e nt wit h 1 0 0 m g  of m et h yl pr e d ni s ol o n e I V a n d a n or al or I V a nti hi st a mi n e ( s u c h a s 
di p h e n h y dr a mi n e 5 0 m g  or e q ui v al e nt d o s e of alt er n ati v e) pri or t o i nf u si o n of o cr eli z u m a b. I n t h e r ar e c a s e s w h e n m e t h yl pr e d ni s ol o n e i s 
c o ntr ai n di c at e d f or t h e p arti ci p a nt, e q ui v al e nt d o s e s of ot h er I V st er oi d s ( e. g., d e x a m et h a s o n e) s h o ul d b e u s e d a s pr e m e di c ati o n pri or t o t h e 
i nf u si o n.  It i s al s o r e c o m m e n d e d t h at p arti ci p a nt s r e c ei v e a n a n al g e si c/ a nti p y r eti c s u c h a s a c et a mi n o p h e n/ p ar a c et a m ol ( 1 g) 3 0 – 6 0 mi n ut e s 
pri or t o o cr eli z u m a b i nf u si o n s.
w
St u d y dr u g a d mi ni str ati o n :  t h e Tr e ati n g I n v e sti g at or m u st r e vi e w t h e cli ni c al a n d l a b or at or y r e-tr e at m e nt crit eri a pri or t o r e-d o si n g p arti ci p a nt s 
wit h st u d y dr u g i n all s u b s e q u e nt tr e at m e nt c y cl e s.
x
O p e n -l a b el cli ni c al g e n ot y pi n g:  a 3-m L  w h ol e bl o o d s a m pl e will b e t a k e n o n e ti m e fr o m p arti ci p a nt s t h at di d n ot h a v e a s a m pl e c oll e ct e d f or D N A
a n al y si s of H L A -D R a n d F c p o l ym o r p hi s m s d uri n g t h e bli n d e d tr e at m e nt p eri o d.  If n ot c oll e ct e d at t h e b a s eli n e vi sit ( Vi sit 1), t h e s a m pl e m a y 
b e c oll e ct e d at a n y s u b s e q u e nt vi sit .


A p p e n di x 8 
O p e n -L a b el E xt e n si o n S u b st u d y i n P arti ci p a nt s W h o Di s c o nti n u e d 
Tr e at m e nt i n t h e Bli n d e d P h a s e of St u d y W A 2 5 0 4 6 ( C o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 7 2 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
S C R E E NI N G E X A MI N A TI O N A N D E LI GI BI LI T Y S C R E E NI N G F O R M
All p arti ci p a nt s m u st si g n a n d d at e t h e m o st c urr e nt I n stit uti o n al R e vi e w B o ar d/ Et hi c s 
C o m mitt e e’ s a p pr o v e d writt e n i nf or m e d c o n s e nt f or t hi s s u b st u d y b ef or e a n y st u d y 
s p e cifi c a s s e s s m e nt s or pr o c e d ur e s ar e p erf or m e d.
A s cr e e ni n g e x a mi n ati o n ( m e di c al hi st or y a n d p h y si c al e x a mi n ati o n i n cl u di n g vit al si g n s 
h ei g ht a n d w ei g ht a n d n e ur ol o gi c al e x a mi n ati o n wit h E D S S a s s e s s m e nt) s h o ul d b e 
p erf or m e d wit hi n 4 w e e k s pri or t o t h e st art of t h e s u b st u d y.  E l e ctr o c ar di o gr a m a n d 
l a b or at or y t e st s (r o uti n e s af et y, pr e g n a n c y t e st i n w o m e n of c hil d b e ari n g p ot e nti al a n d 
C D 4 c o u nt ) will al s o b e p erf or m e d.  T h e s cr e e ni n g p eri o d c a n b e e xt e n d e d t o a t ot al 
p eri o d of 8 w e e k s i n c a s e s w h e n a l a b or at or y bl o o d t e st or M RI s c a n n e e d t o b e 
r e p e at e d f or c o nfir m ati o n d uri n g t h e s cr e e ni n g i nt er v al or f or ot h er r el e v a nt cli ni c al, 
a d mi ni str ati v e, or o p er ati o n al r e a s o n s.  P arti ci p a nt s m u st f ulfill all t h e e ntr y crit eri a f or 
p arti ci p ati o n i n t h e st u d y ( s e e S e cti o n 5 ).
E a c h p arti ci p a nt s cr e e n e d m u st b e r e gi st er e d i n t h e I x R S b y t h e in v e sti g at or or t h e 
i n v e sti g at or’s r e s e ar c h st aff at s cr e e ni n g.  A s cr e e n f ail ur e r e c or d m u st b e m ai nt ai n e d b y 
t h e in v e sti g at or a n d c a pt ur e d i n t h e I x R S.
It s h o ul d b e st at e d i n t h e m e di c al r e c or d t h at t h e p arti ci p a nt i s p arti ci p ati n g i n t hi s cli ni c al 
st u d y.
P R O C E D U R E S F O R E N R O L L M E N T O F E L I GI B L E P A R TI CI P A N T S
O n c e a p arti ci p a nt h a s f ulfill e d t h e e ntr y crit eri a, h e or s h e will b e a s si g n e d vi a I x R S a 
n e w u ni q u e p arti ci p a nt i d e ntifi er t o a n o p e n -l a b el 3 0 0 m g2 of o cr eli z u m a b.
P arti ci p a nt eli gi bilit y i nf or m ati o n will b e pr o vi d e d t o t h e I x R S b y t h e in v e sti g at or or t h e 
in v e sti g at or’ s r e s e ar c h st aff pri or t o s cr e e ni n g .
T h e p arti ci p a nt i d e ntifi er n u m b er s ar e t o b e all o c at e d s e q u e nti all y i n t h e or d er i n w hi c h 
t h e p arti ci p a nt s ar e e nr oll e d a c c or di n g t o t h e s p e cifi c ati o n d o c u m e nt a gr e e d wit h t h e 
e xt er n al c o m p a n y/ c e nt er.
Tr e at m e nt wit h t h e fir st o p e n -l a b el o cr eli z u m a b i nf u si o n s h o ul d o c c ur wit hi n 2 4 h o ur s of 
e nr oll m e nt .  I n e x c e pti o n al c a s e s w h er e n ot all b a s eli n e a s s e s s m e nt s c a n b e c o m pl et e d 
wit hi n 2 4 h o ur s, t h e fir st o cr eli z u m a b i nf u si o n c a n b e a d mi ni st er e d wit hi n 4 8 h o ur s 
pr o vi d e d t h at t h e in v e sti g at or a s s ur e s t h at all i n cl u si o n a n d e x cl u si o n crit eri a ar e still m et 
o n t h e d a y of d o si n g.  I n p arti c ul ar, t h er e s h o ul d b e n o e vi d e n c e of a n o n g oi n g i nf e cti o n 
at t h e ti m e of d o si n g.
N o p arti ci p a nt m a y b e gi n tr e at m e nt pri or t o e nr oll m e nt a n d a s si g n m e nt of a m e di c ati o n 
n u m b er.


A p p e n di x 8 
O p e n -L a b el E xt e n si o n S u b st u d y i n P arti ci p a nt s W h o Di s c o nti n u e d 
Tr e at m e nt i n t h e Bli n d e d P h a s e of St u d y W A 2 5 0 4 6 ( c o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 7 3 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
O V E R VI E W O F S U B S T U D Y A S S E S S M E N T S
Wi t h t h e e x c e pti o n of t h e m a n d at or y s cr e e ni n g p eri o d i n t hi s s u b st u d y, all ot h er s u b st u d y 
p eri o d s ar e i d e nti c al t o t h o s e d efi n e d f or t h e O L E p h a s e i n t h e m ai n pr ot o c ol 
( S e cti o n 5. 2 3 ). T h e pr o c e d ur e s t o a s s e s s effi c a c y, s af et y a n d l a b or at or y p ar a m et er s ar e 
t h e s a m e a s t h o se d e s cri b e d i n S e cti o n 1. 2 of t h e m ai n pr ot o c ol.
I N V E S TI G ATI O N A L M E DI CI N A L P R O D U C T
D uri n g t hi s s u b st u d y, all p arti ci p a nt s will r e c ei v e o p e n -l a b el o cr eli z u m a b u n d er t h e s a m e 
a d mi ni str ati o n s c h e d ul e a n d pr o c e d ur e s a s d efi n e d f or t h o s e p arti ci p a nt s e nt eri n g 
O L E t hr o u g h t h e m ai n pr ot o c ol. D et ail s ar e pr o vi d e d i n S e cti o n 6 of t h e m ai n pr ot o c ol.
S A F E T Y I N S T R U C TI O N S A N D G UI D A N C E
T h e s a m e pr o vi si o n s a p pl y a s i n S e cti o n 7 of t h e m ai n pr ot o c ol.
S T A TI S TI C A L C O N SI D E R A T I O N S A N D A N A L Y TI C A L P L A N
D et ail s of t h e st ati sti c al a n al y s e s f or t hi s s u b st u d y will b e pr o vi d e d i n t h e S A P.


O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 7 4 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A p p e n di x 9
A b br e vi ati o n s
A b br e vi ati o n or T er m
D efi niti o n
A R R
a n n u ali z e d rel a p s e rat e
A U C
ar e a u n d er t h e c o n c e ntr ati o n – ti me c ur v e
B C G
B a cill e C al m ett e - G u eri n
-h C G
h u m a n c h ori o ni c g o n a d otr o pi n
C D
c l u st er of d iff er e nti ati o n
C S F
c er e br o s pi n al fl ui d
C T C A E
C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e 
E v e nt s 
D M T
di s e a s e -m o dif yi n g tr e at m e nt
D S S
Di s a bilit y St at u s S c al e
e C R F
e l e ctr o ni c C a s e R e p ort F or m
E D C
El e ctr o ni c D at a C a pt ur e
E C
Et hi c s c o m mitt e e
E D S S
E x p a n d e d Di s a bilit y St at u s S c al e
F A C S
fl u or e s c e n c e- acti v at e d c ell s orti n g
F S S
F u n cti o n al S y st e m S c or e
G G T
g a m m a g l ut a myl  tr a n sf er a s e
H A H A
h u m a n a nti -h u m a n a nti b o d y
H B c A b
h e p atiti s B c or e a nti b o d y
H B s A g
H e p atiti s B s urf a c e A nti g e n
H B V
h e p atiti s B vir u s
H e p C A b
h e p atiti s C vir u s a nti b o d y
H L A
h u m a n le u k o c y t e a nti g e n
H T L V
h u m a n T -l ym p h otr o pi c vir u s 
I C H
I nt er n ati o n al C o nf er e n c e o n H ar m o ni s ati o n
I C F
I nf or m e d C o n s e nt F or m
i D M C
i n d e p e n d e nt D at a M o nit ori n g C o m mitt e e
I F N
int erf er o n
I M P
I n v e sti g ati o n al M e di ci n al Pr o d u ct
I N D 
I n v e sti g ati o n al N e w Dr u g
I R B
I n stit uti o n al R e vi e w B o ar d
I R R
inf u si o n -rel at e d re a cti o n
I T T
I nt e nt-T o -Tr e at
I x R S
i nt er a cti v e v oi c e or We b -b a s e d r e s p o n s e 
s y st e m
J C V
J o h n C u n ni n g h a m vir u s


A p p e n di x 9 
A b br e vi ati o n s ( c o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 7 5 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A b br e vi ati o n or T er m
D efi niti o n
K L H
k e y h ol e li m p et h e m o c y a ni n
L L N
lo w er li mit of n or m al
M C S
M e nt al C o m p o n e nt S u m m ar y
M FI S
M o difi e d F ati g u e I m p a ct S c al e
M M R M
m i x e d- eff e ct m o d el re p e at e d m e a s ur e s
M RI
m a g n eti c r e s o n a n c e i m a gi n g
M S
m u lti pl e s cl er o si s
M S F C S
M ulti pl e S cl er o si s F u n cti o n al C o m p o sit e S c al e
N O N M E M
n o nli n e ar mi x e d -eff e ct s m o d eli n g
O C T
o pti c al c o h er e n c e to m o gr a p h y
O L E
o p e n -la b el e xt e n si o n
P A S A T
P a c e d A u dit or y S eri al A d diti o n T e st
P C R
p ol y m e r a s e c h ai n re a cti o n
P C S
P h y s i c al C o m p o n e nt S u m m ar y
P D
p h ar m a c o d y n a mi c
P K
p h ar m a c o ki n eti c
P M L
p r o gr e s si v e m ultif o c al le u k o e n c e p h al o p at h y
P P
p er pr ot o c ol
P P M S
pri m ar y  pr o gr e s si v e m ulti pl e s cl er o si s
P R O
p arti ci p a nt -re p ort e d o ut c o m e
R A
r h e u m at oi d art hriti s
R B R
R e s e ar c h BI o s a m pl e R e p o sit or y
R M S
r el a p si n g m ulti pl e s cl er o si s
R C R
R o c h e Cli ni c al R e p o sit or y
R N F L
reti n al n er v e fi b er la y er
R O W
R e st of W o rl d
R P R
ra pi d p l a s m a re a gi n
R R
r el ati v e r e d u cti o n
R R M S
r el a p si n g-r e mitti n g m ulti pl e s cl er o si s
S A P
St ati sti c al A n al y si s Pl a n
S F -3 6
S h ort F or m -3 6 H e alt h S ur v e y


A p p e n di x 9 
A b br e vi ati o n s ( c o nt.)
O cr eli z u m a b — F. H off m a n n -L a R o c h e Lt d
1 7 6 / Pr ot o c ol W A 2 5 0 4 6 K , V er si o n 1 1
A b br e vi ati o n or T er m
D efi niti o n
S P M S
s e c o n d ar y pr o gr e s si v e m ulti pl e s cl er o si s
T B
tu b er c ul o si s
U L N
u p p er li mit of n or m al
V E P
v i s u al e v o k e d p ot e nti al

SAP_001.pdf: 
 
Official Title: 
 
A Phase III, Multicentre, Randomized, Parallel-Group, Double Blinded, 
Placebo Controlled Study to Evaluate the Efficacy and Safety of 
Ocrelizumab in Adults With Primary Progressive Multiple Sclerosis 
NCT Number: NCT01194570 
Document Dates: SAP Version 5: 20-March-2023 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
CONFIDENTIAL 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA25046 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE III, MULTICENTRE, RANDOMIZED, PARALLEL-GROUP, 
DOUBLE BLINDED, PLACEBO CONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF OCRELIZUMAB IN 
ADULTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS 
PROTOCOL NUMBER: 
WA25046 
STUDY DRUG: 
Ocrelizumab 
VERSION NUMBER: 
5 
IND NUMBER: 
100,593 
EUDRACT NUMBER: 
2010-020338-25 
SPONSOR: 
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY: 
 Ph.D. 
M.Sc.
DATE FINAL: 
20 December 2013 
DATES AMENDED: 
Version 2:  30 October 2014 
Version 3:  28 January 2015 
Version 4:  03 September 2015 
Version 5: See electronic date stamp on the last 
page of this document 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan WA25046 
 
STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
Version 1 (20 December 2013) 
Based on Version D of the Protocol WA25046 (15 June 2012). 
Version 2 (30 October 2014, Protocol Version D) 
Updates to Version 1 made at this time include the following substantive changes: 
 
The schedule of assessment was removed to reduce redundancy with the protocol. 
 
More details on the analyses timing were added, and a maximum duration of the 
blinded treatment period was introduced following re-estimation of the trial duration 
based on actual event rates.  These changes were consistent with the protocol, and 
intended to better define the likely end of trial. 
– 
If the prediction does not ensure at least 253 confirmed disability progression 
(CDP) events at Week 120, this procedure will be repeated 6 weeks later. 
– 
The primary database lock will occur no later than three years after the last 
patient was randomized, even if the 253 events have not been reached at this 
timepoint. 
 
Clarifying that the safety population includes all patients dosed to adhere to the 
standard definition. 
 
The intent-to-treat (ITT) population includes all patients randomized to adhere to the 
standard definition. 
 
The secondary efficacy outcome “Change in Total Volume of T2 Lesions on MRI 
Scans of the Brain from Baseline to Week 120” was moved down from the third to 
the fourth rank in the testing hierarchy.  Consequently, the “Change in 25-foot timed 
walk” moved from fourth to the third rank in the testing hierarchy. 
 
“Percent Change on MRI from Week 24 to Week 120 in Total Brain Volume” and 
“Change from Baseline in Quality of Life as Measured by the SF-36 Physical 
Component Score (PCS)” were added at the end of the list of secondary endpoints. 
 
EMA Scientific Advice was implemented to increase statistical rigor (e.g., replacing 
Van Elteren Tests and last-observation carried forward [LOCF] method) with 
Mixed-Effect Model Repeated Measures [MMRM] analysis). 
 
The “Change in Total Volume of T2 Lesions on MRI Scans of the Brain from 
Baseline to Week 120” will be analyzed as “Percent Change in Total Volume of 
T2 Lesions on MRI Scans of the Brain from Baseline to Week 120” to align with the 
other MRI measures (brain volume, white and grey matter). 
 
The following exploratory endpoints were added: 
– 
The change in fatigue, as measured by the Modified Fatigue Impact Scale 
(MFIS) total score and subscale scores (Physical impact, Cognitive impact, and 
Psychological impact) from baseline to Week 120. 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan WA25046 
 
– 
The change in quality of life, as measured by the SF-36v2 Mental Component 
Summary (MCS) Score from baseline to Week 120. 
– 
Time to CDP over the treatment period, defined as an increase in Expanded 
Disability Status Scale (EDSS) that is sustained for at least 12 weeks (0.5 or 1, 
same criteria as for the primary endpoint time to 12-week CDP) or a 20% increase 
in 25-foot timed walk that is sustained for at least 12 weeks or a 20% increase in 
9-hole peg test that is sustained for at least 12 weeks. 
 
Additional sensitivity analysis: 
– 
For the time to onset of CDP for  24 weeks, the influence of early progression 
events on treatment effect will also be evaluated by omitting the EDSS 
assessments performed between randomization and the Week 12 visit 
( 83 days after randomization) with use of the ITT population. 
 
Adverse events:  
– 
Detailed definition of serious adverse events (SAEs) was added; that is, “SAEs will 
be defined as all SAEs including serious MS relapses and serious IRRs.” 
– 
The derivation of the 95% CI for the number of adverse events (AEs) per 
100 patient-years was aligned with the Phase III relapsing multiple sclerosis (RMS) 
studies. 
 
Version 3 (28 January 2015, Protocol Version D) 
Updates made at this time include the following substantive changes: 
 
Change of the baseline definition for assessments other than EDSS to include the 
baseline/Day 1 visit into the baseline.  Blinded review of the data indicated that 
baseline assessment on Day 1 occurred after the day of randomization in many 
cases.  Thus, restricting the baseline to up to and including the day of randomization 
would have led to a considerable number of patients without baseline assessments. 
 
The change in 25-foot timed walk from baseline to Week 120 was added to the 
subgroup analyses. 
 
Version 4 (03 September 2015, Protocol Version E) 
This Statistical Analysis Plan has been updated to align with the amended study protocol 
(WA25046, Version E, 25 February 2015).  Updates made at this time include the 
following substantive changes.  The rationale for the update is to provide full and 
complete information on these important aspects prior to database lock. 
Changes to the statistical analyses methods:  
 
Experience from the RMS Phase III program and blinded review of WA25046 data 
indicated that the use of MMRM on the absolute change in 25-foot timed walk from 
baseline to Week 120 would violate the assumptions of normal distribution of the 
residuals.  Therefore, we will analyze relative change from baseline.  The p-value of 
the non-parametric ranked analysis of covariance (ranked ANCOVA) on the percent 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan WA25046 
 
change from baseline will be reported.  The LOCF method will be used to impute 
missing values.  Assuming a higher withdrawal rate in the control than in the 
treatment arm and a monotonous increase in the 25-foot timed walk, this method is 
expected to be conservative.  Since the ranked ANCOVA does not provide 
estimates of the treatment effects, these will be derived using MMRM analyses on 
the log-transformed post-baseline/baseline values. 
In addition, rules for handling outliers in 25-foot timed walk were added based on 
the Multiple Sclerosis Functional Composite (MSFC) Manual and published data on 
reference ranges from healthy subject cohorts. 
 
Experience from the RMS Phase III program (WA21092 and WA21093) and blinded 
review of WA25046 data indicated that for the percentage change in T2 lesion 
volume, the MMRM analyses would violate the assumptions of normal distribution of 
the residuals.  Therefore, the same analysis approach (ranked ANCOVA, MMRM) 
as for the change in 25-Foot Timed Walk will be used, and the title was changed 
from percentage change to change in T2 lesion volume. 
 
Additional sensitivity analyses:  Based on the results of the Phase III RMS studies 
(WA21092, WA21093) and the blinded review of WA25046 data, a sensitivity 
analysis adjusting for presence of Gadolinium-enhancing lesions and baseline 
EDSS ( 5.5 vs  5.5) at baseline was added.  Blinded review of WA25046 data 
indicated that there are patients with relapses in the study.  Since primary 
progressive multiple sclerosis (PPMS) is characterized by a progressive course from 
disease onset typically without superimposed discrete clinical attacks or relapses 
(Ebers 2004), the analyses of time to CDP for at least 12 weeks and the time to 
CDP for at least 24 weeks will be performed excluding patients with clinical 
relapses. 
 
Body weight and body mass index have been added to the subgroup analyses. 
 
Other changes:  
 
The standard operating procedure describing the checks done on EDSS values has 
been added, which is effective since January 2013, to provide further detail on the 
EDSS cleaning algorithm. 
 
Consistent with the protocol, detailed reasons for patient exclusion from per-protocol 
population have been added. 
 
The definition of disease-modifying treatments (DMTs) was updated to account for 
most recent available therapies. 
 
The definition of protocol-defined relapses has been updated to align with the 
current protocol. 
 
SAS codes have been included for statistical models for primary and secondary 
analyses. 
 
Detailed updates have been made to the safety analysis section, including the 
definition of the duration of observation, details on the derivation of AEs and SAEs 
and the assignment of AEs to a specific dose, the detailed description of the 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
5/Statistical Analysis Plan WA25046 
 
analyses done for selected AEs (i.e., infusion-related reaction [IRRs], infections, 
opportunistic infections [OIs], malignancies). 
 
To have consistent description of safety analysis across the RMS and progressive 
multiple sclerosis trials and integrated safety analyses, the details of the safety 
analyses were added in this document. 
 
Additional minor changes have been made to each version to improve clarity and 
consistency. 
Version 5 (March 2023, Protocol Version F, G, H, I, J and K) 
This SAP is updated to describe the analyses to be performed on data from the 
extended controlled period and open-label extension (OLE) period.  As additional data 
collection and objectives may differ from double-blind phase, SAP requires modification.  
Moreover, several modifications were made based on the availability of the data.  A list 
of these modifications can be found below.  A table is also added to display the status of 
each reporting event. 
The following study periods will be considered for the final analyses: 
 
Efficacy analyses will be performed for the extended controlled treatment period 
(ECP), i.e., from randomization up to the first dose of Ocrelizumab in OLE. 
 
Efficacy analyses will be performed for the OLE period, i.e., from the first dose of 
Ocrelizumab in OLE. 
 
Efficacy analyses will be performed for the combined periods of ECP and OLE. 
 
Safety analysis will be performed separately for the OLE and OLE safety follow-up 
(SFU) periods as well as for all study periods combined. 
 
Additional endpoints for the extension periods: 
 
Time to confirmed EDSS score  7.0 (time to requiring a wheelchair) for at least 
24 weeks during the combined ECP and OLE periods. 
 
Time to confirmed EDSS score  7.0 (time to requiring a wheelchair) for at least 
48 weeks during the combined ECP and OLE periods. 
 
Change from baseline in total non-enhancing T1 lesion volume. 
 
Annualized change in MRI parameters including brain volumes, T1 lesion volume 
and T2 lesions volume. 
 
Protocol Updates: 
Due to various protocol amendments, SAP is updated to reflect changes or updates 
made in the protocol amendment.  Below are some of such changes; 
 
Pharmacokinetic (PK)/human anti-human antibody (HAHA) collection has been 
stopped since Dec 2019. 


 
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6/Statistical Analysis Plan WA25046 
 
 
Ocrelizumab infusion must be suspended in the event of an active TB infection or if 
a female patient is pregnant or breastfeeding in OLE period.  Ocrelizumab infusions 
may be restarted at the discretion of the Investigator and based on individual 
benefit-risk assessments, but only upon resolution of the active TB infection or after 
completion of pregnancy and breastfeeding. 
 
The requirement for continued B cell monitoring for participants whose B cells are 
not repleted (i.e., returned to baseline levels or the lower limit of normal, whichever 
is lower) at the end of the SFU period has been removed. 
 
Patients starting commercial ocrelizumab or other DMTs will discontinue from the 
study completely and will not enter SFU. 
 
The OLE treatment phase is extended till 31 Dec 2022 to allow additional long-term 
efficacy and safety data.  An option is introduced for all ongoing participants of 
Study WA25046 to enroll into a new OLE study (MN43964) prior to or following the 
closure of Study WA25046, latest by End of 2022. 
 
Additional minor changes have been made to improve clarity and consistency. 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
7/Statistical Analysis Plan WA25046 
 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 2 
1. 
BACKGROUND ............................................................................ 10 
2. 
STUDY DESIGN ........................................................................... 11 
2.1 
Outcome Measures ................................................................. 12 
2.1.1 
Efficacy Outcome Measures .................................................... 12 
2.1.2 
Pharmacokinetic Outcome Measures ...................................... 13 
2.1.3 
Safety Outcome Measures ...................................................... 14 
2.2 
Determination of Sample Size ................................................. 14 
2.3 
Analysis Timing ........................................................................ 15 
3. 
STUDY CONDUCT ....................................................................... 16 
3.1 
Randomization ......................................................................... 16 
3.2 
Independent Review Facility .................................................... 17 
3.3 
Expanded Disability Status Scale Cleaning Process ............... 17 
3.4 
Data Monitoring ....................................................................... 17 
4. 
STATISTICAL METHODS ............................................................ 18 
4.1 
Analysis Populations ................................................................ 18 
4.1.1 
Intent-to-Treat Population ........................................................ 18 
4.1.2 
OLE ITT Population ................................................................. 18 
4.1.3 
Per-Protocol Population ........................................................... 18 
4.1.4 
Safety Population ..................................................................... 19 
4.1.5 
OLE Safety Population ............................................................ 20 
4.2 
Overview of Analyses Planned for the Extension Periods ....... 20 
4.3 
Analysis of Study Conduct ....................................................... 22 
4.4 
Analysis of Treatment Group Comparability ............................ 23 
4.5 
Efficacy Analysis ...................................................................... 24 
4.5.1 
Primary Efficacy Endpoint ........................................................ 25 
4.5.2 
Secondary Efficacy Endpoints ................................................. 28 
4.5.2.1 
Time to Onset of Confirmed Disability Progression 
Confirmed for  24 Weeks ....................................................... 28 
4.5.2.2 
Change in 25-Foot Timed Walk from Baseline to Week 120 ... 28 


 
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8/Statistical Analysis Plan WA25046 
 
4.5.2.3 
Change in Total Volume of T2 Lesions on MRI Scans 
of the Brain from Baseline to Week 120 .................................. 31 
4.5.2.4 
Percent Change on MRI from Week 24 to Week 120 in 
Total Brain Volume .................................................................. 31 
4.5.2.5 
Change from Baseline in Quality of Life as Measured by 
the SF36 (Physical Component) .............................................. 32 
4.5.3 
Exploratory Efficacy Endpoints ................................................ 32 
4.5.4 
Sensitivity Analyses ................................................................. 35 
4.5.5 
Subgroup Analyses .................................................................. 37 
4.6 
Pharmacokinetic and Pharmacodynamic Analyses ................. 38 
4.6.1 
Pharmacokinetic Analyses ....................................................... 38 
4.6.2 
Pharmacodynamic Analyses .................................................... 38 
4.7 
Safety Analyses ....................................................................... 38 
4.7.1 
Exposure of Study Drug ........................................................... 39 
4.7.2 
Adverse Events ........................................................................ 39 
4.7.2.1 
Infusion-Related Reactions ...................................................... 41 
4.7.2.2 
Infections ................................................................................. 42 
4.7.2.3 
Opportunistic Infections ........................................................... 43 
4.7.2.4 
Malignancies ............................................................................ 43 
4.7.2.5 
Multiple Sclerosis Relapses ..................................................... 43 
4.7.2.6 
Pregnancies ............................................................................. 44 
4.7.3 
Magnetic Resonance Imaging Data ......................................... 44 
4.7.4 
Laboratory Data ....................................................................... 44 
4.7.5 
Vital Signs ................................................................................ 45 
4.7.6 
Clinical Genotyping .................................................................. 45 
4.7.7 
COVID-19 Analyses ................................................................. 46 
4.8 
Missing Data ............................................................................ 46 
4.9 
Interim Analyses ...................................................................... 46 
5. 
REFERENCES.............................................................................. 47 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
9/Statistical Analysis Plan WA25046 
 
 
LIST OF TABLES 
Table 1 
Predicted Power and Number of Events ..................................... 14 
Table 2 
Censoring Algorithm of Patients after Initial Disability 
Progression ................................................................................. 27 
 
 
LIST OF APPENDICES 
Appendix 1 
 EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093............................................................ 48 
 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
10/Statistical Analysis Plan WA25046 
 
1. 
BACKGROUND 
Study WA25046 is a Phase III, multicenter, randomized, parallel group, double blind, 
placebo controlled study to evaluate the efficacy and safety of ocrelizumab in adults with 
primary progressive multiple sclerosis (PPMS). 
To date, no treatment has been demonstrated to significantly slow the progression of 
disability in patients with PPMS.  Currently, PPMS remains a severely disabling 
condition with very high unmet medical need. 
Ocrelizumab (RO4964913) is a humanized, glycosylated monoclonal antibody directed 
against the CD20 antigen present on B cells.  In addition to this Phase III clinical study of 
ocrelizumab in PPMS (Study WA25046), the safety and efficacy of ocrelizumab in 
multiple sclerosis (MS) is also being evaluated in two ongoing randomized, controlled 
Phase III clinical trials (WA21092 Opera I and WA21093 Opera II) and one Phase II 
study in relapsing-remitting MS (RRMS) (WA21493). 
The Phase II study (Study WA21493) in RRMS, currently in the open-label extension 
(OLE) stage and unblinded for efficacy analysis in October 2009, showed a rapid effect 
on B-cell depletion, magnetic resonance imaging (MRI) findings, and clinical activity.  
After 24 weeks of treatment, both doses of ocrelizumab (2  300 mg and 2  1000 mg) 
demonstrated a strong effect with a statistically significant reduction in signs of disease 
activity as measured by MRI lesions (the primary endpoint) relative to placebo.  Both 
ocrelizumab dose regimens showed statistically significant differences in the total 
number of gadolinium-enhancing lesions at Weeks 12, 16, 20, and 24.  The relative 
reductions in the number of lesions compared with placebo were 89% and 96% (for 
2  300mg and 2  1000mg doses of ocrelizumab, respectively).  Both ocrelizumab doses 
showed a statistically significant reduction in the annualized relapse rate (ARR) 
compared with placebo.  Moreover, both ocrelizumab doses were superior to the active 
comparator, Avonex, for the MRI primary endpoint and ARR. 
The Phase III relapsing multiple sclerosis (RMS) (WA21092, WA21093) studies were 
locked in May/June 2015, and the clinical study reports (CSRs) are being written. 
On 6 March 2013, the United States (U.S.) Food and Drug Administration (FDA) granted 
Fast Track designation to the investigation of ocrelizumab for PPMS. 
The study has been unblinded at the end of the blinded treatment period in 
September 2015 (clinical cutoff date [CCOD] 24 July 2015) when reaching at least 
120 weeks after the last patient randomized provided that the planned number of 
confirmed disability progression (CDP) has reached 253, (number of events included in 
the primary analysis:  256).  After the positive readout, patients were given access to the 
OLE starting from 12 October 2015.  In the period between the CCOD for the Primary 
CSR and OLE initiation, the Sponsor, sites, and patients were sequentially unblinded.  
This period corresponds to the Extended Controlled treatment period (ECP).  The ECP 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
11/Statistical Analysis Plan WA25046 
 
encompasses all efficacy data from the double-blind period (DBP) (previously reported in 
the Primary CSR) plus any additional efficacy data collected during the controlled 
treatment period up to the time at which the patient received their first open-label dose of 
ocrelizumab or until withdrawal. 
This document has been updated (Version 5) to describe the further analyses to be 
performed, on: 
1. 
the ECP, including additional data collected after the primary CCOD up to the entry 
into OLE. 
2. 
the OLE period, including additional data collected from the first dose of 
Ocrelizumab in OLE. 
3. 
the combined periods of ECP and OLE. 
  
2. 
STUDY DESIGN 
Study WA25046 will evaluate the safety and efficacy of a minimum of five treatment 
doses of two 300 mg intravenous (IV) infusions of ocrelizumab separated by 14 days, 
occurring at a scheduled interval of 24 weeks, compared with placebo in adults with 
PPMS.  Patients will be treated for a minimum of 120 weeks, representing at least five 
24 week treatment doses, and either when approximately 253 CDP events have 
occurred or the last patient randomized has been treated for 3 years at the latest. 
This study consists of the following study periods:  a screening period, a blinded 
treatment period, an open label treatment period, and a safety follow-up (SFU) period. 
The primary analysis of the study will be performed when the last patient enrolled has 
been treated for at least 120 weeks.  All patients will stay on their randomized treatment 
until the primary efficacy analyses.  In addition, in the event that the number of disability 
progression events is lower than anticipated at the time the last patient reaches 
Week 120, the blinded treatment period may be extended by additional treatment doses 
for all patients, to maintain statistical power to detect a treatment difference, until 
approximately 253 confirmed CDP events have occurred (see Section 2.3). 
The schedule of assessments are included in the protocol. 
This document describes the primary analysis from double-blind phase, additional 
analysis from extended controlled phase and OLE phase.  The Sponsor has now made 
the decision not to extend this study beyond 31 December 2022.  Instead, a rollover 
extension study (MN43964) is set up to ensure that participants of Study WA25046 
(together with participants from other Parent studies) can continue their ocrelizumab 
treatment or SFU as applicable without interruption and allowing for valuable long-term 
data to continue to be collected. 
Screening: 4 weeks of screening period to evaluate patient eligibility. 


 
Ocrelizumab—F. Hoffmann-La Roche Ltd 
12/Statistical Analysis Plan WA25046 
 
Blinded phase: Patients going through at least 120 weeks of study treatment 
representing 5 cycles, each of 24 weeks.  Study will be unblinded when the last enrolled 
patient completes at least 120 weeks, and the total number of CDP is approximately 
253, whichever occurs later. 
Extended Controlled treatment Period (ECP): The ECP will include the DBP plus 
additional follow-up prior to OLE enrollment or treatment withdrawal.  Patients from the 
DBP continued in their randomized treatment group for some additional time until 
sequentially switching into the OLE.  This time period between the end of the DBP and 
the start of the OLE includes: approximately 3 additional months of blinded controlled 
treatment and approximately 6 additional months of controlled follow-up during which 
time patients will gradually be unblinded and switched into the OLE. 
Open-Label Extension(OLE) phase: Eligible patients will continue to receive additional 
treatment cycles of open label ocrelizumab following the ECP.  The OLE Phase will 
continue as per local regulation or should the Sponsor decide to terminate the 
ocrelizumab program for MS.  Unless terminated earlier for any of the reasons 
mentioned above, all patients will continue their treatment with open-label ocrelizumab 
as per the protocol until an anticipated study completion date 31 December 2022.  All 
patients should complete the trial and migrate to the new roll-over extension 
study (MN43964) on or before 31 December 2022. 
Safety follow-up period: Patients who discontinue treatment for any reason during the 
following periods will be entered into the SFU Period: 
 
During or after completion of the blinded treatment period 
 
During the OLE Phase Screening Period 
 
During the OLE Phase 
 
Patients who choose not to enter the OLE Phase or are not eligible for the OLE 
Phase after blinded treatment period 
 
Patients who start treatment with commercial ocrelizumab or other disease-modifying 
treatments (DMTs) will discontinue from the study completely and will not enter or 
continue in the SFU Period.  Patients in SFU will be followed for 48 weeks or until the 
anticipated study completion date of 31 December 2022.  All patients should complete 
the trial and migrate to the new roll-over extension study (MN43964) on or before 
31 December 2022. 
2.1 
OUTCOME MEASURES 
2.1.1 
Efficacy Outcome Measures 
The primary efficacy endpoint is the time to onset of 12-week CDP during the blinded 
treatment period.  The blinded treatment period is not fixed but will depend on the timing 
of the primary analysis (Section 2.3). 


 
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Disability progression is defined as an increase of  1.0 point from the baseline 
Expanded Disability Status Scale (EDSS) score if the baseline EDSS score is 
 5.5 points or an increase of at least 0.5 points if the baseline EDSS score is 
 5.5 points⎯for which change is not attributable to another etiology (e.g., fever, 
concurrent illness, MS relapse or exacerbation, or concomitant medication). 
The EDSS will be assessed in all patients by an independent examining investigator at 
screening, baseline, and every 12 weeks (at a regularly scheduled visit) during the 
blinded treatment period of the study, during the SFU period, at any unscheduled visits, 
and at withdrawal from treatment and end of study visits.  Additional EDSS assessments 
for individual patients may be requested between visits (i.e., during an MS relapse).  The 
baseline EDSS score is calculated as the average of the assessments at screening and 
the Day 1 visit (for further details, see Section 4.5.1). 
Confirmation of disability progression must occur at a regularly scheduled visit that is 
 12 weeks ( 84 days) after the initial disability progression.  Initial disability progression 
can occur at a scheduled or unscheduled visit after the date of randomization.  The 
EDSS assessments at unscheduled and non-confirmatory scheduled visits (if any) 
between the initial disability progression and the confirmation of disability progression 
should have values equal to or exceeding the minimum change required for progression 
(e.g., a subject with a baseline EDSS value of 3 must have an EDSS value of  4 at all 
visits between the visit with initial disability progression and the scheduled visits to 
confirm 12 week or 24 week CDP). 
The secondary and exploratory outcome measures to be analyzed are described in 
Section 4.5.2 and Section 4.5.3, respectively. 
2.1.2 
Pharmacokinetic Outcome Measures 
Ocrelizumab serum concentration time data will be modeled using a population 
approach.  The primary population pharmacokinetic (PK) parameters for ocrelizumab 
(clearances and volumes) will be estimated by NONMEM analysis of the sparse PK 
data.  Clearances with associated inter-patient variability may be characterized by a 
saturable and nonsaturable clearance, as well as an inter-compartmental clearance, 
depending on the final structural model.  Volumes with associated inter-patient variability 
may be characterized by central and peripheral volumes depending on the final 
structural model.  Exposure to ocrelizumab (area under the concentration time curve 
[AUC]) will be estimated.  The selection of other parameters will depend on the final PK 
model used for this analysis. 


 
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2.1.3 
Safety Outcome Measures 
Safety will be assessed through regular neurologic and physical examinations, vital 
signs, ECG, and the occurrence of adverse events (AEs).  In addition, the following 
laboratory data will be examined: 
 
Complete standard hematology, chemistry, and urinalyses assessment 
 
Circulating B-cell total and subsets, T cells, natural killer cells, and other leukocytes 
 
Plasma immunoglobulins 
 
Antibody titers to common antigens 
 
Anti-drug antibodies (ADAs), previously called human anti-human antibodies 
(HAHAs) 
 
HBV DNA in patient core HBV antibody positive at screening 
  
2.2 
DETERMINATION OF SAMPLE SIZE 
The sample size for the CDP (12 week confirmation) was estimated on the basis of data 
from a previous rituximab Phase II/III trial in adults with PPMS (Study U2786g, 
Hawker et al. 2009).  For the current study, the 2 year progression rate in patients 
receiving ocrelizumab is predicted to be 30%, compared with 43% in patients receiving 
placebo (hazard ratio  0.635).  Assumptions of equal exponential survival, exponential 
dropout, and a log rank test were used to determine the sample size for the time to onset 
of CDP at 12 weeks.  In addition, the following assumptions were made for the study 
conduct:  a 2:1 randomization ratio between the ocrelizumab and placebo arms, a 1 year 
accrual period with a 3.5 year maximum blinded treatment period, and a dropout rate of 
20% over 2 years.  On the basis of these assumptions, the predicted power and number 
of events for the originally planned sample size (N  630) were calculated.  These results 
are presented in Table 1. 
Table 1 
Predicted Power and Number of Events 
Sample Size 
Planned 
N 
630 
Type 1 error rate 
0.01 
Power (%) 
80 
No. of expected events 
253 
  
For the primary efficacy analysis, the null hypothesis will be tested at an alpha level of 
0.05 with an associated power of approximately 90%.  This will also provide sufficient 
power (80%) for an alpha  0.01 which may reflect a strong treatment effect. 
Due to a late screening boost, the actual number of patients enrolled was 732.  If the 
even rate is as assumed in the protocol, we expect 295 events at study unblinding if 


 
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performed 120 weeks after the last patient randomized.  This will result in a power of 
87% at alpha 0.01, and 96% at alpha 0.05. 
Patients may show lower event rates than assumed in the sample size calculations.  
Therefore, at 120 weeks after the last patient randomized the initially assumed 
253 events may not be reached.  In this case, the study unblinding will be later than 
120 weeks after the last patient randomized.  The unblinding will still be triggered by 
reaching 253 events, and the power remains as originally planned. 
If the 253 events are not reached three years after the last patient has been randomized, 
the study will be unblinded with fewer than 253 events.  In this case, the power would be 
lower than predicted. 
2.3 
ANALYSIS TIMING 
The study will be unblinded when the last enrolled patient completes at least 120 weeks 
of study treatment, provided that the total number of CDP events for the primary efficacy 
analysis is approximately 253.  This value is based on the Sponsor’s best estimation 
after the last patient finishes the Week 108 visit; that is, when the last patient has 
reached the Week 108 visit, the number of events at Week 120 (12 weeks later) will be 
predicted on the basis of ongoing event tracking.  At this time, the date of database lock 
will be fixed if the projected number of events exceeds 253 when the last patient reaches 
the Week 120 visit, irrespective of whether the 253 events would have been reached 
12 weeks later.  This procedure should ensure objectivity in fixing the database lock time 
and adequate precision in reaching the approximate required number of events.  If the 
prediction does not ensure at least 253 events at Week 120, this procedure will be 
repeated 6 weeks later. 
All patients will be unblinded at the time of the primary efficacy and safety analysis.  
Once approximately 253 events have been reached, the treatment assignments will be 
unblinded to the Sponsor for the primary analysis and the blinded treatment period will 
end.  The primary analysis will include all data available at the time of the database lock 
(called primary database lock in the remainder of the document) for both safety and 
efficacy endpoints, unless stated otherwise. 
The primary and secondary efficacy endpoints related to CDP will use all available data 
in the database at the time of primary database lock.  All other endpoints with respect to 
a specific timepoint (e.g., change from baseline to Week 120) will use data collected for 
each patient only up to and including the pre-specified timepoint.  Any data collected for 
patients beyond that timepoint will not be included in the endpoint derivation or analysis. 
The primary database lock will occur no later than three years after the last patient was 
randomized, even if the 253 events have not been reached at this timepoint.  At the end 
of the study an additional analysis comprising all data collected including the OLE will be 
performed. 


 
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After the primary database lock, additional data is collected from the ECP, the OLE 
period and SFU after withdrawing from treatment during any study phase 
i.e., double-blind or extended treatment period or OLE treatment. 
 
The extended controlled treatment includes all data from randomization until the day 
of withdrawal from study treatment or the day before the first dose of ocrelizumab in 
the OLE period of the study, whichever is earlier. 
 
The OLE period includes all data from the day of the first dose of ocrelizumab 
treatment until the day of study completion or withdrawal from study treatment 
during OLE. 
 
The combined ECP and OLE period includes all data from randomization until the 
day of study completion or withdrawal from the study treatment. 
 
The following reporting events are done / planned for this study:  
Report 
CCOD 
Status 
Primary analysis CSR 
24 July 2015 
Completed 
3 Months safety update/ 
Efficacy Data memo 
20 January 2016 
Completed 
Interim CSR (Time to milestone 
analysis) 
03 January 2020 
Completed 
Pooled safety analyses for 
safety monitoring and 
publication of updated interim 
results 
Yearly datacut has been 
performed since Feb 2017 to 
conduct interim analyses used 
for publication purposes 
Completed until 2021 and 
planned for subsequent years 
until the end of the study 
Final CSR 
After completion of the ECP, 
OLE phase or SFU phase of 
the study (31 Dec 2022) 
Planned 
CCOD  clinical cutoff date ;CSR  clinical study report, ECP  extended controlled treatment 
period; OLE  open-label extension; SFU  safety follow-up. 
  
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
Approximately 630 patients aged 18−55 years inclusive were planned to be randomized 
in a 2:1 ratio to two groups.  An independent Interactive Voice and Web Response 
System (IxRS) provider conducted the randomization and holds the treatment 
assignment code.  Patients were stratified by region (U.S. vs. rest of world [ROW]) and 
age ( 45 vs.  45 years). 
The patient randomization list was generated by the IxRS with use of a predefined 
randomization specification.  The randomization list is not available at the study center, 
to the Roche monitors, or to anyone on the Sponsor’s side involved in the project.  
Unblinding of the ocrelizumab dose for individual patients should not occur except in the 
case of emergency situations.  Any request from the investigator for information about 


 
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the treatment administered to study patients for another purpose must be discussed with 
Roche.  Unblinding will be performed by means of an IxRS.  As per regulatory reporting 
requirements, Roche will unblind the identity of the study drug for all unexpected serious 
adverse events (SAEs) that are considered by the investigator to be related to study 
drug according to safety reference documents (e.g., Investigator’s Brochure, Core Data 
Sheet, and Summary of Product Characteristics).  Details of the patients whose data are 
unblinded during the study will be included in the CSR. 
After the end of randomization, the data entered into the IxRS system will be reconciled 
with the data entered into the Case Report Form (CRF); in particular, the randomization 
dates and stratification factors (age and region) will be checked.  A summary of the 
discrepancies between the IxRS and CRF (age group and region) will be provided. 
For Lithuania and Germany, the year of birth (but not the day and month) is being 
collected to comply with local regulations.  The date of birth will be used as defined in 
the IxRS specifications. 
Because of a late screening boost, 732 patients (instead of the planned 630 patients) 
were enrolled in the trial.  To assess the effect of the increased enrollment numbers on 
the primary endpoint, a sensitivity analysis will be performed (see Section 4.5.4). 
3.2 
INDEPENDENT REVIEW FACILITY 
The two secondary efficacy endpoints are the change in total volume of T2 lesions on 
MRI scans from baseline to 120 weeks and the percent change in total brain volume 
from Week 24 to Week 120.  MRI scans will be read by a centralized reading center.  
The centralized reading center is blinded to the treatment assignment, and the reading is 
performed in the absence of clinical information.  Further details of scanning acquisition 
sequences, methods, the handling and transmission of the scans, the certification of the 
site’s MRI radiologist and technicians, and the procedures for blinded analysis of the 
scans at the central reading center are described in a separate MRI technical manual. 
3.3 
EXPANDED DISABILITY STATUS SCALE CLEANING PROCESS 
The primary efficacy endpoint will be derived from the EDSS values recorded at any 
visits.  EDSS assessments are performed by an examining investigator (not the treating 
investigator), entered into an electronic device, and transferred to a central database for 
data-cleaning activities.  All EDSS results will then be checked in accordance with the 
standard operating procedure entitled “EDSS Assessment Check for the Roche Trials 
WA25046, WA21092, and WA21093” (see Appendix 1). 
3.4 
DATA MONITORING 
An independent Data Monitoring Committee (iDMC) will review cumulative data from the 
trial at approximately 4 month intervals until the primary analysis is complete.  After the 


 
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primary unblinding, the iDMC will stop reviewing the data.  The iDMC will primarily 
review safety data.  No iDMC review is conducted post unblinding of the study. 
4. 
STATISTICAL METHODS 
4.1 
ANALYSIS POPULATIONS 
One patient population will be defined for the purpose of the safety analysis, and two 
populations will be defined for the efficacy analysis.  All efficacy endpoints will be 
analyzed using the intent-to-treat (ITT) population.  The per-protocol population will be 
used for the primary efficacy endpoint only, to evaluate the influence of major protocol 
deviations and as a sensitivity check for the ITT analysis. 
4.1.1 
Intent-to-Treat Population 
All randomized patients will be included in the ITT population.  Patients who prematurely 
withdraw from the study for any reason or for whom an assessment is not performed for 
any reason will still be included in the ITT analysis.  Patients who receive an incorrect 
therapy (different from that which is intended) will be summarized according to their 
randomized treatment. 
4.1.2 
OLE ITT Population 
All patients receiving at least one dose of OLE as part of the OLE will be included in the 
OLE ITT population.  Patients will be summarized according to their randomized 
treatment. 
4.1.3 
Per-Protocol Population 
The per protocol population will include all patients in the ITT population who adhere to 
the protocol and will be summarized according to the randomization arm.  Patients may 
be excluded if they violate the inclusion or exclusion criteria or deviate from the study 
plan.  Specific reasons for exclusion were agreed on based on the final version of the 
protocol prior to the unblinding of the treatment groups and are documented below.  
Only those patients with deviations that are deemed to potentially affect the efficacy of 
study treatment will be excluded from the per protocol population. 
The following patients will also be excluded from the per-protocol population: 
 
Patients with a diagnosis of relapsing-remitting, secondary progressive, or 
progressive relapsing MS 
 
Patients with a significant, uncontrolled disease, such as cardiovascular (including 
cardiac arrhythmia), pulmonary (including obstructive pulmonary disease), renal, 
hepatic, endocrine, or gastrointestinal or any other significant disease that may 
preclude patients from participating in the study 
 
Patients with any concomitant disease that may require chronic treatment with 
systemic corticosteroids or immunosuppressants during the course of the study 


 
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 
Patients with a history or with currently active primary or secondary 
immunodeficiency 
 
Patients who received previous treatment with B-cell targeted therapies 
 
Patients who received any previous treatment with alemtuzumab, antiCD4, 
cladribine, cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, 
cyclosporine, or methotrexate or those who had total body irradiation or bone 
marrow transplantation 
 
Patients who received any previous treatment with lymphocyte trafficking blockers 
(e.g., natalizumab, FTY720) 
 
Patients who received treatment with -interferons, glatiramer acetate, 
IV immunoglobulin, plasmapheresis, or other immunomodulatory therapies within 
12 weeks prior to randomization 
 
Patients with known presence of neurological disorders 
 
Patients who are pregnant or lactating at entry of the study 
 
Patients who received treatment with any investigational agent within 24 weeks of 
screening or five half-lives of the investigational drug (whichever is longer) or those 
who received treatment with experimental procedure for MS (e.g., treatment for 
chronic cerebrospinal venous insufficiency) 
 
Patients with no diagnosis of PPMS, in accordance with the revised McDonald 
criteria (2005; see Protocol, Appendix 1) 
 
Patients with an EDSS score outside 3−6.5 points at screening 
 
Patients with a score of  2.0 on the Functional Systems (FS) for the pyramidal 
system that is due to lower extremity findings at screening 
 
Patients with a disease duration of  15 years from the onset of MS symptoms in 
those with an EDSS  5.0 at screening or those with a disease duration of  10 years 
from the onset of MS symptoms in those with an EDSS at screening  5.0 
 
Patients who received no dose of ocrelizumab/ocrelizumab placebo 
 
Patients who received ocrelizumab/ocrelizumab placebo but were not randomized 
 
Patients who received ocrelizumab/placebo other than the group to which they were 
randomized at any point during the study 
 
Patients who received study drug that had been mishandled (e.g., incorrect storage 
temperature) and was not approved for subsequent use 
  
4.1.4 
Safety Population 
The safety population will include all patients who received at least one dose of study 
drug (ocrelizumab or placebo).  Randomized patients who receive the incorrect therapy 


 
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will be summarized in the group according to the therapy actually received, as listed 
below. 
 
Patients randomized to placebo who receive any ocrelizumab treatment and 
patients randomized to ocrelizumab who receive both placebo and ocrelizumab will 
be assigned to the ocrelizumab group. 
 
Patients randomized to ocrelizumab who receive placebo only will be assigned to 
the placebo group. 
 
Patients who are not randomized but who receive study drug will be included in the 
safety population and will be summarized as follows: 
– 
Patients who receive any ocrelizumab treatment will be assigned to the 
ocrelizumab group. 
– 
Patients who receive only placebo will be assigned to the placebo group. 
  
4.1.5 
OLE Safety Population 
The OLE safety population will include all patients who received at least one dose of 
OLE study drug.  Patients randomized to placebo who received at least one dose of 
ocrelizumab will be summarized in the ocrelizumab group consistent with the safety 
population. 
4.2 
OVERVIEW OF ANALYSES PLANNED FOR THE EXTENSION 
PERIODS 
Overview of outcome measures and analyses performed for the extension periods in 
addition to the analyses performed for the primary CSR:  
Period (Population) / Analyses 
Extended 
controlled 
(ITT) 
OLE (OLE 
ITT) 
Combined 
extension 
(ITT) 
Study conduct 
Patient Disposition (All patients) 
 
 
X 
Treatment group comparability 
Summary of demographics 
 
X 
 
Baseline Disease Characteristics & baseline MRI 
Assessments 
 
X 
 
Exposure to study drug 
Exposure to Ocrelizumab/Placebo 
 
 
X 
Confirmed disability progression /EDSS/T25-
FW/9-HPT 
Time to Onset of Confirmed Disability Progression 
for at Least 12 weeks 
X 
X 
X 
Time to Onset of Confirmed Disability Progression 
for at Least 24 weeks 
X 
X 
X 


 
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Period (Population) / Analyses 
Extended 
controlled 
(ITT) 
OLE (OLE 
ITT) 
Combined 
extension 
(ITT) 
Time to composite confirmed disability progression 
(EDSS or T25-FW or 9-HPT)  for at Least 12 weeks 
X 
X 
X 
Time to composite confirmed disability progression 
(EDSS or T25-FW or 9-HPT)  for at Least 24 weeks 
X 
X 
X 
Time to Onset of Confirmed Disability Progression 
Confirmed for  48 weeks 
X 
X 
X 
Time to composite confirmed disability progression 
for at least 48 weeks 
X 
X 
X 
Time to Onset of Confirmed EDSS  7 for at least 
24 weeks 
X 
X 
X 
Time to Onset of Confirmed EDSS  7 for at least 
48 weeks 
X 
X 
X 
Time to confirmed 20% increase in T25-FW for at 
least 12 weeks 
X 
X 
X 
Time to confirmed 20% increase in T25-FW for at 
least  24 weeks  
X 
X 
X 
Time to confirmed 20% increase in T25-FW for at 
least  48 weeks 
X 
X 
X 
Time to confirmed 20% increase in 9-Hole Peg for at 
least 12 weeks 
X 
X 
X 
Time to confirmed 20% increase in 9-Hole Peg for at 
least 24 weeks 
X 
X 
X 
Time to confirmed 20% increase in 9-Hole Peg for at 
least 48 weeks 
X 
X 
X 
Change in T25-FW speed from baseline (MMRM) 
X 
X 
X 
Change in EDSS from baseline (MMRM) 
X 
X 
X 
Change in MSFCS from baseline (MMRM) 
X 
X 
X 
MRI measures 
 
X 
 
Ratio and percent change in T2 lesion volume from 
baseline 
 
X 
X 
Ratio and percent change in non-enhancing T1 
lesion volume from baseline 
 
X 
X 
Number of Gadolinium-enhancing T1 lesions by visit  
 
 
X 
Number of new and enhancing T2 hyperintense 
lesions by visit 
 
 
X 
Percent change in total brain volume from Baseline 
 
X 
X 
Percent change in total brain volume from Week 24 
 
 
X 
Percent change in cortical gray matter volume from 
Baseline 
 
X 
X 


 
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Period (Population) / Analyses 
Extended 
controlled 
(ITT) 
OLE (OLE 
ITT) 
Combined 
extension 
(ITT) 
Percent change in cortical gray matter volume from 
Week 24 
 
 
X 
Percent change in white matter volume from 
Baseline 
 
X 
X 
Percent change in white matter volume from 
Week 24 
 
 
X 
Annualized Percentage Change in T1 lesion volume 
from Baseline to OLE end during the Extended 
Controlled Treatment and OLE Period 
 
X 
X 
Annualized Percentage Change in T2 lesion volume 
from Baseline to OLE end during the Extended 
Controlled Treatment and OLE Period 
 
X 
X 
Annualized Percentage Change in Total Brain 
Volume from Baseline to OLE end during the 
Extended Controlled Treatment and OLE Period 
 
X 
X 
Annualized Percentage Change in Cortical Grey 
Matter Volume from Baseline to OLE end during the 
Extended Controlled Treatment and OLE Period 
 
X 
X 
Annualized Percentage Change in White Matter 
Volume from Baseline to OLE end during the 
Extended Controlled Treatment and OLE Period 
 
X 
X 
Descriptive statistics: 
SF-36, MFIS, NfL 
 
 
X 
Safety Summary: 
Additional safety data collected during ECP and OLE 
X 
X 
X 
9-HPT  9-hole peg test; ECP  extended controlled treatment period; EDSS  Expanded Disability 
Status Scale; ITT  intent-to-treat; MFIS  Modified Fatigue Impact Scale; MMRM  Mixed-Effect 
Model Repeated Measures; MRI  magnetic resonance imaging; MSFCS  Multiple Sclerosis 
Functional Composite Scale; NfL  Neurofilament Light chain; OLE  open-label 
extension;T25-FW  timed 25-foot walk. 
  
All analyses performed for the primary CSR are included in this statistical analyses plan.  
In general, the analyses performed on the extension periods follow the same analyses 
rules as for the primary CSR.  Exceptions have been added in the respective sections. 
4.3 
ANALYSIS OF STUDY CONDUCT 
The following analyses will be conducted to evaluate the study conduct: 
 
Summary of protocol deviations 
 
Summaries of ITT, per protocol defined, and safety populations, including numbers 
of patients in each population, and reasons for exclusion from the per-protocol 
population 


 
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 
Summary of subject disposition, including the number of treatment doses received, 
and the number of patients entering into SFU 
 
Summary and Kaplan-Meier plots of: 
– 
Time to discontinuation of study treatment during the blinded treatment period.  
(All other patients will be censored at their last assessment during the blinded 
treatment period) 
– 
Time to discontinuation from the study (All other patients will be censored at 
their last assessment during the study) 
 
Extension Periods 
The summary of subject disposition will be updated using additional data from the ECP 
and OLE periods, including the number of patients entering into and withdrawing from 
OLE and into/from OLE SFU. 
4.4 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
For continuous variables, the mean, median, standard deviation (SD), and minimum and 
maximum values will be calculated.  For categorical variables, the number and 
percentage in each category will be displayed.  For each item in the following lists, the 
units and categories to be used are indicated in parentheses and separated by commas.  
All durations are calculated with respect to the date of randomization, if not stated 
otherwise. 
Demography and stratification factors based on electronic Case Report Form (eCRF) 
data: 
 
Age (years) at baseline 
 
Age stratification category ( 45,  45 years) 
 
Sex (male patients, female patients) 
 
Race (White, Black or African American, Other) 
 
Ethnicity (Hispanic or Latino, nonHispanic or Latino) 
 
Weight (kg) 
 
Body mass index (measured in kg/m2) 
 
Region stratification category (U.S. vs. ROW) 
 
A summary of discrepancies in the age and region values (stratification factors) between 
the IxRS and the eCRF will be provided. 
Baseline disease characteristics: 
 
Baseline EDSS (continuous) 
 
Baseline score in FS for each category (pyramidal, cerebellar, brainstem, sensory, 
bowel and bladder, visual, cerebral [or mental]; rated 0−5 or 0−6 depending on the 
domain of FS) and for ambulation (categorical; rated 0−12) 


 
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 
Baseline Multiple Sclerosis Functional Composite (MSFC) score (continuous; raw 
results for each component) 
 
MS disease history: 
 
Duration since MS symptom onset (calculated in years; i.e., divide by 365.25) 
 
Duration since MS symptom onset category ( 3 years, 3 to  5 years, 5 to 
 10 years,  10 years) 
 
Duration since onset of PPMS diagnosis (calculated in years up to randomization 
date) 
 
Treatment with any MS disease-modifying therapy prior to the baseline visit 
(yes [treatment experienced patients], no [naive patients]) 
– 
MS disease-modifying therapy includes Interferons, Glatiramer acetate, 
Natalizumab, Fingolimod, Dimethyl fumarate, Teriflunomide, Alemtuzumab, 
Mitoxantrone, Rituximab, Normal Immunoglobulin, Mycophenolate mofetil, 
Azathioprine, Immunotherapies for MS 
– 
Patients who received steroids for MS prior to the baseline visit [yes, no] 
 
Baseline MRI data: 
 
Number of gadolinium-enhancing T1 lesions at baseline (continuous and categorical 
analysis [0, 1, 2, 3,  4]) 
 
Whole-brain volume at baseline 
 
T2 volume at baseline 
 
Number of T2 lesions at baseline (continuous and categorical analyses [0-5, 6-9, 
 9]) 
 
Extension Periods 
 
For OLE, demography and stratification factors, baseline disease characteristics, 
MS disease history and baseline MRI data will be summarized using the information 
collected at OLE baseline as described in the previous section, but subsetting for 
the OLE ITT population. 
 
OLE baseline score (EDSS, MRI, etc.) is the latest score collected prior to 
(including) OLE 1st Dose and after (including) Week 120.  If the patient had no 
measurements within the defined time window, then set the OLE baseline score to 
be missing. 
  
4.5 
EFFICACY ANALYSIS 
All statistical hypotheses for the primary and secondary endpoints and treatment 
comparisons will be tested at the 5% significance level (  0.05) against two sided 
alternatives. 
Apart from EDSS, for all other assessments, the baseline value will be used as the last 
non-missing value on or before the date of the first infusion of study drug.  Baseline 


 
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EDSS is calculated differently.  The derivation of baseline EDSS and time to onset of 
CDP is discussed in Section 4.5.1. 
All primary and secondary efficacy endpoints will be stratified by region and age for 
analysis.  The regional stratifications are U.S. and ROW.  The age categories are 
 45 years and  45 years. 
Extensions Periods 
The analyses of the ECP and the combined ECP  OLE periods will be using the same 
baseline value as the primary analysis.  For the analyses of the OLE period, the OLE 
baseline score is used. 
4.5.1 
Primary Efficacy Endpoint 
Time to onset of CDP for at least 12 weeks (12-week CDP) during the double-blind 
treatment period 
Significance Level 
The null hypothesis will be tested at the   0.05 level (two sided test). 
The hypotheses to be tested are: 
 
H0 (null hypothesis):  There is no difference in the time to onset of CDP between the 
ocrelizumab and placebo groups. 
 
H1 (alternative hypothesis):  There is a difference in the time to onset of CDP 
between the ocrelizumab and placebo groups. 
 
Definition 
The time to onset of CDP (12 week confirmation [days]) is defined as the time from 
baseline to the onset of the first disability progression that is confirmed at the next 
regularly scheduled visit  12 weeks after the initial disability progression.  If the patient 
has an infection, dosing may not occur on the Day 1 visit.  Baseline for the time to onset 
of confirmed disability is the date of randomization, independent of the date of first 
dosing.  For example, a subject with delayed dosing may receive the first dose 2 weeks 
after the baseline visit; if an EDSS score is recorded between the randomization date 
and the date of the first dose, this value will be considered for the date of initial disability 
progression.  Disability progression is defined as an increase of  1.0 point from baseline 
EDSS score if the baseline EDSS value is  5.5 points (inclusive) or an increase of 
 0.5 points if the baseline EDSS value is  5.5 points.  Assessments within 30 days after 
a protocol defined relapse will not be used for confirmation of CDP.  The 
non-confirmatory EDSS assessments (between the initial disability progression and the 
confirmation of disability progression should also fulfill the requirements of the 
progression (see Section 2.1.1).  Otherwise, the initial disability progression is not 
confirmed. 


 
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The baseline EDSS value is the average score of the EDSS assessment at screening 
and baseline (Day 1 visit) up to and including the date of randomization.  If one of the 
values is missing, the non-missing values will be used as baseline. 
An independent examining investigator at each study site will assess EDSS for all 
patients at the site at screening, baseline, every 12 weeks (regularly scheduled visit) 
during the blinded treatment period of the study, during the SFU period, at any 
unscheduled visits, and at withdrawal from treatment and end of study visits.  Additional 
EDSS assessments for individual patients may be requested between visits (i.e., during 
an MS relapse). 
The examining investigator is not the physician responsible for the patient care (the 
treating investigator). 
The EDSS is based on a standard neurological examination; the seven categories of the 
EDSS representing FS (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, 
visual, and cerebral [or mental], plus “other”) are rated and scored (collectively, FSs), in 
addition to an ambulation score (0−12).  Each domain of the FS is an ordinal clinical 
rating scale from 0 to 5 or 6.  These ratings are then used in conjunction with 
observations and information regarding ambulation and the use of assistive devices 
(which will also be scored) to determine the EDSS score.  The EDSS is a disability scale 
that ranges in 0.5point steps from 0 (normal) to 10.0 (death). 
Analysis Methods 
The ITT population analysis will be presented. 
Patients who did not have initial disability progression at the time of primary database 
lock, time of early discontinuation, or loss to follow-up will be censored at the date of 
their last EDSS assessment that occurred during the treatment period. 
There are various options to obtain EDSS assessments (confirmatory and 
non-confirmatory) and to record how the discontinuation from treatment and study can 
influence the confirmation of the disability progression.  The following rules apply for all 
patients with initial disability progression: 
 
Initial disability progression must occur when the patient is still on treatment. 
 
All non-confirmatory EDSS assessments (if any) after initial disability progression 
and up to and including the confirmatory EDSS assessment should also fulfill the 
requirements of the progression as defined above.  Otherwise an initial disability 
progression event cannot be confirmed. 
 
Patients who experience initial disability progression will be treated as described in 
Table 2). 


 
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Table 2 
Censoring Algorithm of Patients after Initial Disability 
Progression 
Availability of EDSS Assessment for Patient 
with Initial Disability Progression 
Recorded Disability Progression Status 
Scenario A:  Confirmatory EDSS assessment 
on treatment or after withdrawal from treatment 
Confirmed disability progression 
Scenario B:  No confirmatory EDSS 
assessment; patient on treatment at the time of 
primary database lock 
Censored at last EDSS assessment 
Scenario C:  Discontinues from treatment and 
is lost to follow-up; i.e., no available EDSS 
assessment at  84 days after initial disability 
progression 
Confirmed disability progression 
EDSS  Expanded Disability Status Scale. 
  
The time to onset of CDP for the ocrelizumab arm and the placebo arm will be compared 
using a two-sided log-rank test stratified by geographic region (U.S. vs. ROW) and age 
( 45 vs.  45 years).  The proportion of patients with CDP at predefined timepoints 
(i.e., 48 weeks, 96 weeks, etc.) will be estimated using Kaplan-Meier methodology.  The 
overall hazard ratio will be estimated using a stratified Cox regression model with the 
same stratification factors used in the aforementioned stratified log-rank test. 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
* Log-rank test; 
 
proc lifetest data=CDP12; 
 
 
time CDP12TIME*CNSR(1); 
 
 
strata REGION AGE45 / group=ARMCD; 
 
 
ods output HomTests =_logrank; 
 
run; 
  
* Cox regression model; 
proc phreg data=CDP12; 
 
 
class ARMCD / descending; 
 
 
model CDP12TIME*CNSR(1) = ARMCD / rl; 
 
 
strata REGION AGE45; 
 
 
ods output ParameterEstimates=est; 
 
run; 
  
Extension periods 
This analysis will be repeated to include the EDSS assessments performed during the 
ECP and OLE periods for ECP and the combined double blind (DB)  OLE periods, with 
the same baseline as for the analysis during DB.  Analysis containing only data from 
OLE will be performed considering the OLE baseline. 
Patients discontinuing from either treatment periods (ECP or OLE) after initial disability 
progression and without confirmatory EDSS assessment will be imputed. 


 
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For the OLE period, initial disability progression has to occur while the patient is on OLE 
treatment.  Confirmation of progression could occur at scheduled OLE or SFU visits after 
the OLE. 
The same principle applies to all time to CDP endpoints below. 
4.5.2 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be tested in the same hierarchical order 
listed here, if the primary endpoint and each preceding endpoint have reached the 
significance level of 0.05. 
4.5.2.1 
Time to Onset of Confirmed Disability Progression Confirmed 
for  24 Weeks 
In addition to the primary analysis, the time to onset of CDP will be analyzed in the 
ocrelizumab and placebo treatment arms with use of a 24 week confirmation window for 
disability progression.  The analysis of EDSS progression will be conducted as 
described for the primary analysis, with the exception that the time to onset of CDP 
(24 week confirmation) is defined as the time from baseline to the first disability 
progression that is confirmed at the next regularly scheduled visit  24 weeks 
( 161 days) after the initial disability progression. 
Extension Periods 
This analysis will be repeated to include the EDSS assessments performed during the 
ECP and OLE periods for ECP and the combined DB  OLE periods, with the same 
baseline as for the analysis during DB.  Analysis containing only data from OLE will be 
performed considering the OLE baseline. 
4.5.2.2 
Change in 25-Foot Timed Walk from Baseline to Week 120 
The 25-foot timed walk is one of the three primary measures in an Multiple Sclerosis 
Functional Composite Scale (MSFCS) score and is the mean time from the two trials 
performed on the same visit.  Detailed description on the derivation of the MSFCS score 
can be found in the MSFC Administration and Scoring Manual (Fischer 2002). 
If the test results are not available due to a “physical limitation,” the maximum possible 
value for the scale (180 seconds) will be imputed.  If one of the two trials is not available 
and not missing due to a “physical limitation,” the result from the other trial will be used 
to impute the missing value. 
For outliers, the following rules will be applied.  Values outside the lower and upper 
bounds will be treated as missing, and the imputation rule will be applied as defined 
above.  The lower bound is 2.2 seconds (Bohannon 1997), and the upper bound is 
180 seconds, according to the MSFCS Manual. 
For the assessment of differences in the change in the 25-foot timed walk from baseline 
up to Week 120, a nonparametric ranked analysis of covariance (ANCOVA) will be 


 
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performed, with the ranked percent change in the 25-foot timed walk as the outcome 
variable and the ranked baseline value as the covariate, adjusting for geographical 
region (U.S. vs. ROW) and age ( 45 vs.  45 years). 
The last-observed value available before treatment discontinuation will be carried 
forward to impute the missing values.  The baseline value will be carried forward for 
patients who did not have evaluable post-baseline observations.  Patients with missing 
baseline value will be excluded from the analysis. 
In order to obtain estimates of the treatment effect, a Mixed-Effect Model Repeated 
Measures (MMRM) analysis will be used.  This model does not use the last observation 
carried forward (LOCF) method.  The MMRM analysis incorporates post-randomization 
data collected at scheduled visits up to 120 weeks of treatment, and it will be used to 
assess all data collected over time, with consideration of the variancecovariance matrix 
of the repeated measures.  This method allows for inclusion of data from patients with 
incomplete data from some scheduled timepoints. 
The model will be implemented in SAS using PROC MIXED and will include the log 
transformed ratio of post-baseline timepoints to baseline in the 25-foot timed walk at 
each visit as the dependent variable.  The fixed effects in the model will include 
independent variables of randomized treatment, visit (nominal post baseline visits as per 
the Schedule of Assessments), baseline-by-visit interaction and treatment-by-visit 
interaction, along with the following baseline covariates, log-transformed 25-foot timed 
walk at the baseline visit, geographical region (U.S. vs. ROW), and age ( 45 vs.  45).  
Visit will be treated as a repeated variable within a patient.  Patient, treatment and visit 
will be treated as factor variables.  An unstructured variance−covariance structure will be 
applied to model the within-patient errors.  The Restricted Maximum Likelihood (REML) 
method will be used for estimates of variance components.  Denominator degrees of 
freedom will be estimated using Satterthwaite’s approximation. 
To estimate the difference between the ocrelizumab and placebo groups in change from 
baseline to Week 120, a treatment-by-visit interaction contrast will be constructed 
(i.e., the treatment group contrast at Week 120).  On the basis of this analysis, back 
transformed estimates of least square means and the 95% confidence interval (CI) for 
the ratio of 25-foot timed walk at each visit relative to the baseline will be reported. 
Graphical presentations for least square means and 95% CIs will be used to illustrate 
trends over time. 


 
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Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
*ranked ANCOVA; 
 
proc sort data=MSFC_locf out=ancova; 
 
 
by REGION AGE45; 
 
run; 
  
 
proc rank data=ancova out=ranks; 
 
 
by REGION AGE45 ; 
 
 
var lbfwt lcfwt; 
 
run; 
  
 
proc reg data=ranks; 
 
 
by REGION AGE45; 
 
 
model lcfwt=lbfwt ; 
 
 
output out=residual r=reside; 
 
 
quit; 
  
 
proc freq data=residual noprint ; 
 
 
tables region*AGE45*ARMCD*reside/cmh2 scores=modridit; 
 
run; 
  
*MMRM; 
 
proc mixed data=MSFC method=REML; 
 
 
class REGION AGE45 ARMCD VISIT USUBJID; 
 
 
model log(AVG25F/BASE)  =  log(BASE)  REGION   
 
 
AGE45 ARMCD VISIT log(BASE)*VISIT  ARMCD*VISIT / 
 
 
 ddfm= satterthwaite; 
 
 
repeated VISIT / type=un subject = USUBJID; 
 
 
lsmeans ARMCD*VISIT / pdiff cl; 
 
 
ods output lsmeans = lsm;  * contains the adjusted means; 
 
 
ods output diffs = dif;  * contains treatment differences; 
 
run; 
  
Extension Periods 
This analysis will be modified to include data collected during the ECP and OLE periods.  
Change from baseline during ECP, change from baseline until the last mature visit 
during the combined ECP  OLE periods and change from OLE baseline until the last 
mature visit during the OLE period will be analyzed.  The last mature visit is defined as 
the visit where the majority of patients have completed prior to the data cutoff date. 
The model will include the 1/x transformed value of the 25-foot timed walk at each visit 
as the dependent variable, instead of the log-transformation applied previously. 
For the combined ECP and OLE periods, visits will be backdated in order to have 
continuous time visits post ECP.  Below algorithm will be considered for backdated OLE 
visits. 
Backdate Algorithm (continuous OLE visits): 
 
All scheduled OLE labeled visits to be windowed to the nearest 12-week visit 
following the scheduled visits during the ECP. 


 
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 
For each OLE patient, create an artificial Schedule of Assessment (SoA):  a visit 
every 12 weeks in continuation to the ECP. 
 
Assign a new visit label from the closest visit from artificial SoA to OLE visit. 
 
All OLE Week yy visits to be replaced by Week xx, in continuation to the visit labels 
during the ECP. 
 
Use the new visit labels (no OLE Week yy visit label) for the analysis purpose. 
 
If multiple OLE visits are windowed to the same 12 week visit, then the latest 
chronological visit will be used for the analyses. 
  
4.5.2.3 
Change in Total Volume of T2 Lesions on MRI Scans 
of the Brain from Baseline to Week 120 
For the assessment of differences in the percent change in total volume of T2 lesions 
from baseline up to Week 120, ranked ANCOVA and MMRM analyses will be 
undertaken using the same approach as described above in Section 4.5.2.2, except that 
the baseline covariate for the MMRM will be baseline log-transformed T2 lesion volume, 
geographical region (U.S. vs. ROW), and age ( 45 vs.  45 years). 
T2 lesion volumes below the lower limit of quantification of 0.009 cm3 (3 voxels) will be 
set to this limit. 
Extension Periods 
This analysis will be extended to include data collected during the OLE period.  Ratio 
relative to baseline until the last mature visit during the combined ECP  OLE period and 
ratio relative to OLE baseline until the last mature visit during the OLE period will be 
analyzed.  Note that no additional MRI assessments were performed between 
120 weeks and OLE start, hence analysis for the ECP period is the same as that for the 
DB period. 
4.5.2.4 
Percent Change on MRI from Week 24 to Week 120 in Total 
Brain Volume 
For the assessment of differences in the mean percentage change in brain volume on 
MRI scans from Week 24 to Week 120,  an MMRM analysis will be undertaken using the 
same approach as described above in Section 4.5.2.2, except: 
 
The response variable will be the percentage change from Week 24 to subsequent 
visits (Weeks 48, and 120).  Baseline brain volume data will not be a feature in this 
analysis. 
 
Covariates will be brain volume at Week 24, geographical region (U.S. vs. ROW), 
and age ( 45 vs.  45 years). 
 
The choice of Week 24 as “baseline” in this analysis, rather than the baseline visit, is a 
widely accepted approach to establish a stable baseline and avoid the physiological 
effect of pseudo-atrophy. 


 
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Extension Periods 
This analysis will be extended to include data collected during the OLE period.  
Percentage change from Week 24, baseline and OLE baseline until the last mature visit 
will be analyzed. 
4.5.2.5 
Change from Baseline in Quality of Life as Measured by the 
SF36 (Physical Component) 
The SF-36v2 is a 36-item, self- reported, generic measure of quality of life that has been 
widely used in multiple disease areas.  It is composed of eight health domains:  Physical 
Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality 
(VT), Social Functioning (SF), Role-Emotional (RE), and Mental Health (ME).  Based on 
these domain scores, the Physical Component Summary (PCS) Score and the Mental 
Component Summary (MCS) Score will be computed.  The standard form of the 
instrument, with a 4-week recall, is being administered in the studies. 
Scoring and rules for missing items will follow the SF-36v2 User’s Manual.  In brief, 
scoring for each health domain scale involves (a) recoding item response values, 
(b) summing recoded response values for all items in a given scale to obtain the scale 
raw score, and (c) transforming the scale raw score to a 0−100 score.  The PCS score is 
computed by (a) multiplying each health domain z score by a scale-specific physical 
factor score coefficient, (b) summing the resulting products, and (c) converting the 
product total to a T score.  The MCS score is computed in the same manner, instead 
using scale-specific mental factor score coefficients. 
For the assessment of differences in the mean change in PCS score from baseline up to 
Week 120, MMRM analyses will be undertaken using the same approach as described 
above in Section 4.5.2.2, except baseline covariates here will be as follows: baseline 
PCS score, geographical region (U.S. vs. ROW) and age ( 45 years,  45 years). 
Extension Periods 
Additional data from the OLE period will be descriptively analyzed.  Note that no 
additional SF-36 assessments were performed between 120 weeks and OLE start. 
4.5.3 
Exploratory Efficacy Endpoints 
The MS guideline of the European Medicines Agency (EMA, 26 March 2015) suggests a 
number of primary and secondary efficacy outcome measures.  On the basis of these 
recommendations, the following exploratory efficacy outcomes will be analyzed: 
 
MRI derived parameters:  number of gadolinium-enhancing T1 lesions and number 
of new or enlarging T2 lesions.  For the combined ECP and OLE periods, these 
parameters will be analyzed by scheduled visit as follows: 
– 
Negative binomial model adjusted by Geographical Region (US vs. ROW) and 
Age ( 45,  45 years) for the baseline visit. 


 
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– 
Negative binomial model adjusted by Baseline T1 Gd Lesion (present or not) or 
Baseline T2 lesion count, Geographical Region (US vs. ROW) and Age ( 45, 
 45 years) for the post-baseline visits. 
– 
If the negative binomial model doesn’t converge due to small number of lesion 
counts, unadjusted rate and exact poisson CI will be presented. 
 
 
Cognitive impairment:  change from baseline to Week 120 in the Paced Auditory 
Serial Addition Test (PASAT). 
 
Percent change from baseline to Week 120 in total brain volume, white matter 
volume and cortical gray matter brain volume and the percent change from 
Week 24 to Week 120 in white matter volume and grey matter brain volume.  For all 
parameters, analyses will be extended to include data collected during the OLE 
period where percentage change from Week 24, baseline and OLE baseline until 
the last mature visit will be analyzed. 
 
Additional exploratory outcomes that will be analyzed include the following:  
 
Proportion of patients with CDP at Week 120 
 
Functional impairment:  change from baseline in EDSS score, and change from 
baseline in MSFCS.  For both parameters, analyses will be extended to include data 
collected during the ECP and OLE periods.  Change from baseline during ECP, 
change from baseline until the last mature visit during the combined ECP  OLE 
periods and change from OLE baseline until the last mature visit during the OLE 
period will be analyzed. 
 
The change in fatigue, as measured by the Modified Fatigue Impact Scale (MFIS) 
total score and subscale scores (Physical impact, Cognitive impact, and 
Psychological impact) from baseline to Week 120.  Additional data from the OLE 
period will be descriptively analyzed. 
 
The change in quality of life, as measured by the SF-36v2 MCS score from baseline 
to Week 120.  Additional data from the OLE period will be descriptively analyzed. 
 
Time to composite confirmed disability progression (cCDP) over the treatment 
period, defined as an increase in EDSS that is sustained for at least 12 weeks 
(0.5 or 1, same criteria as for the primary endpoint time to 12-week CDP) or a 
20 percent increase in 25-foot timed walk that is sustained for at least 12 weeks or a 
20 percent increase in 9-hole peg test that is sustained for at least 12 weeks.  This 
analysis will be repeated to include the EDSS assessments performed during the 
ECP and OLE periods for ECP and the combined DB  OLE periods, with the same 
baseline as for the analysis during DB.  Analysis containing only data from OLE will 
be performed considering the OLE baseline. 
 
Additional endpoints for the extension periods: 
 
Change from baseline in non-enhancing T1 lesion volume will be analyzed similarly 
to the T2 lesion volume.  Ratio relative to baseline until the last mature visit during 
the combined ECP  OLE period and ratio relative to OLE baseline until the last 
mature visit during the OLE period will be analyzed. 


 
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 
Time to Onset of CDP confirmed for  48 weeks 
 
Time to onset of CDP will be analyzed with use of a 48 week confirmation window for 
disability progression.  The analysis will be conducted as described for the primary 
analysis, with the exception that the time to onset of CDP (48 week confirmation) is 
defined as the time from baseline to the first disability progression that is confirmed at 
the next regularly scheduled visit  48 weeks ( 329 days) after the initial disability 
progression. 
The analysis will be performed for ECP and the combined DB  OLE periods, with the 
same baseline as for the analysis during DB.  Analysis containing only data from OLE 
will be performed considering the OLE baseline. 
 
Time to Onset of cCDP for at least 24 weeks or 48 weeks 
 
Time to onset of cCDP will be analyzed with use of a 24 or 48 week confirmation window 
for disability progression.  The analysis will be conducted as described for the primary 
analysis. 
The analyses will be performed for ECP and the combined DB  OLE periods, with the 
same baseline as for the analysis during DB.  Analysis containing only data from OLE 
will be performed considering the OLE baseline. 
 
Time to Onset of Confirmed EDSS  7 for at least 24 weeks or 48 weeks 
 
Time to onset of confirmed EDSS  7 will be analyzed with EDSS  7 (requiring 
wheelchair) to be defined as a disability progression event that is sustained for at least 
24 or 48 weeks.  The analysis will be conducted as described for the primary analysis. 
The analyses will be performed for ECP and the combined DB  OLE periods, with the 
same baseline as for the analysis during DB.  Analysis containing only data from OLE 
will be performed considering the OLE baseline. 
 
Annualized Percentage Change in MRI assessments from Baseline during the 
combined ECP and OLE Periods 
 
Due to the event driven study design and no additional MRI assessments were 
performed between 120 weeks and OLE start, the time gap between 120 weeks and 
OLE start varies from patient to patient.  Hence, an annualized change in all MRI 
assessments, including the total brain volume, white matter volume, cortical gray matter 
volume, T1 lesion volume and T2 lesion volume is analyzed for the combined ECP and 
OLE periods, which takes into account the variable time difference between visits for 
each patient. 


 
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At each scheduled visit during the ECP and OLE periods, calculate the annualized 
change from the previous visit as follows: 
 
 
where AVAL corresponds to the MRI value at the current visit, and ADT corresponds to 
the date of the current visit. 
For T1 and T2 lesion volume, the log transformation is applied, and 0 values are imputed 
to 0.009 
 
 
The OLE MRI assessments are backdated as follows: 
– 
Create an SoA from Week 120 with a visit every 48 weeks, e.g., Week 168, 
Week 216, etc 
– 
All OLE visits prior to Week 168 will be assigned to Week 168  New visit label 
– 
For all remaining OLE visits, they will be assigned to the nearest Week xxx with a 
time window of  24 weeks  New visit label 
– 
Use the new visit labels (no OLE Week yy visit label) for the analysis 
– 
If multiple OLE visits are windowed to the same Week xxx visit, then the latest 
chronological visit will be used for the analyses 
 
 
Neurofilament Light chain (NfL) data collected during the ECP and OLE periods will 
be summarized descriptively.  Summary statistics of the absolute NfL values will be 
presented at all scheduled visits along with the percentage change from baseline.  A 
corresponding plot will be produced.  The analyses will be performed for the ECP 
period only as well as for the combined ECP and OLE periods. 
  
4.5.4 
Sensitivity Analyses 
The following sensitivity analyses of the primary endpoint will be conducted according to 
the analysis described in Section 4.5.1: 
1. 
The primary analysis will be repeated using the per-protocol population as the 
analysis population.  The below sensitivity analyses will be done with the 
ITT population. 
2. 
A sensitivity analysis using multiple imputations will be performed for the ITT 
population to explore the potential influence of informative censoring on the results 
of the primary efficacy analyses.  Censoring for a reason that is not independent of 
that patient’s prognosis is called “informative censoring.”  The influence of 


 
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informative censoring needs to be explored, because for time-to-event endpoints, 
the ITT principle requires that essentially all randomly assigned patients be 
observed up to the endpoint or up to the end of the study.  When a patient's 
follow-up is censored X number of months after random assignment, then, in the 
computation of the Kaplan-Meier estimates, log-rank or Cox regressions, that 
patient's outcome after X number of months is assumed to have the same outcome 
as the other patients in their treatment group who also are free of the outcome at 
X number of months and who remain under follow-up beyond X number of months.  
Thus, unless the reason for being censored is independent of that patient's 
prognosis, failure to observe that patient until occurrence of his study endpoints 
could lead to significant bias as well as increased variability in the evaluation of 
treatment effects.  To censor time to CDP at dropout due to premature withdrawal 
and lost to follow-up after an initial disability progression is potentially to favor the 
most toxic or less efficacious treatment and, consequently, should be avoided 
whenever possible.  Thus the purpose of this sensitivity analysis is to determine 
whether informative censoring has any influence on the primary endpoint. 
 
Multiple imputations will be used to impute the events for patients who had initial 
disability progression and then discontinued treatment with no confirmatory EDSS 
assessments.  Multiple imputation inference involves three distinct phases: 
 
The missing data are filled in m times to generate m complete data sets.  Instead of 
filling in a single value for each missing value, multiple imputation replaces each 
missing value with a set of m plausible values that represent the uncertainty about 
the right value to impute. 
 
The m complete data sets are analyzed using standard statistical analyses. 
 
The results from the m complete data sets are combined to produce inferential 
results. 
 
Fifty percent of the patients who had initial disability progression and then discontinued 
the treatment with no confirmatory EDSS assessments will be randomly assigned to 
have an event at the time of their initial disability progression; the other 50% of these 
patients will be censored at their last EDSS assessment, under the assumption that 
50% of the patients with initial disability progression will later be confirmed at 12 weeks.  
A total of 1000 (m  1000) imputed datasets will be produced.  The primary model 
described in Section 4.5.1 will be applied to each of the imputed datasets.  Each imputed 
dataset will produce an estimate of the difference between ocrelizumab and placebo.  
The multiple imputation estimator of the difference between ocrelizumab and placebo is 
the average of the individual 1000 estimators.  The variance of the estimator is the 
combination of the between- and within-imputation variability (Carpenter and Kenward 
2007). 
The 50% confirmation rate for patients with initial disability progression was estimated on 
the basis of previous studies conducted in patients with PPMS (Weinshenker et al. 1996; 
Olympus, Study U2786g, data available upon request). 


 
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3. 
A sensitivity analysis, in which the patients who had initial disability progression and 
then discontinued the treatment with no confirmatory EDSS assessments will be 
considered to not have CDP, will be performed for the ITT population.  This 
sensitivity analysis assumes that all patients lost to follow up after initial disability 
progression events will not have reached CDP.  Hence, it will give an estimate of the 
maximal effect of informative censoring on the parameter estimates. 
4. 
The influence of early progression events on treatment effect will also be evaluated 
by omitting the EDSS assessments performed between randomization and the 
Week 12 visit ( 83 days after randomization) with use of the ITT population. 
5. 
The study originally planned to enroll approximately 630 patients who were to be 
followed for at least 120 weeks.  The study actually enrolled 732 patients (last 
patient enrolled on 27 December 2012).  To explore the effect of the higher 
enrollment number, the analysis of the primary efficacy endpoint will be performed 
using the first 630 patients on the basis of their randomization dates (ITT population) 
at the time of the primary analysis. 
6. 
The primary analysis described above will be adjusted with additional strata for the 
baseline presence of gadolinium-enhancing T1 lesions (present or absent) and 
baseline EDSS ( 5.5 vs.  5.5). 
7. 
PPMS is characterized by a progressive course from disease onset typically without 
superimposed discrete clinical attacks or relapses (Ebers 2004).  The primary 
analysis on CDP for  12 weeks, described above will be performed excluding 
patients who have any clinical relapses during the study.  Clinical relapses include 
protocol-defined relapses. 
8. 
For the time to onset of CDP for  24 weeks, the influence of early progression 
events on treatment effect will also be evaluated by omitting the EDSS assessments 
performed between randomization and the Week 12 visit ( 83 days after 
randomization) with use of the ITT population. 
9. 
For the time to onset of CDP for  24 weeks, the analysis will be performed 
excluding patients who have any clinical relapses during the blinded treatment 
period. 
  
4.5.5 
Subgroup Analyses 
The primary and key secondary endpoints (time to onset of 12- and 24 week CDP, 
change in 25-foot timed walk from baseline to Week 120, and change in total volume of 
T2 lesions, respectively) will be summarized by the following subgroups: 
 
Age ( 45 vs.  45 years) 
 
Sex (male patients vs. female patients) 
 
Baseline EDSS ( 5.5 vs.  5.5) 
 
Region (U.S. vs. ROW) 
 
Presence or absence of gadolinium-enhancing lesions at baseline MRI scan 


 
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 
Prior MS disease-modifying therapies, with the exception of corticosteroids (yes vs. 
no) 
 
Duration since MS symptom onset ( 3 years, 3 to  5 years, 5 to  10 years, 
 10 years) 
 
Weight ( 75 vs.  75 kg at baseline) 
 
Body mass index ( 25 vs.  25 kg/m2, at baseline) 
  
4.6 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
4.6.1 
Pharmacokinetic Analyses 
Nonlinear mixed effects modeling will be used to analyze the sparse sampling 
doseconcentrationtime data of ocrelizumab.  Patients who have measurable 
concentrations of ocrelizumab will be included in the PK analysis unless major protocol 
deviations or the unavailability of information (e.g., exact blood sampling time) occur that 
may interfere with PK evaluation.  The PK data from this study may be pooled with other 
studies.  Population PK parameters (clearances and volumes) will be estimated, and the 
influence of covariates such as age, sex, weight, ADAs, and baseline CD19+ 
lymphocytes on these parameters will be investigated. 
The model developed based on relapsing multiple sclerosis (RMS) data will be used to 
predict PK profiles in the PPMS study.  If predictions match observations, this population 
PK model based on RMS data will be deemed acceptable to describe the PK in PPMS 
patients too.  If predictions do not match observations, a population PK model based on 
the PPMS or pooled RMS  PPMS data will be developed. 
Details of the mixed effects modeling analyses will be described in a Modeling and 
Simulation Analysis Plan, and results will be reported separately. 
4.6.2 
Pharmacodynamic Analyses 
If possible, nonlinear mixed effects modeling will be used to investigate the relationship 
between ocrelizumab exposure and selected safety and efficacy parameters. 
Exploratory analyses may be performed to assess the possible relationship between 
PD markers like B cells, pharmacokinetics, and clinical response; this will be described 
in a Modeling and Simulation Analysis Plan, and results will be reported separately. 
4.7 
SAFETY ANALYSES 
The safety population is defined in Section 4.1.3.  All safety parameters will be 
summarized and presented in tables on the basis of this safety population.  Randomized 
patients who receive incorrect therapy will be summarized in the group according to the 
rules laid out in Section 4.1.3.  Placebo patients who received any ocrelizumab in error 
will be assigned to the ocrelizumab group. 


 
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Patients who are not randomized but who receive study drug will be included in the 
safety population and summarized according to the therapy actually received. 
This SAP describes the analyses of all available safety data collected until the end of the 
trial.  The safety data will be summarized descriptively for the DBP, ECP, OLE and SFU 
periods. 
4.7.1 
Exposure of Study Drug 
The amount of ocrelizumab or placebo infused at each infusion will be listed and 
summarized using descriptive statistics. 
Definition of dose:  A dose of ocrelizumab is given as two infusions administered 
2 weeks apart. 
Patients will be considered to have received a dose of treatment if at least part of one 
infusion of that dose (either Day 1 or Day 15 for dual infusions) was given.  If a dose is 
completely missed instead of delayed, the next dose number will be based on the 
number of previous doses received. 
The duration of observation for a patient will be calculated as follows: 
(Date of last contact*−Date of first infusion in the first dose)  1 
*Earliest 1) date of CCOD for the primary analysis reporting; 2) date of subject 
completed or discontinued early from the study completion end of study page; or 3) date 
of death. 
 
The duration of observation, within a dose, is defined in a similar manner as follows: 
(Day prior to first infusion in the n  1th dose*−Date of first infusion in the nth dose)  1 
*With the exception of the last dose received by the patient where the date of last 
contact is used as defined above.  If the last contact is after the date of the clinical cutoff, 
the date of last contact will be the CCOD. 
4.7.2 
Adverse Events 
Adverse events (AEs) will be defined as all AEs including infusion-related reactions 
(IRRs) and serious MS relapses, but excluding non-serious MS relapses.  Therefore, 
those AEs recorded on the AE and IRR CRF pages will be included.  Refer to 
Section 4.7.2.5 for further guidance on MS relapses considered SAEs. 
For each recorded AE, the term entered by the investigator describing the event (the 
“reported term”) will be assigned a standardized term (the “Preferred Term” [PT]) and 
assigned to a superclass term on the basis of the MedDRA World Health Organization 


 
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(WHO) dictionary of terms.  All analyses of AE data will be performed using the PTs 
unless otherwise specified. 
For all summary tables, the AEs will be sorted by System Organ Class (SOC; in 
decreasing order of overall incidence) and then by PT (in decreasing order of overall 
incidence).  All summaries and listings of AEs will be based on the safety population, 
unless stated otherwise.  Summaries of AEs will be generated to summarize the 
incidence of treatment emergent AEs only.  Treatment Emergent events are defined as 
those AEs with an observed or imputed date of onset on or after the start date of trial 
treatment.  If the onset date of the AE is prior to the day of first dose, the AE will be 
considered treatment emergent only if the most extreme intensity is greater than the 
initial intensity (i.e., the intensity for a given AE increases and its end date is on or after 
the date of the first dose).  An AE with a completely missing, nonimputed start date will 
be assumed to be treatment emergent unless the AE has a complete, nonimputed end 
date that is prior to the date of the first dose. 
AEs will be assigned to a dose if the AE onset date is on or after the date of the first 
infusion of that dose but before the first infusion of the next treatment dose.  AEs that are 
reported during the SFU period (including the B-cell monitoring period) will be assigned 
to the last dose received.  Hence, the last dose for a patient may be of a variable length, 
from 24 to 72 weeks or longer.  AEs that start prior to the first dose and worsen during 
treatment (i.e., treatment-emergent) will be assigned to the first treatment dose. 
The number of patients who experienced a related AE will be summarized by SOC and 
PT.  AEs will be summarized by SOC and PT by intensity grade.  Multiple occurrences of 
the same event within a patient will be counted once at the greatest intensity/highest 
grade for this PT.  For AEs leading to death, the most extreme intensity will be 
overwritten by Grade 5 (death).  Any AEs and the SOC overall rows of the summary 
table will count patients according to AEs by intensity (grade). 
All patient deaths, regardless of treatment received, will be listed. 
SAEs will be defined as all SAEs including serious MS relapses and serious IRRs.  The 
number of patients who experienced an SAE will be summarized by SOC and PT.  
Related SAEs will be summarized by SOC and PT.  Additionally, the most frequent 
SAEs ( 1%) will be presented by PT. 
A patient may experience an AE that leads to the discontinuation of his/her study 
treatment.  Discontinuation of study treatment for an AE may not necessarily lead to 
discontinuation from the study because the patient can enter the SFU period of the 
protocol.  Only AEs that led to the discontinuation of study treatment are of interest.  
Patients who withdraw early from the study because of AEs will be summarized under 
disposition.  The number of patients who experienced an AE that led to discontinuation 
of study treatment will be summarized by SOC and PT.  The number of patients who 


 
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experienced an AE that led to modification or interruption of study drug will be 
summarized by SOC and PT. 
For each treatment group, the incidence count for each AE PT will be defined as the 
number of patients reporting at least one treatment emergent occurrence of the event.  
The incidence rate will be calculated as the incidence count divided by the total number 
of patients in the population.  Each table will also present the overall number of patients 
experiencing at least one AE and the total number of AEs reported (multiple occurrences 
of the same AE in 1 patient will be counted only once). 
The rate per 100 patient-years by treatment group (along with the 95% CI) will be 
calculated for specific events of interest such as all AEs, SAEs, infections and serious 
infections, opportunistic infections (OIs), and malignancies (see Section 4.7.2.2, 
Section 4.7.2.3 and Section 4.7.2.4, respectively). 
 
The number of AEs per 100 patient-years is calculated as: 
Total number of AEs / Total number of patient-years  100 
 
The 95% CI for the number of AEs per 100 patient-years is calculated as follows 
(Sahai and Kurshid 1993):  
 
Exact lower 95% confidence limit  chisq (p  0.025, df  2 Y) / (2T) 
Exact upper 95% confidence limit  chisq [p  0.975, df  2(Y  1)] / (2T) 
where Y is the total number of AEs, T is total number of patient-years at risk and chisq 
(p,df) is the quantile of the upper tail probability of the X2 distribution on df (degrees of 
freedom).  This approach has the advantage of providing an estimate for the upper 
95% confidence limit even when the total number of AEs is zero. 
The rates per 100 patient-years will be summarized by treatment and dose and by 
treatment (including all doses). 
4.7.2.1 
Infusion-Related Reactions 
An IRR and its corresponding symptoms are collected on the dedicated eCRF page. 
The symptom(s) of an IRR and the IRR itself may be of different intensities.  Because 
other symptoms can be recorded as free text on the eCRF page, symptoms will be 
coded in the MedDRA and summarized by PTs. 
For IRRs, the number and percentage of patients with at least one infusion reaction will 
be presented per infusion (patients with multiple events within an infusion will count only 
once).  In addition, the total number of IRRs will be summarized (multiple events will be 
counted).  The total and percentage of events (based on the total number of patients 


 
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with at least one IRR) by most extreme intensity will be summarized per infusion and per 
dose.  The number of serious IRRs will also be presented. 
For multiple events in a given patient, the most extreme intensity will be used and the 
total number of events of each intensity will be equal to the total number of patients with 
at least one IRR if there are no missing extreme intensities.  The total number of IRRs 
experienced by each subject will be summarized across the treatment doses. 
IRRs are recorded on the CRF by the time of the event, (i.e., occurring during the 
infusion, after completion of the infusion while patient is in the clinic, or within 24 hours of 
completion of the infusion and the patient is not in the clinic).  The number of patients 
with at least one IRR, the total number of IRRs, and the intensity of the IRR will be 
presented by the time of event. 
Additionally, similar tables will be presented by the premedication subgroup 
(methylprednisolone alone, methylprednisolone plus analgesic/antipyretics, 
methylprednisolone plus antihistaminics, or methylprednisolone plus 
analgesic/antipyretic and antihistaminics). 
Symptoms of IRRs and symptoms of serious IRRs will be presented by infusion.  
Symptoms of IRRs that led to modification of study drug or symptoms of IRR that led to 
discontinuation of study drug will also be presented.  Symptoms of IRR experienced by 
patients during an infusion, after the infusion, and after the patient leaves the clinic will 
also be presented. 
AEs other than IRRs experienced by the patient within 24 hours of an infusion will be 
presented by infusion.  AEs will be included if the onset date is on the day of an infusion 
or the following day.  The onset date of the AE will be matched to the date of an infusion; 
onset dates will not be imputed. 
The concomitant treatments for IRRs will be summarized. 
4.7.2.2 
Infections 
Infections will be defined from the AE data using the MedDRA SOC of “Infections and 
infestations.”  During Primary CSR, AEs reported as an infection by the investigator will 
also be included.  Infections will be classified according to the pathogen type 
(e.g., bacterial, fungal, viral, parasitical, unknown, or other). 
During Primary CSR, an infection has been defined as serious if the event is a SAE or if 
the non-serious infection was treated with an IV anti-infective.  For subsequent reporting, 
an infection has been defined as serious if the event is a SAE. 
A listing will be presented of non-serious infections treated with an IV anti-infective 
during primary CSR.  The number of patients who experienced an infection will be 
summarized by SOC and PT and by intensity. 


 
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The number of infections experienced by more than 5% of patients will be summarized 
by SOC and PT. 
The number of patients who experienced a serious infection will be summarized by SOC 
and PT. 
Identified pathogen codes will not be summarized but will only be listed within the listings 
of infections and serious infections.  Infections and serious infections will be summarized 
by pathogen types. 
The time to the first serious infection per patient will be summarized by treatment. 
The rate per 100 patient-years by treatment group (along with the 95% CI) will be 
calculated for infections and serious infections overall and by dose based on the number 
of patient-years observation for the specific dose. 
For infections and serious infections, the incidence rate ratio will be calculated.  For 
these analyses, the incidence rate ratio with 95% CI based on the Poisson distribution 
exact method will be presented. 
4.7.2.3 
Opportunistic Infections 
Opportunistic infections (OIs) will be defined using the Ocrelizumab specific MedDRA 
Term Selection (MTS) basket of “Opportunistic infections.” 
The number of patients who experienced an OI will be summarized by SOC and PT. 
The rate per 100 patient-years by treatment group (along with the 95% CI) will be 
calculated for OIs overall. 
4.7.2.4 
Malignancies 
Malignancy and pre-malignancy AEs will be identified using the standard MedDRA query 
(SMQ) of “Malignant tumours (narrow)” and “Pre-malignant disorders,” respectively. 
The number of patients with a malignancy will be summarized by SOC and PT.  The 
pre-malignancy AEs will be listed. 
The rate per 100 patient-years by treatment group (along with the 95% CI) will be 
calculated for malignancies. 
4.7.2.5 
Multiple Sclerosis Relapses 
MS relapses will include all events recorded on the AE CRF pages that are classified as 
MS relapse. 


 
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Information related to a protocol defined relapse will be captured on a clinical relapse 
event CRF page.  If the following criteria are satisfied, the clinical relapse will qualify as a 
protocol defined relapse: 
 
Check box labeled “Did symptoms persist for  24 hours and were not attributable...” 
on the clinical MS relapse event CRF page is checked. 
 
Increase in EDSS from a visit occurring at (or soon after) the date of onset of 
relapse of  0.5 compared with the previous EDSS; or for selected FS domains 
involved in the relapse event (pyramidal, ambulation, cerebellar, brainstem, sensory, 
or converted visual), a  2 point increase in one appropriate FS domain or a  1 point 
increase in two or more appropriate FS domains. 
 
No protocol defined relapse within 30 days before the date of onset of the clinical 
relapse. 
 
For protocol defined relapses and clinically reported relapses (i.e., patients who 
experience any relapse), the number and percentage of patients experiencing an event 
will be summarized. 
Clinical relapse will be considered an SAE when the relapse results in hospitalization for 
any reason other than routine treatment of the relapse (e.g., for a treatment course 
beyond the standard treatment described or when hospitalization is prolonged).  These 
events will be listed and summarized. 
4.7.2.6 
Pregnancies 
Pregnancy information will be summarized. 
4.7.3 
Magnetic Resonance Imaging Data 
Non-MS pathology reported by the local safety radiologist on the CRF will be 
summarized by treatment group. 
4.7.4 
Laboratory Data 
General Laboratory Evaluations 
Abnormal laboratory outcomes will be reported.  A summary of the number and 
percentage of patients with abnormal laboratory outcomes, along with each grade by 
laboratory parameter, will be summarized by treatment group for all laboratory 
assessments. 
The absolute values and changes from baseline at each visit will be summarized for all 
laboratory assessments. 
For the liver laboratory parameters, the number and percentage of patients with an 
elevated post-baseline AST or ALT level will be summarized by treatment. 


 
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CD19 
The median CD19 cell count will be displayed graphically over time from the first infusion 
of study drug.  Absolute CD19 counts and percent changes from baseline in the CD19 
count will be summarized over time. 
Immunoglobulins 
The median immunoglobulin levels (IgA, IgG, IgM, and total Ig) will be displayed 
graphically over time from the first infusion of study drug.  Absolute values, changes 
from baseline, and percent changes from baseline will be summarized over time.  At 
each timepoint, the number and percentage of patients with immunoglobulin levels lower 
than the lower limit of normal will be presented. 
Antibody Titers 
If data are available, antibody titers for mumps, rubella, varicella, and Streptococcus 
pneumoniae will be summarized for the number and percentages of patients with a 
positive level by visit. 
Anti-Drug Antibodies 
ADAs, also called human anti-human antibodies, will be summarized over the blinded 
treatment period by treatment group.  The baseline prevalence and post-baseline 
incidence of ADAs will be displayed.  The number of patients with treatment-induced 
ADA will also be displayed.  A table that summarizes ocrelizumab serum concentrations 
(μg/mL) at timepoints where ADA samples were collected and analyzed will be 
presented.  A listing by treatment of antiocrelizumab antibody data will be presented for 
patients with at least one ADA sample. 
HBV DNA 
HBV DNA in patient core HBV antibody positive at screening will be listed. 
4.7.5 
Vital Signs 
Vital sign and physical examination results, and ECG data will be included in individual 
patient listings. 
Changes from study baseline in vital signs will be summarized by visit and group.  
Changes from pre-infusion baseline to post-infusion timepoints will also be summarized 
for each infusion. 
4.7.6 
Clinical Genotyping  
The following genetic markers will be summarized descriptively.  A summary of 
polymorphism ID, genotype frequency, and allele frequency will be generated: 
– 
RO_000052326 (FCGR2A) 
– 
RO_000059393 (FCGR3A) 
 
The frequency of HLA-DRB1 positive assessments at baseline will be summarized. 


 
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Additionally, a summary of occurrence of AEs for GENE by genotype frequency for 
MS relapses, infections and IRRs will be generated for the same genetic markers. 
Extended Periods 
Above summaries and listings of safety assessments will be repeated for the ECP and 
OLE periods (including the SFU after withdrawal from ECP or OLE treatment). 
These include but are not limited to; 
 
AEs leading to withdrawal from treatment and AEs leading to dose modifications 
 
Malignancies 
 
Serious infections 
 
Deaths 
 
IRRs by visit 
 
Summary of safety laboratory assessments, vital signs, antibody titers, 
immunoglobulins by visit 
 
Summary of treatment emergent ADAs 
 
Listing of pregnancy information 
 
For OLE summaries, data will be presented as defined in OLE Safety Population. 
Analyses pooling all safety data from the first dose of ocrelizumab (ECP and OLE 
periods) across multiple MS trials are described separately in a Global Safety Pooling 
SAP. 
4.7.7 
COVID-19 Analyses 
In line with the guidance from the Sponsor and health authorities, several patient listings 
and summaries will be prepared in order to assess the impact of the Coronavirus 
Disease 2019 (COVID-19) pandemic on the study conduct and results.  Summaries and 
listings will be prepared for major protocol deviations due to the pandemic, patients 
infected with COVID-19 and AEs & death associated with COVID-19.  Further details will 
be provided in the COVID-19 CSR Appendix. 
4.8 
MISSING DATA 
All methods for handling missing data and associated sensitivity analyses are described 
above, section by section, for each endpoint. 
4.9 
INTERIM ANALYSES 
Updated efficacy and safety analysis of ECP and/or OLE are performed on a yearly 
basis after the CSR primary database lock.  Regular safety updates are assessed in 
safety pooling analysis from multiple studies. 


 
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5. 
REFERENCES 
Bohannon RW. Comfortable and maximum walking speed of adults aged 20−79 years: 
reference values and determinants. Age Ageing 1997;26:15−9. 
Carpenter JR, Kenward MG. Missing data in clinical trials⎯a practical guide. NIHR 
Report. 2007. Available from: 
http://www.hta.nhs.uk/nihrmethodology/reports/1589.pdf. 
Ebers GC. Natural history of primary progressive multiple sclerosis. Mult Scler 
2004;10(Suppl 1):S8−13. 
European Medicines Agency, Guideline on clinical investigation of medicinal products for 
the treatment of Multiple Sclerosis, 26 March 2015, EMA/CHMP/771815/2011, 
Rev. 2. 
Fischer JS, Jak AJ, Kniker JE,  Rudick RA,Cutter G: Multiple Sclerosis Functional 
Composite (MSFC) Administration and Scoring Manual 2002; National Multiple 
Sclerosis Society. 
Hawker K, O’Connor P, Freedman MS, Calabresi PA, Antel J, Simon J, Hauser S, 
Waubant E, Vollmer T, Panitch h, Zhang J, Chin P, Smith CH. Rituximab in 
patients with primary progressive multiple sclerosis: results of a randomized 
double-blind placebo-controlled multicenter trial. 2009. Ann Neurol. 66:460-71. 
Sahai H, Khurshid A. Confidence Intervals for the Mean of a Poisson Distribution: A 
Review. 1993. Biometrical J, 35: 857-67. 
Weinshenker BG, Issa M, Baskerville J. Meta-analysis of the placebo-treated groups in 
clinical trials of progressive MS. Neurology 1996;46:1613−9.






Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
50/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
51/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
52/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
53/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
54/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
55/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
56/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
57/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
58/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
59/Statistical Analysis Plan WA25046 
 
 


Appendix 1  
EDSS Assessment Check for the Roche Trials WA25046, 
WA21092, and WA21093 (cont.)  
Ocrelizumab—F. Hoffmann-La Roche Ltd 
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Signature Page for Study WA25046 (ORATORIO) SAP v5 - Published
System identifier: RIM-CLIN-472959
Approval Task
Company Signatory
20-Mar-2023 15:24:56 GMT+0000