Clinical trial NCT02028884
Conditions: Neuromyelitis Optica (NMO) NMO Spectrum Disorder (NMOSD)
Sponsor: Hoffmann-La Roche
Start date: 2014-02-20; Completion date: 2021-12-23
Enrollment: 85 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the efficacy, safety, pharmacodynamic, pharmacokinetic, and immunogenic profiles of satralizumab, compared with placebo, in addition to baseline immunosuppressive treatment in participants with NMO and NMOSD.

Detailed description:

Arms: arm 1: Participants randomized to this arm for the double-blind period will receive satralizumab in addition to baseline treatment. The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021. arm 2: Participants randomized to this arm for the double-blind period will receive placebo in addition to baseline treatment.The double-blind period ends when either the participant has a treated relapse or the total number of protocol-defined relapses confirmed by the Clinical Endpoint Committee (CEC) reaches 26. In the open-label extension period, the participant will receive (with or without baseline treatment) an SC injection of satralizumab at Weeks 0, 2, and 4, and Q4W thereafter, with the last study drug administration on or before 31 December 2021.
Interventions: intervention 1: Satralizumab intervention 2: Placebo intervention 3: Baseline Treatment
Intervention descriptions: intervention 1: Satralizumab will be administered subcutaneously (SC) at Weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W). intervention 2: Placebo will be administered subcutaneously (SC) at Weeks 0, 2, and 4, and thereafter once every 4 weeks (Q4W). intervention 3: As specified in the protocol, one of the following drugs at a stable dose is required as monotherapy for baseline treatment during the double-blind period: azathioprine (AZA); mycophenolate mofetil (MMF); or oral corticosteroids (CS). For participants aged 12 to 17 years at the time of informed consent, baseline treatment with AZA or MMF in combination with oral CS is also permitted. Change or termination of baseline treatment is only permitted during the open-label extension period.

Protocol documents:
Prot_000.pdf: 
 
Offi ci al  Titl e:  
 
A  M ulti c e nt er,  R a n d o mi z e d,  A d diti o n  t o B a s eli n e  Tr e at m e nt,  D o u bl e -
Bli n d,  Pl a c e b o - Co ntr oll e d,  P h a s e  3  St u d y  to  E v al u at e  th e   Effi c a c y  an d 
S af et y  o f   S atr ali z u m a b ( SA 2 3 7)  in  P ati e nt s  Wit h  N e ur o m y eliti s  O pti c a  
( N M O)  an d  N M O  S p e ctr u m  Di s or d er ( N M O S D ) 
N C T  N u m b e r:   N C T 0 2 0 2 8 8 8 4     
D o c u m e nt  D at e :  Pr ot o c ol  V er si o n  1 1 : 1 0- A pril -2 0 2 0  
 
 
 


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 affili 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 ne 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 b e a d mi ni st er e d.
* C h u g ai will a ct a s t h e S p o n s or o nl y i n T ai w a n a n d J a p a n. T h e s p e cifi c d et ail s of t h e l e g al/r e g ul at ory 
e ntit y wit hi n t h e r el e v a nt c o u ntr y ar e pr o vi d e d wit hi n t h e cli ni c al tri al a gr e e m e nt wit h t h e 
I n v e sti g at or/I n stit uti o n a n d t h e Cli ni c al Tri al A p pli c ati o n wit h t h e C o m p et e nt A ut h orit y.
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
P R O T O C O L
TI T L E:
A M U L TI C E N T E R, R A N D O MI Z E D, A D DI TI O N T O 
B A S E LI N E T R E A T M E N T, D O U B L E -B LI N D, P L A C E B O-
C O N T R O L L E D, P H A S E 3 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 S A T R A LI Z U M A B ( S A 2 3 7 )
I N P ATI E N T S WI T H N E U R O M Y E LI TI S O P TI C A ( N M O)
A N D N M O S P E C T R U M DI S O R D E R ( N M O S D)
P R O T O C O L N U M B E R: 
B N 4 0 8 9 8 ( S A -3 0 7 J G )
V E R SI O N N U M B E R: 
1 1
E U D R A C T N U M B E R: 
2 0 1 3 -0 0 3 7 5 2 -2 1
I N D N U M B E R:
1 1 8 1 8 3
T E S T P R O D U C T: 
S atr ali z u m a b ( S A 2 3 7 ) ( R O 5 3 3 3 7 8 7)
M E DI C A L M O NI T O R:
, M. D.
C O -S P O N S O R S:
F. H off m a n n -L a R o c h e Lt d
C h u g ai P h ar m a c e uti c al C o. Lt d. *
A P P R O V A L D A T E : 
S e e el e ctr o ni c d at e st a m p b el o w .
 
1 0- A pr- 2 0 2 0 1 7: 4 2: 0 6
Titl e
A p pr o v er' s N a m e
C o m p a n y Si g n at or y
D at e a n d Ti m e ( U T C)


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2/ Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), 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
1
5 S e pt e m b er 2 0 1 3
2
2 9 N o v e m b er 2 0 1 3
3
2 7 F e br u ar y 2 0 1 4
4
1 8 D e c e m b er 2 0 1 4
5
3 J u n e 2 0 1 5
6
1 9 O ct o b er 2 0 1 5
7
1 4 D e c e m b er 2 0 1 6
8
1 7 A pril 2 0 1 7
9 ( U nit e d Ki n g d o m)
1 4 M ar c h 2 0 1 9
9
1 4 M ar c h 2 0 1 9
1 0 ( U nit e d Ki n g d o m)
2 4 D e c e m b er 2 0 1 9


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3/ Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), 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 1 1:
R A TI O N A L E
Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1 ( gl o b al), i s a m er gi n g of Ver si o n 9 ( gl o b al) 
a n d V er si o n 1 0 ( U nit e d Ki n g d o m). T hi s v er si o n 1 1 ( gl o b al) of t h e pr ot o c ol r e pl a c e s t h e 
c urr e nt v er si o n 9 ( gl o b al) a n d all U nit e d Ki n g d o m-s p e cifi c v er si o n s. R el ati v e t o 
V er si o n 9 ( gl o b al), t h e pr ot o c ol h a s b e e n a m e n d e d t o r efl e ct a c h a n g e i n S p o n s or f or 
S o ut h K or e a ; r el ati v e t o V er si o n 9 ( gl o b al) a n d V er si o n 1 0 ( U nit e d Ki n g d o m), it h a s 
b e e n a m e n d e d t o i n cr e a s e t h e d ur ati o n of t h e o p e n-l a b el e xt e n si o n ( O L E) peri o d u p 
t o 3 1 D e c e m b er 2 0 2 1 . I n a d diti o n, s p e cifi c m e a s ur e s w er e i m pl e m e nt e d t o all o w 
c o nti n u ati o n of tr e at m e nt a n d e n s ur e p ati e nt s af et y d uri n g t h e S A R S -C o V -2 
( C O VI D-1 9) p a n d e mi c .
C h a n g e s t o t h e pr ot o c ol f or all sit e s, 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, ar e 
s u m m ari z e d b el o w:
 
T h e O L E tr e at m e nt p eri o d h a s b e e n e xt e n d e d u p t o 3 1 D e c e m b er 2 0 2 1.  T h e 
m a n a g e m e nt of n e ur o m y eliti s o pti c a s p e ctr u m di s or d er ( N M O S D) wit h 
s atr ali z u m a b r e q uir e s l o n g -t er m tr e at m e nt.  E xt e n di n g t h e O L E tr e at m e nt p eri o d 
t o th e e n d of D e c e m b er 2 0 2 1 will e n s ur e t h e c o nti n u ati o n of tr e at m e nt a n d 
pr o vi d e a d diti o n al l o n g -t er m s af et y a n d effi c a c y d at a ( S e cti o n s 3. 1. 1, 4. 3. 2. 2, a n d 
4. 5. 2. 3 ).
 
T h e ri s k s f or s atr ali z u m a b w er e u p d at e d b a s e d o n t h e c urr e nt a v ail a bl e cli ni c al 
tri al d at a wit h s atr ali z u m a b ( S e cti o n 5. 1).
 
F. H off m a n n -L a R o c h e Lt d h a s t a k e n o v er t h e f ut ur e d e v el o p m e nt of st u d y dr u g 
s atr ali z u m a b ( S A 2 3 7) i n S o ut h K or e a fr o m C h u g ai P h ar m a c e uti c al C o., Lt d. 
( C h u g ai). C h u g ai will r e m ai n t h e S p o n s or i n T ai w a n a n d J a p a n ( S e cti o n 9. 3).  
 
S p e cifi c m e a s ur e s d uri n g e m er g e n c y sit u ati o n s s u c h a s t h e S A R S -C o V -2 
( C O VI D-1 9) p a n d e mi c w er e a d d e d t o e n s ur e tr e at m e nt c o nti n u ati o n a n d p ati e nt 
s af et y ( S e cti o ns 4. 3. 2. 2 , 4. 3. 3, 4. 5. 1. 11 , 4. 5. 2. 2, a n d 5. 1. 1. 7; A p p e n di x 1, T a bl e 
7 ):
– 
I n t h e O L E p eri o d aft er W e e k 4 8, i n a c c or d a n c e wit h l o c al r e g ul ati o n s , 
a d mi ni str ati o n of s atr ali z u m a b pr efill e d s yri n g e s o ut si d e of t h e st u d y sit e ( e. g., 
s elf -a d mi ni str ati o n or a d mi ni str ati o n b y a c ar e gi v er aft er c o m pl et i n g tr ai ni n g, 
a d mi ni str ati o n b y t h e p ati e nt’ s [l o c al] g e n er al p h y si ci a n, h o m e a d mi ni str ati o n 
b y a m o bil e n ur s e) will b e all o w e d.
–
If p ati e nt s c a n n ot p h y si c all y att e n d a vi sit at t h e st u d y sit e f or s af et y bl o o d 
d r a w, s af et y l a b t e st s s h o ul d b e p erf or m e d, i n a c c or d a n c e wit h l o c al 
r e g ul ati o n s, at a l o c al l a b or at or y w h e n p o s si bl e a n d a n y cli ni c all y si g nifi c a nt 
a b n or m al l a b or at or y v al u e s r e p ort e d a s a d v er s e e v e nt s ( A E s) i n t h e e C R F.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4/ Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
–  
A ll eff ort s s h o ul d b e m a d e t o f oll o w u p wit h p ati e nt s ar o u n d t h e ti m e of t h e 
s c h e d ul e d vi sit b y p h o n e if t h e y c a n n ot p h y si c all y att e n d a vi sit at t h e st u d y
sit e t o c oll e ct a n y i nf or m ati o n o n s af et y a n d/ or n e ur ol o gi c al w or s e ni n g t h e 
p ati e nt mi g ht e x p eri e n c e, a n d t o c o nfir m p ati e nt c o m pli a n c e wit h st u d y 
tr e at m e nt.  A n y i s s u e s o c c urri n g d uri n g t h e d o si n g p eri o d o ut si d e of t h e st u d y 
sit e s h o ul d b e r e p ort e d.
 
F oll o wi n g t h e i m pl e m e nt ati o n of Pr ot o c ol V er si o n 1 1 a n d i n a c c or d a n c e wit h l o c al 
r e g ul ati o n s, a d mi ni str ati o n of s atr ali z u m a b o ut si d e of t h e st u d y sit e m a y b e 
all o w e d t o r e d u c e t h e b ur d e n o n p ati e nt s tr a v eli n g t o st u d y sit e s at d efi n e d vi sit s. 
P ati e nt s will b e f oll o w e d u p b y st u d y sit e p er s o n n el t hr o u g h p h o n e c all s ( S e cti o n s 
4. 3. 2. 2, 4. 3. 3, 4. 5. 2. 2, 5. 1. 1. 7, a n d A p p e n di x 1, T a bl e 7).
T h e f oll o wi n g a d diti o n al cl arifi c ati o n s h a v e al s o b e e n m a d e:
 
M e di c al Hi st or y will i n cl u d e t h e fir st att a c k a n d d at e of di a g n o si s of n e ur o m y eliti s
o pti c a ( N M O) or N M O S D t o f urt h er c h ar a ct eri z e t h e e nr oll e d p ati e nt p o p ul ati o n 
( S e cti o n 4. 5. 1. 1).
 
D u e t o drift s i n t h e A nti- A Q P 4 a nti b o d y c ell- b a s e d a s s a y o v er ti m e c o nf o u n di n g 
l o n git u di n al a s s e s s m e nt of a nti- A Q P 4 a nti b o d y tit er s, s a m pl e s will b e a n al y z e d b y
E LI S A ( S e cti o n 6. 7 a n d A p p e n di x 1, T a bl e 6).
 
L a n g u a g e h a s b e e n a d d e d t o cl arif y p er mitt e d m e di c ati o n s d uri n g t h e O L E p eri o d
( S e cti o n 4. 4. 1).
 
P ati e nt s w h o d o n ot m e et t h e crit eri a f or c hil d b e ari n g p ot e nti al d uri n g t h e O L E
p eri o d of t h e st u d y ( e. g., c o nfir m e d p o st- m e n o p a u s al st at u s) will n ot r e q uir e 
f urt h er pr e g n a n c y t e sti n g ( S e cti o n 4. 5. 1. 1 1).
 
P ati e nt s w h o c o m pl et e t h e O L E p eri o d wit h t h e l a st st u d y dr u g a d mi ni str ati o n o n 
or b ef or e 3 1 D e c e m b er 2 0 2 1 a n d d e ci d e t o c o nti n u e tr e at m e nt wit h s atr ali z u m a b 
o ut si d e of t hi s st u d y will n ot h a v e t o c o m pl et e t h e L a st O b s er v ati o n Vi sit ( S e cti o n 
4. 5. 2. 3).
 
P ati e nt s t h at w er e e nr oll e d a s a d ol e s c e nt s a g e d 1 8 y e ar s or ol d er at t h e ti m e t h e y 
c o m pl et e or di s c o nti n u e fr o m t h e O L E p eri o d a n d a d ol e s c e nt p ati e nt s t h at d e ci d e 
t o c o nti n u e tr e at m e nt wit h s atr ali z u m a b o ut si d e of t hi s st u d y will n ot h a v e t o c o m-
pl et e t h e F oll o w- U p A s s e s s m e nt s f or A d ol e s c e nt s ( S e cti o n 4. 5. 2. 5).
 
R e p orti n g r e q uir e m e nt s f or pr e g n a n ci e s i n f e m al e p ati e nt s h a v e b e e n cl arifi e d
a n d ali g n e d wit h t h e r e p orti n g r e q uir e m e nt s f or pr e g n a n ci e s i n f e m al e p art n er s of 
m al e p ati e nt s ( S e cti o n 5. 4. 3. 1).


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5/ Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
T h e st ati sti c al c o n si d er ati o n s s e cti o n h a s b e e n u p d at e d t o pr o vi d e i nf or-
m ati o n o n effi c a c y a n al y s e s d o n e f or t h e O L E p eri o d ( S e cti o n 6).
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 pr 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.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6/ Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T A B L E O F C O N T E N T S
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 ...........................................1 4
P R O T O C O L S Y N O P SI S ....................................................................................1 5
1. 
I N T R O D U C TI O N.........................................................................................2 6
1. 1 
B a c k gr o u n d o n N e ur o m y eliti s O pti c a ( N M O) 
a n d N e ur o m y eliti s O pti c a S p e ctr u m Di s or d er 
( N M O S D) ...............................................................................2 6
1. 1. 1 
I ntr o d u cti o n t o N M O a n d N M O S D..........................................2 6
1. 1. 2 
I nt erl e u ki n-6 a s a T ar g et M ol e c ul e f or t h e 
Tr e at m e nt of N M O a n d N M O S D ............................................2 7
1. 2 
B a c k gr o u n d o n S atr ali z u m a b .................................................2 7
1. 3 
St u d y R ati o n al e a n d B e n efit – Ri s k A s s e s s m e nt .....................2 9
2. 
O B J E C TI V E S ..............................................................................................3 0
2. 1 
Effi c a c y O bj e cti v e ..................................................................3 0
2. 2 
S af et y O bj e cti v e .....................................................................3 0
2. 3 
P h ar m a c o d y n a mi c O bj e cti v e .................................................3 1
2. 4 
P h ar m a c o ki n eti c O bj e cti v e ....................................................3 1
2. 5 
I m m u n o g e ni cit y O bj e cti v e......................................................3 1
2. 6 
E x pl or at or y O bj e cti v e .............................................................3 1
2. 7 
S p e cifi c O bj e cti v e f or t h e Gr o u p of 
A d ol e s c e nt s ...........................................................................3 1
3. 
S T U D Y D E SI G N .........................................................................................3 2
3. 1 
D e s cri pti o n of St u d y ...............................................................3 2
3. 1. 1 
O v er vi e w ................................................................................3 2
3. 1. 2  
I n v e sti g ati o n al S u bj e ct s a n d Sit e s .........................................3 3
3. 1. 3  
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 ..............................3 4
3. 1. 4 
Cli ni c al E n d p oi nt C o m mitt e e ( C E C ).......................................3 4
3. 2 
R ati o n al e f or St u d y D e si g n ....................................................3 4
3. 2. 1 
R ati o n al e f or C h oi c e of St u d y D e si g n El e m e nt s ....................3 4
3. 2. 2 
R ati o n al e f or C h oi c e of B a s eli n e Tr e at m e nt ..........................3 5
3. 2. 3 
R ati o n al e f or Ti m e t o Fir st R el a p s e E n d p oi nt ........................3 5
3. 2. 4 
R ati o n al e f or T e st Pr o d u ct D o s a g e ........................................3 6


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7/ Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
3. 2. 5 
R ati o n al e f or P ati e nt P o p ul ati o n ............................................3 6
3. 3 
St u d y E n d p oi nt s/ O ut c o m e M e a s ur e s .....................................3 7
3. 3. 1 
Effi c a c y O ut c o m e M e a s ur e s ..................................................3 7
3. 3. 1. 1 
Pri m ar y E n d p oi nt ...................................................................3 7
3. 3. 1. 2 
S e c o n d ar y E n d p oi nt s .............................................................3 7
3. 3. 2 
S af et y O ut c o m e M e a s ur e s ....................................................3 7
3. 3. 3  
P h ar m a c o d y n a mi c O ut c o m e M e a s ur e s .................................3 8
3. 3. 4  
P h ar m a c o ki n eti c O ut c o m e M e a s ur e s ....................................3 8
3. 3. 5  
I m m u n o g e ni cit y O ut c o m e M e a s ur e s ......................................3 8
3. 3. 6 
E x pl or at or y O ut c o m e M e a s ur e s .............................................3 8
3. 3. 7 
S p e cifi c O ut c o m e M e a s ur e s f or t h e Gr o u p of 
A d ol e s c e nt s ...........................................................................3 8
4. 
M A T E RI A L S A N D M E T H O D S .....................................................................3 8
4. 1 
P ati e nt s ..................................................................................3 8
4. 1. 1 
I n cl u si o n Criteri a ....................................................................3 8
4. 1. 2 
E x cl u si o n Crit eri a ...................................................................4 0
4. 2 
M et h o d of Tr e at m e nt A s si g n m e nt a n d Bli n di n g .....................4 1
4. 3 
St u d y Tr e at m e nt ....................................................................4 4
4. 3. 1 
F or m ul ati o n, P a c k a gi n g a n d H a n dli n g ...................................4 4
4. 3. 1. 1 
S atr ali z u m a b a n d Pl a c e b o .....................................................4 4
4. 3. 2 
D o s a g e, A d mi ni str ati o n a n d C o m pli a n c e ...............................4 5
4. 3. 2. 1 
S atr ali z u m a b a n d Pl a c e b o: D o u bl e -bli n d 
P eri o d ....................................................................................4 5
4. 3. 2. 2 
S atr ali z u m a b: E xt e n si o n P eri o d .............................................4 6
4. 3. 3 
I n v e sti g ati o n al M e di ci n al Pr o d u ct 
A c c o u nt a bilit y .........................................................................4 6
4. 4 
C o n c o mit a nt T h er a p y .............................................................4 8
4. 4. 1 
M aj o r P er mitt e d T h er a pi e s f or N M O ......................................4 8
4. 4. 2 
Pr o hi bit e d T h er a pi e s ..............................................................5 0
4. 5 
St u d y A s s e s s m e nt s ...............................................................5 1
4. 5. 1 
D e s cri pti o n of St u d y A s s e s s m e nt s .........................................5 1
4. 5. 1. 1 
M e di c al Hi st or y a n d D e m o gr a p hi c D at a .................................5 1
4. 5. 1. 2 
H e p atiti s B S cr e e ni n g ............................................................5 1
4. 5. 1. 3 
H e p atiti s C s cr e e ni n g .............................................................5 2


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8/ Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4. 5. 1. 4 
S cr e e ni n g f or T u b er c ul o si s ....................................................5 2
4. 5. 1. 5 
A nti -A Q P 4 A nti b o d y at S cr e e ni n g ..........................................5 2
4. 5. 1. 6 
M a g n eti c R e s o n a n c e I m a gi n g at S cr e e ni n g
..........................5 2
4. 5. 1. 7 
Vit al Si g n s ..............................................................................5 2
4. 5. 1. 8 
P h y si c al E x a mi n ati o n .............................................................5 3
4. 5. 1. 9 
Effi c a c y A s s e s s m e nt s ............................................................5 3
4. 5. 1. 1 0   
C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e ( C -
S S R S) ....................................................................................5 5
4. 5. 1. 1 1 
L a b or at or y A s s e s s m e nt s .......................................................5 6
4. 5. 1. 1 2 
El e ctr o c ar di o gr a m s ................................................................5 9
4. 5. 1. 1 3 
A d v er s e E v e nt s ......................................................................5 9
4. 5. 2 
Ti mi n g of St u d y A s s e s s m e nt s ................................................5 9
4. 5. 2. 1 
S cr e e ni n g A s s e s s m e nt s ........................................................5 9
4. 5. 2. 2 
A s s e s s m e nt s d uri n g Tr e at m e nt .............................................6 0
4. 5. 2. 3 
A s s e s s m e nt s at L a st O b s er v ati o n 
Vi sit/ W it h dr a w al Vi sit..............................................................6 1
4. 5. 2. 4 
S af et y F oll o w -U p A s s e s s m e nt s .............................................6 2
4. 5. 2. 5 
F oll o w -U p A s s e s s m e nt s f or A d ol e s c e nt s ...............................6 2
4. 5. 2. 6 
A s s e s s m e nt s at E xtr a Vi sit s d u e t o R el a p s e ..........................6 2
4. 5. 2. 7 
U n s c h e d ul e d Vi sit s ................................................................6 2
4. 5. 3 
R el a p s e A s s e s s m e nt .............................................................6 3
4. 5. 3. 1 
R el a p s e A s s e s s m e nt Str u ct ur e ..............................................6 3
4. 5. 3. 2 
Pr o c e d ur e f or D et e cti o n of P ot e nti al R el a p s e ........................6 3
4. 5. 3. 3 
R e p orti n g a P ot e nti al R el a p s e t o t h e C E C .............................6 6
4. 5. 3. 4 
Pr ot o c ol -d efi n e d r el a p s e ........................................................6 6
4. 6 
C h u g ai Cli ni c al S a m pl e R e p o sit or y ........................................6 7
4. 6. 1 
S c h e d ul e of A s s e s s m e nt s a n d Pr o c e d ur e s ...........................6 8
4. 6. 1. 1 
St u d y Pr o c e d ur e s ..................................................................6 8
4. 6. 1. 2 
S a m pli n g Pr o c e d ur e s .............................................................6 8
4. 6. 1. 3 
C C S R .....................................................................................6 9
4. 6. 1. 4 
Bi o m ar k er R e s e ar c h A n al y si s Pr ot o c ol ..................................6 9
4. 6. 2  
S a m pl e C o nfi d e nti alit y a n d S a m pl e 
D e str u cti o n .............................................................................6 9
4. 6. 3 
Wi t h dr a w al of P ati e nt s fr o m t h e C C S R Pr oj e ct......................6 9


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9/ Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4. 6. 4 
B e n efit s t o D o n or s .................................................................7 0
4. 7 
P ati e nt, St u d y a n d Sit e Di s c o nti n u ati o n .................................7 0
4. 7. 1 
P ati e nt Di s c o nti n u ati o n ..........................................................7 0
4. 7. 1. 1 
Di s c o nti n u ati o n fr o m St u d y Dr u g ...........................................7 1
4. 7. 1. 2 
Wi t h dr a w al fr o m St u d y...........................................................7 1
4. 7. 2 
St u d y a n d Sit e Di s c o nti n u ati o n ..............................................7 2
4. 8 
A d ol e s c e nt s ...........................................................................7 2
5. 
A S S E S S M E N T O F S A F E T Y .......................................................................7 4
5. 1 
S af et y Pl a n ............................................................................7 4
5. 1. 1 
I m p ort a nt I de ntifi e d a n d P ot e nti al Ri s k s of 
S atr ali z u m a b ..........................................................................7 4
5. 1. 1. 1 
S eri o u s I nf e cti o n ....................................................................7 5
5. 1. 1. 2 
N e utr o p e ni a a n d P ot e nti al Ri s k of I nf e cti o n ...........................7 6
5. 1. 1. 3 
T hr o m b o c yt o p e ni a a n d P ot e nti al Ri s k of 
Bl e e di n g .................................................................................7 7
5. 1. 1. 4 
Li v er E n z y m e a n d Bilir u bi n El e v ati o n s a n d 
P ot e nti al Ri s k of H e p at ot o xi cit y .............................................7 8
5. 1. 1. 5 
El e v at e d Li pi d L e v el s a n d P ot e nti al Ri s k of 
C ar di o v a s c ul ar/ C er e br o v a s c ul ar E v e nt s ................................7 9
5. 1. 1. 6 
I m m u n o g e ni cit y......................................................................7 9
5. 1. 1. 7 
S eri o u s H y p er s e n siti vit y R e a cti o n s ........................................8 0
5. 1. 1. 8 
C Y P 4 5 0 E n z y m e N or m ali z ati o n .............................................8 1
5. 1. 1. 9 
C o m pli c ati o n s of Di v erti c uliti s ................................................8 1
5. 1. 1. 1 0 
M ali g n a n ci e s ..........................................................................8 1
5. 1. 1. 1 1 
D e m y eli n ati n g Di s or d er s ........................................................8 2
5. 1. 1. 1 2 
C o n c o mit a nt M e di c ati o n s .......................................................8 2
5. 2 
S af et y P ar a m et er s a n d D efi niti o n s .........................................8 3
5. 2. 1  
A d v er s e E v e nt s ......................................................................8 3
5. 2. 2 
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 t h e S p o n s or) ....................................................8 3
5. 2. 3 
N o n -s eri o u s 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 t h e 
S p o n s or) ................................................................................8 4
5. 2. 4 
S el e ct e d A d v er s e E v e nt s .......................................................8 4


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 3 
M et h o d s a n d Ti mi n g f or C a pt uri n g a n d 
A s s e s si n g S af et y P ar a m et er s ................................................8 5
5. 3. 1 
A d v er s e E v e nt R e p orti n g P eri o d ............................................8 5
5. 3. 2 
Eli citi n g A d v er s e E v e nt I nf or m ati o n .......................................8 6
5. 3. 3 
A s s e s s m e nt of S e v erit y of A d v er s e E v e nt s ...........................8 6
5. 3. 4 
A s s e s s m e nt of C a u s alit y of A d v er s e E v e nt s ..........................8 6
5. 3. 5 
Pr o c e d ur e s f or R e c or di n g A d v er s e E v e nt s ............................8 7
5. 3. 5. 1 
Di a g n o si s v er s u s Si g n s a n d S y m pt o m s .................................8 7
5. 3. 5. 2 
A d v er s e E v e nt s O c c urri n g S e c o n d ar y t o Ot h er 
E v e nt s ....................................................................................8 7
5. 3. 5. 3 
P er si st e nt or R e c urr e nt A d v er s e E v e nt s ................................8 8
5. 3. 5. 4 
A b n or m al L a b or at or y V al u e s .................................................8 8
5. 3. 5. 5 
A b n or m al Vit al Si g n V al u e s ...................................................8 9
5. 3. 5. 6 
A b n or m al Li v er F u n cti o n T e st s ..............................................9 0
5. 3. 5. 7 
D e at h s ...................................................................................9 0
5. 3. 5. 8 
Pr e e xi sti n g M e di c al C o n diti o n s ..............................................9 1
5. 3. 5. 9 
L a c k of Effi c a c y or W or s e ni n g of N M O ..................................9 1
5. 3. 5. 1 0 
H o s pit ali z ati o n or Pr ol o n g e d H o s pit ali z ati o n ..........................9 1
5. 3. 5. 1 1 
O v er d o s e s .............................................................................9 2
5. 4 
I m m e di at e R e p orti n g R e q uir e m e nt s fr o m 
I n v e sti g at or t o S p o n s or..........................................................9 2
5. 4. 1 
E m er g e n c y M e di c al C o nt a ct s ................................................9 3
5. 4. 2 
R e p orti n g R e q uir e m e nt s f or S eri o u s A d v er s e 
E v e nt s a n d N o n -s eri o u s A d v er s e E v e nt s of 
S p e ci al I nt er e st ......................................................................9 3
5. 4. 3 
R e p orti n g R e q uir e m e nt s f or Pr e g n a n ci e s ..............................9 3
5. 4. 3. 1 
Pr e g n a n ci e s i n F e m al e P ati e nt s ............................................9 3
5. 4. 3. 2 
Pr e g n a n ci e s i n F e m al e P art n er s of M al e 
P ati e nt s ..................................................................................9 4
5. 4. 3. 3 
A b orti o n s ................................................................................9 4
5. 4. 3. 4 
C o n g e nit al A n o m ali e s/ Birt h D ef e ct s .......................................9 4
5. 4. 4 
R e p orti n g R e q uir e m e nt s f or M e di c al D e vi c e 
C o m pl ai nt s .............................................................................9 5
5. 5 
F oll o w - U p of P ati e nt s aft er A d v er s e E v e nt s ...........................9 5
5. 5. 1 
I n v e sti g at or F oll o w-U p ...........................................................9 5


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 6 
P o st - St u d y A d v er s e E v e nt s ...................................................9 5
5. 7 
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 .................................................................9 6
6. 
S T A TI S TI C A L C O N SI D E R A TI O N S A N D A N A L Y SI S P L A N .......................9 6
6. 1 
A n al y si s P o p ul ati o n s ..............................................................9 6
6. 1. 1  
Effi c a c y A n al y si s P o p ul ati o n s ................................................9 6
6. 1. 2 
All -P ati e nt s -Tr e at e d P o p ul ati o n .............................................9 7
6. 1. 3 
S af et y A n al y si s P o p ul ati o n s ...................................................9 7
6. 1. 4 
P h ar m a c o ki n eti c s P er -Pr ot o c ol S et a n d 
P h ar m a c o d y n a mi c s A n al y si s P o p ul ati o n ...............................9 7
6. 1. 5 
A n al y si s p o p ul ati o n f or a d ol e s c e nt s .......................................9 7
6. 2 
D et er mi n ati o n of S a m pl e Si z e ...............................................9 7
6. 3 
S u m m ari e s of C o n d u ct of St u d y ............................................9 9
6. 4 
S u m m ari e s of Tr e at m e nt Gr o u p C o m p ar a bilit y ......................9 9
6. 5 
Effi c a c y A n al y s e s ...................................................................9 9
6. 5. 1 
Pri m ar y Effi c a c y E n d p oi nt ......................................................9 9
6. 5. 2 
S e c o n d ar y Effi c a c y E n d p oi nt s .............................................1 0 0
6. 5. 3 
F urt h er A n al y si s ...................................................................1 0 4
6. 5. 3. 1 
S e n siti vit y A n al y si s f or Pri m ar y E n d p oi nt .............................1 0 4
6. 5. 3. 2 
S e n siti vit y A n al y si s f or K e y S e c o n d ar y 
E n d p oi nt ...............................................................................1 0 4
6. 5. 3. 3 
S u b gr o u p A n al y si s ...............................................................1 0 4
6. 6 
S af et y A n al y s e s ...................................................................1 0 5
6. 7 
P h ar m a c o ki n eti c /P h ar m a c o d y n a mi c s A n al y s e s ..................1 0 6
6. 8 
I m m u n o g e ni cit y....................................................................1 0 7
6. 9 
H a n dli n g Mi s si n g D at a .........................................................1 0 7
7. 
D A T A C O L L E C TI O N A N D M A N A G E M E N T ..............................................1 0 8
7. 1 
D at a Q u alit y A s s ur a n c e .......................................................1 0 8
7. 2 
El e ctr o ni c C a s e R e p ort F or m s .............................................1 0 8
7. 3 
S o ur c e D at a D o c u m e nt ati o n ................................................1 0 8
7. 4 
U s e of C o m p ut eri z e d S y st e m s .............................................1 0 9
7. 5 
R et e nti o n of R e c or d s ...........................................................1 0 9


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
8. 
E T HI C A L C O N SI D E R A TI O N S ..................................................................1 1 0
8. 1 
C o m pli a n c e wit h L a w s a n d R e g ul ati o n s ..............................1 1 0
8. 2 
I nf or m e d C o n s e nt ................................................................1 1 0
8. 3 
I n stit uti o n al R e vi e w B o ar d or I n d e p e n d e nt 
Et hi c s C o m mitt e e .................................................................1 1 1
8. 4 
C o nfi d e nti alit y ......................................................................1 1 1
8. 5 
Fi n a n ci a l Di s cl o s ur e.............................................................1 1 2
9. 
S T U D Y D O C U M E N T A TI O N, M O NI T O RI N G, A N D 
A D MI NI S T R A TI O N ....................................................................................1 1 2
9. 1 
St u d y D o c u m e nt ati o n ...........................................................1 1 2
9. 2 
Sit e I n s p e cti o n s....................................................................1 1 2
9. 3 
A d mi ni str ati v e Str u ct ur e .......................................................1 1 3
9. 4 
P u bli c ati o n of D at a a n d Pr ot e cti o n of Tr a d e 
S e cr et s .................................................................................1 1 3
9. 5 
Pr ot o c ol A m e n d m e nt s ..........................................................1 1 3
1 0.
R E F E R E N C E S ..........................................................................................1 1 4
LI S T O F T A B L E S
T a bl e 1: 
M a xi m u m Bl o o d V ol u m e s ............................................................5 8
T a bl e 2: 
N e utr o p e ni a Ri s k Miti g ati o n ........................................................7 7
T a bl e 3: 
T hr o m b o c yt o p e ni a Ri s k Miti g ati o n ..............................................7 7
T a bl e 4: 
H e p ati c E n z y m e Ri s k Miti g ati o n ..................................................7 8
T a bl e 5: 
A d v er s e E v e nt S e v erit y Gr a di n g .................................................8 6
T a bl e 6: 
O b s er v ati o n a n d T e st S c h e d ul e i n t h e S cr e e ni n g P eri o d 
a n d t h e D o u bl e -Bli n d P eri o d .....................................................1 1 7
T a bl e 7: 
O b s er v ati o n a n d T e st S c h e d ul e i n t h e E xt e n si o n P eri o d ..........1 2 3
LI S T O F FI G U R E S
Fi g ur e 1: 
St u d y D e si g n ...............................................................................3 3
Fi g ur e 2 
A s s e s s m e n t of a R el a p s e............................................................6 5


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
LI S T O F A P P E N DI C E S
A p p e n di x 1 
S c h e d ul e of A s s e s s m e nt s .........................................................1 1 7
A p p e n di x 2 
E D S S/ F S S A s s e s s m e nt F or m ...................................................1 2 7
A p p e n di x 3 
S F -3 6 Q u e sti o n n air e .................................................................1 3 2
A p p e n di x 4 
Vi s u al A n al o g u e S c al e f or P ai n .................................................1 3 3
A p p e n di x 5 
F A CI T – F ati g u e S c al e ..............................................................1 3 4
A p p e n di x 6 
M o difi e d R a n ki n S c al e ...............................................................1 3 5
A p p e n di x 7  
Z arit B ur d e n I nt er vi e w ...............................................................1 3 6
A p p e n di x 8 
E ur o Q ol -5 D ( E Q -5 D) .................................................................1 3 8
A p p e n di x 9 
C C S R S u bj e ct Wi t h dr a w al F or m...............................................1 4 1
A p p e n di x 1 0 
C- S S R S at B a s eli n e ..................................................................1 4 3
A p p e n di x 1 1 
C- S S R S si n c e L a st Vi sit ............................................................1 4 6
A p p e n di x 1 2 
C- S S R S Alr e a d y E nr oll e d S u bj e ct s ...........................................1 4 9
A p p e n di x 1 3 
T h e G ui d a n c e f or Bl o o d S a m pli n g ............................................1 5 2
A p p e n di x 1 4 
I n str u cti o n f or T u b er c ul o si s ( T B) S cr e e ni n g a n d Tr e at m e nt ......1 5 4


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), 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 M U L TI C E N T E R, R A N D O MI Z E D, A D DI TI O N T O 
B A S E LI N E T R E A T M E N T, D O U B L E -B LI N D, 
P L A C E B O -C O N T R O L L E D, P H A S E 3 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 
S A T R A LI Z U M A B ( S A 2 3 7) I N P ATI E N T S WI T H 
N E U R O M Y E LI TI S O P TI C A ( N M O) A N D N M O 
S P E C T R U M DI S O R D E R ( N M O S D)
P R O T O C O L N U M B E R: 
B N 4 0 8 9 8 ( S A -3 0 7 J G)
V E R SI O N N U M B E R: 
1 1
E U D R A C T N U M B E R: 
2 0 1 3 -0 0 3 7 5 2 -2 1
I N D N U M B E R: 
1 1 8 1 8 3
T E S T P R O D U C T: 
S atr ali z u m a b ( S A 2 3 7 ) ( R O 5 3 3 3 7 8 7)
M E DI C A L M O NI T O R:
, M. D.
C O -S P O N S O R S : 
F. H off m a n n -L a R o c h e Lt d
C h u g ai P h ar m a c e uti c al C o. 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 a s i n str u ct e d b y y o ur l o c al st u d y m o nit or.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
P R O T O C O L S Y N O P SI S
TI T L E:
A M U L TI C E N T E R, R A N D O MI Z E D, A D DI TI O N T O B A S E LI N E 
T R E A T M E N T, D O U B L E -B L I N D, P LA C E B O -C O N T R O L L E D, 
P H A S E 3 S T U D Y T O E V A L U A T E  T H E E F FI C AC Y A N D S A F E T Y 
O F S A T R A LI Z U M A B ( S A 2 3 7 ) I N P ATI E N T S WI T H 
N E U R O M Y E LI TI S O P TI C A ( N M O) AN D N M O S P E C T R U M 
DI S O R D E R ( N M O S D)
P R O T O C O L N U M B E R: 
B N 4 0 8 9 8 ( S A -3 0 7 J G)
V E R SI O N N U M B E R: 
1 1
E U D R A C T  N U M B E R: 
2 0 1 3 -0 0 3 7 5 2 -2 1
I N D N U M B E R:
1 1 8 1 8 3
T E S T P R O D U C T: 
S atr ali z u m a b ( S A 2 3 7 ) ( R O 5 3 3 3 7 8 7)
P H A S E:
III
I N DI CA T I O N:
N e ur o m y eliti s o pti c a a n d n e ur o m y e liti s o pti c a s p e ctr u m di s or d er
C O -S P O N S O R S: 
F. H off m a n n -L a R o c h e Lt d
C h u g ai P h ar m a c e uti c al C o. Lt d.
O bj e cti v e s
Effi c a c y O bj e cti v e
T h e effi c a c y o bj e cti v e f or t hi s st u d y  i s a s f oll o w s:
 
T o e v al u at e t h e effi c a c y of s atr ali z u m a b ( al s o k n o w n a s S A 2 3 7 ) c o m p ar e d wit h pl a c e b o 
i n p ati e nt s wit h n e ur o my e liti s o pti c a ( N M O) a n d N M O s p e ctr u m di s or d er ( N M O S D) .
S af et y O bj e cti v e
T h e s af et y  o bj e cti v e f or t hi s st u d y i s a s f oll o w s:
 
T o e v al u at e t h e s af et y of s atr ali z u m a b c o m p ar e d wit h pl a c e b o i n p ati e nt s wit h N M O a n d 
N M O S D.
E x pl or at or y O bj e cti 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 x a mi n e t h e p h ar m a c o ki n eti c s, p h ar m a c o d y n a mi c s a n d i m m u n o g e ni cit y of 
s atr ali z u m a b .
 
T o e v al u at e eff e ct o n p ai n of s atr ali z u m a b c o m p ar e d t o pl a c e b o i n p ati e nt s wit h 
N M O/ N M O S D , i n a d diti o n t o t h e effi c a c y o bj e cti v e of t hi s st u d y s h o w n a b o v e ( T hi s i s 
o pti o n al a n d will b e c o n d u ct e d at s el e ct e d sit e s).
St u d y D e si g n
D e s cri pti o n of St u d y
T hi s i s a m ulti c e nt er, r a n d o mi z e d, a d diti o n -t o-b a s eli n e tr e at m e nt, d o u bl e -bli n d, 
pl a c e b o -c o ntr oll e d, p ar all el a s si g n m e nt st u d y f oll o w e d b y a n o p e n -l a b el e xt e n si o n p eri o d. 
P ati e nt s will b e r a n d o mi z e d t o eit h er s atr ali z u m a b 1 2 0 m g  ( Gr o u p A) or pl a c e b o ( Gr o u p B). 
Bli n d e d st u d y dr u g will b e a d mi ni st er e d s u b c ut a n e o u sl y ( S C) at W e e k s 0, 2 a n d 4, a n d 
t h er e aft er e v ery 4 w e e k s ( Q 4 W)  i n c o mbi n ati o n wit h o n e of t h e f oll o wi n g b a s eli n e tr e at m e nt s: 




S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
I n cl u si o n Crit eri a
P ati e 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:
1. 
P at i e nt s m u st b e di a g n o s e d a s h a vi n g eit h er:
a. 
N M O a s d efi n e d b y 2 0 0 6 crit eri a*, or
b. 
N M O S D a s d efi n e d b y eit h er of t h e f oll o wi n g Wi n g er c h u k 2 0 0 7 crit eri a wit h 
a nti -a q u a p ori n 4 a nti b o d y ( A Q P 4 A b) s er o p o siti v e st at u s at s cr e e ni n g ‡ .
i) 
I di o p at hi c si n gl e or r e c urr e nt e v e nt s of l o n git u di n all y e xt e n si v e m y e liti s 
(≥3 v ert e br al s e g m e nt 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] l e si o n)
ii) 
O pti c n e uriti s : r e c urr e nt or si m ult a n e o u s bil at er al
F or p ati e nt s a g e d 1 2 t o 1 7 y e ar s, a mi ni m u m of 4 p ati e nt s s h o ul d b e p o siti v e f or 
a nt i-A Q P 4 A b st at u s at s cr e e ni n g ‡ .
‡ S cr e e ni n g r e s ult i s b a s e d o n eit h er t h e bl o o d s a m pl e d at a c oll e ct e d at s cr e e ni n g vi sit, or t h e 
bl o o d s a m pl e d at a c oll e ct e d b ef or e t h e s cr e e ni n g vi sit a n d m e a s ur e d b y S p o n s or’ s d e si g n e e 
f or a n al ysi s ( s e e S e cti o n 4. 5. 1. 5 ).
2. 
Cli ni c al e vi d e n c e of at l e a st 2 d o c u m e nt e d r el a p s e s (i n cl u di n g fir st att a c k) i n t h e l a st 
2 y e ar s pri or t o s cr e e ni n g, at l e a st o n e of w hi c h h a s o c c urr e d i n t h e 1 2 m o nt h s pri or t o 
s cr e e ni n g.
3. 
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) s c or e fr o m 0 t o 6. 5 i n cl u si v e at s cr e e ni n g.
4. 
A g e 1 2 t o 7 4 y e ar s, i n cl u si v e at t h e ti m e of i nf or m e d c o n s e nt.
5. 
O n e of t h e f oll o wi n g b a s eli n e tr e at m e nt s m u st b e at st a bl e d o s e a s a m o n ot h er a p y f or 8 
w e e k s pri or t o b a s eli n e **:
a. 
A z at hi o pri n e.
b. 
M y c o p h e n ol at e m of etil.
c. 
Or al c orti c o st er oi d s.
** F or p ati e nt s a g e d 1 2 t o 1 7 y e ar s, eit h er of t h e f oll o wi n g b a s eli n e tr e at m e nt s f or r el a p s e
pr e v e nti o n c a n b e all o w e d:
d. 
A z at hi o pri n e + o r al c orti c o st er oi d s.
e. 
M y c o p h e n ol at e m of etil + o r al c orti c o st er oi d s.
6. 
A bilit y a n d willi n g n e s s 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 c o m pl y wit h t h e 
r e q uir e m e nt s of t h e pr ot o c ol.
* A c c or di n g t o W i n g er c h u k et al. 2 0 0 6, a di a g n o si s of N M O r e q uir e s all of t h e f oll o wi n g t hr e e 
crit eri a :
I. 
O pti c n e uriti s
II. 
A c ut e m y eliti s
III. 
At l e a st t w o of t hr e e s u p p orti v e crit eri a:
 
C o nti g u o u s s pi n al c or d l e si o n i d e ntifi e d o n a n M RI s c a n e xt e n di n g o v er 
3 v ert e br al s e g m e nt s
 
Br ai n M RI n ot m e eti n g di a g n o sti c crit eri a f or m ulti pl e s cl er o si s
 
N M O -i m m u n o gl o b uli n G s er o p o siti v e st at u s
E x cl u si o n Crit eri a
P ati e 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:
E x cl u si o n crit eri a r el at e d t o pr e vi o u s or c o n c o mit a nt t h er a p y:
1. 
A n y p r e vi o u s tr e at m e nt wit h i nt erl e u ki n-6 ( I L- 6) i n hi bit or y t h er a p y ( e. g., t o cili z u m a b), 
al e m t u z u ma b, 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 at a n y ti m e.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
2. 
A n y pr e vi o u s tr e at m e nt wit h a nti -cl u st er of diff er e nti ati o n ( C D) 2 0 , e c uli z u m a b, 
b eli m u m a b, i nt erf er o n, n at ali z u m a b, gl atir a m er a c et at e, fi n g oli m o d, t erifl u n o mi d e or
di m et h yl f u m ar at e wi t hi n 6 m o nt h s pri or t o b a s eli n e.
3. 
A n y pr e vi o u s tr e at m e nt wit h a nti -C D 4, cl a dri bi n e or mi t o x a ntr o n e wit hi n 2 y e ar s pri or t o 
b a s eli n e .
4. 
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 3 m o nt h s pri or t o b a s eli n e .
E x cl u si o n s f or g e n er al s af et y:
5. 
Pr e g n a n c y or l a ct ati o n .
6. 
F or p ati e nt s of r e pr o d u ct i v e p ot e nti al, a p o siti v e r e s ult fr o m a s er u m pr e g n a n c y t e st at 
s cr e e ni n g, or n ot willi n g t o u s e r eli a bl e m e a n s of c o ntr a c e pti o n (p h y si c al b arri er [p ati e nt 
or p art n er ], i n c o nj u n cti o n wit h a s p er mi ci d al pr o d u ct, c o ntr a c e pti v e pill , p at c h, i nj e ct a bl e s, 
i ntra ut eri n e d e vi c e or i ntr a ut eri n e s y st e m ) d uri n g t h e tr e at m e nt p eri o d a n d f or at l e a st 3 
m o nt h s aft er t h e l a st d o s e of st u d y dr u g .
7. 
A n y s ur gi c al pr o c e d ur e ( e x c e pt f or mi n or s ur g eri e s) w it hi n 4 w e e k s pri or t o b a s eli n e.
8. 
E vi d e n c e of ot h er d e m y e li n ati n g di s e a s e 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
( P M L).
9. 
E vi d e n c e of s eri o u s u n c o ntr oll e d c o n c o mit a nt di s e a s e s t h at m a y pr e cl u d e p ati e nt 
p arti ci p ati o n, s u c h a s:
o t h er n er v o u s s y st e m di s e a s e, c ar di o v a s c ul ar di s e a s e, h e m at ol o gi c/ h e m at o p oi e si s 
di s e a s e, r e s pir at or y di s e a s e, m u s c ul ar di s e a s e, e n d o cri n e di s e a s e, r e n al/ ur ol o gi c 
di s e a s e, di g e sti v e s y st e m di s e a s e, c o n g e nit al or a c q uir e d s e v er e i m m u n o d efi ci e n c y .
1 0. K n o w n a cti v e i nf e cti o n ( e x cl u di n g f u n g al i nf e cti o n s of n ail b e d s or c a ri e s d e nti u m) wit hi n 
4 w e e k s pri or t o b a s eli n e .
1 1. E vi d e n c e of c hr o ni c a cti v e h e p atiti s B or C .
1 2. Hi st or y of dr u g or al c o h ol a b u s e wit hi n 1 y e ar pri or t o b a s eli n e .
1 3. Hi st or y of di v erti c uliti s t h at , i n t h e I n v e sti g at or’ s o pi ni o n, m a y l e a d t o i n cr e a s e d ri s k of 
c o m pli c ati o n s s u c h a s l o w er g a str oi nt e sti n al p erf or ati o n .
1 4. E vi d e n c e of a cti v e t u b er c ul o si s ( T B; e x cl u di n g p ati e nt s r e c ei vi n g c h e m o pr o p h yl a xi s f or 
lat e nt T B i nf e cti o n).
1 5. E vi d e n c e of a cti v e i nt er stiti al l u n g di s e a s e .
1 6. R e c ei pt of a n y li v e or li v e att e n u at e d v a c c i n e wit hi n 6 w e e k s pri or t o b a s eli n e.
1 7. Hi st or y of m ali g n a n c y wit hi n t h e l a st 5 y e ar s, i n cl u di n g s oli d t u m or s, h e m at ol o gi c 
m a li g n a n ci e s a n d i n sit u c ar ci n o m a ( e x c e pt b a s al c ell a n d 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, or i n sit u c ar ci n o m a of t h e c er vi x ut eri t h at h a v e b e e n c o m pl et el y e x ci s e d a n d 
c ur e d) .
1 8. Hi st or y of s e v er e all er gi c r e a cti o n t o a bi ol o gi c a g e nt ( e. g. , s h o c k, a n a p h yl a cti c r e a cti o n s ).
1 9. A cti v e s ui ci d al i d e ati o n wit hi n 6 m o nt h s pri or t o s cr e e ni n g, or hi st or y of s ui ci d e att e m pt 
wit hi n 3 y e ar s pri or t o s cr e e ni n g .
L a b or at or y e x cl u si o n crit eri a ( at s cr e e ni n g):
2 0. F oll o wi n g l a b or at or y a b n or m aliti e s at s cr e e ni n g *.
a. 
W h it e bl o o d c ell s < 3 . 0 x 1 03 / μ L
b. 
A b s ol ut e n e utr o p hil c o u nt < 2. 0 x 1 0 3 / μ L
c. 
A b s ol ut e l y m p h o c yt e c o u nt < 0. 5 x 1 0 3 / μ L
d. 
Pl at el et c o u nt < 1 0 x 1 0 4 / μ L
e. 
A s p art at e a mi n otr a n sf er a s e or al a ni n e a mi n otr a n s f er a s e > 1. 5 ti m e s t h e u p p er li mit of 
n or m al .
* If r et e st i s c o n d u ct e d, t h e l a st v al u e of r et e st 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.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
L e n gt h of St u d y
E n d of St u d y ( D o u bl e -bli n d P eri o d)
T h e e n d of d o u bl e -bli n d p eri o d i s d efi n e d a s t h e d at e of pri m ar y  a n al y si s w h e n t ot al n u m b er 
of pr ot o c ol -d efi n e d r el a p s e s j u d g e d b y C E C r e a c h e s 2 6. T h e d ur ati o n i s e sti m at e d t o b e 
a p pr o xi m at el y 3 0 m o nt h s fr o m fir st p ati e nt i n ( F PI) .
E n d of St u d y ( E xt e n si o n P eri o d )
T h e e xt e n si o n p eri o d i s e x p e ct e d t o l a st u ntil L a st O b s er v ati o n Vi sit .
St u d y E n d p oi nt s/ O ut c o m e M e a s ur e s
Pri m ar y E n d p oi nt
i. 
Ti m e  t o fir st pr ot o c ol -d efi n e d r el a p s e ( T F R) i n t h e d o u bl e-bli n d p eri o d
S e c o n d ar y E n d p oi nt s
i. 
C h a n g e i n Vi s u al A n al o g u e S c al e ( V A S) s c or e f or p ai n 
ii. 
C h a n g e i n F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s T h er a p y ( F A CI T) F ati g u e s c or e
iii. 
C h a n g e i n S h ort F or m G e n eri c H e alt h S ur v e y ( S F-3 6) s c or e
i v. 
C h a n g e i n E Q -5 D s c or e
v. 
T h e pr o p orti o n of r el a p s e -fr e e p ati e nt s
vi. 
A R R
vii. 
C h a n g e i n m o difi e d R a n ki n S c al e ( m R S) s c or e
viii. 
C h a n g e i n Z arit B ur d e n I nt er vi e w ( Z BI) s c or e
i x. 
C h a n g e i n E D S S s c or e
x. 
C h a n g e i n vi s u al a c uit y ( S n ell e n c h art)
S af et y A s s e s s m e nt s
I n ci d e n c e a n d s e v erit y of a d v er s e e v e nt s ( A E s) , s eri o u s A E s ( S A E s), A E s of s p e ci al i nt er e st 
( A ESI s ), a n d s el e ct e d A E s .
Vit al si g n s (t e m p er at ur e, s y st oli c a n d di a st oli c bl o o d pr e s s ur e, a n d p ul s e r at e), p h y si c al
e x a mi n ati o n s , cli ni c al 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 ysi s), 1 2 -l e a d 
el e ctr o c ar di o gr a m , s ui ci d alit y ( C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e [ C-S S R S] ).
P h ar m a c o d y n a mi c E n d p oi nt s
I L-6, s ol u bl e I L -6 r e c e pt or , hi g h -s e n siti vit y C -r e a cti v e pr ot ei n, a nti-A Q P 4 a nti b o di e s a n d 
pl a s m a bl a st s.
P h ar m a c o ki n eti c E n d p oi nt s
S er u m s atr ali z u m a b c o n c e ntr ati o n.
I m m u n o g e ni cit y E n d p oi nt s
I n ci d e n c e of a nti-dr u g a nti b o di e s .
P K, P D, cli ni c al r e s p o n s e a n d s af et y d uri n g t h e st u d y b y a nti -dr u g a nti b o d y st at u s .
E x pl or at or y E n d p oi nt
A d diti o n al p ai n a s s e s s m e nt.
A d diti o n al p ai n a s s e s s m e nt i s o pti o n al a n d will b e c o n d u ct e d at s el e ct e d sit e s ( s e e t h e 
d et ail s i n t h e pr o c e d ur e f or a d diti o n al p ai n a s s e s s m e n t).
I n v e sti g ati o n al M e di ci n al Pr o d u ct s
T hr o u g h o ut t hi s pr ot o c ol, ‘ st u d y dr u g’ r ef er s t o s atr ali z u m a b or pl a c e b o.
T e st Pr o d u ct (D o u bl e -bli n d P eri o d)
S atr ali z u m a b 1 2 0 m g/ m L
D o s e a n d M o d e of A d mi ni str ati o n: 1 2 0 m g  S C at We e k s 0, 2 a n d 4, a n d Q 4 W  t h er e aft er.
C o m p ar at or (D o u bl e -bli n d P eri o d)
Si n gl e d o s e of p l a c e b o S C at W e e k s 0, 2 a n d 4 , a n d Q 4 W t h er e aft er.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T e st Pr o d u ct ( E xt e n si o n P eri o d )
S atr ali z u m a b 1 2 0 m g/ m L
D o s e a n d M o d e of A d mi ni str ati o n: 1 2 0 m g  S C at We e k s 0, 2 a n d 4 , a n d Q 4 W  t h er e aft er, 
wit h t he l ast st u d y dr u g a d mi nistr ati o n o n or bef ore 3 1
De ce m ber
2 0 2 1 .
N o n -I n v e sti g ati o n al M e di ci n al Pr o d u ct s
I n t h e d o u bl e-bli n d p eri o d, i n a d diti o n t o s atr ali z u m a b or pl a c e b o, p ati e nt s will r e c ei v e 
b a s eli n e tr e at m e nt wit h a z at hi o pri n e, m y c o p h e n ol at e m of etil or or al c orti c o st er oi d s at a 
st a bl e d o s e n ot e x c e e di n g: 
 
A z at hi o pri n e *: 3 m g/ k g/ d a y
 
M y c o p h e n ol at e m of etil *: 3 0 0 0 m g/ d a y
 
Or al c orti c o st er oi d s: 1 5 m g/ d a y ( pr e d ni s ol o n e e q ui v al e nt) .
* C o m bi n ati o n wit h or al c orti c o st er oi d s ( 1 5 m g/ d a y [ pr e d ni s o l o n e e q ui v al e nt]) i s p er mitt e d 
i n p ati e nt s a g e d 1 2 t o 1 7 y e ar s at t h e ti m e of i nf or m e d c o n s e nt.
I n t h e d o u bl e-bli n d p eri o d, a d o s e d e cr e a s e i s p er mitt e d o nl y f or s af et y r e a s o n s. D o s e 
i n cr e a s e or ch a n g e of b a s eli n e tr e at m e nt i s n ot p er mitt e d.
I n t h e e xt e n si o n p eri o d, p ati e nt s will r e c ei v e s atr ali z u m a b wit h or wit h o ut b a s eli n e tr e at m e nt s. 
C h a n g e or di s c o nti n u ati o n of b a s eli n e tr e at m e nt i s p er mitt e d.
St ati sti c al M et h o d s
Pri m ar y A n al y si s
A str atifi e d t w o -si d e d l o g -r a n k t e st u si n g str at a of b a s eli n e A R R a n d g e o gr a p hi c al r e gi o n will 
b e u s e d. T h e K a pl a n -M ei er m et h o d will b e u s e d t o e sti m at e t h e T F R di stri b uti o n f or e a c h 
tr e at m e nt gr o u p. T h e m e di a n T F R i s n ot e x p e ct e d t o b e r e a c h e d i n t hi s st u d y at t h e ti m e of 
t h e pri m ar y a n al y si s; h e n c e r el a p s e-fr e e r at e s a n d th eir 9 5 % c o nfi d e n c e i nt er v al ( CI) will b e 
u s e d e v er y 6 m o nt h s t o d e s cri b e T F R di stri b uti o n i n a d diti o n t o t h e h a z ar d r ati o.
D et er mi n ati o n of S a m pl e Si z e
T h e s a m pl e si z e c o n si d er ati o n s ar e b a s e d o n t h e f oll o wi n g a s s u m pti o n s: ( 1) a t w o -si d e d l o g -
r a n k t e st; (2) 8 0 % p o w er at t h e 5 % si g nifi c a n c e l e v el; ( 3) a 6 6. 5 % r e d u cti o n i n t h e ri s k of 
r el a p s e, i. e., t h e T F R h a z ar d r ati o of s atr ali z u m a b o v er pl a c e b o i s 0. 3 3 5; ( 4) T F R i n t h e 
pl a c e b o ar m f oll o wi n g a n e x p o n e nti al di stri b uti o n, wit h h a z ar d r at e ( h[t]) 0. 4 1 8 4; ( 5) a 2 -y e ar 
dr o p o ut r at e of 1 0 %.
B a s e d o n t h e s e a s s u m pti o n s, 2 6 C E C -c o nfir m e d T F R e v e nt s ar e n e e d e d f or t h e pri m ar y  
a n al y si s. T h e m a xi m u m a c cr u al r at e will b e a p pr o xi m at el y 8 p ati e nt s p er m o nt h, aft er t h e F PI 
pl u s 8 m o nt h s of r a m p u p. T h e 7 0 p ati e nt s e nr ol l e d o v er 1 y e ar a n d f oll o w e d f or a n a d diti o n al 
o n e a n d a h alf y e ar s will pr o vi d e 2 6 T F R e v e nt s. 
A d ol e s c e nt s i n th e S t u d y
St u d y D e si g n f or A d ol e s c e nt s
A d ol e s c e nt s (p ati e nt s fr o m 1 2 t o 1 7 y e ar s ol d wit h N M O / N M O S D) will f oll o w t h e a b o v e St u d y 
D e si g n a n d will b e r a n d o mi z e d i nt o t h e d o u bl e -bli n d p eri o d of t h e st u d y . Aft er t h e t ot al 
n u m b er of pr ot o c ol -d efi n e d r el a p s e s j u d g e d b y t h e C E C r e a c h e s 2 6 , a d ol e s c e nt s m a y b e 
e nr oll e d i nt o t h e e xt e n si o n p eri o d if 8 a d ol e s c e nt s ar e n ot e nr oll e d i nt o t h e d o u bl e -bli n d 
p e ri o d.
S p e cifi c O bj e cti v e f or t h e Gr o u p of Ad ol e s c e nt s
T h e o bj e cti v e f or a d ol e s c e nt s w h o ar e e nr oll e d i n t o t hi s st u d y (d o u bl e -bli n d p eri o d or 
e xt e n si o n p eri o d) i s a s f oll o w s:
 
T o e v al u at e t h e s af et y, t ol er a bilit y, effi c a c y , p h ar m a c o ki n eti c s , p h ar m a c o d y n a mi c s a n d 
i m m u n o g e ni cit y of s atr ali z u m a b i n a d ol e s c e nt s.
T ar g et P o p ul ati o n f or A d ol e s c e nt s
T h e i n cl u si o n a n d e x cl u si o n crit eri a f or a d ol e s c e nt s w h o will b e e nr oll e d i nt o t h e d o u bl e -bli n d 
p eri o d ar e s h o w n a b o v e. F or a d ol e s c e nt s w h o m a y  b e e nr oll e d i nt o t h e e xt en si o n p eri o d 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
aft er t h e e n d of t h e d o u bl e -bli n d p eri o d, t h e i n cl u si o n crit eri o n 2 a n d t h e a n n ot ati o n “*” i n t h e 
e x cl u si o n crit eri o n 2 0 ar e a s f oll o w s ( ot h er crit eri a ar e s a m e):
I n cl u si o n Crit erio n 2
2. 
Cli ni c al e vi d e n c e of at l e a st 2 d o c u m e nt e d r el a p s e s (i n cl u di n g fir st att a c k) pri or t o 
s cr e e ni n g.
T h e A n n ot ati o n “*” i n t h e E x cl u si o n C rit eri o n 2 0
* If r et e st i s c o n d u ct e d, t h e l a st v al u e of r et e st b ef or e b a s eli n e m u st m e et st u d y crit eri a.
S p e cifi c O ut c o m e M e a s ur e s ( E n d p oi nt s ) f or t h e Gr o u p of Ad ol e s c e nt s
T h e o ut c o m e m e a s ur e s ( e n d p oi nt s) f or a d ol e s c e nt s w h o ar e e nr oll e d i n t o t hi s st u d y (d o u bl e -
bli n d p eri o d or e xt e n si o n p eri o d) ar e a s f oll o w s :
Pri m ar y  O ut c o m e M e a s ur e s (E n d p oi nt s)
 
S af et y a s s e s s m e nt s
– 
I n ci d e n c e a n d s e v erit y of A E s, A E SI s, S A E a n d s el e ct e d A E s
– 
Vit al si g n s (t e m p er at ur e, s y st oli c a n d di a st oli c bl o o d pr e s s ur e a n d p ul s e r at e), 
p h y si c al e x a mi n ati o n s, cli ni c al 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), 1 2 l e a d E C G s, s ui ci d alit y ( C - S S R S)
 
P K, P D a n d i m m u n o g e ni cit y
S e c o n d ar y O ut c o m e M e a s ur e s (E n d p oi nt s )
 
Ti m e  t o fir st pr ot o c ol-d efi n e d r el a p s e ( T F R)
 
A R R
 
C h a n g e i n E D S S s c or e
 
C h a n g e i n vi s u al a c uit y ( S n ell e n c h art)
 
C h a n g e i n S F -3 6 s c or e
 
C h a n g e i n V A S s c or e f or p ai n
 
C h a n g e i n F A CI T F ati g u e s c or e
 
C h a n g e i n E Q -5 D s c or e
 
C h a n g e i n m R S s c or e
 
C h a n g e i n Z BI s c or e
St ati sti c al M et h o d s:
S u m m ar y  st ati sti c s will b e pr o vi d e d f or all s af et y a n d effi c a c y o ut c o m e m e a s ur e s. O ut c o m e 
m e a s ur e s will b e r e p ort e d f or all a d ol e s c e nt s w h o ar e e nr oll e d i n t o t hi s st u d y, a s w ell a s f or 
all a d ol e s c e nt s w h o ar e r a n d o mi z e d i nt o t h e d o u bl e-bli n d p eri o d. S e p ar at e li sti n g s f or 
a d ol e s c e nt s w h o ar e e nr oll e d i nt o t h e e xt e n si o n p eri o d will b e pr o vi d e d, a s a p pr o pri at e.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S
A b br e vi ati o n 
D efi niti o n
A D A
A nti -Dr u g ( S atr ali z u m a b) A nti b o di e s
A E
A d v er s e E v e nt
A E SI
A d v er s e E v e nt of S p e ci al I nt er e st
A L T
Al a ni n e A mi n otr a n sf er a s e
A N C
A b s ol ut e N e utr o p hil C o u nt
A N C O V A
A n al y si s of C o v ari a n c e
A P RI L
A Pr olif er ati o n -i n d u ci n g Li g a n d
A Q P 4
A q u a p ori n - 4
A Q P 4 A b
A q u a p ori n -4 a nti b o di e s
A R R
A n n u ali z e d R el a p s e R at e
A S T
A s p art at e A mi n otr a n sf er a s e
A U C
Ar e a U n d er T h e S er u m C o n c e ntr ati o n -ti m e C ur v e
B A F F
B- c ell A cti v ati n g F a ct or
B O C F
B a s eli n e O b s er v ati o n C arri e d F or w ar d
B U N
Bl o o d Ur e a Nitr o g e n
C C S R
C h u g ai Cli ni c al S a m pl e R e p o sit or y
C D
Cl u st er of Diff er e nti ati o n
C E C
Cli ni c al E n d p oi nt C o m mitt e e
CI
C o nfi d e n c e I nt er v al
C K
Cr e ati ni n e Ki n a s e
C L/ F
Cl e ar a n c e
C N S
C e ntr al N er v o u s S y st e m
C R O
C o ntr a ct R e s e ar c h Or g a ni z ati o n
C R P
C- r e a cti v e Pr ot ei n
C S F
C er e br o s pi n al Fl ui d
C- S S R S
C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e
C T
C o m p ut eri z e d T o m o gr a p h y
C tr o u g h
A v er a g e T r o u g h S er u m C o n c e ntr ati o n
C V
C o effi ci e nt of V ari a n c e
C Y P
C y t o c hr o m e P
D B P
Di a st oli c Bl o o d Pr e s s ur e
D N A
D e o x yri b o n u cl ei c A ci d
D O W
D o s e O ut si d e T h e V i sit W i n d o w
E C
E ur o pe a n C o m missi o n


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A b br e vi ati o n 
D efi niti o n
E C G
El e ctr o c ar di o gr a m
e C R F
El 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 D S S
E x p a n d e d Di s a bilit y St at u s S c al e
E U
E ur o p e a n U ni o n
F A CI T
F u n cti o n al A s s e s s m e nt Of C hr o ni c Ill n e s s T h er a p y
F D A
F o o d a n d Dr u g A d mi nistr ati o n
F c
Fr a g m e nt Cr y st alli z a bl e
F PI
Fir st P ati e nt I n
F S S
F u n cti o n al S y st e m S c or e
F U A A
F oll o w -U p A s s e s s m e nt f or A d ol e s c e nt s
G C P
G o o d Cli ni c al Pr a cti c e
G T P
G a m m a Gl ut a m yl  Tr a n s p e pti d a s e
H b
H e m o gl o bi n
H B c A b
T ot al H e p atiti s B C or e A nti b o d y
H b s A b
A nti b o d y T o H e p atiti s B S urf a c e A nti g e n
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 ct
H e m at o crit
H C V A b
H e p atiti s C Vir u s A nti b o d y
H D L
Hi g h D e n sit y Li p o pr ot ei n
HI P A A
H e alt h I n s ur a n c e P ort a bilit y a n d A c c o u nt a bilit y A ct
h s C R P
Hi g h S e n siti vit y C -R e a cti v e Pr ot ei n
I C F
I nf or m e d C o n s e nt F or m
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 D
I d e ntifi c ati o n
I D C C
I n d e p e n d e nt D at a C o or di n ati n g C e nt er
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 E C
I n d e p e n d e nt Et hi c s C o m mitt e e
I F N
I nt erf er o n
I g G
I m m u n o gl o b uli n G
I L- 6
I nt erl e u ki n- 6
I L-6 R
I nt erl e u ki n-6 R e c e pt or
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 R
I nt er n ati o n al N or m ali z e d R ati o
I R B
I n stit uti o n al R e vi e w B o ar d
I R R
I nj e cti o n-r el at e d R e a cti o n


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A b br e vi ati o n 
D efi niti o n
I T T
I nt e nt-T o -Tr e at
I V
I ntr a v e n o u s(l y)
I VI G
I ntr a v e n o u s I m m u n o gl o b uli n
I x R S
I nt er a cti v e V oi c e or W e b R e s p o n s e S y st e m
L D H
L a ct at e D e h y dr o g e n a s e
L D L
L o w D e n sit y Li p o pr ot ei n
M M R M
Mi x e d -eff e ct s M o d el R e 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 R S
M o difi e d R a n ki n S c al e
M S
M ulti pl e S cl er o si s
N M O
N e ur o m y eliti s O pti c a
N M O S D
N e ur o m y eliti s O pti c a S p e ctr u m Di s or d er
N S D
N e e dl e S af et y D e vi c e
O L E
O pe n -L a bel E xte nsi o n
P D
P h ar m a c o d y n a mi c( s)
P D R
Pr ot o c ol Defi ne d Rel a pse
P F S
Pr e fill e d Syr i n g e
p JI A
P ol y arti c ul ar J u v e nil e I di o p at hi c Art hriti s
P K
P h ar m a c o ki n eti c( s)
P K -P P S
P h ar m a c o ki n eti c P er -Pr ot o c ol S et
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
P P S
P er -Pr ot o c ol S et
Q 4 W
E v er y 4 W e e k s
Q T c F
Q T I nt er v al C orr e ct e d F or H e art R at e u si n g Fri d eri ci a’ s 
F or m ul a
R A
R h e u m at oi d Art hriti s
R B C
R e d Bl o o d C ell( s)
R N A
R i b o n u cl ei c A ci d
S A E
S eri o u s A d v er s e E v e nt
S A F
S af et y P o p ul ati o n
S A P
St ati sti c al A n al y si s Pl a n
S B P
S y st oli c Bl o o d Pr e s s ur e
S C
S u b c ut a n e o u s(l y)
S D
St a n d ar d D e vi ati o n
S F -3 6
S h ort F or m G e n eri c H e alt h S ur v e y
S F U
S af et y F oll o w -U p
sI L -6 R
S ol u bl e I nt erl e u ki n -6 R e c e pt or


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A b br e vi ati o n 
D efi niti o n
s JI A
S y st e mi c J u v e nil e I di o p at hi c Art hriti s
T B
T u b er c ul o si s
T B L
T ot al Bilir u bi n
T F R
Ti m e  To Fir st Pr ot o c ol -d efi n e d R el a p s e
U L N
U p p er Li mit of N or m al
U S
U nit e d St at e s
V A S
Vi s u al A n al o g u e S c al e
V/ F
Di stri b uti o n V ol u m e
W B C
W h it e Bl o o d C ell( s)
W D
Wi t h dr a w al
Z BI
Z arit B ur d e n I nt er vi e w


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
1.
I N T R O D U C TI O N
1. 1 
B A C K G R O U N D O N N E U R O M Y E LI TI S O P TI C A  ( N M O) A N D 
N E U R O M Y E LI TI S O P TI C A S P E C T R U M DI S O R D E R ( N M O S D)
1. 1. 1 
I ntr o d u cti o n t o N M O a n d N M O S D
N e ur o m y eliti s o pti c a ( N M O), ori gi n all y n a m e d D e vi c’ s di s e a s e, i s a s e v er e 
d e m y eli n ati n g i nfl a m m at or y a ut oi m m u n e di s or d er. N M O a n d N M O s p e ctr u m di s or d er 
( N M O S D) ar e cli ni c all y c h ar a ct eri z e d b y o pti c n e uriti s a n d/ or tr a n s v er s e m y eliti s 
( Wi n ger c h u k et al. 2 0 0 7), l e a di n g t o v ari o u s di s a biliti e s, s u c h a s vi s u al i m p air m e nt 
(i n cl u di n g bli n d n e s s), di st ur b a n c e of m otilit y a n d s e n s or y d efi cit. N M O u s u all y h a s a 
w or s e pr o g n o si s t h a n m ulti pl e s cl er o si s ( M S ). O pti c n e uriti s m a y pr e s e nt a s a 
u nil at er al or bil at er al e v e nt d e p e n di n g u p o n t h e p orti o n of t h e vi s u al p at h w a y t h at i s 
aff e ct e d. Vi s u al i m p air m e nt i s oft e n s e v er e wit h a p o or r e c o v er y. I n a d diti o n, t h e 
s e v er e r el a p s e s oft e n l e a d t o diffi c ult y w al ki n g, p ar a/t etr a p ar e si s a n d p a n -s e n s or y 
l o s s. Di s a bilit y i n N M O i s u s u all y m or e s e v er e t h a n t h at i n M S a n d i s u s u ally r el at e d t o 
t h e s e v erit y of N M O r el a p s e s. M o st di s a biliti e s ari s e fr o m t h e oft e n d e v a st ati n g 
di s cr et e a c ut e att a c k s a n d s e c o n d ar y pr o gr e s si o n i s u n c o m m o n. F ati g u e a n d p ai n ar e 
c o m m o n a n d aff e ct a br o a d er b o d y ar e a t h a n t h o s e i n M S a n d si g nifi c a ntl y i m p a ct t h e 
p ati e nt’ s q u alit y of lif e.
N M O i s di sti n ct fr o m M S r a di ol o gi c all y a n d pr o g n o sti c all y, a n d h a s a p at h o p h y si ol o g y 
u nr e s p o n si v e t o t y pi c al M S tr e at m e nt ( W ei n s h e n k er 2 0 0 7; O h a n d L e v y 2 0 1 2). Ot h er 
di sti n g ui s hi n g f e at ur e s of N M O i n cl u d e a str o n g f e m al e pr e p o n d er a n c e, l o n git u di n all y 
e xt e n si v e s pi n al c or d l e si o n s a n d a b s e n c e of oli g o cl o n al i m m u n o gl o b uli n G (I g G) 
b a n d s i n t h e c er e br o s pi n al fl ui d ( C S F). I n t he m ost rece ntl y p u blis he d di a g n ostic 
criteri a, t he o ver arc hi n g ter m N M O S D w as selecte d t o u nif y tr a diti o n al N M O a n d 
m o der n N M O S D defi niti o ns ( Wi n gerc h u k et al. 2 0 1 5).
C urre ntl y, t here is o ne lice nse d me dic ati o n f or N M O S D (ec uli z u m a b; a p pr o ve d b y 
t he F o o d a n d Dr u g A d mi nistr ati o n [ F D A] o n 2 7 J u ne 2 0 1 9 a n d b y t he E ur o pe a n 
C o m missi o n [ E C] o n 2 7 A u g ust 2 0 1 9). T h e r e ar e f o ur a s p e ct s of N M O tr e at m e nt i n 
t h e c urr e nt tr e at m e nt al g orit h m: 1) a c ut e tr e at m e nt of r el a p s e s, 2) pr e v e nti o n of 
r el a p s e s, 3) s y m pt o m m a n a g e m e nt a n d 4) r e h a bilit ati o n
S atr ali z u m a b ( al s o k n o w n a s S A 2 3 7 ) i s e x p e ct e d t o c o ntri b ut e t o t h e pr e v e nti o n of 
r el a p s e s. I n li g ht of t h e n o n-r e v er si bilit y of t h e n e ur ol o gi c al d efi cit a s s o ci at e d wit h 
r el a p s e s, m ai nt e n a n c e i m m u n o s u p pr e s si o n h a s b e c o m e st a n d ar d pr a cti c e. T h e 
c urr e nt st a n d ar d i n t h e U nit e d St at e s ( U S), E ur o p e a n U ni o n ( E U), C a n a d a a n d P a cifi c 
Ri m c o u n tri e s o ut si d e of J a p a n, i s t o a c hi e v e a n d m ai nt ai n r e mi s si o n wit h 
c orti c o st er oi d s a n d t h e n gr a d u all y wit h dr a w t h e m i n f a v or of a n o n -st er oi d 
i m m u n o s u p pr e s s a nt, alt h o u g h s o m e p ati e nt s n e e d a l o w d o s e of or al st er oi d s t o 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
m ai nt ai n r e mi s si o n. Tr e at m e nt wit h a v ari et y of diff er e nt a g e nt s h a s b e e n d e s cri b e d 
alt h o u g h n o r a n d o mi z e d c o m p ari s o n s of diff er e nt t h er a pi e s e xi st. Tr e at m e nt 
a p pr o a c h e s f or pr e v e nti o n of att a c k s i n cl u d e s y st e mi c i m m u n o s u p pr e s si o n wit h 
a z at hi o pri n e or m y c o p h e n ol at e m of etil. M et h otr e x at e u s e h a s al s o b e e n r e p ort e d, a s 
i s u s e of mit o x a ntr o n e c h e m ot h er a p y. I n t er m s of bi ol o gi c a g e nt s, rit u xi m a b, w hi c h i s 
n ot a p pr o v e d f or tr e at m e nt of M S or N M O, i s wi d el y u s e d b y cli ni ci a n s i n s o m e 
c o u ntri e s. T he u se of t o cili z u m a b ( Ar a ki et al. 2 0 1 2, A y z e n b er g et al. 2 0 1 3, Ki e s ei er et 
al. 2 0 1 3) i n N M O h as al s o b e e n r e p ort e d. 
Li mit e d o b s er v ati o n al e vi d e n c e s u g g e st s t h at t y pi c al M S tr e at m e nt s, i n cl u di n g 
i nt erf er o n (I F N)-β, n at ali z u m a b a n d fi n g oli m o d, ar e n ot eff e cti v e i n N M O a n d m a y b e 
h ar mf ul w h e n u s e d t o tr e at t h e s e p ati e nt s. U nli k e M S, di s a bilit y i n N M O i s dir e ctl y ti e d 
t o t h e n u m b er a n d s e v erit y of r el a p s e s. Gi v e n t h e p ot e nti al of a si n gl e r el a p s e i n N M O 
p ati e nt s t o c a u s e si g nifi c a nt di s a bilit y, t h er e re m ai ns a n u n m et m e di c al n e e d t o 
d e v el o p a d diti o n al t h er a pe uti c o pti o ns t o re d uce t he li keli h o o d of r el a p s e s.
1. 1. 2 
Int erl e u ki n -6 a s a T ar g et M ol e c ul e f or t h e Tr e at m e nt of N M O 
a n d N M O S D
O n e of t h e k e y f e at ur e s of N M O i s t h e pr e s e n c e of N M O -I g G, s p e cifi c a nti b o di e s
a g ai n st a q u a p ori n -4 ( A Q P 4 A b ), a m aj or w at er c h a n n el pr ot ei n i n t h e c e ntr al n er v o u s 
s y st e m ( C N S) ( L e nn o n V A et al. 2 0 0 5) . Tr a n sf er of a nti-A Q P 4 A b h a s b e e n s h o w n t o 
e x a c er b at e e x p eri m e nt al a ut oi m m u n e e n c e p h al o m y eliti s i n a ni m al m o d el s. Fr o m t hi s 
o b s er v ati o n, t h e r ol e of t h e h u m or al ar m of t h e i m m u n e s y st e m i n di s e a s e p at h ol o g y 
f or N M O h a s b e e n d e v el o p e d. Y a m a m ur a a n d c o- w or k er s h a v e i d e ntifi e d a 
C D 1 9i nt C D 2 7 hi C D 3 8 hi C D 1 8 0 - ( a n d C D 2 0-) pl a s m a bl a st B c ell s u b s et, w hi c h i s 
a s s o ci at e d wit h pr o d u cti o n of a nti -A Q P 4 A b ( C hi h ar a et al. 2 0 1 1) . C ell s urf a c e 
e x pr e s si o n of cl u s t er of diff er e nti ati o n 1 9 (C D 1 9 ) i n pl a s m a bl a st s i s l o w er t h a n ot h er B 
c ell s. S ur vi v al of pl a s m a bl a st s i s pr o m ot e d b y i nt erl e u ki n-6 ( I L- 6), b ut n ot b y a 
pr olif er ati o n -i n d u ci n g li g a n d (A P RI L ) or t h e r el at e d T N F f a mil y li g a n d B- c ell a cti v ati n g 
f a ct or (B A F F , k n o w n a s B L y S, t h e t ar g et of t h e m o n o cl o n al a nti b o d y b eli m u m a b). I L-6, 
b ut n ot B A F F or A P RI L, w a s s u g g e st e d t o e n h a n c e a nti b o d y pr o d u cti o n b y t h e s e 
pl a s m a bl a st s, a n d a nti -I L- 6 r e c e pt or (I L- 6 R) bl o c k a d e s el e cti v el y i n hi bit e d s ur vi v al of 
A Q P 4 A b -pr o d u ci n g pl a s m a bl a st s i n vitr o. B a s e d o n t h e s e e x vi v o st u di e s, t h er e ar e 
al s o n o w r e p ort s fr o m s e v er al diff er e nt gl o b al i n v e sti g at or s t h at h a v e u s e d a nti -I L-6 R 
bl o c k a d e t o tr e at p ati e nt s wit h N M O.
1. 2 
B A C K G R O U N D O N S A T R A LI Z U M A B
S atr ali z u m a b i s a f ull y h u m a ni z e d a nti-h u m a n I L -6 r e c e pt or (I L -6 R) n e utr ali zi n g 
m o n o cl o n al a nti b o d y t h at w a s d e si g n e d b y a p pli c ati o n of r e c y cli n g a nti b o d y 
t e c h n ol o g y t o t h e a p pr o v e d a nti-I L 6 r e c e pt or a nti b o d y, t o cili z u m a b, w hi c h i s c urr e ntl y 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
m ar k et e d a s a tr e at m e nt f or r h e u m at oi d art hriti s ( R A) , sy st e mi c j u v e nil e i di o p at hi c 
art hriti s ( sJI A) , p ol y arti c ul ar j u v e nil e i di o p at hi c art hriti s ( pJI A) a n d C a stl e m a n' s 
di s e a s e . A nti b o d y e n gi n e eri n g t e c h ni q u e s w er e utili z e d t o gi v e s atr ali z u m a b p H -
d e p e n d e nt bi n di n g affi nit y t o I L -6 R, s o t h at it bi n d s t o I L -6 R u n d er n e utr al c o n diti o n s i n 
pl a s m a b ut di s s o ci at e s u n d er t h e sli g htl y a ci di c c o n diti o n s i n e n d o s o m e s, a n d i s 
r e c y cl e d t o t h e pl a s m a i n st e a d of b ei n g d e gr a d e d i n l y s o s o m e s, i m p arti n g a l o n g er 
pl a s m a h alf -lif e. I n a d diti o n, s atr ali z u m a b i s a n I g G 2 i s ot y p e, w hi c h r e d u c e s fr a g m e nt 
cr y st alli z a bl e ( F c) r e c e pt or eff e ct or f u n cti o n s c o m p ar e d wit h t o cili z u m a b ( w hi c h i s a n 
I g G 1 a nti b o d y). T h e l o n g er pl a s m a h alf-lif e of s atr ali z u m a b c o m p ar e d wit h t o cili z u m a b 
w a s c o nfir m e d o n t h e b a si s of a n o n -cli ni c al st u d y a n d a P h a s e 1 st u d y i n h e alt h y 
v ol u nt e er s ( S A -0 0 1 J P). 
Li k e t o cili z u m a b, s atr ali z u m a b a c hi e v e s it s p h ar m a c ol o gi c al eff e ct s b y i n hi biti n g I L -6 
si g n ali n g . C o m p ar e d wit h t o cili z u m a b, s atr ali z u m a b w a s d e si g n e d t o h a v e:
1.
A l o n g er pl a s m a h alf -lif e d u e t o p H-d e p e n d e nt bi n di n g t o t h e I L -6 R, a l o w er 
a nti b o d y m ol e c ul e i s o el e ctri c p oi nt a n d str o n g er bi n di n g t o n e o n at al F c r e c e pt or 
( F c R n), a n d
2.
L o w er eff e ct or a cti viti e s ( e. g. , a nti b o d y -d e p e n d e nt c ell ul ar c yt ot o xi cit y 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) o wi n g t o it s l o w er bi n di n g affi nit y t o 
F c γ r e c e pt or ( F c γ R) a n d t h e a d o pti o n of a n I g G 2 b a c k b o n e.
T h e p h ar m a c ol o gi c al eff e ct s a n d s af et y of s atr ali z u m a b ar e e x p e ct e d t o b e 
c o m p ar a bl e or s u p eri or t o t h o s e of t o cili z u m a b, a n d b e c a u s e of it s l o n g er pl a s m a h alf -
lif e, it i s e x p e ct e d t o s h o w p h ar m a c ol o gi c al effi c a c y at a l o w er d o si n g fr e q u e n c y.
T h e s af et y, t ol er a bilit y, p h ar m a c o ki n eti c ( P K ) a n d bi o a v ail a bilit y of s u b c ut a n e o u sl y 
( S C) a d mi ni st er e d s atr ali z u m a b w er e i n v e sti g at e d i n J a p a n e s e a n d C a u c a si a n 
h e alt h y a d ult m al e v ol u nt e er s ( S A-0 0 1 J P) i n J a p a n. I n t hi s P h a s e 1 ( si n gl e d o s e) 
st u d y, 4 8 J a p a n e s e s u bj e ct s w er e gi v e n s atr ali z u m a b b y S C i nj e cti o n or i ntr a v e n o u sl y
(I V), a n d 2 4 C a u c a si a n s u bj e ct s w er e gi v e n s atr ali z u m a b b y S C i nj e cti o n. T hi s st u d y 
d e m o n str at e d c o m p ar a bl e s af et y a n d P K pr ofil e s b et w e e n C a u c a si a n a n d J a p a n e s e 
v ol u nt e er s. A si n gl e S C d o s e of s atr ali z u m a b u p t o 2 4 0 m g a n d a n I V d o s e of 
s atr ali z u m a b u p t o 1 2 0 m g w er e s af e a n d w ell t ol er at e d.
S A -1 0 5 J P w a s a P h a s e 1 o p e n -l a b el, r a n d o mi z e d, p ar all el-gr o u p, m ulti pl e -d o si n g 
st u d y i n p ati e nt s wit h R A . T h e o bj e cti v e s of t h e st u d y w er e t o a s s e s s s af et y, 
i m m u n o g e ni cit y, P K/p h ar m a c o d y n a mi c s ( P D ) a n d effi c a c y of s atr ali z u m a b a s a 
m o n ot h er a p y. All p ati e nt s w er e gi v e n 1 2 0 m g of s atr ali z u m a b at W e e k s 0, 2 a n d 4 
a n d t h e n gi v e n 3 0 ( G r o u p C), 6 0 (G r o u p B) or 1 2 0 m g (G r o u p A) of s atr ali z u m a b
e v er y 4 w e e k s ( Q 4W) . T hirt y-t hr e e p ati e nt s w er e e nr oll e d i nt o t hi s st u d y a n d 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
2 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
1 1 p ati e nt s w er e a s si g n e d t o e a c h gr o u p. I n t h e pri m ar y e v al u ati o n p eri o d, 4 5 a d v er s e 
e v e nt s ( A E s) w er e r e p ort e d i n 2 2 p ati e nt s. T w o s eri o u s A E s ( S A E s) w er e r e p ort e d i n 
t h e pri m ar y e v al u ati o n p eri o d: o n e p ati e nt i n Gr o u p A d e v el o p e d i nt er stiti al l u n g 
di s e a s e a n d di s c o nti n u e d d u e t o t hi s S A E. O n e p ati e nt i n Gr o u p B d e v el o p e d 
br o n c h o p n e u m o ni a. F oll o wi n g tr e at m e nt i n h o s pit al i z ati o n, t h e s e e v e nt s r e s ol v e d.
S e e t h e I n v e sti g at or’ s Br o c h ur e f or d et ail s o n n o n cli ni c al a n d cli ni c al st u di e s wit h 
s atr ali z u m a b .
1. 3 
S T U D Y R A TI O N A L E A N D B E N E FI T – RI S K A S S E S S M E N T
S atr ali z u m a b i s b ei n g d e v el o p e d f or t h e tr e at m e nt of N M O, w hi c h i s a s eri o u s 
c o n diti o n t h at h a s s u b st a nti al i m p a ct o n d a y -t o-d a y f u n cti o ni n g of t h e p ati e nt. 
S atr ali z u m a b h a s t h e p ot e nti al t o tr e at t hi s s eri o u s di s e a s e a n d f ulfill s a n u n m et 
m e di c al n e e d.
I n a d diti o n t o t h e s af et y i nf or m ati o n f or s atr ali z u m a b , t h e s af et y i nf or m ati o n o bt ai n e d 
f or t o cili z u m a b i s c o n si d er e d t o b e u s ef ul i n pr e di cti n g t h e s af et y of s atr ali z u m a b si n c e 
t o cili z u m a b h a s e s s e nti all y t h e s a m e m e c h a ni s m of a cti o n a s s atr ali z u m a b . 
I n or d er t o a d dr e s s t h e p ot e nti al ri s k s f or t h e p ati e nt s, t h e f oll o wi n g s af et y pr e c a uti o n s 
ar e i n cl u d e d i n t h e st u d y d e si g n:
1.
I n a d diti o n t o r e g ul ar st a n d ar d s af et y e v al u ati o n s (l a b or at or y m e a s ur e s, p h y si c al 
e x a mi n ati o n s, vit al si g n s a n d el e ctr o c ar di o gr a m [ E C G]), a s p e ci al f o c u s will b e 
pl a c e d o n m o nit ori n g t h e a b o v e ri s k s.
2.
A n I n d e p e n d e nt D a t a M o nit ori n g C o m mitt e e (I D M C) will p eri o di c all y r e vi e w A Es 
d uri n g t he d o u ble -bli n d peri o d i n a u n bli n d e d m a n ner
a n d , b a s e d o n t h e r e vi e w, 
will m a k e r e c o m m e n d ati o n s o n st u d y c o n d u ct .
I n s u m m ar y, tr e at m e nt wit h s atr ali z u m a b i s a n a p pr o a c h f or a s p e cifi c t h er a p e uti c 
str at e g y i n N M O wit h p o s si bl e a d v a nt a g e s f or p ati e nt s. All n e c e s s ar y m e a s ur e s will b e 
t a k e n t o cl o s el y m o nit or t h e s af et y of t h e tr e at m e nt a n d t h u s t o pr ot e ct t h e p ati e nt s 
e nr oll e d i n t hi s st u d y. T h e p o s si bl e b e n efit s ar e d e e m e d t o o ut w ei g h t h e p ot e nti al 
ri s k s i n v ol v e d i n p arti ci p ati o n i n t hi s st u dy.
T he Cli nic al De vel o p me nt Pr o gr a m of s atr ali z u m a b i n N M O S D c urre ntl y c o nsists of 
t w o o n g oi n g pi v ot al pl ace b o-c o ntr olle d r a n d o mi ze d, d o u ble -bli n d P h ase 3 st u dies. 
T h e d o u ble-bli n d peri o d of b ot h st u dies h a ve bee n c o m plete d ( ple ase refer t o t he l atest 
I n vesti g at or’s Br oc h ure f or a s u m m ar y of t he st u d y res ults), a n d t he st u dies are
c urre ntl y o n g oi n g i n t heir o p e n-l a bel e xte nsi o n ( O L E) peri o d. 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A m ultice nter, o pe n -l a bel, u nc o ntr olle d st u d y t o e v al u ate t he p h ar m ac o ki netics, 
s afet y, t oler a bilit y, a n d p h ar m ac o d y n a mic effects of s atr ali z u m a b i n c hil dre n fr o m 2 
t o less t h a n 1 2 ye ars of a ge is pl a n ne d t o st art i n Q 4 2 0 2 0.
2.
O B J E C TI V E S
2. 1 
E F FI C A C Y O B J E C TI V E
T h e effi c a c y o bj e cti v e f or t hi s st u d y i s:
 
T o e v al u at e t h e effi c a c y of s atr ali z u m a b c o m p ar e d wit h pl a c e b o i n p ati e nt s wit h 
N M O a n d N M O S D .
T h e pri m ar y effi c a c y e n d p oi nt :
i.
Ti m e t o fir st pr ot o c ol -d ef i n e d r el a p s e ( T F R) i n t h e d o u bl e-bli n d p eri o d .
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:
i.
C h a n g e i n Vi s u al A n al o g u e S c al e ( V A S) s c or e f or p ai n
ii.
C h a n g e i n F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s T h er a p y ( F A CI T) 
F ati g u e s c or e
iii.
C h a n g e i n S h ort F or m g e n eri c h e al t h s ur v e y ( S F-3 6) s c or e
i v.
C h a n g e i n E Q -5 D s c or e
v. 
T h e pr o p orti o n of r el a p s e -fr e e p ati e nt s
vi. 
A n n u ali z e d r el a p s e r at e ( A R R)
vii. 
C h a n g e i n m o difi e d R a n ki n S c al e ( m R S) s c or e
viii. 
C h a n g e i n Z arit B ur d e n I nt er vi e w ( Z BI) s c or e
i x.
C h a n g e i n E D S S s c or e
x. 
C h a n g e i n vi s u al a c uit y ( S n ell e n c h art)
2. 2 
S A F E T Y O B J E C TI V E
T h e s af et y o bj e cti v e f or t hi s st u d y i s:
 
T o e v al u at e t h e s af et y of s atr ali z u m a b c o m p ar e d wit h pl a c e b o i n p ati e nt s wit h 
N M O a n d N M O S D .
S af et y o ut c o m e m e a s ur e s:
 
I n ci d e n c e a n d s e v erit y of A E s, a d v er s e e v e nt s of s p e ci al i nt er e st ( A E SI s), S A E s 
( s p o nt a n e o u sl y r e p ort e d b y p ati e nt s a n d c ar e gi v er s), a n d s el e ct e d A E s .
 
V it al si g n s (t e m p er at ur e, s y st oli c bl o o d pr e s s ur e [ S B P], di a st oli c bl o o d pr e s s ur e 
[ D B P] a n d p ul s e r at e), p h y si c al e x a mi n ati o n s, cli ni c al l a b or at or y t e st s 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
( h e m at ol o g y, c h e mi str y, a n d uri n al y si s), 1 2-l e a d E C G s, s ui ci d alit y 
(C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e [ C-S S R S ]).
2. 3 
P H A R M A C O D Y N A MI C
O B J E C TI V E
T h e P D o bj e cti v e f or t hi s st u d y i s a s f oll o w s:
 
T o e x a mi n e t h e P D of s atr ali z u m a b .
P h ar m a c o d y n a mi c s E n d p oi nt s:
 
I L-6, s ol u bl e I L -6 R ( sI L -6 R), hi g h -s e n siti vit y C -r e a cti v e pr ot ei n (h s C R P ), 
a nti -A Q P 4 A b a n d pl a s m a bl a st s.
2. 4 
P H A R M A C O KI N E TI C O B J E C TI V E
T h e P K o bj e cti v e f or t hi s st u d y i s a s f oll o w s:
 
T o e x a mi n e t h e P K of s atr ali z u m a b .
P h ar m a c o ki n eti c s E n d p oi nt:
 
S er u m s atr ali z u m a b c o n c e ntr ati o n.
2. 5 
I M M U N O G E NI CI T Y O B J E CTI V E
T h e i m m u n o g e ni cit y o bj e cti v e f or t hi s st u d y i s a s f oll o w s:
 
T o e x a mi n e t h e i m m u n o g e ni cit y of s atr ali z u m a b .
I m m u n o g e ni cit y E n d p oi nts:
 
I n ci d e n c e of a nti-dr u g a nti b o di e s ( A D A s)
 
P K, P D, cli ni c al r e s p o n s e a n d s af et y d uri n g t h e st u d y b y a nti -dr u g a nti b o d y st at u s.
2. 6 
E X P L O R A T O R Y O B J E C TI V E
T h e e x pl or at or y o bj e cti v e f or t hi s st u d y i s a s f oll o w s:
 
T o a s s e s s a d diti o n al p ai n.
A d diti o n al p ai n a s s e s s m e nt i s o pti o n al a n d will b e c o n d u ct e d at s el e ct e d sit e s ( s e e 
t h e d et ail s i n t h e pr o c e d ur e f or a d diti o n al p ai n a s s e s s me n t).
St u d y e n d p oi nt s r el ati n g t o t h e s e o bj e cti v e s ar e li st e d i n S e cti o n 3. 3 .
2. 7 
S P E CI FI C O B J E C TI V E F O R T H E G R O U P O F A D O L E S C E N T S
S e e S e cti o n 4. 8 f or t h e d et ail of t h e o bj e cti v e f or t h e gr o u p of ad ol e s c e nt s .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
3.
S T U D Y D E SI G N
3. 1 
D E S C RI P TI O N O F S T U D Y
3. 1. 1 
O v er vi e w
T hi s P h a s e 3 pi v ot al st u d y i s a m ulti c e n t er, r a n d o mi z e d, a d diti o n-t o-b a s eli n e 
tr e at m e nt, d o u bl e-bli n d, pl a c e b o -c o ntr oll e d, p ar all el a s si g n m e nt st u d y f oll o w e d b y a n 
O L E
p eri o d. T h e st u d y h a s a n a d d -o n d e si g n ( s atr ali z u m a b b a s eli n e tr e at m e nt 
v er s u s pl a c e b o + b a s eli n e tr e at m e nt). T h e st u d y ai m s t o e v al u at e t h e effi c a c y, s af et y, 
P D, P K a n d i m m u n o g e ni cit y of s atr ali z u m a b .
P ati e nt s will b e r a n d o mi z e d t o o n e of 2 gr o u p s a n d will r e c ei v e eit h er S C s atr ali z u m a b
at a d o s e of 1 2 0 m g (fi x e d d o s e) ( Gr o u p A) or m at c hi n g S C pl a c e b o ( Gr o u p
B) i n a 
1: 1 all o c ati o n at W e e k s 0, 2 a n d 4, a n d Q 4 W t h er e aft er, i n c o m bi n ati o n wit h o n e of 
t h e f oll o wi n g b a s eli n e tr e at m e nt s: a z at hi o pri n e, m y c o p h e n ol at e m of etil or or al 
c orti c o st er oi d s (tr e at m e nt wit h b ot h or al c orti c o st er oi d s a n d eit h er a z at hi o pri n e or 
m y c o p h e n ol at e m of etil
will b e a c c e pt e d f or p ati e nt s a g e d 1 2 t o 1 7 y e ar s at t h e ti m e of 
i nf or m e d c o n s e nt). T h e n u m b er of p ati e nt s w h o ar e n e g ati v e f or a nti -A Q P 4 a nti b o d y 
at s cr e e ni n g will b e li mit e d t o a p pr o xi m at el y 3 0 % of t h e t ot al a d ult ( 1 8 t o 7 4 y e ar s at 
t h e ti m e of i nf or m e d c o n s e nt) st u d y p o p ul ati o n. T h e r a n d o mi z ati o n will b e str atifi e d b y 
b a s eli n e A R R a n d g e o gr a p hi c al r e gi o n .
If a p ot e nti al p ati e nt i s s el e ct e d aft er a c ut e tr e at m e nt f or r el a p s e, t h e n at l e a st 
8 w e e k s o n st a bl e b a s eli n e tr e at m e nt i s r e q uir e d aft er t h e m a n a g e m e nt of t h e r el a p s e .
If t h e p ot e nti al p ati e nt i s e nr oll e d d uri n g m ai nt e n a n c e t h er a p y, t h e r e q uir e m e nt f or 
8 w e e k s o n st a bl e m e di c ati o n pri or t o b a s eli n e will b e f ulfill e d . P ati e nt s wit h o ut a n y 
r el a p s e-pr e v e nti o n m ai nt e n a n c e t h er a p y c a n n ot b e e nr oll e d i n t hi s st u d y.
P ati e nt s w h o e x p eri e n c e a r el a p s e w hi c h i s tr e at e d wit h r e s c u e t h er a p y a n d/ or a 
pr ot o c ol -d ef i n e d r el a p s e w hi c h i s a dj u di c at e d b y Cli ni c al E n d p oi nt C o m mitt e e ( C E C) 
i n t h e d o u bl e-bli n d p eri o d or w h o c o m pl et e t h e d o u b l e-bli n d p eri o d c a n e nt er t h e O L E
p eri o d. I n t h e e xt e n si o n p eri o d, p ati e nt s will r e c ei v e o p e n -l a b el tr e at m e nt wit h 1 2 0 m g 
s atr ali z u m a b S C at W e e k s 0, 2 a n d 4 a n d Q 4 W t h er e aft er, wit h t he l ast st u d y dr u g 
a d mi nistr ati o n o n or bef ore 3 1 Dece m ber 2 0 2 1. It i s at t h e di s cr eti o n of t h e 
I n v e sti g at or t o m o dif y t h e b a s eli n e tr e at m e nt aft er t h e d o u bl e-bli n d p eri o d of  t hi s st u d y.
F or p ati e nt s w h o e x p eri e n c e a r el a p s e i n t h e d o u bl e-bli n d p eri o d , a p pr o pri at e r e s c u e 
t h er a p y f or r el a p s e will b e i niti ate d , a n d s atr ali z u m a b s h o ul d st art o n c e di s e a s e h a s 
st a bili z e d 3 1 t o 6 0 d a y s fr o m t h e o n s et of r el a p s e i n t h e d o u bl e-bli n d p eri o d , w h er e 
t h e d a y of o n s et of r el a p s e i s D a y 1. If s atr ali z u m a b c a n n ot b e a d mi ni st er e d b y 
D a y 6 0, t h e I n v e sti g at or s h o ul d c o n s ult wit h t h e M e di c al M o nit or .




S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
p eri o d . Aft er t h e t ot al n u m b er of pr ot o c ol-d ef i n e d r el a p s e s j u d g e d b y C E C r e a c h e s 2 6, 
th e r e cr uit m e nt p eri o d f or t h e p ati e nt s a g e d 1 2 t o 1 7 y e ar s m a y b e c o nti n u e d i n t h e 
e xt e n si o n p eri o d u ntil a mi ni m u m of 8 p ati e nt s a g e d 1 2 t o 1 7 y e ar s ar e e nr oll e d i nt o
t h e st u d y.
3. 1. 3  
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 D M C will b e u s e d d uri n g t he d o u ble -bli n d peri o d t o p erf or m p eri o di c u n bli n d e d 
s af et y r e vi e w s a n d t o r e c o m m e n d if t h e tri al s h o ul d b e st o p p e d e arl y. All s u m m ari e s 
a n d a n al y s e s will b e pr e p ar e d b y t h e I n d e p e n d e nt D at a C o or di n ati n g C e nt er (I D C C) 
a n d pr e s e nt e d b y tr e at m e nt gr o u p f or I D M C’ s r e vi e w. M e m b er s of t h e I D M C a n d 
I D C C will b e e xt er n al t o t h e S p o n s or a n d t h e st u d y t e a m a n d will f oll o w a c h art er t h at 
o utli n e s t h eir r ol e s a n d r e s p o n si biliti e s. P er s o n n el w h o h a v e o p er ati o n al 
r e s p o n si biliti e s f or t h e st u d y will re m ai n bli n d e d d uri n g t h e d o u ble -bli n d peri o d .
T he I D M C w as dis b a n de d i n Dece m ber 2 0 1 8, after t he e n d of t he d o u ble -bli n d peri o d 
of b ot h o n g oi n g P h ase 3 st u dies.
3. 1. 4 
Cli ni c al E n d p oi nt C o m mitt e e ( C E C)
D uri n g t h e d o u bl e-bli n d p eri o d , a C E C will r e vi e w all c a s e s of p ot e nti al r el a p s e a n d 
a dj u di c at e e a c h i n a bli n d f a s hi o n t o s e e if it m e et s t h e pr ot o c ol d efi niti o n of a r el a p s e. 
I n or d er t o e n s ur e t h at n o r el a p s e e v e nt s w er e mi s s e d b y t h e I n v e sti g at or, t h e
a dj u di c ati o n pr o c e s s will i n cl u d e a c o n c urr e nt r e vi e w of all c a s e s f or p ot e nti al r el a p s e s 
t h at m a y b e mi s s e d.
T h e C E C wi ll b e c o m pri s e d of p h y si ci a n s wit h e x p erti s e i n N M O a n d N M O S D. 
D et ail s r e g ar di n g t h e C E C r e s p o n si biliti e s a n d t h e pr o c e s s of a dj u di c ati o n of r el a p s e s 
ar e d e s cri b e d i n d et ail i n t h e C E C c h art er.
3. 2 
R A TI O N A L E F O R S T U D Y D E SI G N
3. 2. 1 
R ati o n al e f or C h oi c e of St u d y D e si g n El e m e nt s
A P h a s e 3 st u d y wit h a s a m pl e si z e of 7 0 e v al u a bl e p ati e nt s i s c o n si d er e d t o b e 
a d e q u at e t o d e m o n str at e effi c a c y f or t hi s r ar e di s e a s e p o p ul ati o n. A s n o 
p r o of-of -c o n c e pt P h a s e 2 st u di e s h a v e b e e n c o n d u ct e d f or s atr ali z u m a b i n N M O or 
N M O S D , t h e m a g nit u d e of t h e tr e at m e nt eff e ct i s n ot k n o w n a pri ori , alt h o u g h t h er e 
ar e s o m e c a s e r e p ort s of t o cili z u m a b s u g g e sti n g a n i m pr o v e m e nt i n r el a p s e r at e wit h 
s atr ali z u m a b .
T h e st u d y u s e s a n ‘ a d d -o n’ d e si g n i n w hi c h p ati e nt s will r e c ei v e tr e at m e nt wit h eit h er 
s atr ali z u m a b + b a s eli n e tr e at m e nt or pl a c e b o + b a s eli n e tr e at m e nt, i. e. , s atr ali z u m a b
will b e a d d e d o n t o b a s eli n e i m m u n o s u p pr e s s a nt t h er a p y a c c or di n g t o a c c e pt e d 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
cli ni c al pr a cti c e. A pl a c e b o c o ntr ol i s a d d e d t o t h e b a s eli n e c o ntr ol ar m i n or d er t o 
c o ntr ol t h e p ot e nti al f or I n v e sti g at or or p ati e nt bi a s .
T hi s st u d y all o w s f or e nr oll m e nt of p ati e nt s w h o ar e n e g ati v e f or a nti -A Q P 4 a nti b o d y. 
I n or d er t o a v oi d a bi g diff er e n c e b et w e e n t h e st u d y p o p ul ati o n a n d t h e cli ni c al 
p o p ul ati o n, t h e p er c e nt a g e of t h e p ati e nt s w h o ar e a nti -A Q P 4 a nti b o d y n e g ati v e will 
b e c a p p e d at 3 0 % b a s e d o n p u bli s h e d d at a ( J ari u s et al. 2 0 1 2, L e n n o n et al. 2 0 0 4, 
M ari g ni er et al. 2 0 1 3, T a k a h a s hi et al. 2 0 0 7).
T h e e n d of t h e st u d y i s d efi n e d a s t h e d at e w h e n t h e l a st p ati e nt ’ s l a st vi sit o c c ur s; 
t hi s i s e x p e ct e d t o b e 1 2 w e e k s aft er t h e l a st d o si n g i n t h e e xt e n si o n p eri o d .
3. 2. 2 
R ati o n al e f or C h oi c e of B a s eli n e Tr e at m e nt
T h e c o m p ar at or/ c o m bi n ati o n tr e at m e nt r e gi m e n of a z at hi o pri n e, m y c o p h e n ol at e 
m of etil a n d/ or or al c orti c o st er oi d w a s c h o s e n o n t h e b a si s of b ei n g t h e m o st c o m m o n 
tr e at m e nt c h oi c e i n t h e U S, E U a n d J a p a n. U s e of r it u xi m a b d uri n g t h e st u d y i s 
pr o hi bit e d si n c e it s m e c h a ni s m
of a cti o n o v erl a p s t h at of s atr ali z u m a b i n t er m s of t h e 
r e d u cti o n of pl a s m a bl a st s.
3. 2. 3 
R ati o n al e f or Ti m e t o Fir st R el a p s e E n d p oi nt
T h er e ar e c urr e ntl y n o v ali d at e d e n d p oi nt s t o e v al u at e t h e effi c a c y of a g e nt s f or t h e 
tr e at m e nt of N M O or N M O S D. I n t h e a b s e n c e of s u c h e n d p oi nt s, ti m e t o fir st r el a p s e 
( T F R) w a s s el e ct e d a s t h e pri m ar y effi c a c y m e a s ur e i n t hi s st u d y. T F R i s u s e d a s a n 
alt er n ati v e t o A R R, w hi c h h a s b e e n u s e d a s t h e pri m ar y e n d p oi nt i n M S cli ni c al tri al s . 
A R R i s a st ati sti c al m e a s ur e of t h e fr e q u e n c y of r el a p s e . T F R h a s b e e n u s e d a s t h e 
s e c o n d ar y e n d p oi nt i n s e v er al l ar g e M S st u di e s ( Gi o v a n n o ni et al. 2 0 1 0, C o h e n et al .
2 0 1 0, K a p p o s et al . 2 0 1 0, O’ C o n n or et al . 2 0 1 1). F urt h er m or e, f or N M O, t h e n at ur al 
hi st or y of t h e di s e a s e i s s u c h t h at a n y r el a p s e i s p ot e nti all y c at a str o p hi c t o t h e p ati e nt 
a n d i s oft e n a c c o m p a ni e d b y l o n g l a sti n g n e ur ol o gi c al i m p air m e nt .
O n e of t h e pri m ar y a d v a nt a g e s of u si n g T F R i s fr o m t h e et hi c al p er s p e cti v e, 
p arti c ul arl y d e ali n g wit h t h e cli ni c al c o n s e q u e n c e s of r el a p s e e x p eri e n c e d b y N M O 
a n d N M O S D p ati e nt s. Ti m e t o fir st r el a p s e all o w s p ati e 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 d o u bl e -bli n d p eri o d t o r e c ei v e a c ut e t h er a p y. I n a d diti o n, it all o w s p ati e nt s 
t h e o pti o n t o st o p d o u bl e -bli n d t r e at m e nt aft er r el a p s e a n d t o c o nti n u e i n t h e O L E
wit h 
s atr ali z u m a b pl u s b a s eli n e t h er a p y . T hi s miti g at e s t h e et hi c al c o n c er n of k e e pi n g 
p ati e nt s wit h N M O / N M O S D o n a p ot e nti all y i n eff e cti v e st u d y dr u g f or a fi x e d p eri o d of 
ti m e a n d r efl e ct s c urr e nt cli ni c al pr a cti c e i n N M O/ N M O S D, t h at w h e n a p ati e nt 
e x p eri e n c e s a r el a p s e, tr e at m e nt c h oi c e i s oft e n c h a n g e d.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
3. 2. 4 
R ati o n a l e f or T e st Pr o d u ct D o s a g e
B a s e d o n P K a n d P D a s s e s s m e nt s i n P h a s e 1 st u di e s wit h s atr ali z u m a b a n d 
a n e c d ot al effi c a c y d at a fr o m i n v e sti g ati o n al st u di e s of t o cili z u m a b, 1 2 0 m g Q 4 W  will 
b e u s e d a s t h e m ai nt e n a n c e d o s e of s atr ali z u m a b i n t hi s st u d y. 
T hi s d o s e i s a p pr o pri at e b a s e d o n t h e f oll o wi n g c o n si d er ati o n s:
 
R e s ult s fr o m P h a s e 1 si n gl e d o s e st u d y i n h e alt h y s u bj e ct s a n d m ulti pl e d o s e 
st u d y i n p ati e nt s wit h R A s h o w e d t h at s atr ali z u m a b 1 2 0 m g
Q 4 W i n hi bit e d I L-6 
si g n ali n g c o m pl et el y, w h er e a s l o w er d o s e s ( 3 0, 6 0 m g Q 4 W)  di d n ot. T h er ef or e, 
s atr ali z u m a b 1 2 0 m g Q 4 W  i s e x p e ct e d t o i n hi bit I L-6 si g n ali n g c o m pl et el y i n 
p ati e nt s wit h N M O a n d N M O S D.
 
S y st e mi c i nfl a m m at or y c o n diti o n i s n ot e x p e ct e d i n p ati e nt s wit h N M O a n d 
N M O S D c o m p ar e d t o R A p ati e nt s, t h er ef or e, i nf l a m m at or y p ar a m et er s u c h a s 
C- r e a cti v e pr ot ei n (C R P ) a n d I L -6 i s wit hi n n or m al r a n g e i n p ati e nt s wit h N M O 
a n d N M O S D. 
 
I ntr a v e n o u s t o cili z u m a b 8 m g/ k g Q 4 W,  tr o u g h l e v el of w hi c h i s c o m p ar a bl e t o 
s atr ali z u m a b 1 2 0 m g Q 4 W , s h o w e d pr eli mi n ar y cli ni c al effi c a cy i n t h e 
i n v e sti g ati o n al c a s e r e p ort s i n p ati e nt s wit h N M O a n d N M O S D. I n a d diti o n, t h e 
P K/ P D c orr el ati o n b et w e e n t o cili z u m a b a n d s atr ali z u m a b i s c o m p ar a bl e. 
B a s e d o n t h e a b o v e, s atr ali z u m a b 1 2 0 m g Q 4 W i s e x p e ct e d t o b e a n o pti m al d o s e i n 
p ati e nt s wit h N M O a n d N M O S D .
3. 2. 5 
R ati o n al e f or P ati e nt P o p ul ati o n
T h e li mit e d lit er at ur e o n t h e t o pi c of p a e di atri c N M O s u g g e st s t h at t h e di s e a s e i s 
di a g n o s e d fr o m ar o u n d t h e a g e of 2 y e ar s u p w ar d s wit h a m e di a n a g e of o n s et of 1 4 
y e ar s a n d a 3 or 4: 1 f e m al e: m al e r ati o. T h e s p e ctr u m of di s e a s e i n c hil dr e n a p p e ar s 
fr o m t h e lit er at ur e t o b e si mil ar t o t h at i n a d ult s wit h t h e p o s si bl e e x c e pti o n of br ai n 
l e si o n s a n d a r el ati v el y r a pi d pr o gr e s si o n of o pti c n e uriti s b ut t h e i n ci d e n c e i s m u c h 
l o w er at ar o u n d 0. 0 2/ 1 0 0, 0 0 0 b ut v ar yi n g b y r a c e ( J a c o b et al. 2 0 1 2, C oll o n g u e s et al. 
2 0 1 0, L ot z e et al. 2 0 0 8, K et el sl e g er s et al. 2 0 1 2, L a n g er -G o ul d et al. 2 0 1 1, Till e m a 
2 0 1 2 ).
R e c e nt p o p ul ati o n a nt hr o p o m etri c d at a fr o m t h e U S, f or e x a m pl e, s h o w t h at t h e m e a n 
b o d y w ei g ht f or f e m al e a g e d 1 2 i s 5 2. 3 k g ( 5t h t o 9 5t h p er c e ntil e 3 0. 6 7 5. 7 k g) 
(C e nt er s f or Di s e a s e C o ntr ol a n d Pr e v e nti o n ). I n t h e J a p a n e s e p h a s e 1 b R A st u d y 
( S A-1 0 5 J P), 4 of 1 1 p ati e nt s tr e at e d wit h 1 2 0 m g s atr ali z u m a b h a d a b o d y w ei g ht 
u n d er 4 5 k g. N o diff er e n c e i n s er u m c o n c e ntr ati o n of s atr ali z u m a b b et w e e n t w o 
gr o u p s b y b o d y w ei g ht ( < 4 5 k g a n d > 4 5 k g) s u g g e sti n g t h at it w o ul d b e a c c e pt a bl e 
fr o m a P K p oi nt of vi e w t o d o s e a d ol e s c e nt s wit h t h e s a m e 1 2 0 m g d o s e a s a d ult s. 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T h e m e a n w ei g ht i n ol d er c hil dr e n a n d i n b o y s i s e x p e ct e d t o b e hi g h er a n d t h er ef or e 
m or e si mil ar t o t h at i n a d ult s.
A ni m al t o xi c ol o g y st u di e s wit h hi g h er d o s e s of s atr ali z u m a b b y b o d y w ei g ht t h a n ar e 
pr o p o s e d h er e h a v e s h o w n n o o b vi o u sl y dr u g -r el at e d t o xi cit y. A d ol e s c e nt s a g e d 1 2 
a n d u p w ar d s ar e e x p e ct e d t o b e d e v el o p m e nt all y m at ur e i n m o st w a y s.
T h er e i s pr e c e d e nt f or t h e u s e of a n a nti -I L-6 R m o n o cl o n al a nti b o d y (t o cili z u m a b) t o 
tr e at c hil dr e n, wit h a n d wit h o ut c o n c o mit a nt i m m u n o s u p pr e s s a nt t h er a pi e s 
(t o cili z u m a b i s li c e n s e d f or t h e tr e at m e nt of s JI A a n d p JI A i nt er n ati o n all y a n d al s o 
C a stl e m a n' s di s e a s e i n J a p a n). T h e s af et y pr ofil e i n cli ni c al tri al s a n d p o st -m ar k eti n g 
h a s b e e n g e n er all y si mil ar t o t h at i n a d ult s. Alt h o u g h t h e s e t w o a nti b o di e s ar e 
str u ct ur all y diff er e nt, t h e s af et y pr ofil e of t o cili z u m a b c a n at l e a st b e t a k e n t o i n di c at e 
t h e eff e ct of I L-6 R i n hi biti o n i n t h e p e di atri c p o p ul ati o n.
3. 3 
S T U D Y E N D P OI N T S/ O U T C O M E M E A S U R E S
3. 3. 1 
Effi c a c y  O ut c o m e M e a s ur e s
3. 3. 1. 1 
Pri m ar y  En d p oi nt
i. 
T F R i n t h e d o u bl e -bli n d p eri o d.
3. 3. 1. 2 
S e c o n d ar y  En d p oi nt s
i. 
C h a n g e i n V A S s c or e f or p ai n
ii. 
C h a n g e i n F A CI T f ati g u e s c or e
iii. 
C h a n g e i n S F -3 6 s c or e
i v. 
C h a n g e i n E Q -5 D s c or e
v. 
T h e pr o p orti o n of r el a p s e -fr e e p ati e nt s
vi. 
A R R
vii. 
C h a n g e i n m R S s c or e
viii. 
C h a n g e i n Z BI s c or e
i x. 
C h a n g e i n E D S S s c or e
x. 
C h a n g e i n vi s u al a c uit y ( S n ell e n c h art)
3. 3. 2 
S af et y  O ut c o m e M e a s ur e s
i. 
I n ci d e n c e a n d s e v erit y of A E s, S A E s, A E SI s , a n d s el e ct e d A E s .
ii. 
Vit al si g n s (t e m p er at ur e, S B P a n d D B P a n d p ul s e r at e), p h y si c al e x a mi n ati o n s, 
cli ni c al 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), 1 2 -l e a d E C G, 
s ui ci d alit y ( C-S S R S) .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
3. 3. 3 
P h ar m a c o d y n a mi c O ut c o m e M e a s ur e s
i. 
I L- 6
ii. 
S ol u bl e I L -6 R ( sI L -6 R)
iii. 
h s C R P
i v. 
A nti -A Q P 4 A b
v. 
Pl a s m a bl a st s.
3. 3. 4  
P h ar m a c o ki n eti c O ut c o m e M e a s ur e s
i. 
S er u m s atr ali z u m a b c o n c e ntr ati o n.
3. 3. 5 
I m m u n o g e ni cit y O ut c o m e M e a s ur e s
i. 
I n ci d e n c e of A D A s.
P K, P D, cli ni c al r e s p o n s e a n d s af et y d uri n g t h e st u d y b y a nti -dr u g a nti b o d y st at u s.
3. 3. 6 
E x pl or at or y  O ut c o m e M e a s ur e s
i. 
A d diti o n al p ai n a s s e s s m e nt
ii. 
A d diti o n al p ai n a s s e s s m e nt i s o pti o n al a n d will b e c o n d u ct e d at s el e ct e d sit e s 
( s e e t h e d et ail s i n t h e pr o c e d ur e f or a d diti o n al p ai n a s s e s s m e n t).
3. 3. 7 
S p e ci fi c O ut c o m e M e a s ur e s
f or t h e Gr o u p of Ad ol e s c e nt s
S e e S e cti o n 4. 8 f or t h e d et ail of t h e o ut c o m e m e a s ur e s f or t h e gr o u p of ad ol e s c e nt s .
4.
M A T E RI A L S A N D M E T H O D S
4. 1 
P A TI E N T S
T hi s st u d y i n cl u d e s p ati e nt s wit h N M O or N M O S D. T h e pr o p orti o n of p ati e nt s w h o ar e 
n e g ati v e f or a nti-A Q P 4 a nti b o d y at s cr e e ni n g ‡ will b e c a p p e d at a p pr o xi m at el y 3 0 % of 
t ot al n u m b er of a d ult p ati e nt s ( 1 8 t o 7 4 y e ar s at t h e ti m e of i nf or m e d c o n s e nt).
4. 1. 1  
I n cl u si o n Crit eri a
P ati e 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:
1.
P ati e nt s m u st b e di a g n o s e d a s h a vi n g eit h er:
a. 
N M O a s d efi n e d b y 2 0 0 6 crit eri a *, or
b. 
N M O S D a s d efi n e d b y eit h er of t h e f oll o wi n g Wi n g er c h u k 2 0 0 7 crit eri a wit h
a nti -A Q P 4 A b s er o p o siti v e st at u s at s cr e e ni n g ‡ .
i. 
I di o p at hi c si n gl e or r e c urr e nt e v e nt s of l o n git u di n all y e xt e n si v e 
m y eliti s ( ≥3 v ert e br al s e g m e nt s pi n al c or d M RI l e si o n)
ii. 
O pti c n e uriti s : r e c urr e nt or si m ult a n e o u s bil at er al


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
3 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
F or p ati e nt s a g e d 1 2 t o 1 7 y e ar s, a mi ni m u m of 4 p ati e nt s s h o ul d b e p o siti v e f or
a nti -A Q P 4 A b st at u s at s cr e e ni n g ‡ .
‡ S cr e e ni n g r e s ult i s b a s e d o n eit h er t h e bl o o d s a m pl e d at a c oll e ct e d at s cr e e ni n g 
vi sit, or t h e bl o o d s a m pl e d at a c oll e ct e d b ef or e t h e s cr e e ni n g vi sit a n d m e a s ur e d b y 
S p o n s or’ s d e si g n e e f or a n al y si s ( s e e S e cti o n 4. 5. 1. 5 ).
2.
Cli ni c al e vi d e n c e of at l e a st 2 d o c u m e nt e d r el a p s e s (i n cl u di n g fir st att a c k) i n t h e 
l a st 2 y e ar s pri or t o s cr e e ni n g, at l e a st o n e of w hi c h h a s o c c urr e d i n t h e 1 2 m o nt h s 
pri or t o s cr e e ni n g.
3.
E D S S s c or e fr o m 0 t o 6. 5 i n cl u si v e at s cr e e ni n g.
4.
A g e 1 2 t o 7 4 y e ar s, i n cl u si v e at t h e ti m e of i nf or m e d c o n s e nt.
5.
O n e of t h e f oll o wi n g b a s eli n e tr e at m e nt s m u st b e at st a bl e d o s e a s a m o n ot h er a p y 
f or 8 w e e k s pri or t o b a s eli n e**.
a. 
A z at hi o p ri n e.
b. 
M y c o p h e n ol at e m of etil .
c. 
Or al c orti c o st er oi d s .
** F or p ati e nt s a g e d 1 2 t o 1 7 y e ar s, eit h er of t h e f oll o wi n g b a s eli n e tr e at m e nt s f or 
r el a p s e pr e v e nti o n c a n b e all o w e d:
d. 
A z at hi o pri n e + o r al c orti c o st er oi d s.
e. 
M y c o p h e n ol at e m of etil + o r al c orti c o st er oi d s.
6.
A bilit y a n d willi n g n e s s 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 c o m pl y wit h t h e 
r e q uir e m e nts of t h e pr ot o c ol .
* A c c or di n g t o Wi n g er c h u k et al. 2 0 0 6, a di a g n o si s of N M O r e q uir e s all of t h e f oll o wi n g 
t hr e e crit eri a:
I. 
O pti c n e uriti s
II. 
A c ut e m y eliti s
III.
At l e a st t w o of t hr e e s u p p orti v e crit eri a:
 
C o nti g u o u s s pi n al c or d l e si o n i d e ntifi e d o n a 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 e xt e n di n g o v er 3 v ert e br al s e g m e nt s
 
Br ai n M RI n ot m e eti n g di a g n o sti c crit eri a f or M S
 
N M O- I g G s er o p o siti v e st at u s


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
S e e S e cti o n 4. 8 f or t h e st u d y crit eri a f or a d ol e s c e nt s w h o m a y b e e nr oll e d aft er t h e 
e n d of t h e d o u bl e -bli n d p eri o d.
4. 1. 2 
E x cl u si o n Crit eri a
P ati e 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:
E x cl u si o n crit eri a r el at e d t o pr e vi o u s or c o n c o mit a nt t h er a p y :
1.
A n y p r e vi o u s tr e at m e nt wit h I L-6 i n hi bit or y t h er a p y ( e. g. , t o cili z u m a b), 
al e mt u z u m a b, 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 at a n y ti m e .
2.
A n y pr e vi o u s tr e at m e nt wit h a nti -C D 2 0 , e c uli z u m a b, b eli m u m a b, i nt erf er o n, 
n at ali z u m a b, gl atir a m er a c et at e, fi n g oli m o d, t erifl u n o mi d e or di m et h yl f u m ar at e 
wit hi n 6 m o nt h s pri or t o b a s eli n e.
3.
A n y pr e vi o u s tr e at m e nt wit h a nti -C D 4, cl a dri bi n e or m it o x a ntr o n e wit hi n 2 y e ar s 
pri or t o b a s eli n e
4.
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 3 m o nt h s pri or t o b a s eli n e .
E x cl u si o n s f or g e n er al s af et y :
5.
Pr e g n a n c y or l a ct ati o n. 
6.
F or p ati e nt s of r e pr o d u cti v e p ot e nti al, a p o siti v e r e s ult fr o m a s er u m pr e g n a n c y 
t e st at s cr e e ni n g, or n ot willi n g t o u s e r eli a bl e m e a n s of c o ntr a c e pti o n (p h y si c al 
b arri er [p ati e nt or p art n er ] i n c o nj u n cti o n wit h a s p er mi ci d al pr o d u ct, c o ntr a c e pti v e 
pill , p at c h, i nj e ct a bl e s, i ntr a ut eri n e d e vi c e or i ntr a ut eri n e s y st e m ) d uri n g t h e 
tr e at m e nt p eri o d a n d f or at l e a st 3 m o nt h s aft er t h e l a st d o s e of st u d y dr u g.
7.
A n y s ur gi c al pr o c e d ur e ( e x c e pt f or mi n or s ur g eri e s) wit hi n 4 w e e k s pri or t o 
b a s eli n e.
8.
E vi d e n c e of ot h er d e m y eli n ati n g di s e a s e 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 (P M L ).
9.
E vi d e n c e of s eri o u s u n c o ntr oll e d c o n c o mit a nt di s e a s e s t h at m a y pr e cl u d e p ati e nt 
p arti ci p ati o n, s u c h a s:
o t h er n er v o u s s y st e m di s e a s e, c ar di o v a s c ul ar di s e a s e, 
h e m at ol o gi c/ h e m at o p oi e si s di s e a s e, r e s pir at or y di s e a s e, m u s c ul ar di s e a s e, 
e n d o cri n e d i s e a s e, r e n al/ ur ol o gi c di s e a s e, di g e sti v e s y st e m di s e a s e, c o n g e nit al or 
a c q uir e d s e v er e i m m u n o d efi ci e n c y .
1 0. K n o w n a cti v e i nf e cti o n ( e x cl u di n g f u n g al i nf e cti o n s of n ail b e d s or c ari e s d e nti u m) 
wit hi n 4 w e e k s pri or t o b a s eli n e.
1 1. E vi d e n c e of c hr o ni c a cti v e h e p at iti s B or C. 
1 2. Hi st or y of dr u g or al c o h ol a b u s e wit hi n 1 y e ar pri or t o b a s eli n e .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
1 3. Hi st or y of di v erti c uliti s t h at , i n t h e I n v e sti g at or’ s o pi ni o n, m a y l e a d t o i n cr e a s e d ri s k 
of  c o m pli c ati o n s s u c h a s l o w er g a str oi nt e sti n al p erf or ati o n.
1 4. E vi d e n c e of a cti v e t u b er c ul o si s ( T B; e x cl u di n g p ati e nt s r e c ei vi n g 
c h e m o pr o p h yl a xi s f or l at e nt T B i nf e cti o n).
1 5. E vi d e n c e of a cti v e i nt er stiti al l u n g di s e a s e.
1 6. R e c ei pt of a n y li v e or li v e att e n u at e d v a c ci n e wit hi n 6 w e e k s pri or t o b a s eli n e.
1 7. Hi st or y of m ali g n a n c y wit hi n t h e l a st 5 y e ar s , i n cl u di n g s oli d t u m or s, h e m at ol o gi c 
m ali g n a n ci e s a n d i n sit u c ar ci n o m a ( e x c e pt b a s al c ell a n d 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, or i n sit u c ar ci n o m a of t h e c er vi x ut eri t h at h a v e b e e n 
c o m pl et el y e x ci s e d a n d c ur e d).
1 8. Hi st or y of s e v er e all er gi c r e a cti o n t o a bi ol o gi c a g e nt ( e. g., s h o c k, a n a p h yl a cti c 
r e a cti o n s).
1 9. A cti v e s ui ci d al i d e ati o n wit hi n 6 m o nt h s pri or t o s cr e e ni n g, or hi st or y of s ui ci d e 
att e m pt wit hi n 3 y e ar s pri or t o s cr e e ni n g .
L a b or at or y  e x cl u si o n crit eri a ( at s cr e e ni n g):
2 0. F oll o wi n g l a b or at or y a b n or m aliti e s at s cr e e ni n g *. 
a. 
W h it e bl o o d c ell s ( WB C) < 3 . 0 x 1 03 / μ L
b. 
A b s ol ut e n e utr o p hil c o u nt ( A N C) < 2. 0 x 1 0 3 / μ L
c. 
A b s ol ut e l y m p h o c yt e c o u nt < 0. 5 x 1 0 3 / μ L
d. 
Pl at el et c o u nt < 1 0 x 1 0 4 / μ L
e. 
A s p art at e a mi n otr a n sf er a s e ( A S T) or al a ni n e a mi n otr a n s f er a s e ( A L T)1. 5 
ti m e s t h e u p p er li mit of n or m al ( U L N).
* If r et e st i s c o n d u ct e d, t h e l a st v al u e of r et e st 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.
S e e S e cti o n 4. 8 f or t h e st u d y crit eri a f or a d ol e s c e nt s w h o m a y b e e nr oll e d aft er t h e 
e n d of t h e d o u bl e -bli n d p eri o d.
4. 2 
M E T H O D O F T R E A T M E N T A S SI G N M E N T A N D B LI N D I N G
R a n d o mi z ati o n will b e str atifi e d b y b a s eli n e A R R a n d g e o gr a p hi c al r e gi o n . P ati e nt s 
will b e r a n d o mi z e d i n a 1: 1 r ati o t o o n e of t h e t w o tr e at m e nt gr o u ps. A d mi ni str ati o n of 
st u d y tr e at m e nt s h o ul d o c c ur o n s a m e d a y a s r a n d o mi z ati o n. F or t h e r a n d o mi z ati o n of 
p ati e nt s, t h e I n v e sti g at or will u s e I nt er a cti v e W e b R e s p o n s e a n d V oi c e R e s p o n s e 
S y st e m s ( I x R S). D et ail s c a n b e f o u n d i n t h e st u d y m a n u al . T h e I x R S will a s si g n 
p ati e nt s t o a tr e at m e nt gr o u p b a s e d o n t h e pr e -d ef i n e d r a n d o mi z ati o n li st.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
D uri n g t h e d o u bl e -bli n d p eri o d, t h e st u d y will b e p erf or m e d i n a d o u bl e -bli n d m a n n er. 
S t u d y dr u g s (s atr ali z u m a b a n d pl a c e b o) will b e s u p pli e d i n i d e nti c al vi al s a n d will b e 
si mil ar i n c ol or a n d a p p e ar a n c e, t h er e b y e n a bli n g d o u bl e -bli n d c o n diti o n s.
P ati e nt s a n d all st u d y sit e p er s o n n el will b e bli n d e d t o tr e at m e nt a s si g n m e nt u ntil all 
p ati e nt s h a v e eit h er c o m pl et e d t h e d o u bl e -bli n d p eri o d or di s c o nti n u e d e arl y fr o m t h e 
st u d y or a s d e s cri b e d a b o v e r e g ar di n g u n bli n di n g .
P ati e nt s, I n v e sti g at or st aff, p er s o n s p erf or mi n g t h e a s s e s s m e nt s, a n d d at a a n al y st s 
r e m ai n bli n d e d t o t h e i d e ntit y of t h e tr e at m e nt, fr o m t h e ti m e of r a n d o mi z ati o n u ntil 
d at a b a s e l o c k, u si n g t h e f oll o wi n g m et h o d s: ( 1) R a n d o mi z ati o n d at a ar e k e pt stri ctl y 
c o nfi d e nti al u ntil t h e ti m e of u n bli n di n g, a n d ar e n ot a c c e s si bl e b y a n y o n e el s e 
i n v ol v e d i n t h e st u d y, ( 2) T h e i d e ntit y of t h e st u d y tr e at m e nt s (i. e., s atr ali z u m a b a n d 
pl a c e b o) i s c o n c e al e d b y t h e u s e of st u d y tr e at m e nt s t h at ar e all i d e nti c al i n p a c k a gi n g, 
l a b eli n g, s c h e d ul e of a d mi ni str ati o n a n d a p p e ar a n c e, ( 3) R el a p s e i s a s s e s s e d 
s e p ar at el y fr o m t h e tr e ati n g I n v e sti g at or, w h o i s r e s p o n si bl e f or t h e p ati e nt c ar e.
T h er e will b e 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 a s s e s s or at e a c h sit e t o 
m ai nt ai n t h e bli n d n e s s of effi c a c y a s s e s s m e nt – t h e tr e ati n g I n v e sti g at or r e s p o n si bl e 
f or t h e p ati e nt c ar e a n d t h e e x a mi ni n g a s s e s s or 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 E D S S/f u n cti o n al s y st e m s c or e (F S S ). T h e e x a mi ni n g a s s e s s or m u st b e 
a p pr o pri at el y N e ur o st at u s q u alifi e d t o a s s e s s E D S S/ F S 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 tr e at m e nt d e ci si o n s 
b a s e d o n t h e p ati e 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 
a s s e s s or will h a v e a c c e s s vi a t h e p a p er f or m o nl y t o t h e E D S S/ F S S d at a (i n cl u di n g 
t h e R el a p s e A s s e s s m e nt F or m) e x c e pt i n a n e m er g e n c y ( s u c h a s t h er e i s n o 
p h y si ci a n ot h er t h a n f or E D S S/ F S S a s s e s s m e nt i n st u d y sit e) a n d will n ot c o n s ult t h e 
p ati e nt m e di c al r e c or d s. P ati e 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 , ot h er 
t h a n t h o s e r el at e d t o E D S S/ F S S a s s e s s m e nt, wit h t h e e x a mi ni n g a s s e s s or i n or d er t o 
a v oi d p ot e nti al u n bli n di n g of t h e e x a mi ni n g a s s e s s or; t h e e x a mi ni n g a s s e s s or s h o ul d 
r e mi n d t h e p ati e nt of t hi s at t h e st art of t h e e x a mi n ati o n. At t h e pr ot o c ol -s p e cifi e d 
st u d y vi sit t h at i n cl u d e s a n E D S S/ F S S a s s e s s m e nt ( s e e A p p e n di x 1 ) fr o m b a s eli n e i n 
t h e d o u bl e-bli n d p eri o d , t h e e x a mi ni n g a s s e s s or will c o m pl et e a n d si g n a f or m w hi c h 
i n cl u d e s t h e ki n d of a s s e s s m e nt f or m e x a mi ni n g a s s e s s or u s e d f or a s s e s s m e nt a n d 
t h e c o nfir m ati o n of bli n di n g t h e p ati e nt m e di c al r e c or d, t h e st u d y -r el at e d d at a a p art 
fr o m E D S S/ F S S a n d i nf or m ati o n a p art fr o m n e ur ol o gi c al fi n di n g s si n c e t h e l a st 
E D S S/ F S S a s s e s s m e nt vi sit.
I n a d diti o n, sit e p er s o n n el, stu d y m o nit or, t h e S p o n s or a n d t h e st u d y t e a m will b e 
bli n d e d f or s o m e of t h e l a b or at or y r e s ult s (i n cl u di n g s er u m s atr ali z u m a b c o n c e ntr ati o n, 
h s C R P, I L -6, sI L -6 R, a nti -dr u g a nti b o d y [ A D A], a nti -A Q P 4 a nti b o di e s [ e x c e pt 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
s cr e e ni n g], pl a s m a bl a st s a n d c o m pl e m e nt [ C 3, C 4, a n d C H 5 0]) b ef or e t h e pri m ar y 
a n al y si s.
T h e st u d y bli n d s h o ul d n ot b e br o k e n e x c e pt i n a m e di c al e m er g e n c y ( w h er e 
k n o wl e d g e of t h e st u d y dr u g r e c ei v e d w o ul d aff e ct t h e tr e at m e nt of t h e e m er g e n c y) ,
r e g ul at or y r e q uir e m e nt (e. g. , f or S A E r e p orti n g), I D M C/I D C C or s a m pl e m a n a g e m e nt 
at l a b or at or y f or P K a n d i m m u n o g e ni cit y o bj e cti v e s.
T h e bli n d f or e a c h p ati e nt s h o ul d o nl y b e br o k e n f oll o wi n g di s c u s si o n b et w e e n t h e 
I n v e sti g at or a n d t h e P A R E X E L M e di c al M o nit or o n a c a s e -b y -c a s e b a si s.
T h e I n v e sti g at or s h o ul d n otif y t h e M e di c al M o nit or pri or t o c o nt a cti n g I x R S f or 
u n bli n di n g . All c all s r e s ulti n g i n a n u n bli n di n g e v e nt will b e r e c or d e d a n d r e p ort e d b y 
t h e I x R S t o t h e M e di c al M o nit or. If a n I n v e sti g at or, sit e p er s o n n el p erf or mi n g 
a s s e s s m e n t s, or p ati e nt, i s u n bli n d e d, t hi s m u st b e list e d a s m aj or pr ot o c ol vi ol ati o n .
T h e M e di c al M o nit or
a n d I n v e sti g at or s h o ul d c o n s ult e a c h ot h er t o d e ci d e w h et h er a 
p ati e nt w h o h a d hi s/ h er e m er g e n c y k e y c o d e br o k e n c a n e nt er t h e O L E p eri o d.
S eri o u s u n e x p e ct e d s u s p e ct e d a d v er s e r e a cti o n s, w hi c h ar e s u bj e ct t o e x p e dit e d 
r e p orti n g, s h o ul d b e u n bli n d e d b y a ut h ori z e d p er s o n n el of t h e S p o n s or w h o ar e n ot 
i n v ol v e d i n t h e s atr ali z u m a b cli ni c al tri al pr o gr a m b ef or e s u b mi s si o n t o t h e R e g ul at or y 
A ut h oriti e s .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4. 3 
S T U D Y T R E A T M E N T
4. 3. 1 
F or m ul ati o n , P a c k a gi n g a n d H a n dli n g
4. 3. 1. 1 
S atr ali z u m a b a n d Pl a c e b o
S atr ali z u m a b
I n v e sti g ati o n al pr o d u ct n a m e: 
S atr ali z u m a b ( al s o k n o w n a s S A 2 3 7 -1 2 0 )
A p p e ar a n c e:
C ol orl e s s t o sli g htl y y ell o w li q ui d
F or m ul ati o n
Li q ui d f or S C i nj e cti o n
M a n uf a ct uri n g pr o c e s s:
T h e dr u g s u b st a n c e m a n uf a ct uri n g pr o c e s s c o n si st s of a c ell 
c ult ur e pr o c e s s a n d a p urifi c ati o n pr o c e s s. T h e c ell li n e u s e d 
f or t h e c ell c ult ur e pr o c e s s i s g e n er at e d fr o m a C hi n e s e 
H a m st er O v ar y c ell li n e u si n g r e c o m bi n a nt d e o x yri b o n u cl ei c 
a ci d ( D N A) t e c h n ol o g y .
M a n uf a ct ur er:
Dr u g pr o d u ct i n v i al:
C h u g ai P h ar m a M a n uf a ct uri n g C o., Lt d.
5- 1, U ki m a, 5 -C h o m e, Kit a -k u
T o k y o, 1 1 5 -8 5 4 3, J a p a n
Dr u g pr o d u ct i n pl a sti c pr e fill e d syr i n g e (P F S ) wit h n e e dl e 
s af et y d e vi c e ( N S D) :
C h u g ai P h ar m a M a n uf a ct uri n g C o., Lt d.
1 6 -3 Ki y o h ar a -K o g y o d a n c hi, Ut s u n o mi y a 
T o c hi gi, 3 2 1 -3 2 3 1, J a p a n
C o m p o siti o n:
T h e dr u g pr o d u ct i s a vi al or a pl a sti c P F S wit h N S D fill e d 
wit h 1. 0 m L of s ol uti o n, w hi c h c o nt ai n 1 2 0 m g of 
s atr ali z u m a b . A s e x ci pi e nt s, it c o nt ai n s L-hi sti di n e, L -
ar gi ni n e, L - as p arti c a ci d a n d p ol y o x y e t h yl e n e ( 1 6 0) 
p ol y o x y pr o p yl e n e ( 3 0) gl y c ol, a n d it h a s a p H of 5. 5 t o 6. 5.
St or a g e c o n diti o n s:
T h e dr u g pr o d u ct i s st or e d at 2 -8° C, pr ot e ct e d fr o m li g ht u ntil 
u s e .
S atr ali z u m a b P F S wit h N S D c a n b e u s e d i n t h e e xt e n si o n p eri o d.
F or f urt h er d et ail s o n s atr ali z u m a b , s e e t h e c urr e nt I n v e sti g at or' s Br o c h ur e.
Pl a c e b o
S atr ali z u m a b pl a c e b o vi al i s i d e nti c al i n c o m p o siti o n t o s atr ali z u m a b vi al , b ut d o e s n ot 
c o nt ai n t h e s atr ali z u m a b a cti v e i n gr e di e nt. It will b e i d e nti c al i n a p p e ar a n c e a n d 
p a c k a gi n g t o s atr ali z u m a b .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
Kit i d e ntifi c ati o n (I D) n u m b er, l ot n u m b er a n d e x pir y d at e will b e l a b el e d. L o c al 
l a b eli n g m a y b e diff er e nt i n s o m e c o u ntri e s a c c or di n g t o l o c al r e g ul at or y g ui d eli n e s. 
P a c k a gi n g will b e t h e s a m e f or all c o u ntri e s e x c e pt J a p a n w h er e C h u g ai, a n d n ot t h e 
c o ntr a ct r e s e ar c h or g a ni z ati o n ( C R O ), will p erf or m t h e p a c k a gi n g. All s atr ali z u m a b
vi al s, pl a c e b o vi al s a n d s atr ali z u m a b P F S wit h N S D m u st b e st or e d at a c o ntr oll e d 
t e m p er at ur e of 2-8° C, a n d h a n dl e d a c c or di n g t o G o o d M a n uf a ct uri n g Pr a cti c e a n d 
G o o d Cli ni c al Pr a cti c e ( G C P) pr o c e d ur e s. A t e m p er at ur e l o g m u st b e k e pt r e c or di n g 
t h e st or a g e t e m p er at ur e of t h e s atr ali z u m a b vi al s, pl a c e b o vi al s a n d s atr ali z u m a b P F S
wit h N S D , a n d b e a v ail a bl e f or r e g ul ar r e vi e w b y t h e st u d y m o nit or. 
Pl e a s e r ef er t o t h e p h ar m a c y s e cti o n of t h e st u d y m a n u al f or d et ail s.
4. 3. 2 
D o s a g e, A d mi ni str ati o n a n d C o m pli a n c e
All st u d y c e nt er s will b e pr o vi d e d wit h a s u p pl y of s atr ali z u m a b a n d pl a c e b o aft er all 
t h e n e c e s s ar y d o c u m e nt ati o n i s i n pl a c e f or t h e st u d y b ut b efor e t h e fir st 
a d mi ni str ati o n of st u d y dr u g t o a p ati e nt. If a p ati e nt i s f o u n d t o b e eli gi bl e f or t h e 
st u d y, t h e I n v e sti g at or or d e si g n at e d p er s o n will b e i nf or m e d vi a t h e I x R S a s t o w hi c h 
c o d e d st u d y dr u g t o u s e f or i nj e cti o n.
S atr ali z u m a b 1 2 0 m g or pl a c e b o will b e a d mi ni st er e d b y S C i nj e cti o n i n t h e a b d o mi n al 
or f e m or al r e gi o n b y t h e I n v e sti g at or or d e si g n at e d p er s o n aft er all ot h er st u d y -r el at e d 
pr o c e d ur e s h a v e b e e n p erf or m e d f or t h at vi sit . T hi s will b e p erf or m e d at t h e st u d y 
c e nt er i n a s etti n g w h er e m e di c ati o n s f or tr e at m e nt of a n a p h yl a xi s a n d r e s u s cit ati o n 
f a ciliti e s ar e a v ail a bl e. P ati e nt s s h o ul d r e m ai n at t h e st u d y c e nt er f or at l e a st 1 h o ur i n 
or d er t o r e c ei v e tr e at m e nt i m m e di at el y if a n a p h yl a xi s o c c ur s. I n t h e e xt e n si o n p eri o d, 
S C i nj e cti o n s of s atr ali z u m a b m a y b e a d mi ni st er e d b y p ati e nt or h er/ hi s c ar e gi v er at 
t h e sit e i n J a p a n .
If st u d y dr u g c a n n ot b e a d mi ni st er e d wit hi n t h e s c h e d ul e d vi sit wi n d o w a n d i s 
s u b s e q u e ntl y a d mi ni st er e d o ut si d e t h e vi sit wi n d o w , t h e n e xt d o s e of st u d y dr u g 
s h o ul d b e a d mi ni st er e d o n s c h e d ul e ( mi ni m u m d o si n g i nt er v al s h o ul d b e 1 4 d a y s ).
Sit e st aff s h o ul d c o n s ult wit h t h e M e di c al M o nit or if i n d o u bt a s t o h o w t o s c h e d ul e 
d o si n g i n s u c h cir c u m st a n c e s.
4. 3. 2. 1 
S atr ali z u m a b a n d Pl a c e b o : D o u bl e-bli n d P eri o d
T h e p ati e nt will r e c ei v e a n S C i nj e cti o n of s atr ali z u m a b or pl a c e b o at W e e k s 0, 2 a n d 
4, a n d Q 4 W t h er e aft er d uri n g t h e d o u bl e-bli n d p eri o d. T h e d o u bl e -bli n d p eri o d e n d s 
w h e n eit h er t h e p ati e nt h a s a r el a p s e or t h e t ot al n u m b er of pr ot o c ol -d ef i n e d r el a p s e s
j u d g e d b y t h e C E C r e a c h e s 2 6 . 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4. 3. 2. 2 
S atr ali z u m a b : E xt e n si o n P eri o d
P ati e nt s w h o e x p eri e n c e a r el a p s e w hi c h i s tr e at e d wit h r e s c u e t h er a p y a n d/ or a 
pr ot o c ol -d ef i n e d r el a p s e w hi c h i s a dj u di c at e d b y C E C or w h o c o m pl et e t h e 
d o u bl e -bli n d p eri o d c a n e nt er t h e O L E
p eri o d . In t h e O L E
p eri o d, t h e p ati e nt will 
r e c ei v e a n S C i nj e cti o n of s atr ali z u m a b at W e e k s 0, 2 a n d 4, a n d Q 4 W t h er e aft er,
wit h t he l ast st u d y dr u g a d mi nistr ati o n o n or bef ore 3 1 Dece m ber 2 0 2 1 .
T h e p ati e nt s w h o ar e tr e at e d wit h r e s c u e t h er a p y d uri n g t h e d o u bl e-bli n d p eri o d c a n 
st art a d mi ni str ati o n of s atr ali z u m a b o n c e di s e a s e h a s st a bili z e d aft er t h e r e s c u e 
t h er a p y f or t h e r el a p s e, b et w e e n D a y 3 1 t o D a y 6 0, d efi ni n g t h e d a y of o n s et of 
r el a p s e i n t h e d o u bl e-bli n d p eri o d a s D a y 1. If s atr ali z u m a b c a n n ot b e a d mi ni st er e d b y 
D a y 6 0, t h e I n v e sti g at or s h o ul d c o n s ult wit h t h e M e di c al M o nit or. T h e p ati e nt s w h o 
ar e n ot tr e at e d wit h r e s c u e t h er a p y d uri n g t h e d o u bl e -bli n d p eri o d c a n e nt er t h e 
e xt e n si o n p eri o d aft er 4 w e e k s ( ± 7 d a y s) fr o m t h e l a st d o si n g i n t h e d o u bl e -bli n d 
p eri o d.
P ati e 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 e xt e n si o n p eri o d will c o nti n u e 
a d mi ni str ati o n of s atr ali z u m a b at t h e di s cr eti o n of t h e I n v e sti g at or.
I n t he O L E peri o d after Wee k 4 8, a n d i n acc or d a nce wit h l oc al re g ul ati o ns, 
a d mi nistr ati o n of s atr ali z u m a b prefille d s yri n ges o utsi de of t he st u d y site (e. g., self 
a d mi nistr ati o n or a d mi nistr ati o n b y a c are gi ver after c o m pleti n g tr ai ni n g, 
a d mi nistr ati o n b y t he p atie nt’s [l oc al] ge ner al p h ysici a n, or h o me a d mi nistr ati o n b y 
a m o bile n urse) will be all o we d i n e mer ge nc y sit u ati o ns s uc h as t he S A R S C o V -2 
( C O VI D-1 9) p a n de mic.
F oll o wi n g t he i m ple me nt ati o n of Pr ot oc ol Versi o n 1 1
a n d i n acc or d a nce wit h l oc al 
re g ul atio ns, a d mi nistr ati o n of s atr ali z u m a b prefille d s yri n ges o utsi de of t he st u d y 
site (e. g., self-a d mi nistr ati o n or a d mi nistr ati o n b y a c are gi ver after c o m pleti n g 
tr ai ni n g, or h o me a d mi nistr ati o n b y a m o bile n urse) m a y be all o we d o n sc he d ule d 
st u d y dr u g a d mi nistr ati o n d a ys t h at d o n ot re q uire a d diti o n al assess me nts t h at m ust 
be perf or me d o n site ( A p pe n di x 1 ).  
G ui d eli n e s f or d o s a g e m o difi c ati o n a n d tr e at m e nt i nt err u pti o n or di s c o nti n u ati o n ar e 
pr o vi d e d i n S e cti o n 5. 1 .
4. 3. 3 
I n ve sti g ati o n al M e di ci n al Pr o d u ct A c c o u nt a bilit y
All i n v e sti g ati o n al m e d i ci n al pr o d u ct s (I M P s) r e q uir e d f or c o m pl eti o n of t hi s st u d y 
(s atr ali z u m a b or pl a c e b o) will b e pr o vi d e d b y t h e S p o n s or or it s d e si g n e e . T h e 
i n v e sti g ati o n al sit e will a c k n o wl e d g e r e c ei pt of I M P s, u si n g t h e I xR S t o c o nfir m t h e 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
s hi p m e nt c o n diti o n a n d c o nt e nt. S e e t h e st u d y m a n u al f or d et ail s of pr o c e d ur e s f or 
h a n dli n g t e m p er at ur e e x c ur si o n s. A n y d a m a g e d s hi p m e nt s will b e r e pl a c e d. 
I MP m a y b e di s p o s e d of at t h e st u d y sit e a c c or di n g t o t h e st u d y sit e’ s i n stit uti o n al 
st a n d ar d o p er ati n g pr o c e d ur e. T h e sit e' s m et h o d of I M P d e str u cti o n m u st b e a gr e e d 
u p o n b y t h e S p o n s or or it s d e si g n e e . T h e sit e m u st o bt ai n writt e n a ut h ori z ati o n fr o m 
t h e S p o n s or or it s d e si g n e e b ef or e a n y I M P i s d e str o y e d a n d I M P d e str u cti o n m u st b e 
d o c u m e nt e d o n t h e a p pr o pri at e f or m.
A c c ur at e r e c or d s of all I M P s r e c ei v e d at t h e sit e, di s p e n s e d fr o m t h e sit e, a n d 
r et ur n e d t o t h e S p o n s or or d e si g n e e, or di s p o s e d of b y t h e st u d y sit e s h o ul d 
b e r e c or d e d. 
If p atie nts are a d mi nistere d s atr ali z u m a b o utsi de of t he st u d y site, I M P m a y be 
s hi p pe d t o t he p atie nt’s h o me fr o m t he st u d y site ( o nl y i n e mer ge nc y sit u ati o ns , s uc h 
as t he S A R S -C o V -2 [ C O VI D -1 9] p a n de mic) or gi ve n t o t he p atie nt t o t a ke h o me 
d uri n g a st u d y site visit.  P atie nts will be as ke d t o ret ur n all I M P b o xes at t heir ne xt 
o n -site visit.
Pl e a s e r ef er t o t h e p h ar m a c y s e cti o n of t h e st u d y m a n u al f or d et ail s r e g ar di n g I M P 
di s p e n s ati o n, r et ur n a n d d e str u cti o n.




S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
4 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
* C o m bi n ati o n wit h o r al c orti c o st er oi d s (1 5 m g/ d a y [pr e d ni s ol o n e e q ui v al e nt ]) i s 
p er mitt e d i n p ati e nt s a g e d 1 2 t o 1 7 y e ar s at t h e ti m e of i nf or m e d c o n s e nt.
2.
R e s c u e t h er a p y f or cli ni c al r el a p s e (l e a d s t o e n d of t h e d o u bl e-bli n d p eri o d) ; p ul s e 
I V c orti c o st er oi d s, i ntr a v e n o u s i m m u n o gl o b uli n (I VI G), a n d/ or a p h er e si s (i n cl u di n g 
pl a s m a e x c h a n g e a n d pl a s m a p h er e si s).
R e s c u e t h er a p y s h o ul d pr o c e e d at t h e di s cr eti o n of t h e tr e ati n g I n v e sti g at or aft er 
t h e e x a mi ni n g a s s e s s or h a s c o m pl et e d E D S S/ F S S a s s e s s m e nt at e xtr a vi sit at 
r el a p si n g ( e x c e pt i n c a s e of e m er g e n c y w h e n ur g e nt tr e at m e nt i s r e q uir e d b ef or e 
t h e p ati e nt c a n u n d er g o t hi s a s s e s s m e nt).
3.
P ai n m e di c ati o n s (i n cl u di n g b ut n ot li mit e d t o pr e g a b ali n, g a b a p e nti n, 
c ar b a m a z e pi n e, cl o n a z e p a m, d ul o x eti n e, tr a m a d ol/ a c et a mi n o p h e n) .
St arti n g of p ai n m e di c ati o n s i s p er mitt e d, h o w e v er t h e d o s e s h o ul d b e st a bl e 
d uri n g t h e d o u bl e -bli n d p eri o d . I n c a s e p ai n c o ntr ol i s i n s uffi ci e nt, d o s e i n cr e a s e or 
c h a n g e of p ai n m e di c ati o n i s p er mitt e d. D o s e d e cr e a s e a n d t e m p or ar y tr e at m e nt 
s u s p e n si o n ar e p er mitt e d f or o nl y s af et y r e a s o n s . 
P er mitt e d M e di c ati o n/ T h er a p y D uri n g t h e E xt e n si o n P eri o d (In cl u di n g 
A ft er R el a p s e i n t h e Do u bl e - Bli n d P eri o d )
1.
B a s eli n e tr e at m e nt (f or p ati e nt s wit h n o r el a p s e i n t h e d o u bl e-bli n d p eri o d or 
e xt e n si o n p eri o d ). 
O n e of t h e dr u g s li st e d b el o w i s p er mitt e d a s m o n ot h er a p y f or b a s eli n e tr e at m e nt. 
T h e d o s e m u st n ot e x c e e d t h e d o s e d efi n e d b el o w. C h a n g e or t er mi n ati o n of 
b a s eli n e tr e at m e nt i s p er mitt e d.
 
A z at hi o pri n e *: 3 m g/ k g/ d a y 
 
M y c o p h e n ol at e m of etil *: 3 0 0 0 m g/ d a y 
 
Or al c orti c o st er oi d s: 1 5 m g/ d a y ( pr e d ni s ol o n e e q ui v al e nt)
* C o m bi n ati o n wit h or al c orti c o st er oi d s ( 1 5 m g/ d a y [pr e d ni s ol o n e e q ui v al e nt ]) i s 
p er mitt e d i n p ati e nt s a g e d 1 2 t o 1 7 y e ar s at t h e ti m e of i nf or m e d c o n s e nt. 
2.
B a s eli n e tr e at m e nt (f or p ati e nt s w h o h a v e e x p eri e n c e d r el a p s e i n t h e d o u bl e-bli n d 
p eri o d or e xt e n si o n p eri o d ).
O n e of t h e f oll o wi n g m ai nt e n a n c e tr e at m e nt s i s p er mitt e d. T h e d o s e m u st n ot 
e x c e e d t h e d o s e d efi n e d b el o w. C h a n g e of b a s eli n e tr e at m e nt i s p er mitt e d.
 
A z at hi o pri n e ( 3 m g/ k g/ d a y) ± or al c orti c o st er oi d s ( 1
m g/ k g/ d a y; pr e d ni s ol o n e 
e q ui v al e nt).
Or al c orti c o st er oi d m a y b e t a p er e d off a c c or di n g t o t h e st a n d ar d l o c al 
t a p eri n g r e gi m e n at t h e sit e .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
M y c o p h e n ol at e m of etil ( 3 0 0 0
m g/ d a y) ± or al c orti c o st er oi d s ( 1
m g/ k g/ d a y; 
pr e d ni s ol o n e e q ui v al e nt).
Or al c orti c o st er oi d m a y b e t a p er e d off a c c or di n g t o t h e st a n d ar d l o c al 
t a p eri n g r e gi m e n at t h e sit e.
 
Or al c orti c o st er oi d s: 1 m g/ k g/ d a y ( pr e d ni s ol o n e e q ui v al e nt). 
Or al c orti c o st er oi d s m a y b e t a p er e d t o 1 5 m g/ d a y or l e s s a c c or di n g t o t h e 
st a n d ar d l o c al t a p eri n g r e gi m e n at t h e sit e .
3.
R e s c u e t h er a p y f or cli ni c al r el a p s e; p ul s e I V c orti c o st er oi d s , I VI G, a n d/ or 
a p h er e si s (i n cl u di n g pl a s m a e x c h a n g e a n d pl a s m a p h er e si s) .
R e s c u e t h er a p y s h o ul d pr o c e e d at t h e di s cr eti o n of t h e tr e ati n g I n v e sti g at or aft er 
t h e e x a mi ni n g a s s e s s or h a s c o m pl et e d E D S S/ F S S a s s e s s m e nt at e xtr a vi sit at 
r el a p si n g ( e x c e pt i n c a s e of e m er g e n c y w h e n ur g e nt tr e at m e nt i s r e q uir e d b ef or e 
t h e p ati e nt c a n u n d er g o t hi s a s s e s s m e nt). S atr ali z u m a b tr e at m e nt c a n b e 
c o nti n u e d a s s c h e d ul e d, c o n c urr e ntl y wit h r e s c u e t h er a p y, u nl e s s t h e I n v e sti g at or 
c o n si d er s it n e c e s s ar y t o wit h dr a w t h e p ati e nt.
4.
P ai n m e di c ati o n (i n cl u di n g b ut n ot li mit e d t o pr e g a b ali n, g a b a p e nti n, 
c ar b a m a z e pi n e, cl o n a z e p a m, d ul o x eti n e, tr a m a d ol/ a c et a mi n o p h e n) .
5.
D uri n g t he O L E peri o d:  Tre at me nt wit h c ortic oster oi ds ( e. g., or al, n as al) f or 
A Es (i.e., i n dic ati o ns ot her t h a n b aseli ne t her a p y or resc ue t her a p y ) is per mitte d; 
t he tre at me nt d ur ati o n s h o ul d be ke pt as s h ort as p ossible. 
T h e r ati o n al e f or t h e p er mitt e d b a s eli n e tr e at m e nt i s pr o vi d e d i n S e cti o n 3. 2. 2 .
4. 4. 2 
Pr o hi bit e d T h er a p i e s
1.
A nti -C D 2 0 tr e at m e nt ( e. g. , rit u xi m a b, o cr eli z u m a b, of at u m u m a b) wit hi n 6 m o nt h s 
pri or t o b a s eli n e u ntil t h e e n d of t h e st u d y.
2.
I L-6 i n hi bit or y t h er a p y ( e. g. , t o cili z u m a b), al e mt u z u m a b, t ot al b o d y irr a di ati o n, 
b o n e m arr o w tr a n s pl a nt ati o n pri or t o a n d t hr o u g h o ut t h e st u d y .
3.
E c uli z u m a b wit hi n 6 m o nt h s pri or t o b a s eli n e u ntil t h e e n d of t h e st u d y.
4.
A nti - B-l y m p h o c yt e sti m ul at or ( B L y S) m o n o cl o n al a nti b o d y ( e. g. , b eli m u m a b) wit hi n 
6 m o nt h s pri or t o b a s eli n e u ntil t h e e n d of t h e st u d y.
5.
I m m u n o s u p pr e s s a nt s ar e pr o hi bit e d fr o m 8 w e e k s pri or t o b a s eli n e u ntil t h e e n d of 
t h e st u d y, e x c e pt f or a z at hi o pri n e a n d m y c o p h e n ol at e m of etil .
6.
A n y ot h er tr e at m e nt f or pr e v e nti o n of M S r el a p s e ( e. g. , I F N, gl atir a m er a c et at e , 
fi n g oli m o d, n at ali z um a b, t erifl u n o mi d e, di m et h yl f u m ar at e)
wit hi n 6 m o nt h s pri or t o 
b a s eli n e u ntil t h e e n d of st u d y .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
7.
A nti -C D 4, cl a dri bi n e, mit o x a ntr o n e
wit hi n 2 y e ar s pri or t o b a s eli n e u ntil t h e e n d of 
t h e st u d y.
8.
I m m u ni z ati o n wit h li v e or li v e att e n u at e d v a c ci n e wit hi n 6 w e e k s pri or t o b a s eli n e 
u ntil t h e e n d of t h e st u d y .
9.
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 ( ot h er t h a n s atr ali z u m a b ) wit hi n 3 m o nt h s 
pri or t o b a s eli n e u ntil t h e e n d of t h e st u d y.
4. 5 
S T U D Y A S S E S S M E N T S 
4. 5. 1 
D e s cri pti o n of St u d y  As s e s s m e nt s
4. 5. 1. 1 
M e di c al Hi st or y  a n d D em o gr a p hi c D at a
M e di c al hi st or y r ef er s t o cli ni c all y si g nifi c a nt di s e a s e s, i n cl u d i n g b ut n ot li mit e d t o 
m e di c ati o n all er gi e s, a n a p h yl a xi s, c a n c er, d e m y eli n ati n g di s e a s e ot h er t h a n N M O a n d 
N M O S D, n e ur ol o gi c di s or d er s, p s y c hi atri c di s or d er s, r h e u m at ol o gi c di s or d er s, 
m u s c ul o s k el et al di s e a s e s, c ar di o v a s c ul ar di s e a s e, p ul m o n ar y di s e a s e, 
g a str oi nt e sti n al di s e a s e s i n cl u di n g h e p ati c di s e a s e s, h e m at ol o gi c di s or d er s a n d r e n al 
di s e a s e .
D e m o gr a p hi c d at a will i n cl u d e a g e ( d at e of birt h), s e x a n d r a c e/ et h ni cit y . T h e s e d at a 
ar e r e q uir e d i n or d er t o p erf or m s u b gr o u p a n al y s e s t o e v al u at e t h e c o n si st e n c y of t h e 
r e s ult s a cr o s s r a c e/ et h ni c gr o u p s. T h e I n v e sti g at or will r e c or d i n t h e e C R F d et ail s of 
t h e p ati e nt ’ s fir st d o c u m e nt e d att a c k of N M O/ N M OS D , i ncl u di n g t he d ate of N M O or 
N M O S D di a g n osis,
a n d a n y s u b s e q u e nt r el a p s e( s) . H ei g ht will b e r e c or d e d at 
b a s eli n e a n d b o d y w ei g ht will b e r e c or d e d at b a s eli n e a n d e v er y 2 4 w e e k s t h er e aft er.
4. 5. 1. 2 
H e p atiti s B S cr e e ni n g
P ati e nt s w h o ar e 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 will b e e x cl u d e d fr o m 
t h e st u d y. 
P ati e nt s f or w h o m a p o siti v e r e s ult f or a nti b o d y t o h e p atiti s B s urf a c e a nti g e n ( H B s A b) 
i s cl e arl y a s s o ci at e d wit h v a c ci n ati o n a g ai n st h e p atiti s B vir u s c a n b e e nr oll e d. If n ot, 
h e p atiti s B vir al D N A will b e m e a s ur e d at a c e ntr al l a b or at or y.
If t ot al h e p atiti s B c or e a nti b o d y (H B c A b ) st at u s i s p o siti v e, h e p atiti s B vir al D N A will 
b e m e a s ur e d at a c e ntr al l a b or at or y . 
If h e p atiti s B vir al D N A i s u n d et e ct a bl e, t h e p ati e nt m a y b e e nr oll e d. I n t h e s e c a s e s 
h e p atiti s B vir al D N A m e a s ur e m e nt s m u st b e p erf or m e d r e g ul arl y at a p pr o xi m at el y 
1 2 -w e e kl y i nt er v al s d uri n g t h e st u d y . If h e p atiti s B vir al D N A i s d et e ct a bl e, t h e p ati e nt 
m u st b e e x cl u d e d.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4. 5. 1. 3 
H e p atiti s C s cr e e ni n g
P ati e nt s wit h n e g ati v e H e p atiti s C s er ol o g y c a n b e e nr oll e d .
P ati e nt s wit h p o siti v e H e p atiti s C s er ol o g y will b e e x cl u d e d fr o m t h e st u d y . Ho w e v er, if 
h e p atiti s C vir u s ( H C V) r i b o n u cl ei c a ci d ( R N A) i s u n d et e ct a bl e 1 2 w e e k s aft er H C V 
tr e at m e nt c o m pl eti o n , t h e p ati e nt c a n b e e nr oll e d.
4. 5. 1. 4 
S cr e e ni n g f or T u b er c ul o si s
F or e ntr y i nt o t hi s st u d y, p ati e nt s s h o ul d b e s cr e e n e d f or T B at t h e sit e a c c or di n g t o
t h e i n str u cti o n f or T B s cr e e ni n g (s e e A p p e n di x 1 4 ). T h e r e s ult s of t h e s cr e e ni n g t e st s 
will b e r e p ort e d o n t h e e C R F. If t h e p ati e nt i s p o siti v e f or l at e nt T B, t h e n a p pr o pri at e 
a nti -m y c o b a ct eri al t h er a p y m u st st art f or t h e p ati e nt at l e a st 3 w e e k s b ef or e i niti ati n g 
st u d y dr u g a d mi ni str ati o n i n t hi s st u d y.
F or f urt h er d et ail s o n s cr e e ni n g f or T B, s e e A p p e n di x 1 4 .
4. 5. 1. 5 
A n ti-A Q P 4 A nti b o d y at S cr e e ni n g
A n a n ti-A Q P 4 a nti b o d y s cr e e ni n g a s s e s s m e nt will b e c o n d u ct e d at s cr e e ni n g. If t h e 
r e s ult of a nti- AQ P 4 a nti b o d y at s cr e e ni n g i s n e g ati v e i n p ati e nt s w h o m u st b e p o siti v e 
f or a nti -A Q P 4 a nti b o d y at s cr e e ni n g ( s e e in cl u si o n crit eri a 1) , a bl o o d s a m pl e 
c oll e ct e d b ef or e t h e s cr e e ni n g vi sit c a n b e u s e d f or t h e s cr e e ni n g a s s e s s m e nt f or a nti -
A Q P 4 a nti b o d y. I n t h at c a s e, t h e bl o o d s a m pl e s h o ul d b e s e nt t o S p o n s or’ s d e si g n e e 
f or a n al y si s a n d m e a s ur e d.
4. 5. 1. 6 
M a g n eti c R e s o n a n c e I m a gi n g at S cr e e ni n g
P ati e nt s w h o ar e cl a s sifi e d a s P M L b a s e d o n t h e l o c al i m a gi n g a s s e s s m e nt will b e 
e x cl u d e d. If p ati e nt s w h o s h o w l e si o n s s u s pi ci o u s f or P M L b y br ai n M RI, J C vir u s i n 
t h e C S F will b e m e a s ur e d - if “ d et e ct a bl e” or “ u n d et e ct a bl e wit h hi g h cli ni c al 
s u s pi ci o n”, t h e p ati e nt m u st b e e x cl u d e d.
P ati e nt s w h o ar e a nti -A Q P 4 a nti b o d y n e g ati v e a n d h a v e a n M RI wit h cl a s si c M S 
f e at ur e s o n T 2 w ei g ht e d i m a gi n g wit h D a w s o n’ s fi n g er s, a dj a c e nt t o l at er al v e ntri cl e s, 
j u xt a c orti c al a n d/ or c orti c al l e si o n s m u st al s o b e e x cl u d e d.
S e e t h e r el e v a nt m a n u al f or f urt h er d et ail s.
4. 5. 1. 7 
Vit al Si g n s
Vit al si g n s will i n cl u d e m e a s ur e m e nt s of p ul s e r at e, t e m p er at ur e a n d S B P a n d D B P 
w h il e t h e p ati e nt i s i n a s e at e d p o siti o n for at l e a st 5 mi n ut e s . At t h e i nj e cti o n vi sit, v it al 
si g n s will b e m e a s ur e d b ef or e a n d aft er st u d y dr u g a d mi ni str ati o n . M e a s ur e m e nt of 
p ul s e r at e, t e m p er at ur e, S B P a n d D B P s h o ul d t a k e pl a c e i m m e di at el y b ef or e a n d t h e n 
at 1 5 ( ± 5) a n d 6 0 ( ± 5) mi n ut e s aft er st u d y dr u g a d mi ni str ati o n.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4. 5. 1. 8 
P h y si c al E x a mi n ati o n
A c o m pl et e p h y si c al e x a mi n ati o n s h o ul d i n cl u d e a n e v al u ati o n of t h e h e a d, n e c k, e y e s , 
e ar s , n o s e a n d t hr o at, a n d t h e c ar di o v a s c ul ar, d er m at ol o gi c al, m u s c ul o s k el et al,
r e s pir at or y, g a str oi nt e sti n al a n d g e nit o ur i n ar y s y st e m s. T h er e s h o ul d b e a d et ail e d 
e x a mi n ati o n of n e ur ol o gi c al s y st e m s. A n y a b n or m alit y i d e ntifi e d at b a s eli n e s h o ul d b e 
r e c or d e d o n t h e G e n er 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 e C R F.
At s u b s e q u e nt vi sit s, li mit e d, s y m pt o m -dir e ct e d p h y si c al e x a mi n ati o n s s h o ul d b e 
p erf or m e d. C h a n g e s fr o m b a s eli n e a b n or m aliti e s s h o ul d b e r e c or d e d i n p ati e nt n ot e s. 
N e w or w or s e n e d 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 E s o n t h e A d v er s e E v e nt 
p a g e of t h e e C R F.
4. 5. 1. 9 
Effi c a c y  As s e s s m e nt s
R el a p s e A s s e s s m e nt
R el a p s e a s s e s s m e nt i s d et ail e d i n S e cti o n 4. 5. 3 .
E x p a n d e d Di s a bilit y  St at u s S c al e
T h e E D S S i s fr e q u e ntl y u s e d a s a q u a ntit ati v e m e a s ur e of di s a bilit y a n d f or 
a s s e s s m e nt of s e v erit y of r el a p s e f or p ati e nt s wit h M S a s w ell a s N M O, a n d i s 
i n cl u d e d a s a s e c o n d ar y e n d p oi nt i n t hi s st u d y. It i s a w ell-e st a bli s h e d s c al e t h at h a s 
b e e n u s e d i n m o st m aj or M S cli ni c al tri al s f or m a n y y e ar s ( K urt z k e 1 9 8 3). 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, t h e E D S S q u a ntifi e s di s a bilit y i n f u n cti o n al 
s y st e m s a n d all o w s n e ur ol o gi st s t o a s si g n a n F S S i n e a c h of t h e s e. E a c h of t h e F S S 
i s a n or di n al cli ni c al r ati n g r a n gi n g fr o m 0 t o 5 or 6. T h e s e f u n cti o n al 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 g ait a n d t h e u s e of 
a s si st e d d e vi c e s t o r at e t h e E D S S. T h e E D S S i s a n or di n al s c al e wit h v al u e s fr o m 
0 p oi nt s ( n or m al n e ur ol o gi c al e x a mi n ati o n) u p t o 1 0 p oi nt s ( d e at h), i n cr e a s i n g i n 
i n cr e m e nt s of 0. 5 p oi nt s.
I n a d diti o n t o t h o s e F S S, t h e si n gl e e y e F S S ( s e e t h e m at eri al f or E D S S/ F S S s c ori n g) 
i s a s s e s s e d t o c o nfir m w h et h er a r el a p s e h a s o c c u rre d .
A r ef er e n c e t o t h e E D S S/ F S S i s i n cl u d e d i n A p p e n di x 2 .
H e alt h St at u s M e a s ur e m e nt s U si n g S h ort F or m -3 6
T h e S F -3 6 i s a m ulti -p ur p o s e, s h ort -f or m h e alt h s ur v e y wit h 3 6 q u e sti o n s. It yi el d s a n 
8- s c al e pr ofil e ( vit alit y, p h y si c al f u n cti o ni n g, b o dil y p ai n, g e n er al h e alt h, r ol e-p h y si c al, 
r ol e-e m oti o n al, s o ci al r ol e f u n cti o ni n g a n d m e nt al h e alt h) of f u n cti o n al h e alt h a n d w ell -
b ei n g s c or e s a s w ell a s p s y c h o m etri c all y -b a s e d p h y si c al a n d m e nt al h e alt h s u m m ar y 
m e a s ur e s a n d a pr ef er e n c e -b a s e d h e al t h utilit y i n d e x. It i s a g e n eri c m e a s ur e, a s 
o p p o s e d t o o n e t h at t ar g et s a di s e a s e, or tr e at m e nt gr o u p. 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A r ef er e n c e t o t h e S F-3 6 q u e sti o n n air e i s i n cl u d e d i n A p p e n di x 3 .
Vi s u al A n al o g u e S c al e f or P ai n
T h e V A S f or p ai n i s a s c al e 1 0 0 m m i n l e n gt h t h at t h e p ati e nt u s e s t o r at e t h e i nt e n sit y 
of  t h e p ai n t h e y e x p eri e n c e, fr o m n o p ai n t o p ai n a s b a d a s it c o ul d b e.
A r ef er e n c e t o t h e V A S f or p ai n i s i n cl u d e d i n A p p e n di x 4 .
F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s T h er a p y  ( F ACI T) F ati g u e S c al e
T h e F A CI T f ati g u e s c al e i s a s h ort, 1 3 -it e m t o ol t h at m e a s ur e s a n d i n di vid u al’ s l e v el of 
f ati g u e d uri n g t h eir u s u al d ail y a cti viti e s o v er t h e p a st 7 d a y s ( W e b st er et al. 2 0 0 3) . 
T h e l e v el of f ati g u e i s m e a s ur e d o n a fi v e -p oi nt s c al e ( 0 n ot at all t o 4 v er y m u c h). 
A r ef er e n c e t o t h e F A CI T F ati g u e s c al e i s i n cl u d e d i n A p p e n di x 5 .
Vi s u al F u n cti o n T e sti n g
Vi s u al f u n cti o n t e sti n g will b e p erf or m e d wit h e y e c h art s .
Vi s u al a c uit y will b e m e a s ur e d b y a S n ell e n 2 0 -f o ot w all c h art. T h e t e st will b e 
p erf or m e d m o n o c ul arl y a n d p a ti e nts m a y u s e t h eir h a bit u al di st a n c e gl a s s e s or 
c o nt a ct l e n s e s.
T h e s a m e vi s u al a c uit y t e sti n g m et h o d i s t o b e e m pl o y e d f or all st u d y vi sit s f or e a c h 
p ati e nt .
O t h er vi s u al f u n cti o n ( e. g., vi s u al fi el d s) will b e a s s e s s e d f or E D S S/ F S S a s s e s s m e nt 
a s w ell a s vi s u al a c uit y.
Di s a bilit y  T e sti n g u si n g M o difi e d R a n ki n S c al e
T h e m R S i s a c o m m o nl y u s e d s c al e f or m e a s uri n g t h e d e gr e e of di s a bilit y or 
d e p e n d e n c e i n t h e d ail y a cti viti e s of p e o pl e w h o h a v e s uff er e d a str o k e or ot h er 
c a u s e s of n e ur ol o gi c al di s a bilit y. T h e m R S i s s c or e d fr o m
0 ( n o s y m pt o m s at all) t o 
6 ( d e at h).
A r ef er e n c e t o t h e m R S i s i n cl u d e d i n A p p e n di x 6 .
Z arit B ur d e n I nt er vi e w
T h e Z BI i s a p o p ul ar c ar e gi v er s elf -r e p ort m e a s ur e t h at ori gi n at e d a s a 2 9-it e m 
q u e sti o n n air e ( Z arit, R e e v er & B a c h -P et er s o n, 1 9 8 0). T h e r e vi s e d v er si o n c o nt ai n s 
2 2 it e ms. E a c h it e m o n t h e i nt er vi e w i s a st at e m e nt w hi c h t h e c ar e gi v er i s a s k e d t o 
e n d or s e u si n g a 5 -p oi nt s c al e. 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T h e Z BI s h o ul d b e c o n d u ct e d f or t h e p ati e nt’ s c ar e gi v er ( e. g., f amil y m e m b er or 
r el ati v e) ( w h e n t h er e i s o n e), if t h e I n v e sti g at or c o n si d er s t h e c ar e gi v er t o b e r eli a bl e 
i n r e p orti n g t h e p ati e nt' s d ail y lif e. Th e c ar e gi v er h a s k n o wl e d g e of t h e p ati e nt' s 
c o n diti o n a n d s y m pt o m s a n d i s a cti n g i n a n i nf or m al or u n p ai d c a p a cit y . C ar e gi v er s 
will b e a s k e d t o si g n a s e p ar at e writt e n i nf or m e d c o n s e nt f or t h e c oll e cti o n of d at a 
u si n g t h e Z BI. If a c ar e gi v er wit h dr a w s fr o m t h e st u d y, t h e a s s e s s m e nt of t h e Z BI i s 
t er mi n at e d.
A r ef er e n c e t o t h e Z BI q u e sti o n n air e i s i n cl u d e d i n A p p e n di x 7 .
E Q -5 D
T h e E Q -5 D s c al e i s a g e n eri c m e a s ur e of h e alt h r el at e d q u alit y of lif e t h at r at e s 
p ati e nt h e alt h st at e l o o ki n g at fi v e s p e cifi c di m e n si o n s s u c h a s m o bilit y, s elf -c ar e, 
u s u al a cti vit y, p a i n/ di s c o mf ort a n d a n xi et y/ d e pr e s si o n a n d s c or e t h eir g e n er al h e alt h 
st at e .
A r ef er e n c e t o t h e E Q-5 D q u e sti o n n air e i s i n cl u d e d i n A p p e n di x 8 .
4. 5. 1. 1 0 
C ol u m bi a- S ui ci d e S e v erit y R ati n g S c al e ( C -S S R S)
T h e C- S S R S i s a t o ol u s e d t o a s s e s s t h e lif eti m e s ui ci d alit y of a p ati e nt a n d t o tr a c k 
s ui ci d al e v e nt s t hr o u g h t h e tr e at m e nt. T h e s c al e will b e a d mi ni st er e d at t h e ti m e 
p oi nt s i n di c at e d i n t h e S c h e d ul e ( S e e A p p e n di x 1 ) for pr o m pt r e c oll e cti o n of s ui ci d al 
i d e ati o n, i n cl u di n g t h e i nt e n sit y of t h e i d e ati o n, b e h a vi or a n d att e m pt s wit h 
a ct u al/ p ot e nti al l et h alit y. T h e “ C-S S R S at b a s eli n e ” will b e c oll e ct e d at b a s eli n e a n d 
t h e “ C-S S R S si n c e l a st vi sit” will b e c oll e ct e d at s u b s e q u e nt vi sit s.
If a p ati e nt h a s alr e a d y r e c ei v e d st u d y dr u g b ef or e C- S S R S b e c o m e s a v ail a bl e f or t hi s 
st u d y , t h e p ati e nt s h o ul d b e a s s e s s e d b y th e “ C -S S R S alr e a d y e nr oll e d s u bj e ct s” at 
t h e fir st vi sit aft er C- S S R S b e c o m e s a v ail a bl e f or t hi s st u d y, a n d t h e “ C-S S R S si n c e 
l a st vi sit” s h o ul d b e c oll e ct e d at s u b s e q u e nt vi sit s.
R ef er e n c e s t o t h e C- S S R S f or m ar e i n cl u d e d i n A p p e n di x 1 0 ( C-S S R S at b a s eli n e ), 
A p p e n di x 1 1 ( C-S S R S si n c e l a st vi sit) a n d A p p e n di x 1 2 ( C-S S R S alr e a d y e nr oll e d 
s u bj e ct s) .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4. 5. 1. 1 1 
L a b or at or y  As s e s s m e nt s
S a m pl e s f or t h e f oll o wi n g l a b or at or y t e st s ( e x c e pt uri n al y si s a n d pr e g n a n c y t e st s ) will 
b e s e nt t o t h e C e ntr al L a b or at or y f or a n al y si s. I n str u cti o n m a n u al s a n d s u p pl y kit s will 
b e pr o vi d e d f or all c e ntr al l a b or at or y a s s e s s m e nt s. If a p atie nt c a n n ot visit t he st u d y 
site i n e mer ge nc y sit u ati o ns li ke t he S A R S -C o V -2 ( C O VI D -1 9) p a n de mic, l a b or at or y 
tests m a y be perf or me d at a l oc al l a b or at or y i n acc or d a nce wit h l oc al re g ul ati o ns.
 
H e m at ol o g y ( h e m o gl o bi n, h e m at o crit, pl at el et c o u nt, i nter n ati o n al n or m ali z e d 
r ati o (I N R), r e d bl o o d c ell ( R B C) c o u nt, W B C c o u nt, a b s ol ut e diff er e nti al c o u nt 
[ n e utr o p hil s, e o si n o p hil s, l y m p h o c yt e s, m o n o c yt e s, b a s o p hil s, ot h er c ell s])
 
S er u m c h e mi str y ( s o di u m, p ot a s si u m, c hl ori d e, c al ci u m, p h o s p h or o u s, f erriti n, 
bl o o d ur e a nitr o g e n ( B U N), cr e ati ni n e, t ot al bilir u bi n, fi bri n o g e n, t ot al pr ot ei n, 
al b u mi n, A L T, A S T, al k ali n e p h o s p h at a s e, g a m m a -gl ut a m yl tr a n s p e pti d a s e, 
l a ct at e d e h y dr o g e n a s e ( L D H), t ot al c h ol e st er ol, l o w d e n sit y li p o pr ot ei n ( L D L) 
c h ol e st er ol, hi g h d e n si t y li p o pr ot ei n ( H D L) c h ol e st er ol, tri gl y c eri d e s, cr e ati n e 
ki n a s e ( C K), uri c a ci d)
 
Uri n al y si s ( uri n ar y gl u c o s e, uri n ar y pr ot ei n, uri n ar y o c c ult bl o o d, ur o bili n o g e n)
will 
b e c o n d u ct e d at e a c h sit e b y di p sti c k .
 
Pr e g n a n c y t e st :
All f em al e
p ati e nt s of c hil d b e a ri n g p ot e nti al (i n cl u di n g t h o s e w h o h a v e h a d a t u b al 
li g ati o n) will h a v e a s er u m pr e g n a n c y t e st at t h e st u d y sit e at t h e s cr e e ni n g vi sit . 
D uri n g t h e st u d y, s er u m or uri n e pr e g n a n c y t e st s will b e p erf or m e d at sit e , a n d 
c o nfir m e d a s n e g ati v e b ef or e t h e a d mi n i str ati o n of  st u d y dr u g ( e x c e pt W e e k 2 of 
d o u bl e -bli n d a n d e xt e n si o n p eri o d) . F or p ati e nt s a g e d 1 2 t o 1 7 at t h e ti m e of 
i nf or m e d c o n s e nt, uri n e β-h C G will b e r e c o m m e n d e d d uri n g t h e st u d y e x c e pt 
s cr e e ni n g i n or d er t o r e d u c e t h e bl o o d v ol u m e t a k e n ( s e e A p p e n di x 1 3 ). If a uri n e 
pr e g n a n c y t e st i s p o siti v e, it m u st b e c o nfir m e d b y a s er u m pr e g n a n c y t e st. 
D uri n g t h e st u d y pr e g n a n c y t e st s ( s er u m or uri n e) m u st h a v e a s e n siti vit y of at 
l e a st 2 5 mI U/ m L.
P atie nts w h o d o n ot meet t he criteri a f or c hil d be ari n g p ote nti al 
d uri n g t he O L E peri o d of t he st u d y (e. g., c o nfir me d p ostme n o p a us al st at us) will 
n ot re q uire f urt her pre g n a nc y testi n g. I n or d er t o q u alif y f or a n d t o r e m ai n i n t h e 
st u d y, t h e p ati e nt m u st h a v e a n e g ati v e pr e g n a n c y t e st , e vi d e n c e of s ur gi c al 
st erilit y or e vi d e n c e of p o st -m e n o p a u s al st at u s . P o st m e n o p a u s al st at u s i s d efi n e d 
a s a n y of t h e f oll o wi n g: n at ur al m e n o p a u s e wit h m e n s e s 1 y e ar a g o; r a di ati o n -
i n d u c e d wit h l a st m e n s e s 1 y e ar a g o , or bil ater al o o p h orect o m y.
 
C o m pl e m e nt t e st s ( C 3, C 4 a n d C H 5 0)
 
P l a s m a bl a st s ( bl o o d s a m pl e will b e c oll e ct e d i n U nit e d Ki n g d o m, Fr a n c e, 
G er m a n y, J a p a n a n d T ai w a n), h s C R P


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
S a m pl e s f or t h e f oll o wi n g l a b or at or y t e st s will b e s e nt t o t h e S p o n s or ’ s d e si g n e e f or 
a n al y si s:
 
P h ar m a c o ki n eti c / P h ar m a c o d y n a mi c a s s e s s m e nt s
– 
S er u m s atr ali z u m a b c o n c e ntr ati o n, I L -6, sI L -6 R, a nti -A Q P 4 a nti b o d y 
 
I m m u n o ge nicit y a s s e s s m e nt s
– 
A D A
 
C h u g ai Cli ni c al S a m pl e R e p o sit or y ( C C S R) ( bl o o d/ s er u m/ pl a s m a)
T h e m a xi m u m bl o o d v ol u m e s t h at m a y b e t a k e n at e a c h vi sit , d e p e n di n g u p o n t h e 
a s s e s s m e nt s t h e p ati e nt h a s o pt e d i nt o, ar e s u m m ari z e d i n T a bl e 1 .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T a bl e 1: 
M a xi m u m Bl o o d V ol u m e s
Vi sit( s)
M a xi m u m 
bl o o d v ol u m e 
t a k e n ( m L) [ 1]
S cr e e ni n g
2 8
D o u bl e -bli n d p eri o d
W e e k  0
4 6
W e e k 2
3 4. 5
W e e k s 4 & 8
4 4
W e e k s 5 & 6 , D o s e o ut si d e t h e vi sit wi n d o w
3. 5
W e e k s 1 2, 2 4 & 4 8, e v er y 2 4 w e e k s aft er W e e k 4 8 a n d at t h e wit h dr a w al vi sit 
4 7
W e e k s 1 6, 2 0, 2 8, 3 2, 4 0, 4 4, e v er y 4 w e e k s aft er W e e k  4 8
2 4 . 5 [ 2]
W e e k  3 6
2 7 . 5
At e xtr a vi sit o n r el a p s e
4 4
F oll o w -u p a s s e s s m e nt f or a d ol e s c e nt s
5. 0
E xt e n si o n p eri o d
W e e k s 0, 2 4, 4 8
3 2 . 5
W e e k 2
1 6 
W e e k s 4, 8, 1 6, 2 0, 2 8, 3 2, 4 0, 4 4
2 4 . 5
E v er y 1 2 w e e k s aft er W e e k 4 8
1 9
W e e k s 1 2, 3 6 & E v er y 2 4 w e e k s aft er W e e k  4 8
2 7. 5
D o s e o ut si d e t h e vi sit wi n d o w
3 . 5
At e xtr a vi sit o n r el a p s e
2 9. 5
L a st o b s er v ati o n vi sit a n d wit h dr a w al vi sit
2 7. 5
F oll o w -u p a s s e s s m e nt f or a d ol e s c e nt s
5. 0
[ 1]
T h e s a m pl e f or C C S R pr oj e ct i s i n cl u d e d. T h e l o c al l a b or at or y s a m pl e s ( bl o o d T B t e st 
a n d s er u m pr e g n a n c y t e st) ar e n ot i n cl u d e d.
[ 2]
2 7. 5 m L e v er y 1 2 w e e k s aft er W e e k  4 8
A s s e s s m e nt of h s C R P, P K, I L -6, sI L -6 R, A D A, a nti -A Q P 4 A b ( e x c e pt s cr e e ni n g), 
pl a s m a bl a st s a n d c o m pl e m e nt ( C 3, C 4, a n d C H 5 0) will b e p erf or m e d i n a bli n d e d 
m a n n er a n d r e s ult s will n ot b e a v ail a bl e t o sit e, P A R E X E L a n d S p o n s or u ntil d at a b a s e 
l o c k f or a n al y si s of t h e d o u bl e-bli n d p eri o d .
F or p ati e nt s a g e d 1 2 t o 1 7 at t h e ti m e of i nf or m e d c o n s e nt, pl e a s e r ef er t o 
A p p e n di x 1 3 f or bl o o d s a m pl e c oll e cti n g ( E ur o p e a n U ni o n, 2 0 0 8) .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
5 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
F or d et ail s o n n a m e a n d a d dr e s s of l a b or at or y, s a m pli n g pr o c e d ur e s, s a m pl e st or a g e 
a n d s hi p m e nt, s e e t h e m at eri al s i n t h e Sit e L a b or at or y Bi nd er.
4. 5. 1. 1 2 
El e ctr o c ar di o gr a m s
El e ctr o c ar di o gr a m s s h o ul d b e p erf or m e d pri or t o a n y bl o o d dr a w s. T o mi ni mi z e 
v ari a bilit y, it i s i m p ort a nt t h at p ati e nt s b e i n a r e sti n g p o siti o n f or ≥1 0 mi n ut e s pri or t o 
e a c h E C G e v al u ati o n. B o d y p o siti o n s h o ul d b e c o n si st e ntl y m ai n t ai n e d f or e a c h E C G 
e v al u ati o n t o pr e v e nt c h a n g e s i n h e art r at e. E n vir o n m e nt al di str a cti o n s 
( e. g., t el e vi si o n, r a di o, c o n v er s ati o n) s h o ul d b e a v oi d e d d uri n g t h e pr e E C G r e sti n g 
p eri o d a n d d uri n g E C G r e c or di n g. E C G s f or e a c h p ati e nt s h o ul d b e o bt ai n e d fr o m t h e 
s a m e m a c hi n e w h e n e v er p o s si bl e.
F or p ati e nt s w h o c o n s e nt t o a d diti o n al P K t e sti n g ( s e e A p p e n di x 1 ), tri pli c at e di git al 
E C G r e c or di n g s will b e o bt ai n e d wit h a p pr o xi m at el y 2 t o 5 mi n ut e s i nt er v al at e a c h 
s p e cifi e d ti m e p oi nt fr o m b a s eli n e. T h e a v er a g e of t h e t hr e e r e a di n g s will b e u s e d t o 
d et er mi n e E C G i nt er v al s ( e. g. , P R, Q T a n d Q T c).
F or s af et y m o nit ori n g p ur p o s e s, t h e I n v e sti g at or or d e si g n e e m u st r e vi e w, si g n, a n d 
d at e all E C G tr a ci n g s. P a p er c o pi e s will b e k e pt a s p art of t h e p ati e nt' s p er m a n e nt 
st u d y fil e at t h e sit e. E C G c h ar a ct eri sti c s , i n cl u di n g h e art r at e, Q R S d ur ati o n, a n d R R, 
P R, a n d Q T i nt er v al s, will b e r e c or d e d o n t h e e C R F. Q T i nt er v al c orr e ct e d f or h e art 
r at e u si n g Fri d eri ci a' s f or m ul a ( Q T c F) will b e c al c ul at e d p o st h o c . C h a n g e s i n T-w a v e 
a n d U -w a v e m or p h ol o g y a n d o v er all E C G i n t er pr et ati o n will b e d o c u m e nt e d o n t h e 
e C R F.
F or t h o s e p ati e nt s w h o c o n s e nt t o a d diti o n al P K t e sti n g ( s e e A p p e n di x 1 ), E C G 
s h o ul d b e al s o p erf or m e d at W e e k s 5 a n d 6, a n d c o pi e s of E C G tr a ci n g s will b e 
c oll e ct e d at b a s eli n e a n d W e e k s 5, 6, 2 4 a n d 4 8.
4. 5. 1. 1 3 
A d v er s e E v e nt s
T h e r e p orti n g of A E s i s d et ail e d i n S e cti o n 5. 3 .
4. 5. 2 
Ti mi n g of St u d y  As s e s s m e nt s
4. 5. 2. 1 
S cr e e ni n g A s s e s s m e nt s
Wr itt e n i nf or m e d c o n s e nt f or p arti ci p ati o n i n t h e st u d y m u st b e o bt ai n e d b ef or e 
p erf or mi n g a n y st u d y -s p e cifi c s cr e e ni n g t e st s or e v al u ati o n s . Si g n e d I nf or m e d 
C o n s e nt F or m s (I C F s) f or e nr oll e d p ati e nt s a n d f or p ati e nt s w h o ar e n ot s u b s e q u e ntl y 
e nr oll e d will b e m ai nt ai n e d at t h e st u d y sit e.
S cr e e ni n g t e st s a n d e v al u ati o n s will b e p erf or m e d wit hi n 2 8 d a y s pri or t o D a y 1, 
u nl e s s ot h er wi s e s p e cifi e d. All s cr e e ni n g e v al u ati o n s m u st b e c o m pl et e d a n d 
r e vi e w e d t o c o nfir m t h at p ati e nt m e et s all eli gi bilit y crit eri a b ef or e r a n d o mi z ati o n ( F or 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
a d ol e s c e nt s w h o m a y b e e nr oll e d aft er t h e e n d of t h e d o u bl e -bli n d p eri o d, s e e 
S e cti o n 4. 8 ). T h e I n v e sti g at or will m ai nt ai n a s cr e e ni n g l o g t o r e c or d d et ail s of all 
p ati e nt s s cr e e n e d a n d t o c o nfir m eli gi bilit y or r e c or d r e a s o n s f or s cr e e ni n g f ail ur e, a s 
a p pli c a bl e.
If a p ati e nt f ail s a n y l a b or at or y i n cl u si o n/ e x cl u si o n crit eri a at s cr e e ni n g, t h e t e st c a n b e 
r e p e at e d wit hi n 2 8 d a y s of s cr e e ni n g p eri o d (i. e., r et e st).
If a p ati e nt h a s n ot m et all i n cl u si o n/ e x cl u si o n crit eri a wit hi n 2 8 d a y s of t h e ori gi n al 
s cr e e ni n g vi sit , r e s cr e e ni n g ( w hi c h r ef er s t o r e p e ati n g t h e w h ol e s cr e e ni n g pr o c e s s) 
c a n b e c o n d u ct e d t wi c e . E a c h p ati e nt m u st b e r e-c o n s e nt e d b ef or e r e s cr e e ni n g 
o c c ur s. A s p art of t h e r e s cr e e ni n g pr o c e s s, a T B t e st, a n X-r a y, h e p atiti s t e st s, M RI 
a n d a nti- A Q P 4 A b t esti n g ar e n ot r e q uir e d if e a c h of t h e m ar e c o n d u ct e d wit hi n 
1 2 w e e k s pri or t o b a s eli n e. P ati e nt s m a y b e eli gi bl e f or r e s cr e e ni n g u p t o t w o 
a d diti o n al ti m e s. A r et e st i s d efi n e d a s a n y a s s e s s m e nt r e p e ate d wit hi n 2 8 d a y s of
s cr e e ni n g .
If r el a p s e o c c ur s d uri ng s cr e e ni n g p eri o d, t h e p ati e nt s h o ul d b e tr e at e d a s a s cr e e ni n g 
f ail ur e a n d s h o ul d r e c ei v e t h e sit e-s p e cifi c a c ut e r el a p s e tr e at m e nt. T h e p ati e nt c a n 
b e r e -s cr e e n e d wit h a n e w I C F.
Pl e a s e s e e A p p e n di x 1 f or t h e s c h e d ul e of s cr e e ni n g a s s e s s m e nt s.
4. 5. 2. 2 
A s s e s s m e nt s d uri n g Tr e at m e nt
A s s e s s m e nt d uri n g tr e at m e nt a p pli e s t o b ot h d o u bl e -bli n d a n d e xt e n si o n p eri o d . All 
a s s e s s m e nt s m u st b e p erf or m e d o n t h e d a y of t h e s p e cifi e d vi sit, u nl e s s a ti m e 
wi n d o w i s s p e cifi e d i n t h e s c h e d ul e of a s s e s s m e nt s ( s e e A p p e n di x 1 ). A s s e ss m e nt s 
s c h e d ul e d o n t h e d a y of st u d y dr u g a d mi ni str ati o n s h o ul d b e p erf or m e d pri or t o 
a d mi ni str ati o n of st u d y dr u g , u nl e s s ot h er wi s e n ot e d i n t h e s c h e d ul e of a s s e s s m e nt s.
If st u d y dr u g c a nn ot b e a d mi ni st er e d o n t h e s c h e d ul e d vi sit , e v er y eff ort s h o ul d b e 
m a d e t o p erf or m t h e a s s e s s m e nt s at t h e vi sit.
If a p ati e nt mi s s e s a s c h e d ul e d vi sit wit h o ut n oti c e, t h e I n v e sti g at or a n d/ or sit e st aff 
s h o ul d tr y t o c o nt a ct t h e p ati e nt vi a t el e p h o n e or a n ot h er w a y i n or d er t o c o nfir m if 
t h er e h a s b e e n a n A E or r el a p s e.
T h e I n v e sti g at or a n d/ or sit e st aff s h o ul d e n c o ur a g e t h e p ati e nt t o vi sit t h e st u d y sit e 
f or a n a s s e s s m e nt a s s o o n a s p o s si bl e .
F oll o wi n g t he i m ple me nt ati o n of Pr ot oc ol Versi o n 1 1 , a d mi nistr ati o n of s atr ali z u m a b
prefille d s yri n ges o utsi de of t he st u d y site m a y be all o we d, i n acc or d a nce wit h l oc al 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
re g ul ati o ns, o nl y if n o o n -site assess me nts are sc he d ule d f or t h at d osi n g d a y 
(A p pe n di x 1 ).  P atie nts s h o ul d be f oll o we d u p b y p h o ne t o m o nit or if t here h as bee n 
a n A E or ne ur ol o gic al w orse ni n g. 
D uri n g e xtr a or di n ar y circ u mst a nces li ke t he S A R S -C o V -2 ( C O VI D -1 9) p a n de mic, 
w he n p atie nts c a n n ot atte n d a st u d y site f or a sc he d u le d visit, a d mi nistr ati o n of 
s atr ali z u m a b o utsi de of t he st u d y site will be all o we d f or all sc he d ule d d osi n g d a ys 
d uri n g t he O L E peri o d after Wee k 4 8 ( A p pe n di x 1 ).  P atie nts s h o ul d be f oll o we d u p 
b y p h o ne ar o u n d t he ti me of t he sc he d ule d visit t o c o nfir m p atie nt c o m pli a nce wit h 
st u d y dr u g tre at me nt, a n d t o c ollect i nf or m ati o n o n s afet y a n d/ or ne ur ol o gic al 
w orse ni n g t he p atie nt mi g ht e x perie nce.  S afet y l a b or at or y assess me nts m a y be 
perf or me d at a l oc al l a b or at or y w he n p ossi ble a n d a n y cli nic all y si g nific a nt a b n or m al 
l a b or at or y v al ues re p orte d as A Es i n t he e C R F as descri be d i n Secti o n 5. 3. 5 .
Pl e a s e s e e A p p e n di x 1 f or t h e s c h e d ul e of a s s e s s m e nt s p erf or m e d d uri n g t h e 
tr e at m e nt p eri o d.
4. 5. 2. 3 
A s s e s s m e nt s at L a st O b s er v ati o n Vi sit/ Wit h dr a w al Vi sit
T h e Wi t h dr a w al ( WD) V i sit i s f or p ati e nt s w h o wit h dr a w fr o m t h e st u d y. E v er y eff ort 
s h o ul d b e m a d e t o c o n d u ct t h e vi sit at 1 2 w e e k s ( ± 7 d a y s) aft er t h e l a st d o si n g . 
P ati e nt s a g e d 1 2 t o 1 7 y e ar s at t h e ti m e of i nf or m e d c o n s e nt w h o wit h dr a w fr o m t h e 
st u d y will att e n d t h e W D  vi sit at 1 2 w e e k s ( ± 7 d a y s) aft er l a st d o si n g f or f oll o w-u p 
a s s e s s m e nt s f or a d ol e s c e nt s ( s e e S e cti o n 4. 5. 2. 5 ). At t h e W D
Vi sit of d o u bl e -bli n d 
p eri o d , a c o m pl et e s et of t h e a s s e s s m e nt s p erf or m e d e v er y 2 4 w e e k s aft er W e e k 4 8 
of  d o u bl e-bli n d p eri o d ar e t o b e p erf or m e d (pl u s a c h e st X -r a y). At t h e W D Vi sit
of 
e xt e n si o n p eri o d , a c o m pl et e s et of t he a s s e s s m e nt s p erf or m e d e v er y 2 4 w e e k s fr o m 
W e e k 0 t o W e e k 4 8 of e xt e n si o n p eri o d ar e t o b e p erf or m e d ( i n cl u di n g a c h e st X -r a y) 
wit h t h e e x c e pti o n of t h e a nti-A Q P 4 A b a s s a y .
P ati e nt s w h o e x p eri e n c e a r el a p s e w hi c h i s tr e at e d wit h r e s c u e t h er a p y a n d/ or a 
pr ot o c ol -d ef i n e d r el a p s e w hi c h i s a dj u di c at e d b y C E C or w h o c o m pl et e t h e 
d o u bl e -bli n d p eri o d c a n e nt er t h e O L E
p eri o d . P ati e nt s c o m pl eti n g t h e O L E
p eri o d will 
att e n d a L a st O b s er v ati o n Vi sit 1 2 w e e k s aft er t h e l a st d o s e of s atr ali z u m a b . 
T h e L a st O b s er v ati o n Vi sit will b e c o n d u ct e d 1 2 w e e k s aft er t h e l a st d o s e of 
s atr ali z u m a b f or p ati e nt s w h o c o m pl et e t h e O L E p eri o d. At t hi s vi sit, a c o m pl et e s et of 
t h e a s s e s s m e nt s p erf or m e d at W e e k 0 of e xt e n si o n p eri o d ar e t o b e p erf or m e d 
(i n cl u di n g a c h e st X -r a y) wit h t h e e x c e pti o n of t h e a nti-A Q P 4 A b a s s a y. P atie nts w h o 
c o m plete t he O L E peri o d wit h t he l ast st u d y dr u g a d mi nistr ati o n o n or bef ore 
3 1 De ce m ber
2 0 2 1 a n d deci de t o c o nti n ue tre at me nt wit h s atr ali z u m a b o utsi de of t his 
st u d y will n ot h a ve t o c o m plete t he L ast O bser v ati o n Visit.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
Aft er t h e L a st O b s er v ati o n Vi sit or W D Vi sit, A E s s h o ul d b e f oll o w e d a s o utli n e d i n 
S e cti o n s 5. 5 a n d 5. 6 .
Pl e a s e s e e A p p e n di x 1 f or t h e s c h e d ul e of a s s e s s m e nt s p erf or m e d at t h e Wit h dr a w al 
Vi sit a n d t h e L a st O b s er v ati o n.
4. 5. 2. 4   
S af et y F oll o w- U p A s s e s s m e nt s
S af et y F oll o w- U p will b e c o n d u ct e d f or p ati e nt s w h o wit h dr a w fr o m t h e st u d y i n t h e 
d o u bl e- bli n d p eri o d d u e t o cli ni c al r el a p s e a n d will l a st f or 2 4 w e e k s fr o m t h e l a st 
d o si n g. A 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 fr o m 
l a st d o si n g t o r e c or d d et ail s of a n y m e di c ati o n s a n d tr e at m e nt s f or N M O/ N M O S D t h e 
p ati e nt i s t a ki n g a n 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 a n d d at a 
will b e e nt er e d i nt o t h e r el e v a nt p a g e s of t h e e C R F.
Pl e a s e s e e A p p e n di x 1 f or t h e s c h e d ul e of s af et y f oll o w- u p a s s e s s m e nt s.
4. 5. 2. 5   
F oll o w- U p A s s e s s m e nt s f or A d ol e s c e nt s
F oll o w- U p A s s e s s m e nt f or A d ol e s c e nt s i s f or p ati e nt s a g e d 1 2 t o 1 7 y e ar s at t h e ti m e 
of i nf or m e d c o n s e nt w h o wit h dr a w fr o m t h e st u d y or c o m pl et e t h e O L E p eri o d, a n d
will b e c o n d u ct e d at 1 2 ( W D vi sit f or p ati e nt wit h dr a w n), 2 4 a n d 4 8 w e e k s ( ± 7 d a y s) 
aft er t h e l a st d o s e of st u d y dr u g. P atie nts a ge d 1 8 ye ars or ol der at t he ti me t he y 
c o m plete or disc o nti n ue fr o m t he O L E peri o d a n d p atie nts t h at c o m plete t he O L E
wit h t he l ast st u d y dr u g a d mi nistr ati o n o n or bef ore 3 1 Dece m ber 2 0 2 1 or patie nts 
t hat deci de t o c o nti n ue tre at me nt wit h s atr ali z u m a b o utsi de of t his st u d y will n ot 
h a ve t o c o m plete t he F oll o w- U p Assess me nts f or A d oles ce nts.
If t h e p ati e nt s wit h dr a w fr o m t h e st u d y i n t h e d o u bl e- bli n d p eri o d d u e t o a cli ni c al 
r el a p s e, b ot h S af et y F oll o w- U p a n d F oll o w- U p A s s e s s m e nt s f or A d ol e s c e nt s will b e 
c o n d u ct e d.
Pl e a s e s e e A p p e n di x 1 f or t h e s c h e d ul e of f oll o w- u p a s s e s s m e nt s f or a d ol e s c e nt s. 
4. 5. 2. 6   
A s s e s s m e nt s at E xtr a Vi sit s d u e t o R el a p s e
If p ati e nt s 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 d uri n g t h e d o u bl e- bli n d 
p eri o d a n d e xt e n si o n p eri o d, t h e y will att e n d f or a n e xtr a vi sit wit hi n t h e r e a s o n a bl e 
s h ort e st ti m efr a m e t o h a v e a r el a p s e a s s e s s m e nt at t h e i n v e sti g ati o n al sit e ( s e e 
S e cti o n 4. 5. 3 ). Pl e a s e s e e A p p e n di x 1 f or a s s e s s m e nt s t h at ar e r e q uir e d t o b e 
p erf or m e d i n c a s e of s u c h e xtr a vi sit s.
4. 5. 2. 7   
U n s c h e d ul e d Vi sit s
A n y u n s c h e d ul e d vi sit s d uri n g t h e st u d y a p art fr o m t h e m m e nti o n e d a b o v e s h o ul d b e 
c a pt ur e d i n t h e u n s c h e d ul e d vi sit s m o d ul e i n t h e e C R F.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4. 5. 3 
R el a p s e A s s e s s m e nt
P ati e nt s s h o ul d r e p ort a ll 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 N M O 
r e pr e s e nti n g a cli ni c al r el a p s e i m m e di at el y t o t h e sit e s a n d a vi sit f or r el a p s e 
a s s e s s m e nt s h o ul d b e s c h e d ul e d a s s o o n a s p o s si bl e . P ati e nt s w h o att e n d t h e st u d y 
c e nt er f or a pr ot o c ol -s p e cifi e d st u d y vi sit t h at i n cl u d e s a n E D S S/ F S S a s s e s s m e nt 
( s e e A p p e n di x 1 ) s h o ul d b e a s s e s s e d t o d et er mi n e w h et h er a cli ni c al r el a p s e h a s 
o c c urr e d or n ot. A c li ni c al r el a p s e s h o ul d b e c o nfir m e d w h et h er it m e et s t h e crit eri a f or 
pr ot o c ol -d ef i n e d r el a p s e ( Pl e a s e s e e S e cti o n 4. 5. 3. 4 ). A n E D S S/ F S S a s s e s s m e nt 
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 a s s e s s or i n e v er y c a s e of p ot e nti al r el a p s e. 
T h e R el a p s e A s s e s s m e nt F or m a n d E D S S/ F S S s c ori n g s h e et s a n d n e c e s s ar y d at a (if 
a n y) f or all p ot e nti al r el a p s e s d uri n g t h e d o u bl e-bli n d p eri o d s h o ul d b e s e nt 
i m m e di at el y t o P A R E X E L f or s u b mi s si o n t o t h e C E C f or a dj u di c ati o n.
4. 5. 3. 1 
R el a p s e A s s e s s m e nt Str u ct ur e
T h er e will b e a tr e ati n g In v e sti g at or a n d a n e x a mi ni n g a s s e s s or at e a c h sit e t o k e ep 
t h e bli n d n e s s of t h e r el a p s e a s s e s s m e nt – t h e tr e ati n g I n v e sti g at or i s r e s p o n si bl e f or 
t h e p ati e nt c ar e a n d t h e e x a mi ni n g a s s e s s or i s 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 E D S S/ F S S. T h e e x a mi ni n g a s s e s s or m u st b e a p pr o pri at el y N e ur o st at u s q u alifi e d
to a s s e s s E D S S/ F S 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 tr e at m e nt d e ci si o n s b a s e d o n t h e p ati e 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 a s s e s s or will h a v e a c c e s s vi a t h e 
p a p er f or m o nl y t o t h e E D S S/ F S S d at a (i n cl u di n g t h e R el a p s e A s s e s s m e nt F or m) 
e x c e pt i n a n e m er g e n c y ( s u c h a s t h er e i s n o p h y si ci a n ot h er t h a n f or E D S S/ F S S 
a s s e s s m e nt i n st u d y sit e) a n d will n ot c o n s ult t h e p ati e nt m e di c al r e c or d s. T h e 
E D S S / F S S a s s e s s m e nt s h o ul d al w a y s b e p erf or m e d b y t h e s a m e a s s e s s or fr o m
b a s eli n e w h e n e v er it i s f e a si bl e a n d, i n t h e d o u bl e -bli n d p eri o d, will b e p erf or m e d wit h 
t h e a s s e s s or bli n d e d t o t h e p ati e nt’ s tr e at m e nt a s si g n m e nt. T h e e x a mi ni n g a s s e s s or 
m u st p e rf or m t h e E D S S/ F S S a s s e s s m e nt wit hi n s e v e n d a y s aft er t h e p ati e nt r e p ort s 
t h e s y m pt o m s of p ot e nti al r el a p s e t o t h e sit e.
T he se p ar ati o n of t he r ole of t he tre ati n g a n d e x a mi ni n g I n vesti g at or s h o ul d be 
m ai nt ai ne d d uri n g t he O L E e xte nsi o n peri o d w he ne ver p o ssi ble. 
P ati e 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, ot h er t h a n t h o s e r el at e d t o 
t h e E D S S/ F S S a s s e s s m e nt, wit h t h e e x a mi ni n g a s s e s s or ; t h e ex a mi ni n g a s s e s s or
s h o ul d r e mi n d t h e p ati e nt of t hi s at t h e st art of t h e e x a mi n ati o n.
4. 5. 3. 2 
Pr o c e d ur e f or D et e cti o n o f P ot e nti al R el a p s e
D uri n g t h e s cr e e ni n g p eri o d, p ati e nt s will b e tr ai n e d o n t h e p o s si bl e s y m pt o m s a n d 
si g n s of a p ot e nti al r el a p s e of N M O/ N M O S D . P ati e nt s will b e i n str u ct e d t o r e m e m b er 
a c c ur at el y t h e ti m e a n d n at ur e of e v er y s y m pt o m of a p o s si bl e r el a p s e a n d t o c o nt a ct 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
t h e st u d y sit e i m m e di at el y if t h e y h a v e s u c h s y m pt o m s. T h e sit e st aff will al s o b e 
tr ai n e d o n si g n s a n d s y m pt o m s t h at m a y b e i n di c ati v e of a p ot e nti al r el a p s e.
D uri n g t h e d o u bl e -bli n d p eri o d, t h e sit e st aff s h o ul d r e mi n d t h e p ati e nt of t h e p o s si bl e 
s y m pt o m s of p ot e nti al r el a p s e at e v er y vi sit, a n d c o nt a ct t h e p ati e nt b y p h o n e c all s 
b et w e e n t h e s c h e d ul e d sit e vi sit s (r e c o m m e n d e d 2 w e e k s aft er pr e vi o u s s c h e d ul e d 
vi sit), n ot t o mi s s p ot e nti al r el a p s e. T h e r e c or d of t h e p h o n e c all s h o ul d b e r e c or d e d 
o n t h e s o ur c e d o c u m e nt.
A ll p ati e 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 a r el a p s e s h o ul d h a v e t h e 
E D S S / F S S p erf or m e d. T h e r e s ult s s h o ul d b e r e c or d e d o n a R el a p s e A s s e s s m e nt 
F or m a s w ell a s o n a n E D S S/ F S S s c ori n g s h e et (t o b e e nt er e d i nt o t h e e C R F). T h e 
R el a p s e A s s e s s m e nt F or m will i n cl u de t h e d at e a n d ti m e of s y m pt o m o n s et, t h e 
n at ur e of s y m pt o m s a n d t h e tr e ati n g I n v e sti g at or’ s j u d g m e nt a s t o w h et h er a pr ot o c ol 
d ef i n e d r el a p s e h a s o c curr e d or n ot . T h e s e r e c or d s s h o ul d b e c o m pl et e d r e g ar dl e s s 
of  t h e ti m e fr o m t h e r e p ort of s y m pt o m . T h e s e r e c or d s a n d n e c e s s ar y d at a (if a n y) will 
b e s e nt t o P A R E X E L f or C E C r e vi e w .
P ot e nti al r el a p s e s will b e d et e ct e d b y t h e f oll o wi n g c a s e s:
1.
P ot e nti al r el a p s e r e p orte d b y t h e p ati e nt
If a p ati e nt b e c o m e s a w ar e of si g n s or s y m pt o m s w hi c h mi g ht i n di c at e a r el a p s e, 
th e p ati e nt will c o nt a ct t h e sit e i m m e di at el y a n d r et ur n t o t h e sit e f or a n e xtr a vi sit 
a s s o o n a s p o s si bl e wit h a t ar g et d at e s et f or n o m or e t h a n 3 d a y s aft er r e p orti n g 
t h e s y m pt o m s t o t h e sit e. T h e e x a mi ni n g a s s e s s or m u st p erf or m t h e E D S S/ F S S 
a s s e s s m e nt wit hi n s e v e n d a y s aft er t h e p ati e nt r e p ort s t h e s y m pt o m s t o t h e sit e. 
T h e li st of a s s e s s m e nt s t o b e o bt ai n e d at t h e e xtr a vi sit at r e l a p s e i s li st e d i n 
A p p e n di x 1 . T h e I n v e sti g at or s h o ul d tr e at t h e p ati e nt a s n e c e s s ar y b a s e d o n 
hi s/ h er e v al u ati o n of t h e s y m pt o m s aft er t h e c o m pl eti o n of r el a p s e a s s e s s m e nt s.
M RI fi n di n g s mi g ht b e s u p p orti v e f or e v al u ati o n of
r el a p s e.
If a p ati e nt h a s diffi c ult y vi siti n g t h e st u d y sit e wit hi n t hr e e d a y s d u e t o s e v erit y of 
t h e r el a p s e, t h e p ati e nt c a n vi sit a l o c al cli ni c/ h o s pit al f or i m m e di at e m a n a g e m e nt 
of a r el a p s e, a n d t h e n vi sit t h e st u d y sit e a s s o o n a s p o s si bl e ( w hi c h m a y b e 
d uri n g or i m m e di at el y aft er r e s c u e t h er a p y f or cli ni c al r el a p s e ). Alt er n ati v el y, t h e 
e x a mi ni n g a s s e s s or m a y vi sit t h e l o c al cli ni c/ h o s pit al t o c o n d u ct t h e E D S S/ F S S 
a s s e s s m e nt d uri n g r e s c u e t h er a p y f or a cli ni c al r el a p s e. E v e n i n t hi s c a s e, t h e 
e x a mi ni n g a s s e s s or m u st p erf or m t h e E D S S/ F S S a s s e s s m e nt wit hi n s e v e n d a y s 
af t er t h e p ati e nt r e p ort s t h e s y m pt o m s t o t h e sit e.
If t h e p ati e nt i s s e e n at a cli ni c al f a cilit y ot h er t h a n t h e st u d y sit e, t h e p ati e nt 
s h o ul d s h o w t h e p ati e nt I D c ar d w hi c h i n cl u d e s t h e i n v e sti g at or’ s c o nt a ct 




S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
2.
P ot e nti al r el a p s e c o m e s fr o m t h e E D S S/ F S S a s s e s s m e nt
If t h er e i s a n E D S S/ F S S c h a n g e s h o w n i n S e cti o n 4. 5. 3. 4 at a n E D S S/ F S S 
a s s e s s m e nt vi sit ( e. g., W e e k 2 4), t h e R el a p s e A s s e s s m e nt F or m will b e c o m pl et e d
a n d s e nt t o t h e C E C ( p l e a s e s e e S e cti o n 4. 5. 3. 3 ).
4. 5. 3. 3 
R e p orti n g a P ot e nti al R el a p s e t o th e C E C
T h e R el a p s e A s s e s s m e nt F or m will b e s e nt ( e. g. , b y f a x, e -m ail) i m m e di at el y, 
t o g et h er wit h t h e E D S S/ F S S s c ori n g s h e et s f or t h e c urr e nt vi sit , t h e m o st r e c e nt 
E D S S/ F S S a s s e s s m e nt vi sit , a n d n e c e s s ar y d at a (if a n y) t o P A R E X E L. T hi s s h o ul d 
b e d o n e r e g ar dl e s s of t h e a s s e s s m e nt of t h e sit e st aff a b o ut w h et h er t h e p ot e nti al 
r el a p s e m e et s pr ot o c ol-d ef i n e d r el a p s e a n d r e g ar dl e s s of t h e ti m e w h e n t h e 
E D S S/ F S S a s s e s s m e nt w a s p erf or m e d.
D uri n g t h e d o u bl e -bli n d p eri o d, t h e f or m a n d t h e d at a will b e r e vi e w e d b y t h e C E C.
T h e C E C will r e vi e w a c c or di n g t o t h e C E C c h art er, a n d will b e a bl e t o r e q u e st 
a d diti o n al i nf or m ati o n t o a s si st i n t h e d et er mi n ati o n of a r el a p s e if n e c e s s ar y.
If t h e C E C c o n si d er s t h at t h e pr ot o c ol -d ef i n e d r el a p s e h a s b e e n m et, th e p ati e nt 
s h o ul d b e wit h dr a w n fr o m t h e d o u bl e-bli n d p eri o d a n d c a n e nt er t h e e xt e n si o n p eri o d
e v e n if I n v e sti g at or c o n si d er s t h at n o pr ot o c ol -d efi n e d r el a p s e h a s o c c urr e d .
D et ail s r e g ar di n g t h e C E C r e s p o n si biliti e s a n d t h e pr o c e s s of a dj u di c ati o n ar e 
d e s cri b e d i n t h e S e cti o n 3. 1. 4 a n d C E C c h art er.
4. 5. 3. 4 
Pr ot o c ol - d efi n e d r el a p s e
Pr ot o c ol -d efi n e d r el a p s e i 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 N M O or N M O S D . 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, 
c h a n g e i n m o o d, a d v er s e r e a cti o n s t o m e di c ati o n s). 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 o c c ur l e s s t h a n 3 1 d a y s f oll o wi n g t h e o n s et of a pr ot o c ol -d ef i n e d 
r el a p s e will b e c o n si d er e d p art of t h e s a m e r el a p s e (i. e., if 2 r el ap s e s h a v e o n s et d a y s 
t h at ar e 3 0 d a y s of o n e a n ot h er, t h e y will b e c o u nt e d o nl y a s 1 r el a p s e), a n d t h e o n s et 
d at e u s e d i n t h e a n al y si s will b e t h e o n s et d at e of t h e fir st r el a p s e. T h e n e w or 
w or s e ni n g n e ur ol o gi c s y m pt o m s m u st m e et eit h er of f oll o wi n g :
1.
A n i n cr e a s e of at l e a st 1. 0 p oi nt o n t h e E D S S s c or e e x c e pti n g i n cr e a s e t o 1. 0 or 
1. 5 fr o m z er o (i. e. , a 2. 0 p oi nt i n cr e a s e o n t h e E D S S i s r e q uir e d if t h e b a s eli n e 
w a s z er o)
2.
A n i n cr e a s e of at l e a st 2. 0 p oi nt s o n o n e of t h e a p pr o pri at e F S S
3.
A n i n cr e a s e of at l e a s t 1. 0 p oi nt o n t w o or m or e of t h e a p pr o pri at e F S S if t h e 
b a s eli n e s c or e w a s o n e or m or e


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4.
A n i n cr e a s e of at l e a st 1. 0 p oi nt i n si n gl e e y e F S S w h e n t h e b a s eli n e s c or e i n t h at 
e y e i s o n e or m or e
T h e b a s e of c o m p ari s o n f or t h e i n cr e a s e i s t h e s c or e at t h e m o st r e c e nt E D S S/ F S S 
a s s e s s m e nt vi sit. T h e a p pr o pri at e F S S c h a n g e m u st aff e ct at l e a st o n e of t h e 
f oll o wi n g f u n cti o n al s y st e ms: 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/ bl a d d er
or vi s u al ( si n gl e e y e). S e x u al d y sf u n cti o n a n d c er e br al f u n cti o n will n ot s uffi c e t o 
e st a bli s h a pr ot o c ol -d efi n e d r el a p s e.
T h e r el a p s e w hi c h i s r e g ar d e d a s a pr ot o c ol -d efi n e d r el a p s e b y t h e C E C f oll o w e d b y 
c o nfir m ati o n t h at t h e E D S S/ F S S a s s e s s m e nt w a s p erf or m e d wit hi n s e v e n d a y s aft er 
t h e p ati e nt r e p orte d t h e s y m pt o m s t o t h e sit e will b e u s e d f or pri m ar y a n al y si s . A n y 
p ot e nti al r el a p s e s n ot e v al u at e d wit hi n t h e s e v e n d a y s will b e c e n s or e d fr o m t h e 
pri m ar y a n al y si s ( s e e S e cti o n 6. 5. 1 ).
4. 6 
C H U G AI  C LI NI C AL S A M P L E R E P O SI T O R Y
T h e c oll e cti o n of s a m pl e s f or t h e C C S R i s a n o pti o n al c o m p o n e nt of t hi s 
St u d y B N 4 0 8 9 8 (al s o k n o w n a s S A -3 0 7 J G). 
T h e p ati e nt s will b e gi v e n t h e o pti o n t o p arti ci p at e i n C C S R pr oj e ct. 
F or D N A a n al y si s, 2 m L bl o o d s a m pl e s will b e t a k e n fr o m t h e p ati e nt s w h o c o n s e nt t o 
t h e pr o c e d ur e a n d t o C C S R pr oj e ct pri or t o t h e fir st i nj e cti o n o n D a y 1 ( B a s eli n e). T h e 
bl o o d s a m pl e s will b e st or e d b y t h e S p o n s or f or u p t o 1 5 y e ar s aft er t h e e n d of t h e 
a s s o ci at e d m ai n st u d y ( d at a b a s e cl o s ur e) at w hi c h ti m e t h e y will b e d e str o y e d.
F or t h e C C S R , s er u m a n d pl a s m a s a m pl e s will b e t a k e n fr o m t h e p ati e nt s w h o 
c o n s e nt t o t h e pr o c e d ur e. Bl o o d f or s er u m a n d pl a s m a s a m pl e s ( e a c h 5 m L f or s er u m 
a n d 4. 5 m L f or pl a s m a) will b e t a k e n at t h e ti m e p oi nt s i n di c at e d i n t h e S c h e d ul e of 
A s s e s s m e nt s ( s e e A p p e n di x 1 ). T h e s er u m a n d pl a s m a s a m pl e s will b e st or e d b y t h e 
S p o n s or f or u p t o 5 y e ar s aft er t h e e n d of t h e a s s o ci at e d m ai n st u d y. T h e s a m pl e s will 
b e u s e d f or a n al y si s of pr ot ei n s s u c h a s, b ut n ot li m it e d t o, c yt o ki n e s a n d c h e m o ki n e s.
T h e s e s a m pl e s will b e u s e d o nl y f or t h e p ur p o s e of r etr o s p e cti v e C C S R r e s e ar c h 
a n al y si s t o u n d er st a n d i nt er -i n di vi d u al v ari a bilit y i n s atr ali z u m a b effi c a c y, s af et y a n d 
P K a s will b e e x pl ai n e d i n t h e I C F . T h e IC F f or t h e o pti o n al s p e ci m e n d o n ati o n will b e 
i n c or p or at e d a s a s p e cifi c s e cti o n i nt o t h e m ai n Cli ni c al Tri al I C F. A s e c o n d, s e p ar at e, 
s p e cifi c si g n at ur e c o n s e nti n g t o s p e ci m e n d o n ati o n will b e r e q uir e d t o d o c u m e nt t h e 
st u d y p arti ci p a nt’ s a gr e e m e nt t o pr o vi d e t h e o pti o n al s p e ci m e n; if t h e p arti ci p a nt 
d e cli n e s, h e/ s h e will c h e c k a “ n o” b o x i n t h e a p pr o pri at e s e cti o n a n d will n ot pr o vi d e a 
s e c o n d si g n at ur e. T h e b l o o d, s er u m a n d pl a s m a s a m pli n g f or C C S R will b e 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
c o nti n g e nt o n a sit e’ s I n stit uti o n al R e vi e w B o ar d (I R B) a n d/ o r I n d e p e n d e nt Et hi c s 
C o m mitt e e ( IE C) a p pr o v al of s a m pli n g f or t h e C C S R a n d t h e I C F . If a sit e’ s I R B 
a n d/ or IE C d o e s n ot a p pr o v e t h e s a m pli n g, t hi s s e cti o n of C C S R pr oj e ct will n ot b e 
a p pli c a bl e.
4. 6. 1 
S c h e d ul e of A s s e s s m e nt s a n d Pr o c e d ur e s
4. 6. 1. 1 
St u d y Pr o c e d ur e s
Aft er writt e n i nf or m e d c o n s e nt f or t h e a s s o ci at e d m ai n cli ni c al st u d y h a s b e e n 
o bt ai n e d fr o m a p ati e nt, t h e bl o o d, s er u m a n d pl a s m a s a m pli n g will b e e x pl ai n e d. T h e 
p ati e nt will b e a s k e d if t h e y wi s h t o p arti ci p at e i n C C S R pr oj e ct, a n d writt e n i nf or m e d 
c o n s e nt w ill b e o bt ai n e d s p e cifi c all y f or C C S R pr oj e ct.
T h e bl o o d, s er u m a n d pl a s m a s a m pl e s ar e s c h e d ul e d t o b e c oll e ct e d 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 s s e s s m e nt s (A p p e n di x 1 ).
D at e s of c o n s e nt a n d s a m pl e 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 C C S R s e cti o n of 
t h e st u d y e C R F.
4. 6. 1. 2 
S a m pli n g Pr o c e d ur e s
Bl o o d s a m pl e s f or D N A  a n al ysi s: 
A 2 m L v e n o u s bl o o d s a m pl e will b e c oll e ct e d i nt o a bl o o d c oll e cti o n t u b e c o nt ai ni n g 
et h yl e n e di a mi n et etr a a c eti c a ci d a s a nti -c o a g ul a nt. T h e bl o o d will b e tr a n sf err e d t o a 
st or a g e t u b e. S a m pl e s will t h e n b e st or e d at a p pr o xi m at el y -2 0° C. D et ail s o n s a m pl e 
h a n dl i n g pr o c e d ur e s, s a m pl e st or a g e, a n d s hi p m e nt ar e d e s cri b e d i n t h e 
s u p pl e m e nt al l a b or at or y m a n u al.
S er u m s a m pl e s:
A 5 m L v e n o u s bl o o d s a m pl e will b e c oll e ct e d i nt o a bl o o d c oll e cti o n t u b e. T h e bl o o d 
will b e pl a c e d t o cl ot at r o o m t e m p er at ur e f or 3 0 t o 6 0 mi n ut e s aft er bl o o d c oll e cti o n 
a n d t h e n b e c e ntrif u g e d f or 1 0 mi n ut e s at 4° C at 1 7 0 0 g. T h e s er u m will b e c oll e ct e d 
a n d tr a n sf err e d t o st or a g e t u b e s. D et ail s o n s a m pl e h a n dli n g pr o c e d ur e s, s a m pl e 
st or a g e a n d s hi p m e nt ar 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.
P l a s m a s a m pl e s:
A 4. 5 m L v e n o u s bl o o d s a m pl e will b e c oll e ct e d i nt o a bl o o d c oll e cti o n t u b e c o nt ai ni n g 
s o di u m citr at e a s a nti -c o a g ul a nt. T h e bl o o d will b e c e ntrif u g e d f or 1 0 mi n ut e s at 4° C 
at 1 7 0 0 g. T h e pl a s m a will b e c oll e ct e d a n d tr a n sf err e d t o st or a g e t u b e s. Pl a s m a 
s e p ar ati o n s h o ul d b e c arri e d o ut i m m e di at el y aft er bl o o d dr a w. If t hi s i s n ot p o s si bl e, 
bl o o d s h o ul d b e k e pt o n a n i c e b at h u ntil c e ntrif u g ati o n ( n ot m or e t h a n 3 0 mi n ut e s 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
6 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
af t er bl o o d c oll e cti o n). D et ail s o n s a m pl e h a n dli n g pr o c e d ur e s, s a m pl e st or a g e a n d 
s hi p m e nt ar e d e s cri b e d i n t h e s u p pl e m e nt al l a b or at or y m a n u al.
4. 6. 1. 3 
C C S R
T h e s e s a m pl e s will b e tr a n sf err e d t o a n d st or e d i n t h e C C S R o n b e h alf of t h e S p o n s or .
4. 6. 1. 4 
Bi o m ar k er R e s e ar c h A n al y si s Pr ot o c ol
W h e n t h e s c h e d ul e s or c o nt e nt s of a bi o m ar k er a n al y si s u si n g C C S R s a m pl e s ar e 
s p e cifi e d, a “ Bi o m ar k er R e s e ar c h A n al y si s Pr ot o c ol” will al s o b e pr e p ar e d b ef or e t h e 
r e s e ar c h will b e p erf or m e d. 
T h e s a m pl e s a n d r e s ult s of a nti -A Q P 4 A b m a y b e u s e d f or d e v el o p m e nt of a 
c o m p a ni o n di a g n o sti c f or s atr ali z u m a b i n t h e fut ur e.
4. 6. 2 
S a m pl e C o nfi d e nti alit y a n d S a m pl e D e str u cti o n
It i s t h e i nt e nt of S p o n s or t o a s s ur e t h at p h ar m a c o g e n o mi c a n d bi o m ar k er i nf or m ati o n 
o bt ai n e d fr o m p ati e nt bl o o d, s er u m, a n d pl a s m a s a m pl e s r e m ai n s c o nfi d e nti al. T h e 
S p o n s or alr e a d y m ai nt ai n s ri g or o u s c o nf i 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 ati e nt I D n u m b er at t h e st u d y sit e) all p ati e nt s 
e nr oll e d i n t h e S p o n s or ’ s cli ni c al st u di e s. T hi s m e a n s p ati e nt n a m e s ar e n e v er 
r e v e al e d t o a n y o n e at t h e S p o n s or . Gi v e n t h e s e n siti v e n at ur e of p h ar m a c o g e n o mi c 
d at a, t h e S p o n s or 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 ati e nt c o nfi d e nti alit y. All s a m pl e s t a k e n f or bl o o d s a m pl e s f or D N A a n al y si s u n d er g o 
a s e c o n d l e v el of “ c o di n g”. At t h e S p o n s or , t h e n e w l a b el wit h a n e w r a n d o m n u m b er 
r ef err e d t o a s t h e d o u bl e-c o d e d I D i s pl a c e d o v er t h e ori gi n al l a b el of t h e bl o o d 
s a m pl e. I d e ntifi e d o nl y b y t h e d o u bl e -c o d e I D, t h e s a m pl e s will b e f or w ar d e d t o 
st or a g e a n d D N A a n al y si s. 
B ot h t h e p ati e nt I D n u m b er a n d t h e d o u bl e- c o d e d I D n u m b er will c o -e xi st a s a t a bl e i n 
a s a m pl e r e p o sit or y c o d e m a n a g er. T hi s all o w s p ati e nt s t o wit h dr a w t h eir s a m pl e fr o m 
t h e bl o o d s a m pl e s f or D N A a n al y si s d uri n g t h eir p arti ci p ati o n i n t h e a s s o ci at e d m ai n 
cli ni c al st u d y if t h e y c h a n g e t h eir mi n d aft er si g ni n g t h e I C F. 
T h e bl o o d s a m pl e s f or D N A a n al y si s a n d s er u m/ bl o o d s a m pl e s f or pr ot ei n a n al y si s will 
b e st or e d b y t h e S p o n s or f or u p t o 1 5 y e ar s a n d 5 y e ar s, r e s p e cti v el y, af t er t h e e n d of 
t h e a s s o ci at e d m ai n st u d y ( d at a b a s e cl o s ur e) at w hi c h ti m e t h e y will b e d e str o y e d.
4. 6. 3 
Wit h dr a w al of P ati e nt s fr o m t h e C C S R Pr oj e ct
P ati e nt s w h o gi v e c o n s e nt t o t h e C C S R pr oj e ct 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 s fr o m t h e C C S R pr oj e ct at a n y ti m e f or a n y r e a s o n. If a p ati e nt wi s h e s t o 
wit h dr a w hi s/ h er c o n s e nt fr o m t h e C C S R pr oj e ct , 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 i n writi n g of t h e p ati e nt’ s wi s h e s u si n g t h e C C S R S u bj e ct W it h dr a w al F or m


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
(A p p e n di x 9 ). If a p ati e 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) d uri n g t h eir p arti ci p ati o n i n t h e cli ni c al st u d y, t h e I n v e sti g at or m u st e nt er 
t h e d at e of t h e wit h dr a w al i n t h e p ati e nt s e C R F. Wit hi n t h e S p o n s or, t h e r e q u e st f or 
s a m pl e wit h d r a w al will b e f or w ar d e d t o t h e bi o m ar k er o p er ati o n. A p ati e nt ’ s 
wit h dr a w al fr o m t h e m ai n 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 fr o m t h e 
C C S R pr oj e ct . Li k e wi s e, a p ati e nt’s wit h dr a w al fr o m t h e C C S R pr oj e ct 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 st u d y .
I n t h e c a s e of bl o o d s a m pl e f or D N A a n al y si s, if a p ati e nt wi s h e s t o wit h dr a w t h e 
c o n s e nt t o u s e t h e s a m pl e, t h e n t h e s a m pl e m u st b e d e str o y e d. I n t h e c a s e of s er u m 
a n d pl a s m a s a m pl e s, if a p ati e nt wi s h e s t o wit h dr a w t h e c o n s e nt b ot h t o c oll e ct 
s u b s e q u e n t s a m pl e s a n d t o u s e t h e s a m pl e s alr e a d y c oll e ct e d , t h e n t h e s a m pl es
alr e a d y c oll e ct e d m u st b e d e str o y e d . If a p ati e nt wi s h e s t o wit h dr a w o nl y t h e c o n s e nt 
t o c oll e ct s u b s e q u e n t s a m pl e s, t h e S p o n s or c a n u s e s a m pl e s a n d t h e dat a fr o m t h e 
s a m pl e s alr e a d y c oll e ct e d. If D N A, pr ot ei n s, a n d ot h er s u b st a n c e s h a v e alr e a d y b e e n 
a n al y z e d at t h e ti m e t h e S p o n s or r e c ei v e s a C C S R S u bj e ct W it h dr a w al F or m, t h e 
d at a fr o m t h o s e a n al y si s will n ot b e d e str o y e d. If t h e bl o o d s a m pl e f or D N A a n al ysi s , 
s er u m s a m pl e a n d pl a s m a s a m pl e t o b e d e str o y e d ar e at t h e S p o n s or or c e ntr al 
l a b or at or y, t h e bi o m ar k er o p er ati o n will i s s u e c o nfir m ati o n of t h e wit h dr a w al, w hi c h will 
b e f or w ar d e d t o t h e I n v e sti g at or. If t h e bl o o d s a m pl e s f or D N A a n al y si s , s er u m s a m ple 
a n d pl a s m a s a m pl e t o b e d e str o y e d ar e still at t h e st u d y sit e at t h e ti m e a p ati e nt 
wi s h e s t o wit h dr a w hi s/ h er s a m pl 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 a s 
b ef or e, d e str o y t h e s a m pl e a n d si g n t h e C C S R S u bj e ct W it h dr a w al F or m t o c o nfir m 
t h at t hi s ha s b e e n d o n e. T h e S p o n s or will f or w ar d c o nfir m ati o n of t h e d e str u cti o n, 
r e c or d e d o n t h e S u bj e ct Wit h dr a w al F or m, t o t h e bi o m ar k er o p er ati o n.
4. 6. 4 
B e n efit s t o D o n or s
D o n or s will n ot b e n efit p er s o n all y fr o m t h e bi o m ar k er r e s e ar c h b e c a u s e t h e ai m i s t o 
e v al u at e p ot e nti al p ati e nt -s el e cti o n a n d effi c a c y/ s af et y m ar k er s a n d t o g e n er at e or 
t e st h y p ot h e s e s b y a n al y zi n g t h e d at a a n d c o m pili n g t h e o v er all r e s ult s. H o w e v er, t h e 
fi n di n g s m a y c o ntri b ut e t o f ut ur e m e di c al tr e at m e nt wit h s atr ali z u m a b .
4. 7 
P A TI E N T, S T U D Y A N D S I T E DI S C O N TI N U ATI O N
4. 7. 1 
P ati e nt Di s c o nti n u ati o n
T h e I n v e sti g at or h a s t h e ri g ht t o di s c o nti n u e a p ati e nt fr o m st u d y dr u g or wit h dr a w a 
p ati e nt fr o m t h e st u d y at a n y ti m e. I n a d diti o n, p ati e nt s h a v e t h e ri g ht t o v ol u nt aril y 
di s c o nti n u e st u d y dr u g or 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. 
R e a s o n s f or di s c o nti n u ati o n of st u d y dr u g or wit h dr a w al fr o m t h e st u d y m a y i n cl u d e, 
b ut ar e n ot li mit e d t o, t h e f oll o wi n g:
 
P a ti e nt wit h dr a w al of c o n s e nt at a n y ti m e.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
A n y m e di c al c o n diti o n t h at t h e I n v e sti g at or or S p o n s or/ M e di c al M o nit or
d et er mi n e s m a y j e o p ar di z e t h e p ati e nt’ s s af et y if h e or s h e c o nti n u e s i n t h e st u d y .
 
I n v e sti g at or or S p o n s or/ M e di c al M o nit or d et er mi n e s it i s i n t h e b e st i nt er e st of t h e 
p ati e nt .
A d diti o n all y, t h e p ati e nt m a y b e di s c o nti n u e d fr o m t h e st u d y f or t h e f oll o wi n g r e a s o ns:
 
M aj or pr ot o c ol vi ol ati o n .
 
A d mi ni str ati v e r e a s o n s .
 
L o st t o f oll o w -u p .
4. 7. 1. 1 
Di s c o nti n u ati o n fr o m St u d y  Dr u g
I n a d diti on t o t h e crit eri a li st e d a b o v e, r e a s o n s f or wit h dr a w al of t h e s t u d y dr u g b ut 
w h i c h d o n ot pr e cl u d e t h e p ati e nt r e m ai ni n g i n t h e st u d y i n cl u d e, b ut ar e n ot li mit e d t o,
if t h e p ati e nt:
 
M e et s t h e di s c o nti n u ati o n crit eri a i n t h e ri s k miti g ati o n a n d d o s e m o difi c ati o n 
str at e g y ( s e e S e cti o n 5. 1 ).
 
Mi s s e s t hr e e c o n s e c uti v e d o s e s of st u d y dr u g o n s c h e d ul e d vi sit s i n t h e d o u bl e -
bli n d p eri o d.
 
E x p eri e n c e s t w o r el a p s e s i n t h e O L E p eri o d wit h a m or e s e v er e i nt e n sit y 
c o m p ar e d wit h t h e l a st r el a p s e pri or t o b a s eli n e .
T h e I n v e sti g at or s h o ul d c o n s ult wit h t h e M e di c al M o nit or if t h e s e r el a p s e s m e et 
t hi s crit eri o n.
 
E x p eri e n c e s m ali g n a n c y or a 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 t o 
s atr ali z u m a b .
 
Pr e g n a n c y.
 
U n a c c e pt a bl e t o xi cit y.
If t h e p ati e nt i s u n willi n g t o c o nti n u e i n t h e st u d y, h e/ s h e will b e a s k e d t o r et ur n t o t h e 
cli ni c f or a W it h dr a w al vi sit ( s e e S e cti o n 4. 5. 2. 3 ) a n d m a y u n d er g o f oll o w-u p 
a s s e s s m e nt s ( s e e S e cti o n 4. 5. 2. 4 ). T h e pri m ar y r e a s o n f or pr e m at ur e st u d y dr u g 
di s c o nti n u ati o n s h o ul d b e d o c u m e nt e d o n t h e a p pr o pri at e e C R F. P ati e nt s w h o 
di s c o nti n u e st u d y dr u g pr e m at ur el y will n ot b e r e pl a c e d.
4. 7. 1. 2 
Wit h dr a w al fr o m St u d y
E v er y eff ort s h o ul d b e m a d e t o o bt ai n i nf or m ati o n o n p ati e nt s w h o wit h dr a w fr o m t h e 
st u d y. T h e pri m ar y r e a s o n f or wit h dr a w al fr o m t h e st u d y s h o ul d b e d o c u m e nt e d o n t h e 
a p pr o pri at e e C R F. P ati e nt s will n ot b e f oll o w e d f or a n y r e a s o n aft er c o n s e nt h a s b e e n 
w it h dr a w n. P ati e nt s w h o wit h dr a w fr o m t h e st u d y will n ot b e r e pl a c e d .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
4. 7. 2 
St u d y a n d Sit e Di s c o nti n u ati o n
T h e S p o n s or h a s t h e ri g ht t o t er mi n at e t hi s st u d y at a n y ti m e. R e a s o n s f or t er mi n ati n g 
t h e st u d y m a y i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g:
 
T h e i n ci d e n c e or s e v erit y of A E s i n t hi s or ot h er st u di e s i n di c at e s a p ot e nti al 
h e alt h h a z ar d t o p ati e nt s
 
P ati e nt e nr oll m e nt i s u n s ati sf a ct or y
T h e S p o n s or or it s d e si g n e e will n otif y t h e I n v e sti g at or if t h e st u d y i s pl a c e d o n h ol d, 
or if t h e S p o n s or d e ci d e s t o d i s c o nti n u e t h e st u d y or d e v el o p m e nt pr o gr a m.
T h e S p o n s or h a s t h e ri g ht t o di s c o nti n u e a sit e at a n y ti m e. R e a s o n s f or di s c o nti n ui n g
a sit e m a y i n cl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g:
 
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
 
I n a c c ur at e or i n c o m pl et e d at a r e c or di n g
 
N o n -c o m pli a n c e wit h t h e 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 H) 
g ui d eli n e f or G C P .
4. 8 
A D O L E S C E N T S
A d ol e s c e nt s (i. e. , p ati e nt s fr o m 1 2 t o 1 7 y e ar s ol d wit h N M O /N M O S D) will b e 
r a n d o mi z e d i nt o t h e d o u bl e-bli n d p eri o d of t h e s t u d y a s w ell a s a d ult s. R e cr uit m e nt of 
a d ol e s c e nt s i nt o t h e d o u bl e- bli n d p eri o d of t h e st u d y will b e a c c or di n g t o S e cti o n 3. 1. 2 .
Aft er t h e t ot al n u m b er of pr ot o c ol -d ef i n e d r el a p s e s j u d g e d b y t h e C E C r e a c h e s 2 6, th e 
r e cr uit m e nt p eri o d f or t h e a d ol e s c e nt s m a y b e c o nti n u e d i n t h e e xt e n si o n p eri o d u ntil 
a mi ni m u m of 8 a d ol e s c e nt s ar e e nr oll e d i nt o t h e st u d y.
T h e o v er all st u d y o bj e cti v e s r e m ai n t h e s a m e a n d i n cl u d e a d ol e s c e nt s e nr oll e d i nt o 
t h e d o u bl e-bli n d p eri o d of t h e st u d y . T h e o bj e cti v e a n d e n d p oi nt s f or a d ol e s c e nt s ar e 
a s f oll o w s:
S p e cifi c O bj e cti v e f or t h e Gr o u p of A d ol e s c e nt s
T h e o bj e cti v e f or a d ol e s c e nt s w h o ar e e nr oll e d i n t o t hi s st u d y (d o u bl e -bli n d p eri o d or 
e xt e n si o n p eri o d) i s a s f oll o w s :
 
T o e v al u at e t h e s af et y, t ol er a bilit y, ef fic a c y , P K, P D a n d i m m u n o g e ni cit y of  
s atr ali z u m a b i n a d ol e s c e nt s.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
S p e cifi c O ut c o m e M e a s ur e s ( E n d p oi nt s) f or t h e Gr o u p of A d ol e s c e nt s
Pri m ar y  O ut c o m e M e a s ur e s ( E n d p oi nt s )
 
S af et y a s s e s s m e nt s
– 
In ci d e n c e a n d s e v erit y of A E s, A E SI s, S A E a n d s el e ct e d A E s
– 
Vit al si g n s ( t e m p er at ur e, s y st oli c a n d di a st oli c bl o o d pr e s s ur e a n d p ul s e r at e), 
p h y si c al e x a mi n ati o n s, cli ni c al 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), 1 2 l e a d E C G s, s ui ci d alit y ( C -S S R S)
 
P K, P D a n d i m m u n o g e ni cit y
S e c o n d ar y  O ut c o m e M e a s ur e s ( E n d p oi nt s )
 
T F R
 
A R R
 
C h a n g e i n E D S S s c or e
 
C h a n g e i n vi s u al a c uit y ( S n ell e n c h art)
 
C h a n g e i n S F -3 6 s c or e
 
C h a n g e i n V A S s c or e f or p ai n
 
C h a n g e i n F A CI T F ati g u e s c or e
 
C h a n g e i n E Q -5 D s c or e
 
C h a n g e i n m R S s c or e
 
C h a n g e i n Z BI s c or e
T h e i n cl u si o n crit eri a a n d e x cl u si o n crit eri a f or a d ol e s c e nt s w h o will b e e nr oll e d i nt o 
t h e d o u bl e-bli n d p eri o d ar e s h o w n i n S e cti o n 4. 1 . F or a d ol e s c e nt s w h o m a y b e 
e nr oll e d aft er t h e e n d of t h e d o u bl e -bli n d p eri o d, t h e i n cl u si o n crit eri o n 2 a n d t h e 
a n n ot ati o n “*” i n t h e e x cl u s i o n crit eri o n 2 0 ar e a s f oll o w s ( ot h er crit eri a ar e s a m e). 
B a s eli n e of t h e e xt e n si o n p eri o d will o c c ur aft er t h e s cr e e ni n g p eri o d. S cr e e ni n g t e st s 
a n d e v al u ati o n s will b e p erf or m e d wit hi n 2 8 d a y s pri or t o b a s eli n e , u nl e s s ot h er wi s e 
s p e cifi e d. All s cr e e ni n g e v a l u ati o n s m u st b e c o m pl et e d a n d r e vi e w e d t o c o nfir m t h at 
p ati e nt m e et s all eli gi bilit y crit eri a b ef or e t h e fir st st u d y dr u g a d mi ni str ati o n.
I n cl u si o n Crit eri o n 2
Cli ni c al e vi d e n c e of at l e a st 2 d o c u m e nt e d r el a p s e s (i n cl u di n g fir st att a c k) pri or t o 
s cr e e ni n g .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T h e a n n ot ati o n “* ” i n t h e e x cl u si o n crit eri o n 2 0
* If r et e st i s c o n d u ct e d, t h e l a st v al u e of r et e st b ef or e b a s eli n e m u st m e et 
st u d y crit eri a.
5.
A S S E S S M E N T O F S A F E T Y
5. 1 
S A F E T Y P L A N
5. 1. 1 
I m p ort a nt I d e ntifi e d a n d P ot e nti al Ri s k s of S atr ali z u m a b
O n t h e b a si s of m e c h a ni s m of a cti o n, k e y n o n -cli ni c al a n d cli ni c al s af et y fi n di n g s, 
e x p eri e n c e wit h si mil ar m ol e c ul e s, a n I nt e gr at e d S u m m ar y of S af et y I nf or m ati o n i s 
i n cl u d e d i n t h e c urr e nt In v e sti g at or’ s Br o c h ur e f or s atr ali z u m a b . Ple ase refer t o t he 
c urre nt s atr ali z u m a b I n vesti g at or's Br oc h ure f or a n u p-t o-d ate s u m m ar y of a v ail a ble 
s afet y i nf or m ati o n.
T here h a ve bee n n o i m p ort a nt i de ntifie d or p ote nti al ris ks f or s atr ali z u m a b.  T he 
s afet y m a n a ge me nt pl a n f or ot her p ote nti al ris ks a n d l a b or at or y a b n or m alities 
ass oci ate d w it h s atr ali z u m a b, a n d ris ks f or dr u gs i n t he s a me dr u g cl ass are o utli ne d 
bel o w. 
 
S eri o u s I nf e cti o n s
 
N e utr o p e ni a a n d P ot e nti al Ri s k of I nf e cti o n 
 
T hr o m b o c yt o p e ni a a n d P ot e nti al Ri s k of Bl e e di n g
 
Li v er E n z y m e a n d Bilir u bi n El e v ati o n s a n d P ot e nti al Ri s k of H e p at ot o xi cit y
 
El e v at e d Li pi d L e v el s a n d P ot e nti al Ri s k of C ar di o v a s c ul ar/ C er e br o v a s c ul ar 
E v e nt s
 
I m m u n o g e ni cit y
 
S eri o u s H y p er s e n siti vit y R e a cti o n s
 
C Y P 4 5 0 E n z y m e N or m al i z ati o n
 
C o m pli c ati o n s of Di v erti c uliti s
 
M a li g n a n ci e s
 
D e m y eli n ati n g Di s or d er s
I n or d er t o ad dr e s s t h e i d e ntifi e d a n d p ot e nti al ri s k s f or t h e p ati e nt s, t h e f oll o wi n g 
s af et y pr e c a uti o n s ar e i n cl u d e d i n t h e st u d y d e si g n:
 
I n a d diti o n t o r e g ul ar st a n d ar d s af et y e v al u ati o n s (l a b or at or y m e a s ur e s, p h y si c al 
e x a mi n ati o n s, vit al si g n s a n d E C G), a s p e ci al f o c u s will b e pl a c e d o n t h e a b o v e 
ri s k s.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
A n I D M C will p eri o di c all y e v al u at e t h e s af et y of p ati e nt s e v er y si x m o nt h s d uri n g 
t he d o u ble-bli n d peri o d of t he st u d y.
 
D e ar D o ct or L ett er s s h o ul d b e pr o vi d e d t o t h e p ati e nt a b o ut t h e st u d y a n d t h e 
i n v e sti g ati o n al dru g. P ati e nt s s h o ul d b e i n str u ct e d t o i nf or m a b o ut t hi s st u d y a n d 
t h e i n v e sti g ati o n al dr u g t o h e alt h c ar e pr of e s si o n al s i n c a s e t h e y c o nt a ct a n y ot h er 
h o s pit al/ cli ni c , et c.
R e c o m m e n d ati o n f or vi gil a n c e wit h r e g ar d s t o si g n a n d s y m pt o m s of p arti c ul ar s af et y 
e v e nt s ar e s u m m ari z e d i n t h e f oll o wi n g s e cti o n s.
5. 1. 1. 1 
S eri o u s Inf e cti o n
I n a P h a s e 1 m ulti pl e d o s e st u d y of s atr ali z u m a b i n p ati e nt s wit h R A ( S A-1 0 5 J P), o n e
c a s e of s eri o u s i nf e cti o n , br o n c h o p n e u m o ni a ( 1 of 3 3 p ati e nt s), w a s r e p ort e d. S eri o u s 
i nf e cti o n i s a n i d e ntifi e d ri s k of t o cili z u m a b. I n t h e all-e x p o s ur e p o p ul ati o n of 
t o cili z u m a b, t h e m o st c o m m o n s eri o u s i nf e cti o n s i n cl u d e d p n e u m o ni a, uri n ar y tr a ct 
i nf e cti o n, c ell uliti s, h er p e s z o st er, g a str o e nt eriti s, di v erti c uliti s, s e p si s a n d b a ct eri al 
art hriti s. 
Tr e a t m e nt wit h s atr ali z u m a b s u p pr e s s e s a c ut e p h a s e r e a cti o n s (f e v er, i n cr e a s e i n 
C R P, et c.) i n d u c e d b y I L -6 a n d a c c or di n gl y s u p pr e s s e s si g n s a n d s y m pt o m s 
a s s o ci at e d wit h i nf e cti o n, w hi c h m a y d el a y t h e d et e cti o n of i nf e cti o n s. A s a r e s ult, it 
m a y p ot e nti all y m a k e t h e i nf e cti o n m or e se vere.
P ati e nt s wit h a n a cti v e i nf e cti o n ( e x cl u di n g f u n g al i nf e cti o n s of n ail b e d s or c ari e s 
d e nti u m) wit hi n 4 w e e k s pri or t o b a s eli n e will b e e x cl u d e d fr o m t hi s st u d y.
P ati e nt s wit h e vi d e n c e of a cti v e T B ( e x cl u di n g p ati e nt s r e c ei vi ng c h e m o pr o p h yl a xi s 
f or l at e nt T B i nfe cti o n) will b e e x cl u d e d fr o m t hi s st u d y.
P ati e nt s wit h c hr o ni c a cti v e h e p atiti s B or C will b e e x cl u d e d fr o m t hi s st u d y.
P ati e nt s w h o r e c ei v e d a n y li v e or li v e att e n u at e d v a c ci n e wit hi n 6 w e e k s pri or t o 
b a s eli n e will b e e x cl u d e d fr o m t hi s st u d y.
 
S atr ali z u m a b s h o ul d n ot b e i niti at e d or a d mi ni st er e d i n p ati e nt s wit h a cti v e 
i nf e cti o n s.
 
P ati e nt s s h o ul d b e cl o s el y m o nit or e d f or t h e d e v el o p m e nt of si g n s a n d s y m pt o m s 
of  i nf e cti o n, a s si g n s a n d s y m pt o m s of a c ut e i nfl a m m ati o n m a y b e l e s s e n e d d u e 
t o s u p pr e s si o n of t h e a c ut e p h a s e r e a ct a nt s. 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
P ati e nt s m u st b e i n str u ct e d t o c o nt a ct t h eir p h y si ci a n i m m e di at el y w h e n a n y 
s y m pt o m s s u g g e sti n g i nf e cti o n a p p e ar, i n or d er t o e ns ure r a pi d e v al u ati o n a n d 
a p pr o pri at e tr e at m e nt. 
 
If a p ati e nt d ev el o p s a s eri o u s i nf e cti o n, a d mi ni str ati o n of s atr ali z u m a b i s t o b e 
i nt err u pt e d u ntil t h e i nf e cti o n i s r e s ol v e d. T h e tre ati n g p h ysici a n s h o ul d c o n d uct a 
b e n efit -ri s k assess me nt b ef or e r e s u mi n g tr e at m e nt wit h s atr ali z u m a b .
 
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 n ot t o b e gi v e n wit hi n 6 w e e k s pri or t o 
b a s eli n e a n d d uri n g t h e c o ur s e of t h e st u d y a s cli ni c al s af et y h a s n ot b e e n 
e st a bli s h e d.
F or p ati e nt s wit h N M O p arti ci p at i n g i n t hi s pr ot o c ol, t h er a pi e s u s e d t o tr e at N M O 
( c orti c o st er oi d s, a z at hi o pri n e, m y c o p he n ol at e m of etil) h a v e b e e n s h o w n t o b e 
a s s o ci at e d wit h i nf e cti o n s, p arti c ul arl y s eri o u s i nf e cti o n s.
5. 1. 1. 2 
N e utr o p e ni a a n d P ot e nti al Ri s k of I nf e cti o n
R e v er si bl e n e utr o p e ni a w a s r e p ort e d i n 1 of 3 3 p ati e nt s wit h R A i n P h a s e 1 m ulti pl e 
d o s e st u d y ( S A -1 0 5 J P).
I n t he c o m plete d d o u ble-bli n d peri o d of t he P h ase 3 st u dies, decre ases i n ne utr o p hil 
c o u nts h a ve occ urre d f oll o wi n g tre at me nt wit h s atr ali z u m a b, w hic h w as n ot 
ass oci ate d wit h seri o us i nfecti o ns. T he m aj orit y of ne utr o p hil decre ases were 
tr a nsie nt or i nter mitte nt.
N e utr o p e ni a h a s b e e n o b s er v e d d uri n g a d mi ni str ati o n of t o cili z u m a b. I nf e cti o n s h a v e 
b e e n u n c o m m o nl y r e p ort e d i n a s s o ci ati o n wit h tr e at m e nt -r el at e d n e utr o p e ni a i n 
l o n g-t er m e xt e n si o n st u di e s a n d p o st m ar k eti n g cli ni c al e x p eri e n c e.
P ati e nt s wit h a l o w n e utr o p hil c o u nt < 2 x 1 0 3 / µL will b e e x cl u d e d fr o m t hi s st u d y.
C a uti o n s h o ul d b e e x er ci s e d i n p ati e nt s wit h a l o w n e utr o p hil c o u nt a n d a p pr o pri at e 
m e a s ur e s ( s u c h a s i nt err u pti o n of s atr ali z u m a b ) s h o ul d b e c o n si d er e d if n e utr o p e ni a 
p er si st s.
R e c o m m e n d e d d o s e i nt err u pti o n b a s e d o n A N C r e s ult s i s s h o w n i n T a bl e 2 .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T a bl e 2: 
N e utr o p e ni a Ri s k Miti g ati o n
A N C (/ µ L)
A cti o n
> 1, 0 0 0
M ai nt ai n d o s e
5 0 0 – 1, 0 0 0 
 
If n e utr o p e ni a p er si st s, s atr ali z u m a b s h o ul d b e i nt err u pt e d u ntil A N C i s 
a b o v e 1, 0 0 0/ µ L.
 
If A N C w a s u n d er 1, 0 0 0/ µ L at t h e pr e vi o u s l a b or at or y t e st, A N C m u st 
b e c h e c k e d b ef or e tr e at m e nt wit h t h e s atr ali z u m a b ( e. g., A N C t e st at 
sit e).
< 5 0 0
S atr ali z u m a b s h o ul d b e di s c o nti n u e d .
A N C a b s ol ut e n e utr o p hil c o u nt .
5. 1. 1. 3 
T hr o m b o c yt o p e ni a a n d P ot e nti al Ri s k of Bl e e di n g
Tr e at m e nt -r el at e d r e d u cti o n i n pl at el et c o u nt w a s o b s er v e d i n P h a s e 1 m ulti pl e -d o s e 
st u d y wit h R A ( S A-1 0 5 J P), alt h o u g h t h e s e w er e wit hi n n or m al r a n g e. 
I n t he P h ase 3 st u dies, decre ases i n pl atelet c o u nts h a ve bee n o bser ve d f oll o wi n g 
tre at me nt wit h s atr ali z u m a b.
Tr e at m e nt -r el at e d r e d u cti o n i n pl at el et s w a s n ot a s s o ci at e d wit h bl e e di n g e v e nt s i n 
cli ni c al tri al s.
P ati e nt s wit h a pl at el et c o u nt b el o w 1 0 x 1 0 4 / μ L will b e e x cl u d e d fr o m t hi s st u d y.
C a uti o n s h o ul d b e e x er ci s e d i n p ati e nt s wit h a l o w pl at el et c o u nt a n d a p pr o pri at e 
m e a s ur e s ( s u c h a s i nt err u pti o n of s atr ali z u m a b ) s h o ul d b e c o n si d er e d if 
t hr o m b o c yt o p e ni a p er si st s.
R e c o m m e n d e d d o s e i nt err u pti o n b a s e d o n pl at el et c o u nt s ar e s h o w n i n T a bl e 3 .
T a bl e 3: 
T hr o m b o c yt o p e ni a Ri s k Miti g ati o n
Pl at el et c o u nt ( / µ L）
A cti o n
> 7 5, 0 0 0
M ai nt ai n d o s e
5 0, 0 0 0 – 7 5, 0 0 0
If t hr o m b o c yt o p e ni a p er si st s, s atr ali z u m a b s h o ul d b e i nt err u pt e d 
u ntil pl at el et c o u nt i s a b o v e 7 5 , 0 0 0/ µ L.
< 5 0, 0 0 0
S atr ali z u m a b s h o ul d b e di s c o nti n u e d.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 1. 1. 4 
Li v er E n z y m e a n d Bilir u bi n El e v ati o n s a n d P ot e nti al Ri s k of 
H e p at ot o xi cit y
R e v er si bl e el e v ati o n s of A S T a n d t ot al bilir u bi n w er e e a c h o b s er v e d i n 2 h e alt h y 
s u bj e ct s a n d r e v er si bl e el e v ati o n of A L T i n 1 h e alt h y s u bj e ct o ut of 7 2 h e alt h y 
s u bj e ct s i n t h e P h a s e 1 si n gl e a s c e n di n g d o s e st u d y ( S A -0 0 1 J P).
I n t he P h ase 3 st u dies, mil d a n d m o der ate ele v ati o ns of li ver tr a ns a mi n ases h a ve bee n 
o bser ve d wit h s atr ali z u m a b tre at me nt.  M ost ele v ati o ns were 5 U L N a n d res ol ve d 
w hile o n tre at me nt wit h s atr ali z u m a b.   E le v ati o ns of A L T or A S T 3 U L N were 
n ot ass oci ate d wit h i ncre ases i n t ot al bilir u bi n.
It h a s b e e n r e p ort e d t h at I L-6 a p p e ar s t o h a v e a h e p at o pr ot e cti v e eff e ct o n v ari o u s 
f or m s of li v er i nj ur y a n d pr o m ot e s h e p at o c yt e r e g e n er ati o n. P ati e nt s wit h el e v at e d 
tr a n s a mi n a s e s A L T or A S T > 1. 5 x U L N will b e e x cl u d e d fr o m t hi s st u d y. 
Li v er f u n cti o n m ar k er s s h o ul d b e cl o s el y m o nit or e d w h e n s atr ali z u m a b i s a d mi ni st er e d, 
e s p e ci all y c o n c o mit a ntl y wit h h e p at ot o xi c dr u g s or a d mi ni st er e d i n p ati e nt s wit h 
el e v at e d tr a n s a mi n a s e s.
R e c o m m e n d e d d o s e i nt err u pti o n s b a s e d o n tr a n s a mi n a s e s ar e s h o w n i n T a bl e 4 .
T a bl e 4: 
H e p ati c E n z y m e Ri s k Miti g ati o n
A S T or A L T v al u e s
A cti o n
> 1 t o 3 x U L N* 
 
R e d u cti o n (if n e c e s s ar y, i nt err u pti o n) of h e p at ot o xi c dr u g s c o ul d b e 
c o n si d er e d. 
 
F or p er si st e nt i n cr e a s e s i n t hi s r a n g e, s atr ali z u m a b c o ul d b e 
i nt err u pt e d u ntil A S T a n d A L T i s b el o w U L N*.
> 3 t o 5 x U L N 
L a b or at or y t e st s ( A L T, A S T, A L P a n d T B L) s h o ul d b e r e p e at e d wit hi n 
7 2 h o ur s t o c o nfir m v al u e. T h e pr e s e n c e of cli ni c al s y m pt o m s s h o ul d b e 
q u eri e d. P ati e nt s w h o ar e f ar a w a y fr o m t h e tri al sit e m a y b e r et e st e d 
l o c all y if pr o m pt r et ur n t o t h e tri al sit e i s diffi c ult. If cl o s e m o nit ori n g i s 
n ot p o s si bl e, t h e dr u g s h o ul d b e di s c o nti n u e d.
s atr ali z u m a b s h o ul d b e i nt err u pt e d u ntil A S T a n d A L T i s b el o w 3 x U L N. 
If at l e a st o n e of f oll o wi n g a s s o ci at e d, s atr ali z u m a b s h o ul d b e 
di s c o nti n u e d :
 
T ot al bilir u bi n > 2 x U L N a n d/ or
 
I N R > 1. 5 x U L N a n d/ or
 
A p p e ar a n c e of f ati g u e, n a u s e a, v o miti n g, ri g ht u p p er q u a dr a nt p ai n 
or t e n d er n e s s, f e v er, r a s h, a n d/ or e o si n o p hili a


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
7 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A S T or A L T v al u e s
A cti o n
> 5 x U L N
L a b or at or y t e st s ( A L T, A S T, A L P, a n d T B L) s h o ul d b e r e p e at e d wit hi n 
7 2 h o ur s a s s o o n a s p o s si bl e t o c o nfir m v al u e. If c o nti n u e d, 
s atr ali z u m a b s h o ul d b e di s c o nti n u e d i m m e di at el y a n d g a str o e nt er ol o g y 
e x p ert s h o ul d b e c o nt a ct e d.
T h e pr e s e n c e of cli ni c al s y m pt o m s s h o ul d b e q u eri e d. P ati e nt s w h o ar e 
f ar a w a y fr o m t h e tri al sit e m a y b e r et e st e d l o c all y if pr o m pt r et ur n t o t h e 
tri al sit e i s diffi c ult.
A L P al k ali n e p h o s p h at a s e; A L T al a ni n e a mi n otr a n sf er a s e; A S T a s p art at e 
a m i n otr a n sf er a s e; I N Ri nt er n ati o n al n or m ali z e d r ati o; T B L t ot al bilir u bi n; U L N u p p er li mit of 
n or m al .
* U L N or p ati e nt’ s b a s eli n e w hi c h e v er i s hi g h er.
5. 1. 1. 5 
El e v at e d Li pi d L e v el s a n d P ot e nti al Ri s k of 
C ar di o v a s c ul ar/ C er e br o v a s c ul ar E v e nt s
S li g ht in cr e a s e s i n li pi d l e v el s ( 3 A E s of h y p erli pi d a e mi a [mil d ]) w er e o b s er v e d i n 3 o ut 
of  3 3 p ati e nt s i n P h a s e 1 m ulti pl e d o s e st u d y ( S A -1 0 5 J P) , w hile n o 
c ar di o v a s c ul ar/ c er e br o v a s c ul ar e v e nt s h a v e b e e n o b s er v e d i n P h a s e 1 tri al s of 
s atr ali z u m a b . I n cr e a s e s i n t ot al c h ol e st er ol, L D L c h ol e st er ol, H D L c h ol e st er ol a n d 
tri gl y c eri d e s d u e t o a d mi ni str ati o n of t o cili z u m a b h a v e b e e n o b s er v e d. H o w e v er, it i s 
u n k n o w n w h et h er t h e s e c h a n g e s w er e a s s o ci at e d wit h c ar di o v a s c ul ar e v e nt s. 
I n t he P h ase 3 st u dies, ele v ati o ns i n t ot al c h olester ol a n d tri gl yceri des were o bser ve d.  
T he ele v ati o ns i n li pi d p ar a meters di d n ot re q uire d ose i nterr u pti o n. P ati e nt 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 g ui d eli n e s u c h a s t h e Nati o n al C h ol e st er ol E d u c ati o n 
Pr o gr a m A d ult Tr e at m e nt P a n el III or J a p a n At h er o s cl er o si s S o ci et y g ui d eli n e or ot h er 
g ui d eli n e.
5. 1. 1. 6 
I m m u n o g e ni cit y
I n a P h a s e 1 si n gl e -d o s e st u d y ( S A-0 0 1 J P) of s atr ali z u m a b i n h e alt h y J a p a n e s e a n d 
C a u c a si a n a d ult m al e v ol u nt e er s, A D A w er e d et e ct e d i n 3 9 of t h e 7 2 p ati e nt s w h o 
r e c ei v e d s atr ali z u m a b . Mo st of A D A s w er e c h ar a ct eri z e d a s n e utr ali zi n g a nti b o d y. I n a 
P h a s e 1 m ulti pl e d o s e st u d y of s atr ali z u m a b ( S A-1 0 5 J P) i n p ati e nt s wit h R A , A D A 
w er e d et e ct e d i n 2 of t h e 3 3 p ati e nt s w h o r e c ei v e d s atr ali z u m a b . T h e s e A D A s w er e 
al s o c h ar a ct eri z e d a s n e utr ali zi n g a nti b o d y, a n d i n t h e s e 2 p ati e nt s, el e v ati o n of 
s er u m l e v el of s atr ali z u m a b w a s n ot o b s er v e d.
I n t he d o u ble-bli n d peri o ds of t he P h ase 3 st u dies, A D As were o bser ve d i n 4 1 % 
( St u d y B N 4 0 8 9 8) a n d 7 1 % ( St u d y B N 4 0 9 0 0) of p atie nts recei vi n g s atr ali z u m a b.  
E x p os ure w as l o wer i n A D A p ositi ve p atie nts; h o we ver, t here w as n o i m p act of 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A D As o n s afet y a n d n o cle ar i m p act o n effic ac y or p h ar m ac o d y n a mi c m ar kers 
i n dic ati ve of t ar get e n g a ge me nt.
5. 1. 1. 7 
S eri o u s H y p er s e n siti vit y R e a cti o n s
A n a p h yl a xi s a n d s eri o u s h y p er s e n siti vit y r e a cti o n s h a v e n ot b e e n r e p ort e d i n cli ni c al 
tri al s wit h s atr ali z u m a b tr e at m e nt; h o w e v er, a n a p h yl a xi s a n d h y p er s e n siti vit y 
r e a cti o n s ar e c o n si d er e d a p ot e nti al ri s k wit h all bi ol o gi c m e di c ati o n s, i n cl u di n g 
s atr ali z u m a b . 
P ati e nt s wit h a hi st or y of a s e v er e all er gi c r e a cti o n t o a bi ol o gi c a g e nt ar e e x cl u d e d 
fr o m st u d y p arti ci p ati o n.
T h e s y m pt o m s/ si g n s of h y p er s e n siti vit y i n cl u d e, b ut ar e n ot li mit e d t o, bl o o d pr e s s ur e 
d e cr e a s e, d y s p n e a, l o s s of c o n s ci o u s n e s s, di z zi n e s s, q u e a si n e s s, v o miti n g, it c hi n e s s, 
fl u s hi n g, et c. A d e ci si o n t o c o nti n u e/ di s c o nti n u e tr e at m e nt wit h s atr ali z u m a b s h o ul d b e 
m a d e t a ki n g i nt o a c c o u nt t h e ri s k s a n d b e n efit s if a n y
of t h e s e e v e nt s ar e o b s er v e d.
 
U p t o Wee k 4 8 i n t he O L E peri o d of t he st u d y:
– 
T h e S C i nj e cti o n s s h o ul d b e a d mi ni st er e d u n d er cl o s e s u p er vi si o n i n a 
s etti n g w h er e m e di c ati o n s ( e g. c orti c o st er oi d, a nti hi st a mi n e a n d e pi n e p hri n e) 
a n d r e s u s cit ati o n f a ciliti e s ar e a v ail a bl e
– 
P ati e nt s s h o ul d st a y i n t h e cli ni c/ h o s pit al at l e a st 1 h o ur aft er st u d y dr u g 
a d mi ni str ati o n i n or d er t o r e c ei v e m e di c ati o n i m m e di at el y if a n a p h yl a xi s 
o c c ur s.
 
P ati e nt s s h o ul d b e i n str u ct e d t o s e e k m e di c al att e nti o n if t h e y e x p eri e n c e 
s y m pt o m s of h y p er s e n siti vit y r e a cti o n o ut si d e of t h e cli ni c.
 
If a n a n a p h yl acti c r e a cti o n or ot h er s eri o u s h y p er s e n siti vit y r e a cti o n o c c ur s, 
s atr ali z u m a b s h o ul d b e di s c o nti n u e d .
 
A d mi nistr ati o n of s atr ali z u m a b prefille d s yri n ges o utsi de of t he st u d y site mi g ht 
be all o we d (see Secti o n 4. 3. 2. 2 ) if t he i n vesti g at or deter mi nes t h at it is 
a p pr o pri ate.  P atie nts/c are gi vers s h o ul d be i nstr ucte d t o rec o g ni ze t he si g ns a n d 
s y m pt o ms of h y perse nsiti vit y re acti o ns a n d i nstr ucte d t o see k i m me di ate me dic al 
atte nti o n if t he p atie nt de vel o ps s y m pt o ms of seri o us aller gic re acti o ns.  
P atie nts/c are gi vers s h o ul d c o nfir m wit h t he i n vesti g at or w het her tre at me nt wit h 
s atr ali z u m a b m a y be c o nti n ue d.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 1. 1. 8 
C Y P 4 5 0 E n z y m e N or m al i z ati o n
Dr u g i nt er a cti o n st u di e s h a v e n ot b e e n c o n d u ct e d wit h s atr ali z u m a b . I n p ati e nt s wit h 
R A w h o w er e a d mi ni st er e d t o cili z u m a b, i n cr e a s e d e x pr e s si o n of C Y P 3 A 4, C Y P 2 C 1 9 
a n d C Y P 2 D 6 h a s b e e n s u g g e st e d. R e p ort s h a v e s u g g e st e d t h at o v er pr o d u cti o n of I L -
6 i n p ati e nt s wit h i nfl a m m at or y r e s p o n s e i n hi bit s t h e e x pr e s si o n of C Y P s. 
S atr a li z u m a b a d mi ni str ati o n m a y n or m ali z e C Y P e x pr e s si o n a n d t h e b e n efi ci al eff e ct s 
of  c o n c o mit a nt dr u g s m a y d e cr e a s e a s t h e i nfl a m m at or y r e a cti o n i m pr o v e s.
P ati e nt s t a ki n g m e di ci n al pr o d u ct s t h at ar e i n di vi d u all y a dj u st e d a n d ar e m et a b oli z e d 
vi a C Y P 4 5 0 3 A 4, 1 A 2, 2 C 9 or 2 C 1 9 s h o ul d b e m o nit or e d a s d o s e s m a y n e e d t o b e 
m o difie d .
5. 1. 1. 9 
C o m pli c ati o n s of Di v erti c uliti s
G a str oi nt e sti n al p erf or ati o n s h a v e n ot b e e n r e p ort e d i n cli ni c al tri al s wit h s atr ali z u m a b
tr e at m e nt.
T o d ate, g a str oi nt e sti n al p erf or ati o n s h a v e b e e n r e p or t e d r ar el y i n p ati e nt s 
a d mi ni st er e d t o cili z u m a b. Alt h o u g h it i s u n k n o w n w h et h er g a str oi nt e sti n al p erf or ati o n s 
ar e a s s o ci at e d wit h I L -6 i n hi biti o n, s atr ali z u m a b m a y s u p pr e s s t h e a c ut e s y m pt o m s 
( a b d o mi n al p ai n, p yr e xi a et c.) a s s o ci at e d wit h di v erti c uliti s, et c., c a u si n g d el a y e d 
di a g n o si s a n d pr o gr e s si o n t o p erf or ati o n. 
I n t hi s st u d y, a hi st or y of a cti v e di v erti c uliti s m a y pr e cl u d e p ati e nt fr o m p arti ci p ati o n.
 
P ati e nt s pr e s e nti n g wit h s y m pt o m s p ot e nti all y i n di c ati v e of c o m pli c at e d 
di v erti c uliti s, s u c h a s a b d o mi n al p ai n, s h o ul d b e e v al u at e d ( X -r a y, c o m p ut eri z e d 
t o m o gr a p h y [ C T] s c a n, et c.) pr o m ptl y f or e arl y i d e ntifi c ati o n of g a str oi nt e sti n al 
p erf or ati o n a n d a p pr o pri at e m e a s ur e s t a k e n.
 
P ati e nt s s h o ul d b e m a d e a w ar e of t h e s y m pt o m at ol o g y p ot e nti all y i n di c ati v e of 
c o m pli c at e d di v erti c ul ar di s e a s e, a n d t h e y s h o ul d b e i n str u ct e d t o al ert t h eir 
h e alt h c ar e pr o vi d er a s s o o n a s p o s si bl e if t h e s e s y m pt o m s ari s e.
 
I n p ati e nt s w h o r e c ei v e c orti c o st er oi d s a n d/ or n o n -st er oi d al a nti -i nfl a m m at or y 
dr u g s, pr o p h yl a cti c tr e at m e nt wit h pr ot o n p u m p i n hi bit or s or H 2 bl o c k er s h o ul d b e 
c o n si d er e d .
5. 1. 1. 1 0 
M ali g n a n ci e s
N o i ncre ase d ris k of m ali g n a n ci e s h as b e e n o bser ve d i n cli ni c al tri al s wit h s atr ali z u m a b
tr e at m e nt.
Alt h o u g h m ali g n a n ci e s h a v e b e e n r e p ort e d i n p ati e nt s gi v e n t o cili z u m a b, t h er e h a v e 
b e e n n o r e p ort t o d at e t h at t o cili z u m a b a p pr e ci a bl y i n cr e a s e s t h e o c c urr e n c e of 
m ali g n a n ci e s. 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
All p ati e nt s wit h hi st or y of m ali g n a n c y wit hi n t h e l a st 5 y e ar s, i n cl u di n g s oli d t u m or s, 
h e m at ol o gi c m ali g n a n ci e s a n d i n sit u c ar ci n o m a ( e x c e pt b a s al c ell a n d 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, or i n sit u c ar ci n o m a of t h e c er vi x ut eri t h at h a v e b e e n 
c o m pl et el y e x ci s e d a n d c ur e d) will b e e x cl u d e d fr o m t hi s st u d y. 
S atr ali z u m a b s h o ul d b e di s c o nti n u e d i n p ati e nt s wit h m ali g n a n ci e s ( wit h t h e e x c e pti o n 
of  l o c al b a s al or s q u a m o u s c ell c ar ci n o m a of t h e s ki n t h at i s c o m pl et el y e x ci s e d wit h 
fr e e m ar gi n s)
5. 1. 1. 1 1 
D e m y eli n ati n g Di s or d er s
D e m y eli n ati o n -r el at e d di s e a s e s h a v e n ot b e e n r e p ort e d i n cli ni c al tri al s wit h 
s atr ali z u m a b tr e at m e nt.
T h e i m p a ct of tr e at m e nt wit h t o cili z u m a b o n d e m y eli n ati n g di s or d er s i s n ot k n o w n, b ut 
M S
a n d c hr o ni c i nfl a m m at or y d e m y eli n ati n g p ol y n e ur o p at h y w er e r e p ort e d r ar el y i n 
R A cli ni c al st u di e s. P M L h a s n ot b e e n r e p ort e d. 
P ati e nt s wit h e vi d e n c e of ot h er d e m y eli n ati n g di s e a s e or P M L will b e e x cl u d e d fr o m 
t hi s st u d y.
If s y m pt o m s s u g g e sti v e of a d e m y eli n ati o n -r el at e d di s e a s e ar e o b s er v e d, diff er e nti al
di a g n o si s of t h e c a u s e s h o ul d b e p erf or m e d.
5. 1. 1. 1 2 
C o n c o mit a nt M e di c ati o n s
P ati e nt s s h o ul d al s o 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 c orti c o st er oi d s, 
a z at hi o pri n e or m y c o p h e n ol at e m of etil. B el o w ar e li st e d s p e cifi c m aj or ri s k s t h at 
p ati e nt s n e e d t o b e a w ar e of:
 
C ort i c o st er oi d s c a n c a u s e i m m u n o s u p pr e s si o n, h y p ert e n si o n, di a b et e s m ellit u s, 
c at ar a ct s, gl a u c o m a, br ui si n g, t hi n ni n g of t h e s ki n, w ei g ht g ai n, p s y c h ol o gi c al 
c h a n g e s, o st e o p or o si s, a c c el er at e d at h er o s cl er o si s, i n cr e a s e d ri s k of 
g a str oi nt e sti n al bl e e di n g, a s e pt i c n e cr o si s of b o n e a n d a dr e n al i n s uffi ci e n c y. 
Alt h o u g h r ar e, st er oi d -i n d u c e d h y p er s e n siti vit y r e a cti o n s d o o c c ur. T h e y r a n g e 
fr o m mi n or r a s h e s t o t h e m or e s eri o u s c ar di o v a s c ul ar c oll a p s e. F or a d diti o n al 
s af et y d at a, r ef er t o t h e l o c al pr e s cri bi n g i nf or m at i o n.
 
N o e vi d e n c e a v ail a bl e at t h e ti m e of a p pr o v al of t hi s st u d y pr ot o c ol i n di c at e d t h at 
s p e ci al w ar ni n g s or pr e c a uti o n s w er e a p pr o pri at e, ot h er t h a n t h o s e n ot e d i n t h e 
I n v e sti g at or’ s Br o c h ur e.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 2 
S A F E T Y P A R A M E T E R S A N D D E FI NI TI O N S
S af et y a s s e s s m e nt s will c o n s i st of m o nit ori n g a n d r e c or di n g A E s, i n cl u di n g S A E s, 
A E SI s a n d s el e ct e d A E s; m e a s ur e m e nt of pr ot o c ol -s p e cifi e d s af et y l a b or at or y 
a s s e s s m e nt s; m e a s ur e m e nt of pr ot o c ol -s p e cifi e d vit al si g n s; a n d ot h er 
pr ot o c ol -s p e cifi e d t e st s t h at ar e d e e m e d criti c al t o t h e s af et y e v al u ati o n of t h e st u d y.
C ert ai n t y p e s of e v e nt s r e q uir e i m m e di at e r e p orti n g t o t h e S p o n s or, a s o utli n e d i n 
S e cti o n 5. 4 .
5. 2. 1 
A d v er s e E v e nt s
A c c or di n g t o t h e I C H g ui d eli n e f or G C P, a n A E 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 cli ni c al i n v e sti g ati o n s u bj e ct a d mi ni st er e d a p h ar m a c e uti c al pr o d u ct, r e g ar dl e s s of 
c a u s al attri b uti o n. A n A E c a n t h er ef or e b e a n y of t h e f oll o wi n g:
 
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 e m p or all y a s s o ci at e d wit h t h e u s e of a 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 pr o d u ct
 
A n y n e w di s e a s e or e x a c er b ati o n of a n e xi sti n g di s e a s e ( a w or s e ni n g i n t h e 
c h ar a ct er, fr e q u e n c y, or s e v erit y of a k n o w n c o n diti o n), e x c e pt a s d e s cri b e d i n 
S e cti o n 5. 3. 5. 9
 
R e c urr e n c e of a n i nt er mitt e nt m e di c al c o n diti o n ( e. g. , h e a d a c h e) n ot pr e s e nt 
at b a s eli n e
 
A n y d et eri or ati o n i n a l a b or at or y v al u e or ot h er cli ni c al t e st ( e. g. , E C G, X -r a y) t h at 
i s a s s o ci at e d wit h s y m pt o m s or l e a d s t o a c h a n g e i n st u d y dr u g or c o n c o mit a nt 
tr e at m e nt or dis c o nti n u ati o n fr o m st u d y dr u g
 
A d v er s e e v e nt s t h at ar e r el at e d t o a pr ot o c ol -m a n d at e d i nt er v e nti o n, i n cl u di n g 
t h o s e t h at o c c ur pri or t o a s si g n m e nt of st u d y dr u g (e. g. , i n v a si v e s cr e e ni n g 
pr o c e d ur e s s u c h a s bi o p si e s)
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 c o n si d er e d N M O -r el at e d ar e n ot A E s. 
Cli ni c al r el a p s e will b e r e c or d e d o nl y o n a pr e -s p e cifi e d e C R F “ N M O r el a p s e” f or m.
5. 2. 2 
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 t h e 
S p o n s or)
A n S A E i s a n y A E t h at m e et s a n y of t h e f oll o wi n g crit eri a:
 
F at al ( i. e., t h e A E a ct u all y c a u s e s or l e a d s t o d e at h)
 
Lif e t hr e at e ni n g ( i. e., t h e A E , i n t h e vi e w of t h e I n v e sti g at or, pl a c e s t h e p ati e nt at 
i m m e di at e ri s k of d e at h)
T hi s d o e s n ot i n cl u d e a n y A E t h at h a d it o c c urr e d i n a m or e s e v er e f or m or w a s 
all o w e d t o c o nti n u e mi g ht h a v e c a u s e d d e at h


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
R e q uir e s or pr ol o n g s i n p ati e nt h o s pit ali z ati o n ( s e e S e cti o n 5. 3. 5. 1 0 )
 
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. e., t h e A E r e s ult s i n 
s u b st a nti al di sr u pti o n of t h e p ati e nt’ s a bilit y t o c o n d u ct n or m al lif e f u n cti o n s)
 
C o n g e nit al a n o m al y/ birt h d ef e ct i n a n e o n at e/i nf a nt b or n t o a m ot h er e x p o s e d t o 
st u d y dr u g
 
Si g nifi c a nt m e di c al e v e nt i n t h e I n v e sti g at or' s j u d g m e nt (e. g. , m a y j e o p ar di z e t h e 
p ati e nt or m a y r e q uir e m e di c al/ s ur gi c al 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 a b o v e)
T h e e x c e pti o n t o t hi s d efi niti o n of a n S A E i s i n t h e r ar e e v e nt t h at a p ati e nt i s 
h o s pit ali z e d f oll o wi n g a n N M O r el a p s e, a s l o n g a s t h e r e a s o n f or h o s pit ali z ati o n i s t o 
r e c ei v e st a n d ar d tr e at m e nt wit h r e s c u e t h er a p y f or cli ni c al r el a p s e.
T h e t er m s “ s e v er e” a n d “ s eri o u s” ar e n ot s y n o n y m o u s. S e v eri t y r ef er s t o t h e i nt e n sit y 
of  a n A E (r at e d a s mil d, m o d er at e, or s e v er e] crit eri a; s e e S e cti o n 5. 3. 3 ); t h e e v e nt 
it s elf m a y b e of r el ati v el y mi n or m e di c al si g nifi c a n c e ( s u c h a s s e v er e h e a d a c h e 
wit h o ut a n y f urt h er fi n di n g s).
S e v erit y a n d s eri o u s n e s s n e e d t o b e i n d e p e n d e ntl y a s s e s s e d f or e a c h A E r e c or d e d 
o n t h e e C R F.
S eri o u s a d v er s e e v e nt s ar e r e q uir e d t o b e r e p ort e d b y t h e I n v e sti g at or t o t h e S p o n s or 
wit hi 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 5. 4. 2 f or r e p orti n g i n str u cti o n s).
5. 2. 3 
N o n -s eri o u s 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 t h e S p o n s or)
N o n -s eri o u s A E SI s ar e r e q uir e d t o b e r e p ort e d b y t h e I n v e sti g at or t o t h e S po n s or 
wit hi 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 5. 4. 2 f or r e p orti n g i n str u cti o n s). 
N o n -s eri o u s A E s of S p e ci al I nt er e st f or t hi s st u d y i n cl u d e t h e f oll o wi n g:
 
C a s e s of 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 i n S e cti o n 5. 3. 5. 6
 
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 .
5. 2. 4 
S el e ct e d A d v er s e E v e nt s
A d diti o n al d at a will b e c oll e ct e d f or t h e f oll o wi n g s el e ct e d A E s. T h e d at a s h o ul d b e 
r e c or d e d i n t h e e C R F o n t h e A E p a g e a n d o n th e s p e ci al f or m f or t h at p arti c ul ar A E.
 
I nf e cti o n s t h at r e q uir e tr e at m e nt s wit h I V a nti bi oti cs, a ntif u n g als, or a nti vir al s *
 
O p p ort u ni sti c i nfe cti o n s t h at r e q uir e tr e at m e nt s wit h or al a nti bi oti c s, a ntif u n g al s, 
or a nti vir al s *


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
I nj e cti o n-r el at e d r e a cti o n (I R R; a n A E w hi c h o c c ur s wit hi n 2 4 h o ur s aft er st u d y 
dr u g i nj e cti o n e x c e pt w h er e t h e e v e nt i s n ot c o n si d er e d a n all er gi c r e a cti o n)
†
* S el e ct e d A E s will b e r e vi e w e d b y S p o n s or a n d M e di c al M o nit or t o i d e ntif y i nf e cti o n s 
r e q uiri n g I V tr e at m e nt a n d o p p ort u nisti c i nf e cti o n s t h at r e q uir e tr e at m e nt s. A E li sti n g s 
will al s o b e s e ar c h e d t o i d e ntif y a n y i nf e cti o n s r e q uiri n g I V tr e at m e nt/ o p p ort u ni sti c 
i nf e cti o n s w hi c h h a v e n ot b e e n r e p ort e d a s S el e ct e d A E s.
† E a c h I R R will b e r e vi e w e d b y t h e M e di c al M o nit or t o a s s e s s t h e ri s k of a n a p h yl a xi s.
5. 3 
M E T H O D S A N D TI MI N G F O R C A P T U RI N G A N D A S S E S SI N G 
S A F E T Y P A R A M E T E R S 
T h e I n v e sti g at or i s r e s p o n si bl e f or e n s uri n g t h at all A E s ( s e e S e cti o n 5. 2. 1 ) ar e 
r e c or d e d o n t h e A d v er s e E v e nt p a g e s of t h e 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 n 
a c c or d a n c e wit h i n str u cti o n s pr o vi d e d i n t hi s s e cti o n a n d i n S e cti o n s 5. 4 5. 6 . T h e 
I n v e sti g at or i s al s o r e s p o n si bl e f or r e p orti n g m e di c al d e vi c e c o m pl ai nt s ( s e e S e cti o n 
5. 4. 4 ).
F or e a c h A E r e c or d e d o n t h e A d v er s e E v e nt p a g e s i n t h e e C R F, t h e I n v e sti g at or will 
m a k e a n a s s e s s m e nt of s eri o u s n e s s ( s e e S e cti o n 5. 2. 2 f or s eri o u s n e s s crit eri a), 
s e v erit y ( s e e S e cti o n 5. 3. 3 ), a n d c a u s alit y ( s e e S e cti o n 5. 3. 4 ).
5. 3. 1 
A d v er s e E v e nt R e p orti n g P eri o d
I n v e sti g at or s will s e e k i nf or m ati o n o n A E s at e a c h p ati e nt c o nt a ct. All A E s, w h et h er 
r e p ort e d b y t h e p ati e nt or n ot e d b y st u d y p er s o n n el, will b e r e c or d e d i n t h e p ati e nt’ s 
m e di c al r e c or d a n d o n t h e A d v er s e E v e nt p a g e s of t h e e C R F.
Aft er i nf or m e d c o n s e nt h a s b e e n o bt ai n e d b ut pri or t o i niti ati o n of st u d y dr u g, o nl y 
S A E s c a u s e d b y a p r ot o c ol-m a n d at e d i nt er v e nti o n s h o ul d b e r e p ort e d ( e. g. , S A E s
r el at e d t o i n v a si v e pr o c e d ur e s of t h e pr ot o c ol). T h e s e S A E s will b e r e c or d e d i n t h e 
Dr u g S af et y d at a b a s e a n d n ot o n t h e A d v er s e E v e nt e C R F.
Aft er i niti ati o n of st u d y dr u g, all A E s, r e g ar dl e s s of r el ati o n s hi p t o st u d y dr u g, will b e 
r e p ort e d o n t h e e C R F u ntil t h e W it h dr a w al V i sit or L a st O b s er v ati o n ( 1 2 w e e k s aft er 
t h e l a st d o s e of st u d y dr u g). Aft er t hi s p eri o d, i n v e sti g at or s s h o ul d r e p ort a n y d e at h s, 
S A E s, or ot h er A E s of c o n c er n t h at ar e b eli e v e d t o b e r el at e d t o pri or tr e at m e nt wit h 
st u d y dr u g ( s e e S e cti o n 5. 6 ).


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 3. 2 
Eli citi n g A d v er s e E v e nt I nf or m ati o n
A c o n si st e n t m et h o d ol o g y of n o n-dir e cti v e q u e sti o ni n g s h o ul d b e a d o pt e d f or eli citi n g 
A E i nf or m ati o n at all p ati e nt e v al u ati o n ti m e p oi nt s. E x a m pl e s of n o n -dir e cti v e 
q u e sti o n s i n cl u d e t h e f oll o wi n g:
“ H o w h a v e y o u f elt si n c e y o ur l a st cli ni c vi sit ?”
“ H a v e y o u h a d a n y n e w or c h a n g e d h e alt h pr o bl e m s si n c e y o u w er e l a st h er e ?” 
5. 3. 3 
A s s e s s m e nt of S e v erit y of A d v er s e E v e nt s
T a bl e 5 pr o vi d e s g ui d a n c e f or a s s e s si n g A E s e v erit y.
T a bl e 5: 
A d v er s e E v e nt S e v erit y Gr a di n g
S e v erit y
D e s cri pti o n
Mil d
Di 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
M o d er at e 
Di 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
S e v er e 
I n c a p a cit ati n g wit h i n a bilit y t o w or k or t o p erf or m n or m al d ail y a cti vit y
N ot e: R e g ar dl e s s of s e v erit y, s o m e e v e nt s m a y  al s o m e et s eri o u s n e s s crit eri a. R ef er t o d efi niti o n 
of a S A E ( s e e S e cti o n 5. 2. 2 ).
5. 3. 4 
A s s e s s m e nt of C a u s alit y  of A d v er s e E v e nt s
I n v e sti g at or s s h o ul d u s e t h eir k n o wl e d g e of t h e p ati e nt, t h e cir c u m st a n c e s 
s urr o u n di n g t h e e v e nt, a n d a n e v al u ati o n of a n y p ot e nti al alt er n ati v e c a u s e s t o 
d et er mi n e w h et h er or n ot a n A E i s c o n si d er e d t o b e r el at e d t o t h e st u d y dr u g, 
i n di c ati n g " y e s" or " n o" a c c or di n gl y o n t h e A E p a g e of t h e e C R F. T h e f oll o wi n g 
g ui d a n c e s h o ul d b e t a k e n i nt o c o n si d er ati o n:
 
T e m p or al r el ati o n s hi p of e v e nt o n s et t o t h e i niti ati o n of st u d y dr u g
 
C o ur s e of t h e e v e nt, c o n si d eri n g e s p e ci all y t h e eff e ct s of d o s e r e d u cti o n, 
di s c o nti n u a ti o n of st u d y dr u g, or r ei ntr o d u cti o n of st u d y dr u g ( w h er e a p pli c a bl e)
 
K n o w n a s s o ci ati o n of t h e e v e nt wit h t h e st u d y dr u g or wit h si mil ar tr e at m e nt s
 
K n o w n a s s o ci ati o n of t h e e v e nt wit h t h e di s e a s e u n d er st u d y
 
Pr e s e n c e of ri s k f a ct or s i n t h e p ati e nt or u s e of c o n c o mit a nt m e di c ati o n s k n o w n t o 
i n cr e a s e t h e o c c urr e n c e of t h e e v e nt
 
Pr e s e n c e of n o n -tr e at m e nt-r el at e d f a ct or s t h at ar e k n o w n t o b e a s s o ci at e d wit h 
t h e o c c urr e n c e of t h e e v e nt.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 3. 5 
Pr o c e d ur e s f or R e c or di n g A d v er s e E v e nt s
I n v e sti g at or s s h o ul d u s e c orr e ct me di c al t er mi n ol o g y/ c o n c e pt s w h e n r e c or di n g A E s 
o n t h e A d v er s e E v e nt p a g e of t h e e C R F. C oll o q ui ali s m s a n d a b br e vi ati o n s s h o ul d b e 
a v oi d e d.
O nl y o n e A E t er m s h o ul d b e r e c or d e d i n t h e e v e nt fi el d o n t h e A d v er s e E v e nt p a g e of 
t h e e C R F.
5. 3. 5. 1 
Di a g n o si s v er s u s Si g n s a n d S y m pt o m s
I nj e cti o n-R el at e d R e a cti o n s
I nj e cti o n-r el at e d r e a cti o n i s d efi n e d a s t h e e v e nt t h at o c c ur s wit hi n 2 4 h o ur s aft er 
st u d y dr u g i nj e cti o n. A n I R R s h o ul d b e r e c or d e d o n t h e I R R p a g e of t h e e C R F a s 
“i nj e cti o n-r el at e d r e a cti o n”, a n d i n di vi d u al si g n s a n d s y m pt o m s s h o ul d al s o b e 
c a pt ur e d o n t h e I R R p a g e of t h e e C R F.
B ut e x c e pti v e c o n diti o n s ar e a s f oll o w s :
 
A n a p h yl a xi s or a n a p h yl a cti c s h o c k:
If t h e e v e nt i s j u d g e d a s a n a p h yl a xi s or a n a p h yl a cti c s h o c k b y I n v e sti g at or’ s 
di s cr eti o n, it will b e r e c or d e d o n t h e A d v er s e E v e nt p a g e of t h e e C R F .
 
O b vi o u sl y n ot all er gi c r e a cti o n ( e. g. , i nf e cti o n):
If t h e e v e nt i s j u d g e d a s n ot all er gi c r e a cti o n, it will b e r ec or d e d o n t h e A d v er s e 
E v e nt p a g e of t h e e C R F .
Ot h er A d v er s e E v e nt s
F or A E s ot h er t h a n I R R s, a di a g n o si s (if k n o w n) 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 p a g e of t h e e C R F r at h er t h a n i n di vi d u al si g n s a n d s y m pt o m s ( e. g. , r e c or d o nl y 
li v er f ail ur e or h e p atiti s r at h er t h a n j a u n di c e, a st eri xi s, a n d el e v at e d tra n s a mi n a s e s). 
H o w e v er, if a c o n st ell ati o n of si g n s a n d/ or s y m pt o m s c a n n ot b e m e di c all y 
c h ar a ct eri z e d a s a si n gl e di a g n o si s or s y n dr o m e at t h e ti m e of r e p orti n g, e a c h 
i n di vi d u al e v e nt 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 p a g e of t h e e C R F. If a 
di a g n o si s i s s u b s e q u e ntl y e st a bli s h e d, all pr e vi o u sl y r e p ort e d A E s b a s e d o n si g n s a n d 
s y m pt o m s s h o ul d b e n ullifi e d a n d r e pl a c e d b y o n e A E r e p ort b a s e d o n t h e si n gl e 
di a g n o si s, wit h a st arti n g d at e t h at c orr e s p o n d s t o t h e st arti n g d at e of t h e fir st 
s y m pt o m of t h e e v e nt u al di a g n o si s.
5. 3. 5. 2 
A d v er s e E v e nt s O c c urri n g S e c o n d ar y  t o Ot h er E v e nt s
I n g e n er al, A E s o c c urri n g s e c o n d ar y t o ot h er e v e nt s (e. g. , c a s c a d e e v e nt s or cli ni c al 
s e q u el a e) s h o ul d b e i d e ntifi e d b y t h eir pri m ar y c a u s e, wit h t h e e x c e pti o n of s e v er e or 
s eri o u s s e c o n d a r y e v e nt s. H o w e v er, m e di c all y si g nifi c a nt A E s o c c urri n g s e c o n d ar y t o 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
a n i niti ati n g e v e nt t h at ar e s e p ar at e d i n ti m e s h o ul d b e r e c or d e d a s i n d e p e n d e nt 
e v e nt s o n t h e A d v er s e E v e nt p a g e of t h e e C R F. F or e x a m pl e:
 
If v o miti n g r e s ult s i n mil d d e h y dr ati o n wit h n o a d diti o n al tr e at m e nt i n a h e alt h y 
a d ult, o nl y v o miti n g s h o ul d b e r e p ort e d o n t h e e C R F.
 
If v o miti n g r e s ult s i n s e v er e d e h y dr ati o n, b ot h e v e nt s s h o ul d b e r e p ort e d 
s e p ar at el y o n t h e e C R F.
 
If a s e v er e g a str oi nt e sti n al h e m orr h a g e l e a d s t o r e n al f ail ur e, b ot h ev e nt s s h o ul d 
b e r e p ort e d s e p ar at el y o n t h e e C R F.
 
If di z zi n e s s l e a d s t o a f all a n d s u b s e q u e nt fr a ct ur e, all t hr e e e v e nt s s h o ul d b e 
r e p ort e d s e p ar at el y o n t h e e C R F.
 
If n e utr o p e ni a i s a c c o m p a ni e d b y a n i nf e cti o n, b ot h e v e nt s s h o ul d b e r e p ort e d 
s e p ar at el y o n t h e e C R F.
All A E s s h o ul d b e r e c or d e d s e p ar at el y o n t h e A d v er s e E v e nt p a g e of t h e e C R F if it i s 
u n cl e ar a s t o w h et h er t h e e v e nt s ar e a s s o ci at e d.
5. 3. 5. 3 
P er si st e nt or R e c urr e nt A d v er s e E v e nt s
A p er si st e nt A E i s o n e t h at e xt e n d s c o nti n u o u sl y, wit h o ut r e s ol uti o n, b et w e e n p ati e nt 
e v al u ati o n ti m e p oi nt s. S u c h e v e nt s s h o ul d o nl y b e r e c or d e d o n c e o n t h e A d v er s e 
E v e nt p a g e of t h e e C R F. T h e i niti al s e v erit y of t h e e v e nt s h o ul d b e r e c or d e d, a n d t h e 
s e v erit y s h o ul d b e u p d at e d t o r efl e ct t h e m o st e xtr e m e s e v erit y a n y ti m e t h e e v e nt 
w or s e n s. If t h e e v e nt b e c o m e s s eri o u s, t h e A d v er s e E v e nt p a g e of t h e e C R F s h o ul d 
b e u p d at e d t o r efl e ct t hi s.
A r e c urr e nt A E i s o n e t h at r e s ol v e s b et w e e n p ati e nt e v al u ati o n ti m e p oi nt s a n d 
s u b s e q u e ntl y r e c ur s. E a c h r e c urr e n c e of a n A E s h o ul d b e r e c or d e d s e p ar at el y o n t h e 
A d v er s e E v e nt p a g e of t h e e C R F.
5. 3. 5. 4 
A b n or m al L a b or at or y V al u e s
N ot e v er y l a b or at or y a b n or m alit y q u alifi e s a s a n A E. A l a b or at or y t e st r e s ult s h o ul d b e 
r e p ort e d a s a n A E if it m e et s a n y of t h e f oll o wi n g crit eri a:
 
A c c o m p a ni e d b y cli ni c al s y m pt o m s
 
R e s ult s i n a c h a n g e i n st u d y dr u g ( e. g. , d o s a g e m o difi c ati o n, tr e at m e nt 
i nt err u pti o n, or tr e at m e nt di s c o nti n u ati o n)
 
R e s ult s i n a m e di c al i nt er v e nti o n ( e. g. , p ot a s si u m s u p pl e m e nt ati o n f or 
h y p o k al e mi a) or a c h a n g e i n c o n c o mit a nt t h er a p y
 
Cli ni c all y si g nifi c a nt i n t h e I n v e sti g at or’ s j u d g m e nt 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
8 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
It i s t h e I n v e sti g at or’ s r e s p o n si bilit y t o r e vi e w all l a b or at or y fi n di n g s. 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 a n i s ol at e d l a b or at or y 
a b n or m alit y s h o ul d b e cl a s sifi e d a s a n A E.
If a 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 i s a si g n of a di s e a s e or s y n dr o m e (e. g. ,
al k ali n e p h o s p h at a s e a n d bilir u bi n 5 ti m e s t h e U L N a s s o ci at e d wit h c h ol e c y stiti s), o nl y 
t h e di a g n o si s (i. e., c h ol e c y stiti 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 p a g e of t h e 
e C R F.
If a 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 c a n n ot b e r el at e d t o a di s e a s e or 
s y n dr o m e, t h e a b n or m alit y it s elf 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 p a g e of t h e 
e C R F, al o n g wit h a d e s cri p t or i n di c ati n g if t h e t e st r e s ult i s a b o v e or b el o w t h e n or m al 
r a n g e (e. g. , “ el e v at e d p ot a s si u m” a s o p p o s e d t o “ a b n or m al p ot a s si u m”). If t h e 
l a b or at or y a b n or m alit y c a n b e c h ar a ct eri z e d b y a pr e ci s e cli ni c al t er m p er st a n d ar d 
d ef i niti o n s, t h e cli ni c al t er m s h o ul d b e r e c or d e d a s t h e A E. F or e x a m pl e, a n el e v at e d 
s er u m p ot a s si u m l e v el of 7. 0 m E q/ L s h o ul d b e r e c or d e d a s “ h y p er k al e mi a.”
O b s er v ati o n s of t h e s a m e 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 fr o m vi sit t o vi sit 
s h o ul d n ot b e r e p e at e dl y r e c or d e d o n t h e A d v er s e E v e nt p a g e of t h e e C R F, u nl e s s 
t h e eti ol o g y or s e v erit y c h a n g e s. T h e i niti al s e v erit y of t h e e v e nt s h o ul d b e r e c or d e d, 
a n d t h e s e v erit y or s eri o u s n e s s s h o ul d b e u p d at e d a n y ti m e t h e e v e nt w or s e n s or 
i m pr o v e s.
5. 3. 5. 5 
A b n or m al Vit al Si g n V al u e s
N ot e v er y vit al si g n a b n or m alit y q u alifi e s a s a n A E. A vit al si g n r e s ult s h o ul d b e 
r e p ort e d a s a n A E if it m e et s a n y of t h e f oll o wi n g crit eri a:
 
A c c o m p a ni e d b y cli ni c al s y m pt o m s
 
R e s ult s i n a c h a n g e i n st u d y dr u g ( e. g. , d o s a g e m o difi c ati o n, tr e at m e nt 
i nt err u pti o n, or tr e at m e nt di s c o nti n u ati o n)
 
R e s ult s i n a m e di c al i nt er v e nti o n or a c h a n g e i n c o n c o mit a nt t h er a p y
 
Cli ni c all y si g nifi c a nt i n t h e I n v e sti g at or’ s j u d g m e nt 
It i s t h e I n v e sti g at or’ s r e s p o n si bilit y t o r e vi e w all vit al si g n fi n di n g s. 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 a n i s ol at e d vit al si g n 
a b n or m alit y s h o ul d b e cl a s sifi e d a s a n A E.
If a cli ni c all y si g nifi c a nt vit al si g n a b n or m alit y i s a si g n of a di s e a s e or s y n dr o m e (e. g. , 
hi g h bl o o d pr e s s ur e), o nl y t h e di a g n o si s ( i. e., h y p e rt e n si o n) 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 p a g e of t h e e C R F.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
O b s er v ati o n s of t h e s a m e cli ni c all y si g nifi c a nt vit al si g n a b n or m alit y fr o m vi sit t o vi sit 
s h o ul d n ot b e r e p e at e dl y r e c or d e d o n t h e A d v er s e E v e nt p a g e of t h e e C R F, u nl e s s 
t h e eti ol o g y or se v erit y c h a n g e s. T h e i niti al s e v erit y of t h e e v e nt s h o ul d b e r e c or d e d, 
a n d t h e s e v erit y or s eri o u s n e s s s h o ul d b e u p d at e d a n y ti m e t h e e v e nt w or s e n s or 
i m pr o v e s.
5. 3. 5. 6 
A b n or m al Li v er F u n cti o n T e st s
T h e fi n di n g of a n el e v at e d A L T or A S T ( 3 x U L N) i n c o m bi n ati o n wi t h eit h er a n 
el e v at e d t ot al bilir u bi n ( 2 x 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, I n v e sti g at or s m u st r e p ort a s a n A E 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:
 
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
 
A L T or A S T 3 U L N i n c o m bi n ati o n wit h cli ni c al j a u n di c e
A n y ot h er r e a s o n t h a n st u d y dr u g -i n d u c e d li v er i nj ur y s h o ul d b e c h e c k e d, s u c h a s vir al 
h e p atiti s A, B, or C, pr e e xi sti n g or a c ut e li v er di s e a s e, or a n ot h er dr u g c a p a bl e of 
c a u si n g t h e o b s er v e d i nj ur y i n c a s e t h e s e h a v e a n y cli ni c al pr o b a bilit y. 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 ec or d e d o n t h e A d v er s e E v e nt p a g e of t h e e C R F 
( s e e S e cti o n 5. 3. 5. 1 ) eit h er a s a n S A E or a n o n -s eri o u s A E SI ( s e e S e cti o n 5. 4. 2 ) a n d 
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 aft er l e ar ni n g of t h e e v e nt,
5. 3. 5. 7 
D e at h s
All d e at h s t h at o c c ur d uri n g t h e pr ot o c ol -s p e cifi e d A E r e p orti n g p eri o d 
( s e e S e cti o n 5. 3. 1 ), r e g ar dl e s s of r el ati o n s hi p t o st u d y dr u g, m u st b e r e c or d e d on t h e 
A d v er s e E v e nt p a g e of t h e e C R F a n d i m m e di at el y r e p ort e d t o t h e S p o n s or ( s e e 
S e cti o n 5. 4. 2 ). T hi s i n cl u d e s d e at h attri b ut e d t o pr o gr e s si o n of N M O.
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 p a g e of t h e e C R F. G e n er all y, o nl y o n e 
s u c h e v e nt s h o ul d b e r e p ort e d. 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 f or t h e 
o c c urr e n c e of a n a br u pt a n d u n e x p e ct e d d e at h d u e t o e. g. , pr e s u m e d c ar di a c c a u s e s 
i n a p ati e nt wit h or wit h o ut pr e e xi sti n g h e art di s e a s e, wit hi n 1 h o ur of t h e o n s et of 
a c ut e s y m pt o m s or, i n t h e c a s e of a n u n wit n e s s e d d e at h, wit hi n 2 4 h o ur s aft er t h e 
p ati e nt w a s l a st s e e n ali v e a n d st a bl e. 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 p a g e of t h e 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. ,


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
a ft 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 c a u s e of 
d e at h.
If t h e d e at h i s attri b ut e d t o pr o gr e s si o n of N M O “N M O pr o gr e s si o n” 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 p a g e of t h e e C R F.
5. 3. 5. 8 
Pr e e xi sti n g M e di c al C o n diti o n s
A pr e e xi sti n g m e di c al c o n diti o n i s o n e t h at i s pr e s e nt pri or t o b a s eli n e . S u c h 
c o n diti o n s s h o ul d b e r e c or d e d o n t h e G e n er 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 e C R F.
A pr e e xi sti n g m e di c al c o n diti o n s h o ul d b e r e c or d e d a s a n A E o nl y if t h e fr e q u e n c y, 
s e v erit y, or c h ar a ct er of t h e c o n diti o n w or s e n s d uri n g t h e st u d y. W h e n r e c or di n g s u c h 
e v e nt s o n t h e A d v er s e E v e nt p a g e of t h e e C R F, it i s i m p ort a nt t o c o n v e y t h e c o n c e pt 
t h at t h e pr e e xi sti n g c o n diti o n h a s c h a n g e d b y i n cl u di n g a p pli c a bl e d e s cri pt or s (e. g. ,
“ m or e fr e q u e nt h e a d a c h e s”).
5. 3. 5. 9 
L a c k of Effi c a c y  or W or s e ni n g of N M O
E v e nt s t h at ar e cl e arl y c o n si st e nt wit h t h e e x p e ct e d p att er n of pr o gr e s si o n of t h e 
u n d erl yi n g di s e a s e s h o ul d n ot b e r e c or d e d a s A E s. T h e s e d at a will b e c a pt ur e d a s 
el e m e nt s of t h e effi c a c y a s s e s s m e nt d at a o nl y. I n m o st c a s e s, t h e e x p e ct e d p att er n of 
pr o gr e s si o n will b e b a s e d o n r el a p s e r el at e d cli ni c al d at a. I n r ar e c a s e s, t h e 
d et er mi n ati o n of cli ni c al pr o gr e s si o n will b e b a s e d o n s y m pt o m ati c d et eri or ati o n. 
H o w e v er, e v er y eff ort s h o ul d b e m a d e t o d o c u m e nt pr o gr e s si o n u si n g o bj e cti v e 
crit eri a. If t h er e i s a n y u n c ert ai nt y a s t o w h et h er a n e v e nt i s d u e t o di s e a s e 
pr o gr e s si o n, it s h o ul d b e r e p ort e d a s a n A E.
5. 3. 5. 1 0 
H o s pit ali z ati o n or Pr ol o n g e d H o s pit ali z ati o n
A n y A E t h at r e s ult s i n h o s pit ali z ati o n or pr ol o n g e d h o s pit ali z ati o n s h o ul d b e 
d o c u m e nt e d a n d r e p ort e d a s a n S A E ( p er t h e d efi niti o n of S A E i n S e cti o n 5. 2. 2 ), 
e x c e pt a s o utli n e d b el o w. 
T h e f oll o wi n g h o s pit ali z ati o n s c e n ari o s ar e n ot c o n si d er e d t o b e S A E s:
 
H o s pit ali z ati o n b e c a u s e of N M O r el a p s e
 
H o s pit ali z ati o n f or r e s pit e c ar e
 
Pl a n n e d h o s pit ali z a ti o n r e q uir e d b y t h e pr ot o c ol (e. g. , f or st u d y dr u g 
a d mi ni str ati o n)
 
H o s pit ali z ati o n f or a pr e e xi sti n g c o n diti o n, pr o vi d e d t h at all of t h e f oll o wi n g crit eri a 
ar e m et:


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
– 
T h e h o s pit ali z ati o n w a s pl a n n e d pri or t o t h e st u d y or w a s s c h e d ul e d d uri n g 
t h e st u d y w h e n el e cti v e s ur g er y b e c a m e n e c e s s ar y b e c a u s e of t h e e x p e ct e d 
n or m al pr o gr e s si o n of t h e di s e a s e
– 
T h e p ati e nt h a s n ot s uff er e d a n A E.
5. 3. 5. 1 1 
O v er d o s e s
St u d y dr u g o v er d o s e i s t h e a c ci d e nt al or i nt e nti o n al u s e of t h e dr u g i n a n a m o u nt 
hi g h er t h a n t h e d o s e b ei n g st u di e d. A n o v er d o s e or i n c orr e ct a d mi ni str ati o n of st u d y 
dr u g i s n ot a n A E u nl e s s it r e s ult s i n u nt o w ar d m e di c al eff e ct s. 
A n y st u d y dr u g o v er d o s e or i n c orr e ct a d mi ni str ati o n of st u d y dr u g s h o ul d b e n ot e d o n 
t h e St u d y Dr u g A d mi ni str ati o n e C R F. 
All A E s a s s o ci at e d wit h a n o v er d o s e or i n c orr e ct a d mi ni str ati o n of st u d y dr u g 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 p a g e of t h e e C R F. If t h e a s s o ci at e d A E f ulfill s 
s eri o u s crit eri a, t h e e v e nt s h o ul d b e r e p ort e d a s a S A E t o t h e S p o n s or wit hi n 2 4 h o ur s 
af t er l e ar ni n g of t h e e v e nt ( s e e S e cti o n 5. 4. 2 ).
5. 4 
I M M E DI AT E R E P O R TI N G R E Q UI R E M E N T S F R O M 
I N V E S TI G AT O R T O S P O N S O R
T h e I n v e sti g at or m u st r e p ort t h e f oll o wi n g e v e nt s t o t h e S p o n s or wit hi n 2 4 h o ur s aft er 
l e ar ni n g of t h e e v e nt, r e g ar dl e s s of r el ati o n s hi p t o st u d y dr u g:
 
S A E s
 
N o n -s eri o u s A E SI
 
Pr e g n a n ci e s
T h e I n v e sti g at or m u st r e p ort n e w si g nifi c a nt f oll o w -u p i nf or m ati o n f or t h e s e e v e nt s t o 
t h e S p o n s or wit hi n 2 4 h o ur s aft er b e c o mi n g a w ar e of t h e i nf or m ati o n. N e w si g nifi c a nt 
i nf or m ati o n i n cl u d e s t h e f oll o wi n g:
 
N e w si g n s or s y m pt o m s or a c h a n g e i n t h e di a g n o si s
 
Si g nifi c a nt n e w di a g n o sti c t e st r e s ult s
 
C h a n g e i n c a u s alit y b a s e d o n n e w i nf or m ati o n
 
C h a n g e i n t h e e v e nt’ s o ut c o m e, i n cl u di n g r e c o v er y
 
A d diti o n al n arr ati v e i nf or m ati o n o n t h e cli ni c al c o ur s e of t h e e v e nt
I n v e sti g at or s m u st al s o c o m pl y wit h l o c al r e q uir e m e nt s f or S A E r e p orti n g t o t h e l o c al 
h e alt h a ut h orit y a n d I R B/I E C.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 4. 1 
E m er g e n c y  M e di c al C o nt a ct s
T h e c o nt a ct d et ail s f or t h e E m er g e n c y M e di c al C o nt a ct s will b e pr o vi d e d i n t h e St u d y 
M a n u al a n d t h e I n v e sti g at or ( Sit e) Fil e. M e di c al M o nit or n a m e s, c o nt a ct i nf or m ati o n, 
a n d c o u ntr y -s p e cifi c p h o n e n u m b er s w ill b e i n cl u d e d.
5. 4. 2 
R e p orti n g R e q uir e m e nt s f or S eri o u s A d v er s e E v e nt s a n d 
N o n -s eri o u s A d v er s e E v e nt s of S p e ci al I nt er e st
F or r e p ort s of S A E s a n d n o n -s eri o u s A E SI, i n v e sti g at or s s h o ul d r e c or d all c a s e d et ail s 
t h at c a n b e g at h er e d wit hi n 2 4 h o ur s o n t h e p a p er S A E f or m a n d f a x t h e c o m pl et e d 
S A E f or m t o P A R E X E L I nt er n ati o n al P h ar m a c o vi gil a n c e. I n v e sti g at or s s h o ul d r ef er t o 
t h e St u d y M a n u al a n d t h e I n v e sti g at or ( Sit e) Fil e f or t h e c urr e nt c o nt a ct i nf or m ati o n 
(fa x a n d t el e p h o n e n u m b er s , a n d e m ail a d dr e s s e s) f or S A E a n d n o n -s eri o u s A E SI 
r e p orti n g.
I n t h e e v e nt of f a x tr a n s mi s si o n f ail ur e of t h e S A E f or m, t h e sit e c o ul d alt er n ati v el y 
e- m ail t h e S A E f or m t o P A R E X E L I nt er n ati o n al P h ar m a c o vi gil a n c e u si n g t h e e -m ail 
a d dr e s s pr o vi d e d.
C o n c urr e ntl y t h e A d v er s e E v e nt e C R F s h o ul d b e c o m pl et e d i m m e di at el y ( s e e 
S e cti o n 5. 3. 1 ). 
5. 4. 3 
R e p orti n g R e q uir e m e nt s f or Pr e g n a n ci e s
5. 4. 3. 1 
Pr e g n a n ci e s i n F e m al e P ati e nt s
F e m al e p ati e nt s of c hil d b e ari n g p ot e nti al will 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 n v e sti g at or if t h e y b e c o m e pr eg n a nt d uri n g t h e st u d y or wit hi n 3 m o nt h s
aft er t h e l a st 
d o s e of st u d y dr u g. A p a p er pr e g n a n c y r e p ort f or m s h o ul d b e c o m pl et e d wit hi n 
2 4 h o ur s a n d s u b mitt e d vi a f a x t o P A R E X E L I nt er n ati o n al P h ar m a c o vi gil a n c e, u si n g 
t h e f a x n u m b er s pr o vi d e d ( s e e S e cti o n 5. 4. 2 ). Pr e g n a n c y s h o ul d n ot b e r e c or d e d o n 
t h e A d v er s e E v e nt p a g e of t h e e C R F. T h e I n v e sti g at or s h o ul d di s c o nti n u e st u d y dr u g 
a n d c o u n s e l t h e p ati e nt, di s c u s si n g t h e ri s k s of 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. M o nit ori n g of t h e p ati e nt s h o ul d c o nti n u e u ntil c o n cl u si o n of t h e 
pr e g n a n c y. A n y seri o us a d verse e ve nts ass oci ate d wit h t he pre g n a nc y (e. g., a n e ve nt 
i n t he fet us, a n e ve nt i n t he m ot her d uri n g or after t he pre g n a nc y, or a c o n ge nit al 
a n o m al y/ birt h defect i n t he c hil d) s h o ul d be re p orte d o n t he A d verse E ve nt e C R F.  I n 
a d diti o n, t he I n vesti g at or will u p d ate t he p a per pre g n a nc y re p ort f or m w he n u p d ate d 
i nf or m ati o n o n t he c o urse a n d o utc o me of t he pre g n a nc y bec o me a v ail a ble.
I n t h e e v e nt of t h e f a x tr a n s mi s si o n f ail ur e of t h e pr e g n a n c y r e p ort f or m, t h e 
c o m pl et e d pr e g n a n c y r e p ort f or m c o ul d alt er n ati v el y b e s e nt b y e -m ail t o P A R E X E L 
I nt er n ati o n al P h ar m a c o vi gil a n c e u si n g t he e -m ail a d dr e s s pr o vi d e d.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 4. 3. 2 
Pr e g n a n ci e s i n F e m al e P art n er s of M al e P ati e nt s
M a l e p ati e nt s will b e i n str u ct e d t hr o u g h t h e I nf or m e d C o n s e nt F or m t o i m m e di at el y 
i nf or m t h e I n v e sti g at or if t h eir p art n er b e c o m e s pr e g n a nt d uri n g t h e st u d y or wit hi n 
3 m o nt h s aft er
t h e l a st d o s e of st u d y dr u g. A p a p er pr e g n a n c y r e p ort f or m s h o ul d b e 
c o m pl et e d wit hi n 2 4 h o ur s of l e ar ni n g of t h e pr e g n a n c y a n d s u b mitt e d vi a f a x t o 
P A R E X E L I nt er n ati o n al P h ar m a c o vi gil a n c e, u si n g t h e f a x n u m b er s pr o vi d e d ( s e e 
S e cti o n 5. 4. 2 ). I n t h e e v e nt of t h e f a x tr a n s mi s si o n f ail ur e of t h e pr e g n a n cy r e p ort f or m, 
t h e c o m pl et e d pr e g n a n c y r e p ort f or m c o ul d alt er n ati v el y b e s e nt b y e-m ai l t o 
P A R E X E L I nt er n ati o n al P h ar m a c o vi gil a n c e u si n g t h e e -m ail a d dr e s s pr o vi d e d.
Att e m pt s s h o ul d b e m a d e t o c oll e ct a n d r e p ort d et ail s of t h e c o ur s e a n d o ut c o m e of 
a n y pr e g n a n c y i n t h e p art n er of a m al e p ati e nt e x p o s e d t o st u d y dr u g. T h e pr e g n a nt 
p art n er wi ll n e e d t o si g n a n A ut h ori z ati o n f or U s e a n d Di s cl o s ur e of Pr e g n a n c y H e alt h 
I nf or m ati o n t o all o w f or f oll o w-u p o n h er pr e g n a n c y. O n c e t h e a ut h ori z ati o n h a s b e e n 
si g n e d, t h e I n v e sti g at or will u p d at e t h e p a p er pr e g n a n c y r e p ort f or m w he n u p d ate d 
i nf or m ati o n on t h e c o ur s e a n d o ut c o m e of t h e pr e g n a n c y bec o me a v ail a ble . A n 
I n v e sti g at or w h o i s c o nt a ct e d b y t h e m al e p ati e nt or hi s pr e g n a nt p art n er m a y pr o vi d e 
i nf or m ati o n o n t h e ri s k s of 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, t o 
s u p p ort a n i nf or m e d d e c i si o n i n c o o p er ati o n wit h t h e tr e ati n g p h y si ci a n a n d/ or 
o b st etri ci a n.
5. 4. 3. 3 
A b orti o n s
A n y s p o nt 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 n S A E ( a s t h e S p o n s or c o n si d er s 
s p o nt a n e o u s a b orti o n s t o b e m e di c all y si g nifi c a nt e v e nt s), r e c or d e d o n t h e A d v er s e 
E v e nt p a g e of t h e e C R F, a n d 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 aft er l e ar ni n g of 
t h e ev e nt ( s e e S e cti o n 5. 4. 2 ). 
5. 4. 3. 4 
C o n g e nit al A n o m ali e s/ Birt h D ef e ct s
A n y c o n g e nit al a n o m al y/ birt h d ef e ct i n a c hil d b or n t o a f e m al e p ati e nt or f e m al e 
p art n er of a m al e p ati e nt e x p o s e d t o st u d y dr u g p ati e nt s h o ul d b e cl a s sifi e d a s a n 
S A E, r e c or d e d b ot h o n t h e A d v er s e E v e nt p a g e of t h e e C R F a n d o n t h e p a p er f or m, 
a n d r e p ort ed t o t h e S p o n s or b y f a x i n g wit hi 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 5. 4. 2 ).


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
5. 4. 4 
R e p orti n g R e q uir e m e nt s f or M e di c al D e vi c e C o m pl ai nt s
I n t hi s st u d y, P F S wit h N S D i s c o n si d er e d a m e di c al d e vi c e. T h e In v e sti g at or m u st 
r e p ort all m edi c al d e vi c e c o m pl ai nt s t o t h e S p o n s or or it s d e si g n e e. T h e I n v e sti g at or 
s h o ul d d o c u m e nt a s m u c h i nf or m ati o n a s p o s si bl e o n t h e I MP D e vi ati o n F or m , 
in cl u di n g t h e pr o d u ct b at c h n u m b e r, a n d f or w ar d t h e f or m t o t h e Sp o n s or or it s 
d e si g n e e . 
If t h e m e di c al d e vi c e r e s ult s i n a n A E t o t h e st u d y p ati e nt, t h e e v e nt m u st b e r ec or d e d
o n t h e e C R F ( s e e S e cti o n 5. 3. 5 ). If t h e e v e nt i s s eri o u s, S A E f or m m u st b e c o m pl et e d 
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), a s o utli n e d i n 
S e cti o n 5. 4. 2 . If t h e m e di c al d e vi c e r e s ult s i n a n A E t o a n i n di vi d u al ot h er t h a n t h e 
st u d y p ati e nt, t h e A E s h o ul d b e r e p ort e d a s a s p o nt a n e o u s A E t o S p o n s or Dr u g 
S af et y vi a e -m ail ( s e e I MP D e vi ati o n F or m ).
5. 5 
F O L L O W -U P O F P A TI E N T S A F T E R A D V E R S E E V E N T S
5. 5. 1 
I n ve sti g at or F oll o w- U p
T h e I n v e sti g at or s h o ul d f oll o w e a c h A E u ntil t h e e v e nt h a s r e s ol v e d t o b a s eli n e gr a d e 
or b ett er, t h e e v e nt i s a s s e s s e d a s st a bl e b y t h e I n v e sti g at or, t h e p ati e nt i s l o st t o 
f oll o w-u p, or t h e p ati e nt wit h dr a w s c o n s e nt. E v er y eff ort s h o ul d b e m a d e t o f oll o w all 
S A E s c o n si d er e d t o b e r el at e d t o st u d y dr u g or st u d y -r el at e d pr o c e d ur e s u ntil a fi n al 
o ut c o m e c a n b e r e p ort e d.
D uri n g t h e st u d y p eri o d, r e s ol uti o n of A E s ( wit h d at e s) s h o ul d b e d o c u m e nt e d o n t h e 
A d v er s e E v e nt p a g e of t h e e C R F a n d i n t h e p ati e nt’ s m e di c al r e c or d t o f a cilit at e 
s o ur c e d at a v erifi c ati o n. If, aft er f oll o w -u p, 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 A d v er s e E v e nt p a g e 
of  t h e e C R F. 
All pr e g n a n ci e s r e p ort e d d uri n g t h e st u d y s h o ul d b e f oll o w e d u ntil pr e g n a n c y o ut c o m e. 
F oll o w r e p orti n g i n str u cti o n s pr o vi d e d i n S e cti o n 5. 4. 3. 1 .
5. 6 
P O S T -S T U D Y A D V E R S E E V E N T S
At t h e L a st O b s er v ati o n/ W it h dr a w al vi sit, t h e I n v e sti g at or s h o ul d i n str u ct e a c h p ati e nt 
t o r e p ort t o t h e I n v e sti g at or a n y s u b s e q u e nt A E s t h at t h e p ati e nt’ s p er s o n al p h y si ci a n 
b eli e v e s c o ul d b e r el at e d t o pri or st u d y dr u g tr e at m e nt or st u d y pr o c e d ur e s ( e. g. ,
i nf e cti o n s or r e a cti v ati o n of pr e vi o u sl y a c q uir e d i nf e cti v e a g e nt s). 
T h e I n v e sti g at or s h o ul d n otif y t h e S p o n s or of a n y d e at h, S A E ( e. g. , d e v el o p m e nt of 
c a n c er) a n d n o n -s eri o u s A E SI of c o n c er n o c c urri n g at a n y ti m e aft er t h e W ith dr a w al 
Vi sit or L a st O b s er v ati o n Vi sit if t h e e v e nt i s b eli e v e d t o b e r el at e d t o pri or st u d y dr u g 
tr e at m e nt or st u d y pr o c e d ur e s. T h e S p o n s or sh o ul d al s o b e n otifi e d if t h e I n v e sti g at or


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
b e c o m e s a w ar e of a c o n g e nit al a n o m al y/ birt h d ef e ct i n a s u b s e q u e ntl y c o n c ei v e d 
off s pri n g of a p ati e nt t h at p arti ci p at e d i n t hi s st u d y.
T h e I n v e sti g at or s h o ul d r e p ort t h e e v e nt vi a a p a p er S A E f or m.
5. 7 
E X P E DI T E D R E P O R TI N G T O H E A L T H A U T H O RI TI E S, 
I N V E S TI G AT O R S, I N S TI T U TI O N A L R E VI E W B O A R D S, A N D 
E T HI C S C O M MI T T 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 S A E s a n d A E SI 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 
i n v e sti g at or s, I R B s, E C s, a n d a p pli c a bl e 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.
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 E c a s e s, t h e S p o n s or will a s s e s s t h e 
e x p e ct e d n e s s of t h e s e e v e nt s t hr o u g h use of t he refere nce s afet y i nf or m atio n i n t he 
s atr ali z u m a b I n vesti g at or’s Br oc h ure .
T h e S p o n s or will c o m p ar e t h e s e v erit y of e a c h e v e nt a n d t h e c u m ul ati v e e v e nt 
fr e q u e n c y r e p ort e d f or t h e st u d y wit h t h e s e v erit y a n d fr e q u e n c y r e p ort e d i n t h e 
a p pli c a bl e r ef er e n c e d o c u m e nt.
R e p orti n g r e q uir e m e nt s will al s o b e b a s e d o n t h e I n 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.
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 will f oll o w e a c h c o u ntr y’ s s p e cifi c r e g ul ati o n s. 
A n I D M C will p eri o di c al l y m o nit or t h e i n ci d e n c e of A E s ( n ot o nl y 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 b ut al s o all A E s) d uri n g t h e d o u ble -bli n d peri o d of t he st u d y. A n 
a g gr e g at e r e p ort of a n y cli ni c all y r el e v a nt i m b al a n c e s t h at d o n ot f a v or t h e t e st 
pr o d u ct will b e s u b mitt e d t o h e alt h a ut h oriti e s.
6.
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
T hi s s e cti o n o utli n e s t h e st ati sti c al a n al y si s str at e g y a n d pr o c e d ur e s f or t h e st u d y. A 
d et ail e d m et h o d ol o g y f or st ati sti c al a n al y s e s of t h e d at a c oll e ct e d i n t hi s tri al will b e 
d o c u m e nt e d i n a St ati sti c al A n al y si s Pl a n ( S A P). 
6. 1 
A N A L Y SI S P O P U L A TI O N S
6. 1. 1 
Effi c a c y  An al y si s P o p ul ati o n s
T h e i nt e nt -t o-tr e at (I T T) p o p ul ati o n will s er v e a s t h e pri m ar y p o p ul ati o n f or t h e 
a n al y si s of effi c a c y, w hi c h c o n si st s of all r a n d o mi z e d p ati e nt s i n t h e d o u bl e-bli n d 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
p eri o d i n t h e st u d y. P ati e nt s will b e a n al y z e d a s r a n d o mi z e d f or a n al y si s p ur p o s e s i n 
t h e I T T.
T h e P er -Pr ot o c ol S et ( P P S) will i n cl u d e all p ati e nt s i n t h e I T T p o p ul ati o n w h o r e c ei v e d 
at l e a st 3 d o s e s of st u d y dr u g, a n d wit h o ut a n y m aj or pr ot o c ol d e vi ati o n s w hi c h ar e 
c o n si d er e d t o h a v e a n i m p a ct o n effi c a c y. P ati e nt s will b e a n al y z e d a s tr e at e d f or 
a n al y si s p ur p o s e s i n t h e P P S.
6. 1. 2 
Al l-P ati e nt s -Tr e at e d P o p ul ati o n
T h e All -P ati e nt s -Tr e at e d ( All s atr ali z u m a b ) p o p ul ati o n will b e d efi n e d a s all e nr oll e d 
p ati e nt s w h o t o o k at l e a st o n e d o s e of a cti v e st u d y dr u g at a n y ti m e.
6. 1. 3 
S af et y  An al y si s P o p ul ati o n s
A ll s af et y v ari a bl e s will b e a n al y z e d b a s e d o n t h e S af et y P o p ul ati o n ( S A F). T h e S A F 
p o p ul ati o n will i n cl u d e all r a n d o mi z e d p ati e nt s w h o h a v e r e c ei v e d a t l e a st o n e d o s e of 
st u d y dr u g. P ati e nt s will b e a n al y z e d a s tr e at e d f or a n al y si s p ur p o s e s i n t h e S A F. 
6. 1. 4 
P h ar m a c o ki n eti c s P er- Pr ot o c ol S et a n d P h ar m a c o d y n a mi c s 
A n al y si s P o p ul ati o n
T h e P h ar m a c o ki n eti c s P er -Pr ot o c ol S et ( P K -P P S) a n d i m m u n o g e ni cit y ( A D A) will 
i n cl u d e all p ati e nt s i n t h e S A F wit h at l e a st 1 v ali d p o st -d o s e c o n c e ntr ati o n r e s ult wit h 
a d o si n g r e c or d a n d s a m pli n g ti m e. P h ar m a c o d y n a mi c s v ari a bl e s (I L-6, sI L -6 R, 
h s C R P, a nti -A Q P 4 A b, p l a s m a bl a st) will b e a n al y z e d u si n g t h e S A F p o p ul ati o n. 
6. 1. 5 
A n al y s i s p o p ul ati o n f or a d ol e s c e nt s
T h e a d ol e s c e nt p o p ul ati o n will b e d efi n e d a s all a d ol e s c e nt p ati e nt s w h o h a v e 
r e cei v e d at l e a st o n e d o s e of st u d y dr u g.
6. 2 
D E T E R MI N A TI O N O F S A M P L E SI Z E
A p pr o xi m at el y 7 0 p ati e nt s n e e d t o b e r e cr uit e d a n d r a n d o mi z e d i n a 1: 1 r ati o t o t h e 
t w o tr e at m e nt gr o u p s (s atr ali z u m a b a n d pl a c e b o). T h e s a m pl e si z e c o n si d er ati o n s ar e 
b a s e d o n t h e f oll o wi n g a s s u m pti o n s:
1.
A t w o -si d e d l o g -r a n k t e st
2.
8 0 % p o w er at t h e 5 % si g nifi c a n c e l e v el
3.
A 6 6. 5 % r e d u cti o n i n t h e ri s k of r el a p s e, i. e. , t h e T F R h a z ar d rati o of s atr ali z u m a b
o v er pl a c e b o i s 0. 3 3 5
4.
T F R i n t h e pl a c e b o ar m f oll o wi n g a n e x p o n e nti al di stri b uti o n, wit h h a z ar d r at e 
h(t) 0. 4 1 8 4
5.
A 2 -y e ar dr o p o ut r at e of 1 0 %


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
B a s e d o n t h e s e a s s u m pti o n s, 2 6 T F R e v e nt s ar e n e e d e d f or t h e pri m ar y a n al y si s. 
T F R e v e nt s ar e d efi n e d a s pr ot o c ol -d ef i n e d r el a p s e s c o nfir m e d b y t h e C E C wit h 
E D S S/ F S S a s s e s s m e nt p erf or m e d b y t h e e x a mi ni n g a s s e s s or wit hi n 7 d a y s aft er 
r el a p s e s y m pt o m s w er e r e p ort e d t o sit e b y t h e p ati e nt. T h e m a xi m u m a c cr u al r at e i s 
e sti m at e d t o b e a p p r o xi m at el y 8 p ati e nt s p er m o nt h, aft er t h e fir st p ati e nt i n ( F PI) pl u s 
8 m o nt h s of r a m p u p. T h e 7 0
p ati e nt s e nr oll e d o v er o n e y e ar a n d f oll o w e d f or a n 
a d diti o n al o n e a n d a h alf y e ar s will pr o vi d e 2 6 T F R e v e nt s. T h e pri m ar y a n al y si s will 
b e p erf or m e d o n c e 2 6 T F R e v e nt s h a v e b e e n o b s er v e d . T h e S p o n s or will c o n d u ct a 
bli n d r e vi e w of t h e d at a i n cl u di n g a c c u m ul ati o n of e v e nt s d uri n g t h e d o u bl e-bli n d 
p eri o d a n d m a y
t a k e a p pr o pri at e a cti o n s u c h a s t o i n cr e a se t h e n u m b er of p ati e nt s or 
t o e xt e n d t h e d o u bl e-bli n d p eri o d b a s e d o n t hi s bli n d r e vi e w.
It h a s b e e n a s s u m e d t h at t h e n u m b er of r el a p s e s will f oll o w a G a m m a -P oi s s o n 
di stri b uti o n a n d t h at t h e v ari a n c e / m e a n r ati o will b e a c o n st a nt v al u e of √2 . T hi s 
di stri b uti o n w a s a s s u m e d a n d t h e r ati o w a s e sti m at e d u si n g d at a fr o m M S  tri al s ( G ol d 
et al. 2 0 1 2; K a p p o s et al. 2 0 1 0) b e c a u s e t h er e ar e n o a p pr o v e d m e di c ati o n s f or N M O
a n d n o r a w d at a fr o m p ati e nt s wit h t hi s i n di c ati o n ar e a v ail a bl e .
B e c a u s e t h e m e a n A R R of N M O p ati e nt s i s e sti m at e d at 0 . 7 5 3 ( C o s s b ur n et al. 2 0 1 2) 
a n d p ati e nt s e nt eri n g t hi s st u d y h a v e a n A R R ≥1 o wi n g t o i n cl u si o n crit eri o n 2, w e 
c al c ul at e t h e z er o -tr u n c at e d m e a n of t h e G a m m a-P oi s s o n di stri b uti o n wit h t h e m e a n 
of  0. 7 5 a n d t h e m e a n a n d v ari a n c e r ati o of √2, t h e n t h e b a s eli n e A R R i s e sti m at e d at 
1. 6. T h e t w o P h a s e 3 M S tri al s a b o v e r e p ort e d t h at pr e - a n d p o st -b a s eli n e A R R i n t h e 
pl a c e b o gr o u p w er e 1. 4 a n d 0. 4, s o t h e p o st -b a s eli n e A R R i n pl a c e b o gr o u p i n t hi s 
tri al i s e sti m at e d at 0. 5.
U si n g t h e pr o p orti o n of z er o u n d er s u p p o s e d A R R di stri b uti o n, w e e sti m at e t h e 
r el a p s e-fr e e r at e at a y e ar i n pl a c e b o gr o u p at 6 5. 8 %. T h e r el a p s e-fr e e r at e i s 
a s s u m e d t o f oll o w t h e e x p o n e nti al di stri b uti o n wit h a c o n st a nt h a z ar d, a n d t h e n w e s et 
t h e h a z ar d r ati o of 0. 4 1 8 4 i n pl a c e b o gr o u p.
A c c or d i n g t o t o cili z u m a b c a s e r e p ort s i n N M O p ati e nt s, t h e pr e- a n d p o st - b a s eli n e 
r el a p s e c o u nt s w er e r e d u c e d fr o m t ot al 4 c o u nt s p er 6 m o nt h s t o 1 c o u nt p er 
6 m o nt h s. T h e n t h e pr e - a n d p o st - b a s eli n e r ati o of 0. 2 5 i s u s e d a s t h e e sti m ati o n of 
t h e m e a n A R R r atio of t o cili z u m a b c o m p ar e d wit h pl a c e b o. M or e o v er, t h e 
a z at hi o pri n e’ s d at a s h o w e d t h e pr e - a n d p o st - b a s eli n e m e a n A R R r ati o w a s 0. 3 3 
(0. 7 7/ 2. 3 2, t h e m e a n A R R w er e e sti m at e d fr o m t h e m e di a n A R R a n d t h e di stri b uti o n 
s u p p o siti o n a b o v e) a n d t h e rit u xi m a b d at a s h o w e d t h e pr e - a n d p o st -b a s eli n e m e a n 
A R R r ati o w a s 0. 1 2 5 ( 0. 3/ 2. 4), t h e n w e e sti m at e t h e rit u xi m a b m e a n A R R r ati o 
c o m p ar e d wit h a z at hi o pri n e at 0. 3 8 ( 0. 1 2 5/ 0. 3 3).


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
9 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
U n d er t h e a s s u m pti o n of A R R a n d r el a p s e -fr e e r at e di stri b uti o n a b o v e, t h e m e a n A R R 
r ati o i s c oi n ci d e d wit h t h e h a z ar d r ati o. T o cili z u m a b h a z ar d r ati o d at a ( 0. 2 5) c o ul d 
h a v e a p o s si bilit y of o v er e sti m ati o n b e c a u s e of t h e c a s e r e p ort wit h o nl y t hr e e p ati e nt s 
a n d t h e h a z ar d r ati o b et w e e n rit u xi m a b a n d a z at hi o pri n e ( 0. 3 8) i s t h e c o m p ari s o n wit h 
a n a cti v e c o ntr ol, t h e n w e c o n si d er t h e s atr ali z u m a b h a z ar d r ati o c o m p ar e d t o 
pl a c e b o s h o ul d e xi st b et w e e n 0. 2 5 a n d 0. 3 8. S o w e h a v e s et t h e s atr ali z u m a b h a z ar d 
r ati o c o m p ar e d wit h pl a c e b o at 0. 3 3 5.
6. 3 
S U M M A RI E S O F C O N D U C T O F S T U D Y
T h e n u m b er of p ati e nt s r a n d o mi z e d will b e t a b ul at e d b y st u d y sit e a n d tr e at m e nt ar m. 
P ati e nt di s p o siti o n (t h e n u m b er of p ati e nt s r a n d o mi z e d, tr e at e d, a n d c o m pl eti n g e a c h 
st u d y p eri o d) will b e t a b ul at e d b y tr e at m e nt gr o u p. St u d y di s c o nti n u ati o n a s w ell a s 
r e a s o n s f or di s c o nti n u ati o n s will b e s u m m ari z e d. Eli gi bilit y crit eri a d e vi ati o n s a n d 
ot h er m aj or pr ot o c ol d e vi ati o n s will b e s u m m ari z e d.
6. 4 
S U M M A RI E S O F T R E A T M E N T G R O U P C O M P A R A BI LI T Y
D e m o gr a p hi c s ( a g e, s e x a n d r a c e/ et h ni cit y ) a n d b a s eli n e c h ar a ct eri sti c s ( h e p atiti s 
st at u s, b a s eli n e A R R a n d n u m b er of pr e vi o u s e pi s o d e s wit hi n 2 y e ar s b ef or e 
e nr oll m e nt ) of p at e nt s will b e c oll e ct e d at s cr e e ni n g or b a s eli n e vi sit b ef or e 
a d mi ni str ati o n of fir st d o s e of st u d y dr u g.
I n g e n er al, d at a will b e s u m m ari z e d b y tr e at m e nt gr o u p a n d f or all p ati e nt s i n t h e 
st u d y (i. e. , i n d e p e n d e nt of tr e at m e nt gr o u p). D e s cri pti v e st ati sti c s will b e pr e s e nt e d f or 
c o nti n u o u s d at a wit h s a m pl e si z e, m e a n, st a n d ar d d e vi ati o n ( S D), m e di a n, mi ni m u m, 
a n d m a xi m u m. Fr e q u e n c y t a bl e wit h p er c e nt a g e will b e pr e s e nt e d f or di s cr et e d at a. 
6. 5 
E F FI C A C Y A N A L Y S E S
All effi c a c y a n al y s e s will b e b a s e d o n t h e I T T p o p ul ati o n. S u p p orti v e e v al u ati o n s will 
b e p erf or m e d u si n g t h e P P S p o p ul ati o n f or pri m ar y a n d k e y s e c o n d ar y e n d p oi nt s.
6. 5. 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 F R b a s e d o n pr ot o c ol -d ef i n e d r el a p s e s c o nfir m e d 
b y t h e C E C wit h E D S S/ F S S a s s e s s m e nt p erf or m e d b y t h e e x a mi ni n g a s s e s s or wit hi n 
7 d a y s aft er r el a p s e s y m pt o m s w er e r e p ort e d t o sit e b y t h e p ati e nt. T F R i s d ef i n e d a s 
t h e ti m e fr o m t h e d at e of t h e r a n d o mi z ati o n u ntil t h e fir st o c c urr e n c e of r el a p s e
t hr o u g h o ut t h e d o u bl e-bli n d p eri o d . T h e t i m e p oi nt of r el a p s e o n s et i s d efi n e d a s t h e 
ti m e at w hi c h t h e p ati e nt e x p eri e n c e s a n y n e w or w or s e ni n g n e ur ol o gi c al N M O 
r e pr e s e nti n g cli ni c al r el a p s e( s). E v e nt s w hi c h ar e j u d g e d b y t h e C E C t o m e et t h e 
pr ot o c ol -d ef i n e d r el a p s e will b e i n cl u d e d i n t h e pri m ar y a n al y si s of t h e pri m ar y 
e n d p oi nt if E D S S/ F S S i s a s s e s s e d b y t h e e x a mi ni n g a s s e s s or wit hi n s e v e n d a y s aft er 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
t h e p ati e nt r e p ort s t h e s y m pt o m s t o t h e sit e. F or p ati e nt s w h o h a v e n ot r el a p s e d, n ot 
s wit c h e d b a s eli n e tr e at m e nt or n ot i n cr e a s e d b a s eli n e tr e at m e nt at t h e ti m e of 
a n al y si s , t h e T F R will b e c e n s or e d o n t h e d at e w h e n t ot al n u m b er of pr ot o c ol-d ef i n e d 
r el a p s e s j u d g e d b y C E C r e a c h e s 2 6. F or p ati e nt s w h o h a v e s wit c h e d b a s eli n e 
tr e at m e nt or i n cr e a s e d b a s eli n e tr e at m e nt, t h e T F R will b e c e n s or e d o n t h e d at e of 
s wit c hi n g or i n cr e a si n g t h e b a s eli n e tr e at m e nt. F or p ati e nt s w h o h a v e r e c ei v e d r e s c u e 
t h er a p y wit h o ut e x p eri e n ci n g a pr ot o c ol-d ef i n e d r el a p s e f or w hi c h t h e E D S S/ F S S 
a s s e s s m e nt w a s n ot p erf or m e d wit hi n s e v e n d a y s aft er t h e p ati e nt r e p ort s t h e 
s y m pt o m s t o t h e sit e , t h e T F R will b e c e n s or e d o n t h e d at e of r e c ei vi n g r e s c u e 
t h er a p y.
T h e pri m ar y a n al y si s of t h e st u d y i s t o t e st t h e e q u alit y of t h e T F R di stri b uti o n i n t h e 
s atr al i z u m a b (S A 2 3 7 ) b a s eli n e tr e at m e nt ( s atr ali z u m a b [S A 2 3 7 ]) a n d 
Pl a c e b o b a s eli n e tr e at m e nt ( pl a c e b o) ar m s:
H 0 : T F RS A 2 3 7 T F R pl a c e b o v er s u s H 1 : T F RS A 2 3 7 ≠ T F R pl a c e b o
A str atifi e d t w o -si d e d l o g -r a n k t e st u si n g str at a of b a s eli n e A R R ( o n e v s. m or e t h a n 
o n e) a n d g e o gr a p hi c al r e gi o n will b e u s e d . 
T h e K a pl a n -M ei er m et h o d will b e u s e d t o e sti m at e t h e T F R di stri b uti o n f or e a c h 
tr e at m e nt gr o u p. T h e K a pl a n-M e i er c ur v e will pr o vi d e a vi s u al d e s cri pti o n of t h e 
diff er e n c e s a cr o s s tr e at m e nt gr o u p s. I n a d diti o n, e s ti m at e s of t h e tr e at m e nt eff e ct will 
b e e x pr e s s e d a s h a z ar d r ati o a n d 9 5 % c o nfi d e n c e i nt er v al s ( CI s) u si n g a str atifi e d
( b a s eli n e A R R a n d g e o gr a p hi c al r e gi o n) C o x pr o p orti o n al-h a z ar d s m o d el. T h e M e di a n 
T F R i s n ot e x p e ct e d t o b e r e a c h e d i n t hi s st u d y at t h e ti m e of t h e pri m ar y a n al y si s; 
h e n c e, e v er y 6 -m o nt h s,
r el a p s e-fr e e r at e s a n d t h eir 9 5 % CI will b e u s e d t o d e s cri b e 
T F R di stri b uti o n i n a d diti o n t o t h e h a z ar d r ati o. 
6. 5. 2 
S e c o n d ar y  Effi c a c y E n d p oi nt s
K e y  S e c o n d ar y Effi c a c y E n d p oi nt s
T h e k e y s e c o n d ar y effi c a c y e n d p oi nt s ar e c h a n g e i n V A S f or p ai n a n d c h a n g e i n t h e 
F A CI T f ati g u e s c al e. I n or d er t o c o ntr ol t h e r at e of f al s e p o siti v e c o n cl u si o n s, t h e s eri al 
g at e k e e pi n g m et h o d ol o g y (fi x e d-s e q u e n c e t e st) will b e e m pl o y e d t o c o ntr ol f or 
m ult i pl e ( pri m ar y a n d k e y s e c o n d ar y) e n d p oi nt s i n t hi s or d er.
C h a n g e i n V A S S c or e f or P ai n 
T h e V A S i s a s u bj e cti v e m e a s ur e of p ai n a n d it c o n si st s of a 1 0 0 m m li n e wit h t w o 
e n d -p oi nt s r e pr e s e nti n g “ n o p ai n” a n d “ p ai n a s b a d a s it c o ul d b e”. P ati e nt s ar e a s k e d
t o r at e t h eir p ai n b y pl a ci n g a m ar k o n t h e li n e c orr e s p o n di n g t o t h eir c urr e nt l e v el of 
p ai n. T h e di st a n c e al o n g t h e li n e fr o m t h e ‘ n o p ai n’ m ar k er i s t h e n m e a s ur e d wit h a 
r ul er gi vi n g a p ai n s c or e o ut of 1 0. 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T h e c h a n g e i n V A S f or p ai n s c or e fr o m b a s eli n e t o W e e k 2 4 i n t h e d o u bl e -bli n d p eri o d 
will b e a n al y z e d b y a n al y si s of c o v ari a n c e ( A N C O V A) m et h o d wit h b a s eli n e 
o b s er v ati o n c arri e d f or w ar d ( B O C F) i m p ut ati o n . T h e a n al y si s will i n cl u d e t h e 
c at e g ori c al eff e ct s f or tr e at m e nt, b a s eli n e A R R a n d g e o gr a p hi c al r e gi o n, a s w ell a s 
t h e c o nti n u o u s c o v ari at e s of b a s eli n e V A S f or p ai n s c or e.
C h a n g e i n F A CI T F ati g u e S c or e
F A CI T f ati g u e s c al e i n cl u d e s 1 3 st at e m e nt s, w hi c h m e a s ur e s f ati g u e /a st h e ni a f or 
p ati e nt s wit h c hr o ni c, lif e -t hr e at e ni n g ill n e s s e s. F or e a c h q u e sti o n, a p ati e nt r at e s hi s / 
h er c o n diti o n f or t h e p a st w e e k o n a 5 -p oi nt Li k ert s c al e r a n gi n g fr o m 0 ( n ot at all) t o 4 
( v er y m u c h). F or t h e c h a n g e i n F A CI T f ati g u e , d e s cri pti v e st ati sti c s will b e c al c ul at e d 
f or t h e c h a n g e i n F A CI T f ati g u e b y a v er a gi n g t h e i n di vi d u al q u e sti o n s c or e s.
T h e c h a n g e i n F A CI T f ati g u e s c al e s c or e fr o m b a s eli n e t o W e e k 2 4 i n t h e 
d o u bl e -bli n d p eri o d will b e a n al y z e d b y A N C O V A m et h o d wit h B O C F i m p ut ati o n . T h e 
a n al y si s will i n cl u d e t h e c at e g ori c al eff e ct s f or tr e at m e nt, b a s eli n e A R R a n d 
g e o gr a p hi c al r e gi o n, a s w ell a s t h e c o nti n u o u s c o v ari at e s of b a s eli n e F A CI T 
f ati g u e s c or e.
F urt h er S e c o n d ar y Effi c a c y  E n d p oi nt s
C h a n g e i n S h ort F or m G e n eri c H e alt h S ur v e y ( S F-3 6) S c or e
T h e s c or e s will b e pr e s e nt e d a n d s u m m ari z e d f or e a c h of t h e 8 d o m ai n s ( vit alit y, 
p h y si c al f u n cti o ni n g, b o dil y p ai n, g e n er al h e alt h, r ol e-p h y si c al, r ol e-e m oti o n al, s o ci al 
r ol e f u n cti o ni n g a n d m e nt al h e alt h) a n d 2 s u m m ar y c o m p o n e nt s [ p h y si c al a n d m e nt al] . 
T h e m e a n c h a n g e i n S F-3 6 d o m ai n s c or e s will b e a n al y z e d fr om b a s eli n e t o e v er y 
2 4 w e e k s aft er t h e b a s eli n e vi sit.
C h a n g e i n E Q -5 D S c or e
T h e E Q -5 D i s a p arti ci p a nt -a n s w er e d q u e sti o n n air e m e a s uri n g 5 di m e n si o n s of 
m o bilit y, s elf -c ar e, u s u al a cti v iti e s, p ai n/ di s c o mf ort, a n d a n xi et y/ d e pr e s si o n wit h 
3 p o s si bl e r e s p o n s e c at e g ori e s: 1) n o pr o bl e m s; 2) s o m e pr o bl e m s; 3) s e v er e 
pr o bl e m s. T h e E Q -5 D i s t h er ef or e a bl e t o r e pr e s e nt 2 4 3 ( 3 5 ) di sti n ct h e alt h st at e s. 
T h e s e st at e s m a y t h e n b e c o n v ert e d i nt o a si n gl e i n d e x v al u e b y u si n g t h e ti m e tr a d e -
off ( T T O) b a s e d t ariff m et h o d s. T h e b e st p o s si bl e a n s w er w o ul d b e ( 1, 1, 1, 1, 1) a n d t h e 
w or st p o s si bl e a n s w er w o ul d b e ( 3, 3, 3, 3, 3). A s hift t a bl e will b e u s e d t o e v al u at e t h e 
n u m b er a n d p er c e nt a g e of p ati e nt s h a vi n g a diff er e nt p o st -b a s eli n e st at u s w h e n 
c o m p ar e d t o t h eir b a s eli n e st at u s. T h e m e a n c h a n g e i n E Q-5 D s c or e will b e a n al y z e d 
fr o m b a s eli n e t o e v er y 2 4 w e e k s aft er t h e b a s eli n e vi sit.
T h e Pr o p orti o n of R el a p s e -fr e e P ati e nt s
T h e pr o p orti o n of p ati e nt s w h o ar e r el a p s e -fr e e d uri n g t h e d o u bl e-bli n d e d p eri o d a n d 
t he e ntir e st u d y ( d o u ble-bli n d a n d O L E peri o ds c o m bi ne d) will b e c al c ul at e d f or t h e 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
t w o tr e at m e nt gr o u p s. W he n b ot h peri o ds are a n al y ze d t o get her, p atie nts s h o ul d be 
a n al y ze d as r a n d o mi ze d, e ve n i f p atie nts r a n d o mi ze d t o pl ace b o recei ve s atr ali z u m a b 
i n t he O L E peri o d.  
T he K a pl a n -Meier esti m ates a n d c orres p o n di n g 9 5 % CIs f or t he pr o p orti o n of 
p atie nts w h o were rel a pse -free d uri n g t he d o u ble-bli n d peri o d are c alc ul ate d f or b ot h 
tre at me nt gr o u ps.
R e l a p s e-fr e e r at es will b e a n al y z e d at e v er y 2 4 w e e k s aft er b a s eli n e.
A n n u ali z e d R el a p s e R at e
T h e r el a p s e e pi s o d e s f or e a c h eli gi bl e p ati e nt will b e r e c or d e d t hr o u g h o ut t h e w h ol e 
st u d y. T h e A R R i s c al c ul at e d a s t h e t ot al n u m b er of r el a p s e s e x p eri e n c e d di vi d e d b y 
t h e p er s o n-y e ar s at ri s k f or e a c h y e ar of t h e st u d y p eri o d. T h e 9 5 % CI will b e 
pr e s e nt e d b a s e d o n t h e P oi s s o n di stri b uti o n.
F or c o m p ari n g t h e diff er e n c e b et w e e n t he t w o tr e at m e nt ar m s, n e g ati v e bi n o mi al 
r e gr e s si o n m o d el will b e u s e d wit h A R R a s r e s p o n s e v ari a bl e a n d tr e at m e nt gr o u p, 
b a s eli n e A R R a n d g e o gr a p hi c al r e gi o n a s c o v ari at e s.
C h a n g e i n M o difi e d R a n ki n S c al e S c or e
T h e m R S i s a 7 -p oi nt di s a bilit y s c al e t h at a s s e s s e s t h e d e gr e e of di s a bilit y i n p ati e nt s 
wit h n e ur ol o gi c al i m p air m e nt. P o s si bl e s c or e s r a n g e fr o m 0 ( n o s y m pt o m s at all) u p t o 
6 ( d e at h). T h e hi g h er s c or e s r efl e ct i n cr e a s e d di s a bilit y. D e s cri pti v e st ati sti c s will b e 
c al c ul at e d f or t h e c h a n g e i n m R S.
T h e m e a n c h a n g e i n m R S s c or e will b e a n al y z e d fr o m b a s eli n e t o e v er y 2 4 w e e k s 
af t er t h e b a s eli n e vi sit.
C h a n g e i n Z arit B ur d e n I nt er vi e w S c or e
T h e Z BI i s t h e m e a s ur e m e nt t o a s s e s s c ar e gi v er b ur d e n. T h e 2 2 it e m s a s k f or t h e 
str ai n c ar e gi v er s p er c ei v e. R e s p o n s e s r a n g e fr o m 0 ( n e v er) t o 4 ( n e arl y al w a y s) wit h 
m a xi m u m s c or e of 8 8. T h e hi g h er t h e t ot al s c or e, t h e h e a vi er t h e p er c ei v e d b ur d e n. 
D e s cri pti v e st ati sti c s will b e c al c ul at e d f or t h e c h a n g e i n Z BI.
T h e m e a n c h a n g e i n Z BI s c or e will b e a n al y z e d fro m b a s eli n e t o e v er y 2 4 w e e k s aft er 
t h e b a s eli n e vi sit.
C h a n g 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) S c or e
T h e E D S S will b e a s s e s s e d o n s c h e d ul e d vi sit s d uri n g e ntir e st u d y. T h e m e a n c h a n g e
i n E D S S s c or e s fr o m b a s eli n e t o e v er y 2 4 w e e k s aft er t h e b a s eli n e vi sit will b e 
a n al y z e d .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
Ti me t o E D S S w orse ni n g b ase d o n t he defi niti o n f or P D R is esti m ate d wit h a C o x 
re gressi o n wit h tre at me nt gr o u p, b a s eli n e A R R a n d g e o gr a p hi c al r e gi o n a s 
c o v ari at e s .  T he h a z ar d r ati o a n d 9 5 % CI f or t he tre at me nt gr o u ps is esti m ate d i n 
t his m o del, t he p v al ue is c alc ul ate d b ase d o n t he l o g r a n k test.  I n a d diti o n, K a pl a n -
Meier esti m ate of e ve nt -free r ates will be pr o vi de d.
T hese a n al yses are d o ne f or t he d o u ble -bli n d peri o d a n d t he c o m bi ne d d o u ble -bli n d 
a n d O L E peri o d.  W he n b ot h peri o ds are a n al y ze d t o get her, p atie nts are a n al y ze d as 
r a n d o mi ze d, e ve n if p atie nts r a n d o mi ze d t o pl ace b o recei ve s atr ali z u m a b i n t he O L E 
peri o d.
C h a n g e i n Vi s u al A c uit y  ( S n ell e n C h art)
Vi s u al a c uit y will b e m e a s ur e d b y a S n ell e n 2 0 -f o ot w all c h art. T h e t e st will b e 
p erf or m e d m o n o c ul arl y a n d p ati e nt s m a y u s e t h eir h a bit u al di st a n c e gl a s s e s or 
c o nt a ct l e n s e s.
T h e s a m e vi s u al a c uit y t e sti n g m et h o d i s t o b e e m pl o y e d f or all st u d y vi sit s f or 
e a c h p ati e nt .
A n al y si s of S e c o n d ar y E n d p oi nt s
A m i x e d-eff e ct s 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 u s e d f or t h e 
c h a n g e fr o m b a s eli n e i n E D S S, S F -3 6, V A S f or p ai n, F A CI T f ati g u e , m R S, Z BI a n d 
E Q -5 D s c or e s , a s w ell a s vi s u al f u n cti o n t e sti n g. T h e m o d e l will i n cl u d e tr e at m e nt 
gr o u p, pr ot o c ol -s p e cifi e d vi sit, tr e at m e nt -b y -vi sit i nt er a cti o n a s fi x e d eff e ct s; t h e 
b a s eli n e m e a s ur e m e nt s a s a c o v ari at e; a n d vi sit a s a r e p e at e d m e a s ur e. A n 
u n str u ct ur e d c o v ari a n c e m atri x will b e a s s u m e d i n t h e m o d el.
If t h e u n str u ct ur e d c o v ari a n c e m atri x d o e s n ot c o n v er g e, ot h er c o v ari a n c e str u ct ur e 
will b e u s e d. If tr e at m e nt -b y -vi sit i nt er a cti o n i s n ot st ati sti c all y si g nifi c a nt, w e still k e e p 
t h e f ull m o d el.
If t h e n or m alit y a s s u m pti o n f or t h e s e c o n d ar y effi c a c y v ari a bl e d oe s n ot h ol d, 
g e n er ali z e d e sti m ati n g e q u ati o n or g e n er ali z e d li n e ar mi x e d -eff e ct m o d el a n al y si s will 
b e u s e d. T h e a s s e s s m e nt will b e p erf or m e d pri or t o u n bli n di n g a n d d et ail s will b e 
m e nti o n e d i n t h e S A P.
U s e of R e s c u e M e di c ati o n
T he use of resc ue me dic ati o n is b ase d o n tre ate d cli nic al rel a pses.  If a p atie nt h as at 
le ast o ne tre ate d cli nic al rel a pse, t he n t his p atie nt is c o u nte d as a p atie nt wit h resc ue 
me dic ati o n use.  T he use of resc ue me dic ati o n will be a n al y ze d wit h a l o gistic 
re gressi o n m o del wit h tre at me nt gr o u p , b aseli ne A R R a n d ge o gr a p hi c al re gi o n as 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
c o v ari ates .  T he o d ds r ati o, c orres p o n di n g 9 5 % CI, a n d p v al ue f or t he tre at me nt 
gr o u p will be re p orte d.  T his a n al ysis is c o n d ucte d f or t he d o u ble -bli n d peri o d.
6. 5. 3 
F urt h er A n al y si s
6. 5. 3. 1 
S e n siti vit y A n al y si s f o r Pri m ar y E n d p oi nt
S e v er al s e n siti vit y a n al y s e s ar e pl a n n e d f or t h e pri m ar y effi c a c y a n al y si s of T F R t o
a c c o u nt f or t h e p ot e nti al i m p a ct of diff er e n c e s i n d ef i niti o n of pri m ar y e n d p oi nt. In t hi s 
a n al y si s t h e f oll o wi n g p o p ul ati o n s will b e a n al yz e d f or T F R: 
 
P ati e nt s wit h cli ni c al r el a p s e 
 
P ati e nt s wit h tr e at e d cli ni c al r el a p s e
 
P ati e nt s wit h tr e at e d cli ni c al r el a p s e: O pti c N e uriti s
 
P ati e nt s wit h p r ot o c ol-d ef i n e d r el a p s e b a s e d o n C E C a dj u di c ati o n (r e g ar dl e s s of 
a s s e s s m e nt li mit of s e v e n d a y s)
 
P ati e nt s wit h pr o t o c ol-d ef i n e d r el a p s e b a s e d o n E D S S/ F S S i n cr e a s e r el ati v e t o 
b a s eli n e
F urt h er d et ail s will b e m e nti o n e d i n t h e S A P .
6. 5. 3. 2 
S e n siti vit y A n al y si s f or K e y  Se c o n d ar y  E n d p oi nt
S e v er al s e n siti vit y a n al y s e s ar e pl a n n e d f or t h e k e y s e c o n d ar y effi c a c y a n al y si s of 
V A S f or p ai n a n d F A CI T f ati g u e t o a c c o u nt f or t h e p ot e nti al i m p a ct of diff er e n c e s i n 
h a n dli n g of mi s si n g d at a . In t hi s a n al y si s t h e f oll o wi n g a n al ys e s will b e c o n d u ct e d : 
 
T h e c h a n g e i n V A S f or p ai n s c or e fr o m b a s eli n e t o W e e k 2 4 i n t h e d o u bl e -bli n d 
p eri o d will b e a n al y z e d b y A N C O V A m et h o d wit h h ot -d e c k i m p ut ati o n
 
T h e c h a n g e i n F A CI T f ati g u e s c al e s c or e fr o m b a s eli n e t o W e e k 2 4 i n t h e 
d o u bl e -bli n d p eri o d will b e a n al y z e d b y A N C O V A m et h o d wit h h ot -d e c k 
i m p ut ati o n
F urt h er d et ail s will b e m e nti o n e d i n t h e S A P .
6. 5. 3. 3 
S u b gr o u p A n al y si s
T h e s u b gr o u p s u m m ar y t a bl e s f or T F R will b e pr e s e nt e d b y A Q P 4 A b st at u s at 
s cr e e ni n g ( p o siti v e/ n e g ati v e) i n N M O a n d N M O/ N M O S D. I n c a s e t h at s atr ali z u m a b
d o e s n ot s h o w t h e eff e cti v e n e s s i n N M O p ati e nt s wit h A Q P 4 A b n e g ati v e at all, 
c o m p a ni o n di a g n o sti c s c o -d e v el o p m e nt will b e c o n si d er e d b y u si n g t hi s d at a. T h e 
s u b gr o u p a n al y si s f or a d ol e s c e nt will al s o b e c o n d u ct e d.
F urt h er d et ail s will b e d e s cri b e d i n t h e S A P.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A d ol e s c e nt s :
S u m m ar y st at i sti c s will b e pr o vi d e d f or effi c a c y o ut c o m e m e a s ur e s. O ut c o m e 
m e a s ur e s will b e r e p ort e d f or all a d ol e s c e nt s w h o ar e e nr oll e d i n t o t hi s st u d y, a s w ell 
a s f or all a d ol e s c e nt s w h o ar e r a n d o mi z e d i nt o t h e d o u bl e -bli n d p eri o d. S e p ar at e 
li sti n g s f or a d ol e s c e nt s w h o ar e e nr oll e d i nt o t h e e xt e n si o n p eri o d will b e pr o vi d e d, a s 
a p pr o pri at e.
6. 6 
S A F E T Y A N A L Y S E S
All s af et y a n al y s e s will b e p erf or m e d o n t h e S A F. S af et y v ari a bl e s t o b e a s s e s s e d ar e 
A E s, A E SI s, S A E s, s el e ct e d A E s , i nj e cti o n sit e r e a cti o n s, p ati e nt wit h dr a w al s d u e t o 
A E s, c h a n g e i n 1 2 -l e a d E C G s, m e a s ur e m e nt s of l a b or at or y p ar a m et er s, a n d vit al 
si g n s (i n cl u di n g b o d y w ei g ht) .
S u m m ar y t a bl e s f or n u m b er a n d p er c e nt a g e of p ati e nt s wit h a d v er s e dr u g r e a cti o n s 
(i. e., A E s r el at e d t o st u d y dr u g) will b e t a b ul at e d.
A d v er s e e v e nt s will b e s u m m ari z 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, 
b a s e d o n M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s c o di n g, a n d gr a d e of s e v erit y. 
T h e i n ci d e n c e of tr e at m e nt e m er g e nt A E s will al s o b e di s pl a y 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 dr u g, r e s p e cti v el y. I n a d diti o n, t h e i n ci d e n c e of A E s l e a di n g t o
wit h dr a w al fr o m tr e at m e nt a n d S A E s will b e t a b ul at e d.
I n ci d e n c e of S el e ct e d A E s ( s e e S e cti o n 5. 2. 4 ) will b e t a b ul at e d. I R R s will b e f urt h er 
a n al y z e d a c c or di n g t o w h et h er t h e y m e et S a m p s o n' s crit eri a f or di a g n o si s of 
a n a p h yl a xi s ( S a m p s o n et al, 2 0 0 6).
L a b or at or y v al u e s (i n cl u di n g h e m at ol o g y, bl o o d c h e mi str y, a n d uri n al y si s) , 
fr e q u e n ci e s of l a b or at or y a b n or m aliti e s, vit al si g n s (t e m p er at ur e, S B P, D B P a n d p ul s e 
r at e), p h y si c al e x a mi n ati o n, 1 2-l e a d E C G, a n d s ui ci d alit y ( C-S S R S) will b e 
s u m m ari z e d. M e a s ur e m e nt a n d c h a n g e fr o m B a s eli n e i n c o nti n u o u s l a b or at or y 
p ar a m et er s ( h e m at ol o g y, cli ni c al c h e mi str y, a n d uri n al y si s), c o nti n u o u s E C G, vit al 
si g n s ( bl o o d pr e s s ur e s a n d p ul s e r at e), a n d b o d y w ei g ht will b e s u m m ari z e d u si n g 
d e s cri pti v e st ati sti c s. W h e n a n al y zi n g c at e g ori c al d at a, t h e n u m b er a n d p er c e nt a g e of 
p ati e nt s i n e a c h c at e g or y w ill b e pr e s e nt e d. I n a d diti o n, s hift t a bl e s m a y b e u s e d t o 
e v al u at e t h e n u m b er a n d p er c e nt a g e of p ati e nt s h a vi n g a diff er e nt p o st -b a s eli n e 
st at u s w h e n c o m p ar e d t o t h eir b a s eli n e st at u s. N u m b er s of p ati e nt s w h o m e et t h e 
m ar k e d a b n or m alit y crit eri a will al s o
b e pr e s e nt e d.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A d ol e s c e nt s :
S af et y o ut c o m e m e a s ur e s will b e s u m m ari z e d. S u m m ari e s will b e r e p ort e d f or all 
a d ol e s c e nt s w h o ar e e nr oll e d i n t o t hi s st u d y, a s w ell a s f or all a d ol e s c e nt s w h o ar e
r a n d o mi z e d i nt o t h e d o u bl e-bli n d p eri o d. S e p ar at e li sti n g s f or a d ol e s c e nt s w h o ar e
e nr oll e d i nt o t h e e xt e n si o n p eri o d will b e pr o vi d e d, a s a p pr o pri at e.
6. 7 
P H A R M A C O KI N E TI C /P H A R M A C O D Y N A MI C S A N A L Y S E S
D e s cri pti v e st ati sti c s, s u c h a s g e o m etri c m e a n, g e o m etri c c o effi ci e nt of v ari a n c e ( C V )
a n d t h e 9 5 % CI f or t h e g e o m etri c m e a n f or t h e s er u m s atr ali z u m a b c o n c e ntr ati o n, a s 
w e ll a s arit h m eti c m e a n, S D, m e di a n, mi ni m u m, a n d m a xi m u m o n t h e m e a s ur e d 
s er u m s atr ali z u m a b c o n c e ntr ati o n, I L -6, sI L -6 R, a nti -A Q P 4 A b a n d p l a s m abl a st s will 
b e c al c ul at e d b y vi sit a n d p er d efi n e d ti m e wi n d o w p o st -d o s e f or t h e P K -P P S . 
A n e x pl or at or y a n al y si s t o i d e ntif y a n y p ot e nti al r el ati o n s hi p a m o n g s er u m 
s atr ali z u m a b c o n c e ntr ati o n a n d P D ( C R P, I L-6, sI L -6 R, pl a s m a bl a st s a n d a nti -
A Q P 4 A b will b e p erf or m e d. T h e s e r e s ult s will b e d e s cri b e d a n d r e p ort e d i n t h e cli ni c al 
st u d y r e p ort.
I n a d diti o n, n o nli n e ar mi x e d-eff e ct s m o d eli n g 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 s atr ali z u m a b . T h e d at a fr o m t hi s st u d y will 
b e p o ol e d wit h d at a fr o m S A -0 0 1 J P st u d y a n d S A -1 0 5 J P st u d y t o d e v el o p a 
p o p ul ati o n P K m o d el f or s atr ali z u m a b . A c o v ari at e a n al y si s will b e c o n d u ct e d t o 
e v al u at e t h e eff e ct of c o v ari at e s o n s atr ali z u m a b e x p o s ur e. S o m e c o v ari at e s s u c h a s 
b o d y w ei g ht, a g e a n d g e n d er will b e i n cl u d e d i n t h e c o v ari at e a n al y si s. P o p ul ati o n a n d 
i n di vi d u al e sti m at e s of pri m ar y P K p ar a m et ers [ e. g. , cl e ar a n c e (C L/ F ), di stri b uti o n 
v ol u m e ( V / F)] a n d s e c o n d ar y P K p ar a m et er s [ e. g. , ar e a u n d er t h e s er u m 
c o n c e ntr ati o n -ti m e c ur v e ( A U C), a v er a g e tr o u g h s er u m c o n c e ntr ati o n ( Ctr o u g h)] will b e 
c o m p ut e d.
D et ail s of t hi s mi x e d -eff e ct s m o d eli n g a n al y si s a n d t h e r e s ult s will b e d e s cri b e d a n d 
r e p ort e d i n a d o c u m e nt s e p ar at e d fr o m t h e cli ni c al st u d y r e p ort.
A d ol e s c e nt s :
P K/ P D o ut c o m e m e a s ur e s wil l b e s u m m ari z e d. S u m m ari e s will b e r e p ort e d f or all 
a d ol e s c e nt s w h o ar e e nr oll e d i nt o t hi s st u d y , a s w ell a s f or all a d ol e s c e nt s w h o ar e
r a n d o mi z e d i nt o t h e d o u bl e-bli n d p eri o d. S e p ar at e li sti n g s f or a d ol e s c e nt s w h o ar e
e nr oll e d i nt o t h e e xt e n si o n p eri o d will b e pr o vi d e d, a s a p pr o pri at e.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
6. 8 
I M M U N O G E NI CI T Y
T h e p er c e nt a g e of p ati e nt s w h o h a v e p o siti v e or n e g ati v e a nti b o d y r e s ult s f or 
s atr ali z u m a b will b e t a b ul at e d. P K/ P D, effi c a c y p ar a m et er a n d s af et y will b e 
s u m m ari z e d b y a nti -dr u g a nti b o d y st at u s.
A d ol e s c e nt s:
I m m u n o g e ni cit y o ut c o m e m e a s ur e s will b e s u m m ari z e d. S u m m ari e s will b e r e p ort e d 
f or all a d ol e s c e nt s w h o ar e e nr oll e d i nt o t hi s st u d y , a s w ell a s f or all a d ol e s c e nt s w h o 
ar e r a n d o mi z e d i nt o t h e d o u bl e-bli n d p eri o d. S e p ar at e li sti n g s f or a d ol e s c e nt s w h o ar e
e nr oll e d i nt o t h e e xt e n si o n p eri o d will b e pr o vi d e d, a s a p pr o pri at e.
6. 9 
H A N D LI N G MI S SI N G D A T A
F or T F R, p ati e nt s w h o h a v e n ot r el a p s e d, n ot s wit c h e d b a s eli n e tr e at m e nt or n ot 
i n cr e a s e d b a s eli n e tr e at m e nt d o s e at t h e ti m e of a n al y si s, t h e T F R will b e c e n s or e d 
o n t h e d at e w h e n t ot al n u m b er of pr ot o c ol-d ef i n e d r el a p s e s j u d g e d b y C E C r e a c h e s 
2 6 . F or p ati e nt s w h o h a v e s wit c h e d b a s eli n e tr e at m e nt or i n cr e a s e d b a s eli n e 
tr e at m e nt d o s e, t h e T F R will b e c e n s or e d o n t h e d at e of s wit c hi n g t h e b a s eli n e 
tr e at m e nt or i n cr e a si n g t h e b a s eli n e tr e at m e nt d o s e . F or p ati e nt s w h o h a v e r e c ei v e d 
r e s c u e t h er a p y wit h o ut e x p eri e n ci n g a pr ot o c ol-d ef i n e d r el a p s e f or w hi c h t h e 
E D S S/ F S S a s s e s s m e nt w a s n ot p erf or m e d wit hi n s e v e n d a y s aft er t h e p ati e nt r e p ort s 
t h e s y m pt o m s t o t h e sit e, t h e T F R will b e c e n s or e d o n t h e d at e of r e c ei vi n g r e s c u e 
t h er a p y. 
F or k e y s e c o n d ar y e n d p oi nt s, mi s si n g d at a at W e e k
2 4 i n t h e d o u bl e bli n d p eri o d will 
b e i m p ut e d b y a B O C F a n d f or t h e p ur p o s e t o a s s e s s t h e r o b u st n e s s of t h e i m p ut ati o n 
m et h o d, w e will al s o c o n d u ct h ot -d e c k i m p ut ati o n a s s e n siti vit y a n al y si s.
F or s e c o n d ar y c o nti n u o u s e n d p oi nt s, a M M R M a n al y si s i n c or p or ati n g d at a i n 
d o u bl e -bli n d p h a s e will b e u s e d t o utili z e d at a c oll e ct e d o v er ti m e wit h c o n si d er ati o n of 
t h e v ari a n c e-c o v ari a n c e m atri x of t h e r e p e at e d m e a s ur e s. T hi s m et h o d all o w s a 
g e n er al u n str u ct ur e d v ari a n c e -c o v ari a n c e m atri x a n d will i n cl u d e d at a fr o m p ati e nt s 
wit h i n c o m pl et e d at a fr o m s o m e s c h e d ul e d ti m e p oi nt s.
F or t h e F A CI T f ati g u e q u e sti o n n air e, if t h er e ar e l e s s t h a n 7 r e s p o n s e s r e c or d e d, t h e n 
t h e t ot al f ati g u e s c or e will b e c o n si d er e d mi s si n g. If t h er e ar e 7 or m or e r e s p o n s e s 
r e c ord e d, t h e n t h e t ot al f ati g u e s c or e f or t h at q u e sti o n n air e will b e c al c ul at e d a s t h e 
a v er a g e of t h e n o n -mi s si n g
s c or e s m ulti pli e d b y 1 3 .
D et ail e d m et h o d s f or h a n dli n g of mi s si n g d at a will b e m e nti o n e d i n t h e S A P.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
7.
D A T A  C O L L E C TI O N AN D M A N A G E M E N T
7. 1 
D A T A  Q U ALI T Y A S S U R A N C E
A C R O will b e r e s p o n si bl e f or t h e d at a m a n a g e m e nt of t hi s st u d y, i n cl u di n g q u alit y 
c h e c ki n g of t h e d at a. D at a e nt er e d m a n u all y will b e c oll e ct e d vi a el e ctr o ni c d at a 
c a pt ur e ( E D C) u si n g e C R F s. Sit e s will b e r e s p o n si bl e f or d at a e ntr y i nt o t h e E D C 
s y st e m. I n t h e e v e nt of di s cr e p a nt d at a, t h e C R O will r e q u e st d at a cl arifi c ati o n fr o m 
t h e sit e s, w hi c h t h e sit e s will r e s ol v e el e ctr o ni c all y i n t h e E D C s y st e m.
T h e S p o n s or or it s d e si g n e e will p erf or m o v er si g ht of t h e d at a m a n a g e m e nt of t hi s 
st u d y. T h e S p o n s or will pr o d u c e a n E D C St u d y S p e cifi c ati o n d o c u m e nt t h at d e s cri b e s 
t h e q u alit y c h e c ki n g t o b e p erf or m e d o n t h e d at a. C e ntr al l a b or at or y d at a will b e s e nt 
dir e ctl y t o t h e C R O, u si n g t h e C R O' s st a n d ar d pr o c e d ur e s t o h a n dl e a n d pr o c e s s t h e 
el e ctr o ni c tr a n sf e r of t h e s e d at a.
e C R F s a n d c orr e cti o n d o c u m e nt ati o n will b e m ai nt ai n e d i n t h e E D C s y st e m’ s a u dit 
tr ail. S y st e m b a c k u p s f or d at a st or e d b y t h e S p o n s or or it s d e si g n e e a n d r e c or d s 
r et e nti o n f or t h e st u d y d at a will b e c o n si st e nt wit h t h e S p o n s or’ s st a n d ar d pro c e d ur e s.
D at a fr o m p a p er p ati e nt or c ar e gi v er c o m pl et e d q u e sti o n n air e s will b e e nt er e d i nt o t h e 
E D C s y st e m b y sit e st aff. 
7. 2 
E L E C T R O NI C C A S E R E P O R T F O R M S 
e C R F s ar e t o b e c o m pl et e d u si n g a S p o n s or -d e si g n at e d E D C s y st e m. Sit e s will 
r e c ei v e tr ai ni n g a n d h a v e a c c e s s t o a m a n u al f or a p pr o pri at e e C R F c o m pl eti o n. 
e C R F s will b e s u b mitt e d el e ctr o ni c all y t o t h e S p o n s or or it s d e si g n e e a n d s h o ul d b e 
h a n dl e d i n a c c or d a n c e w it h i n str u cti o n s fr o m t h e S p o n s or.
All e C R F s s h o ul d b e c o m pl et e d b y d e si g n at e d, tr ai n e d sit e st aff. e C R F s s h o ul d b e 
r e vi e w e d a n d el e ctr o ni c all y si g n e d a n d d at e d b y t h e I n v e sti g at or or a d e si g n e e.
At t h e e n d of t h e st u d y, t h e I n v e sti g at or will r e c ei v e p ati e nt d at a f or hi s or h er sit e i n a 
r e a d a bl e f or m at o n a c o m p a ct di s c t h at m u st b e k e pt wit h t h e st u d y r e c or d s. 
A c k n o wl e d g e m e nt of r e c ei pt of t h e c o m p a ct di s c i s r e q uir e d.
7. 3 
S O U R C E D A T A  D O C U M E N TA T I O N
St u d y m o nit or s will p erf or m o n g oi n g s o ur c e d at a v erifi c ati o n t o c o nfir m t h at criti c al 
pr ot o c ol d at a ( i. e., s o ur c e d at a) e nt er e d i nt o t h e e C R F s b y a ut h ori z e d sit e p er s o n n el 
ar e a c c ur at e, c o m pl et e, a n d v erifi a bl e fr o m s o ur c e d o c u m e nt s. 
S o ur c e d o c u m e nt s ( p a p er or el e ctr o ni c) ar e t h o s e i n w hi c h p ati e nt d at a ar e r e c or d e d 
a n d d o c u m e nt e d f or t h e fir st ti m e. T h e y i n cl u d e, b ut ar e n ot li mit e d t o, h o s pit al r e c or d s, 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 0 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
cli ni c al a n d offi c e c h art s, l a b or at or y n ot e s, m e m or a n d a, p ati e nt -r e p ort e d o ut c o m e s, 
e v al u ati o n c h e c kli st s, p h ar m a c y di s p e n si n g r e c or d s, r e c or d e d d at a fr o m a ut o m at e d 
i n str u m e nt s, c o pi e s of tr a n s cri pti o n s t h at ar e c ertifi e d aft er v erifi c ati o n a s b ei n g 
a c c ur at e a n d c o m pl et e, mi cr ofi c h e, p h ot o gr a p hi c n e g ati v e s, mi cr ofil m or m a g n eti c 
m e di a, X -r a y s, p ati e nt fil e s, a n d r e c or d s k e pt at p h ar m a ci e s, l a b or at ori e s, a n d 
m e di c o -te c h ni c al d e p art m e nt s i n v ol v e d i n a cli ni c al tri al.
B ef or e st u d y i niti ati o n, t h e t y p e s of s o ur c e d o c u m e nt s t h at ar e t o b e g e n er at e d will b e 
cl e arl y d efi n e d i n t h e Tri al M o nit ori n g Pl a n. T hi s i n cl u d e s a n y pr ot o c ol d at a t o b e 
e nt er e d dir e ctl y i nt o t h e e C R F s ( i. e., n o pri or writt e n or el e ctr o ni c r e c or d of t h e d at a) 
a n d c o n si d er e d s o ur c e d at a.
S o ur c e d o c u m e nt s t h at ar e r e q uir e d t o v erif y t h e v ali dit y a n d c o m pl et e n e s s of d at a 
e nt er e d i nt o t h e e C R F s m u st n ot b e o blit er at e d or d e str o y e d a n d m u st b e r et ai n e d p er 
t h e p oli c y f or r et e nti o n of r e c or d s d e s cri b e d i n S e cti o n 7. 5 .
T o f a cilit at e s o ur c e d at a v erifi c ati o n, t h e i n v e sti g at or s a n d i n stit uti o n s m u st pr o vi d e t h e 
S p o n s or or it s d e si g n e e dir e ct a c c e s s t o a p pli c a bl e s o ur c e d o c u m e nt s a n d r e p ort s f or 
tri al-r el at e d m o nit ori n g, S p o n s or or d e si g n e e a u dit s, a n d I R B/I E C r e vi e w. T h e 
i n v e sti g ati o n al sit e m u st al s o all o w i n s p e cti o n b y a p pli c a bl e h e alt h a ut h oriti e s.
7. 4 
U S E O F C O M P U T E RI Z E D S Y S T E M S
W h e n cli ni c al o b s er v ati o n s ar e e nt er e d dir e ctl y i nt o a n i n v e sti g ati o n al sit e’ s 
c o m p ut eri z e d m e di c al r e c or d s y st e m ( i. e., i n li e u of ori gi n al h ar d c o p y r e c or d s), t h e 
el e ctr o ni c r e c or d c a n s er v e a s t h e s o ur c e d o c u m e nt if t h e s y st e m h a s b e e n v ali d at e d 
i n a c c or d a n c e wit h h e alt h a ut h orit y r e q uir e m e nt s p ert ai ni n g t o c o m p ut eri z e d s y st e m s 
u s e d i n cli ni c al r e s e ar c h. A n a c c e pt a bl e c o m p ut eri z e d d at a c oll e cti o n s y st e m all o w s 
pr e s er v ati o n of t h e ori gi n al e ntr y of d at a. If ori gi n al d at a ar e m o difi e d, t h e s y st e m 
s h o ul d m ai nt ai n a vi e w a bl e a u dit tr ail t h at s h o w s t h e ori gi n al d at a a s w ell a s t h e 
r e a s o n f or t h e c h a n g e, n a m e of t h e p er s o n m a ki n g t h e c h a n g e, a n d d at e of t h e 
c h a n g e.
7. 5 
R E T E N TI O N O F R E C O R D S
R e c or d s a n d d o c u m e nt s p ert ai ni n g t o t h e c o n d u ct of t hi s st u d y a n d t h e di stri b uti o n of 
I MP, i n cl u di n g e C R F s, I C F s, l a b or at or y t e st r e s ult s, a n d m e di c ati o n i n v e nt or y r e c or d s, 
m u st b e r et ai n e d b y t h e Pri n ci p al I n v e sti g at or 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, or f or t h e l e n gt h of ti m e r e q uir e d b y r el e v a nt n ati o n al or 
l o c al h e alt h a ut h oriti e s, w hi c h e v er i s l o n g er. 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 atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 1 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
N o r e c or d s m a y b e di s p o s e d of wit h o ut t h e writt e n a p pr o v al of t h e S p o n s or. Wr itt e n 
n otifi c ati o n s h o ul d b e pr o vi d e d t o t h e S p o n s or pri or t o tr a n sf erri n g a n y r e c or d s t o 
a n ot h er p art y or m o vi n g t h e m t o a n ot h er l o c ati o n.
8.
E T HI C A L C O N SI D E R A TI O N S
8. 1 
C O M P LI A N C E WI T H L A W S
A N D R E G U L A TI O N S
T hi s st u d y will b e 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 I C H E 6 g ui d eli n e f or G o o d 
Cli ni c al Pr a cti c e a n d 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 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 will c o m pl y wit h t h e r e q uir e m e nt s of t h e 
I C H E 2 A g ui d eli n e ( 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). 
8. 2 
I N F O R M E D C O N S E N T
T h e S p o n s or’ s s a m pl e m a st er I C F i n cl u di n g C C S R, i nfor m e d a s s e nt f or m f or mi n or s
a n d c o n s e nt f or m f or t h e p ati e nt’ s l e g all y a ut h ori z e d r e pr e s e nt ati v e, I C F f or Z BI a n d 
a ut h ori z ati o n f or u s e a n d di s cl o s ur e of pr e g n a n c y h e alt h i nf or m ati o n, will b e pr o vi d e d 
t o e a c h sit e. If a p pli c a bl e, it will b e pr o vi d e d i n a c ertifi e d tr a n sl ati o n i n t h e l o c al 
l a n g u a ge. T h e S p o n s or or it s d e si g n e e m u st r e vi e w a n d a p pr o v e a n y pr o p o s e d 
d e vi ati o n s fr o m t h e S p o n s or' s s a m pl e I C F or a n y alt er n at e c o n s e nt f or m s pr o p o s e d b y 
t h e sit e ( c oll e cti v el y, t h e “ C o n s e nt F or m s”) b ef or e I R B/I E C s u b mi s si o n. T h e fi n al 
I R B/I E C a p pr o v e d C o n s ent F or m s m u st b e pr o vi d e d t o t h e S p o n s or or it s d e si g n e e f or 
h e alt h a ut h orit y s u b mi s si o n p ur p o s e s a c c or di n g t o l o c al r e q uir e m e nt s .
T h e I C F s m u st b e si g n e d a n d d at e d b y t h e p ati e nt or t h e p ati e nt’ s l e g all y a ut h ori z e d 
r e pr e s e nt ati v e b ef or e hi s or h er p arti cip ati o n i n t h e st u d y. T h e c a s e hi st or y or cli ni c al 
r e c or d s f or e a c h p ati e nt s h all d o c u m e nt t h e i nf or m e d c o n s e nt pr o c e s s a n d t h at writt e n 
i nf or m e d c o n s e nt w a s o bt ai n e d pri or t o p arti ci p ati o n i n t h e st u d y.
T h e I C F s s h o ul d b e r e vi s e d w h e n e v er t h er e ar e c h a n g e s t o st u d y pr o c e d ur e s or w h e n 
n e w i nf or m ati o n b e c o m e s a v ail a bl e t h at m a y aff e ct t h e willi n g n e s s of t h e p ati e nt t o 
p arti ci p at e. T h e fi n al r e vi s e d I R B/I E C -a p pr o v e d I C F s m u st b e pr o vi d e d t o t h e S p o n s or 
f or h e alt h a ut h orit y s u b mi s si o n p ur p o s e s.
P ati e nt s m u st b e r e-c o n s e nt e d t o t h e m o st c urr e nt v er si o n of t h e I C F ( or t o a 
si g nifi c a nt n e w i nf or m ati o n/fi n di n g s a d d e n d u m i n a c c or d a n c e wit h a p pli c a bl e l a w s a n d 
I R B/I E C p oli c y) d uri n g t h eir p arti ci p ati o n i n t h e st u d y. F or a n y u p d at e d or r e vi s e d I C F s, 
t h e c a s e hi st or y or cli ni c al r e c or d s f or e a c h p ati e nt s h all d o c u m e nt t h e i nf or m e d 
c o n s e nt pr o c e s s a n d t h at writt e n i nf or m e d c o n s e nt w a s o bt ai n e d u si n g t h e 
u p d at e d/r e vi s e d I C F s f or c o nti n u e d p arti ci p ati o n i n t h e st u d y.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 1 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A c o p y of e a c h si g n e d I C F m u st b e pr o vi d e d t o t h e p ati e nt or t h e p ati e nt’ s l e g all y 
a ut h ori z e d r e pr e s e nt ati v e. All si g n e d a n d d at e d I C F s m u st r e m ai n i n e a c h p ati e nt’ s 
st u d y fil e or i n t h e sit e fil e a n d m u st b e a v ail a bl e f or v erifi c ati o n b y st u d y m o nit or s at 
a n y ti m e.
F or sit e s i n t h e U S, e a c h I C F m a y al s o i n cl u d e p ati e nt a ut h ori z ati o n t o all o w 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 i n c o m pli a n c e wit h t h e U. S. H e alt h I n s ur a n c e 
P ort a bilit y a n d A c c o u nt a bilit y A ct of 1 9 9 6 ( HI P A A). If t h e sit e utili z e s a s e p ar at e 
A ut h ori z ati o n F or m f or p ati e nt 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 u n d er t h e HI P A A r e g ul ati o n s, t h e r e vi e w, a p pr o v al, a n d ot h er pr o c e s s e s 
o utli n e d a b o v e a p pl y e x c e pt t h at I R B r e vi e w a n d a p pr o v al m a y n ot b e r e q uir e d p er 
st u d y sit e p oli ci e s.
8. 3 
I N S TI T U TI O N AL R E VI E W B O A R D O R I N D E P E N D E N T 
E T HI C S C O M MI T T E E
T hi s pr ot o c ol, t h e I C F s, a n y i nf or m ati o n t o b e gi v e n t o t h e p ati e nt, a n d r el e v a nt 
s u p p orti n g i nf or m ati o n m u st b e s u b mitt e d t o t h e I R B/I E C b y t h e Pri n ci p al I n v e sti g at or 
a n d r e vi e w e d a n d a p pr o v e d b y t h e I R B/I E C b ef or e t h e st u d y i s i niti at e d. I n a d diti o n, 
a n y p ati e nt r e cr uit m e nt m at eri al s m u st b e a p pr o v e d b y t h e I R B/I E C. 
T h e Pri n ci p al I n v e sti g at or i s r e s p o n si bl e f or pr o vi di n g writt e n s u m m ari e s of t h e st at u s 
of  t h e st u d y t o t h e I R B/I E C a n n u all y or m or e fr e q u e ntl y i n a c c or d a n c e with t h e 
r e q uir e m e nt s, p oli ci e s, a n d pr o c e d ur e s e st a bli s h e d b y t h e I R B/I E C. I n v e sti g at or s ar e 
al s o r e s p o n si bl e f or pr o m ptl y i nf or mi n g t h e I R B/I E C of a n y pr ot o c ol a m e n d m e nt s ( s e e 
S e cti o n 9. 5 ).
I n a d diti o n t o t h e r e q uir e m e nt s f or r e p orti n g all A E s t o t h e S p o n s or or it s d e si g n e e, 
I n v e sti g at or s m u st c o m pl y wit h r e q uir e m e nt s f or S A E r e p orti n g t o t h e l o c al h e alt h 
a ut h orit y a n d I R B/I E C. I n v e sti g at or s m a y r e c ei v e writt e n I n v e sti g ati o n al N e w Dr u g 
s af et y r e p ort s or ot h er s af et y -r el at e d c o m m u ni c ati o n s fr o m t h e S p o n s or or t h e C R O. 
I n v e sti g at or s ar e r e s p o n si bl e f or e n s uri n g t h at s u c h r e p ort s ar e r e vi e w e d a n d 
pr o c e s s e d i n a c c or d a n c e wit h h e alt h a ut h orit y r e q uir e m e nt s a n d t h e p oli ci e s a n d 
pr o c e d ur e s e st a bli s h e d b y t h eir I R B/I E C, a n d ar c hi v e d i n t h e sit e’ s st u d y fil e. 
8. 4 
C O N FI D E N TI A LI T Y
T h e S p o n s or or it s d e si g n e e m ai nt ai n s c o nfi d e nti alit y st a n d ar d s b y c o di n g e a c h 
p ati e nt e nr oll e d i n t h e st u d y t hr o u g h a s si g n m e nt of a u ni q u e p ati e nt i d e ntifi c ati o n 
n u m b er. T hi s m e a n s t h at p ati e 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 S p o n s or l o c ati o n.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 1 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
P ati e nt m e di c al i nf or m ati o n o bt ai n e d b y t hi s st u d y i s c o nfi d e nti al a n d m a y o nl y b e 
di s cl o s e d t o t hir d p arti e s 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 ati e nt, u nl e s s p er mitt e d 
or r e q uir e d b y l a w.
M e di c al i nf or m ati o n m a y b e gi v e n t o a p ati e nt’ s p er s o n al p h y si ci a n or ot h er 
a p pr o pri at e m e di c al p er s o n n el r e s p o n si bl e f or t h e p ati e nt’ s w elf ar e, f or tr e at m e nt 
p ur p o s e s.
D at a g e n er at e d b y t hi s st u d y 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 t h e U S F o o d a n d Dr u g A d mi ni str ati o n a n d ot h er n ati o n al a n d l o c al 
h e alt h a ut h oriti e s, S p o n s or or it s d e si g n at e d m o nit or s, a u dit 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 n d t h e I R B/I E C f or e a c h st u d y sit e, a s a p pr o pri at e.
8. 5 
FI N A N CI A L DI S C L O S U R E
I n v e sti g at or s will pr o vi d e t h e S p o n s or wit h s uffi ci e nt, a c c ur at e fi n a n ci al i nf or m ati o n i n 
a c c or d a n c e wit h l o c al r e g ul ati o n s t o all o w t h e S p o n s or t o s u b mit c o m pl et e a n d 
a c c ur at e fi n a n ci al c ertifi c ati o n or di s cl o s ur e st at e m e nt s t o t h e a p pr o pri at e h e alt h 
a ut h oriti e s. I n v e sti g at or s ar e r e s p o n si bl e f or pr o vi di n g i nf or m ati o n o n fi n a n ci al 
i nt er e st s d uri n g t h e c o ur s e of t h e st u d y a n d f or 1 y e ar aft er c o m pl eti o n of t h e st u d y 
(i. e., t h e l a st p ati e nt’ s l a st vi sit).
9.
S T U D Y D O C U M E N T A TI O N, M O NI T O RI N G, A N D 
A D MI NI S T R A TI O N
9. 1 
S T U D Y D O C U M E N T A TI O N
T h e I n 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, i n cl u di n g b ut n ot li mit e d t o t h e pr ot o c ol, pr ot o c ol 
a m e n d m e nt s, I C F s, a n d d o c u m e nt ati o n of I R B/I E C a n d r e g ul at or y a p pr o v al. 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 I n v e sti g at or will r e c ei v e t h e p at i e 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 of all c h a n g e s t o d at a.
9. 2 
SI T E I N S P E C TI O N S
Sit e vi sit s will b e c o n d u ct e d b y t h e S p o n s or or a n a ut h ori z e d r e pr e s e nt ati v e f or 
i n s p e cti o n of st u d y d at a, p ati e nt s’ m e di c al r e c or d s, a n d e C R F s. T h e I n v e sti g at or will 
p er mit n ati o n al a n d l o c al h e alt h a ut h oriti e s, S p o n s or or it s d e si g n at e d 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 n d t h e I R B s/I E C s t o i n s p e ct f a ciliti e s a n d r e c or d s 
r el e v a nt t o t hi s st u d y.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 1 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
9. 3 
A D MI NI S T R A TI V E S T R U C T U R E
T hi s tri al i s c o- s p o n s or e d b y F. H off m a n n -L a R o c h e Lt d a n d C h u g ai P h ar m a c e uti c al 
C o., Lt d. (i n T ai w a n a n d J a p a n). P A R E X E L I nt er n ati o n al L L C will pr o vi d e cli ni c al 
o p er ati o n s o v er si g ht, d at a m a n a g e m e nt s u p p ort, st ati sti c al a n al y si s a n d M e di c al 
M o nit ori n g. T h e e C R F d at a wil l b e r e c or d e d vi a an E D C s y st e m. A n I x R S will b e u s e d 
f or st u d y dr u g i n v e nt or y, m a n a g e m e nt a n d t o r a n d o mi z e p ati e nt s t o st u d y dr u g. A n 
I D M C will b e s et u p t o m o nit or t h e s af et y of t h e st u d y.
9. 4  
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
T h e r e s ult s o f 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 m e eti n g s. If t hi s i s 
f or e s e e n, t h e I n v e sti g at or a gr e e s 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 p er t h e I n v e sti g at or’ s Cli ni c al R e s e ar c h A gr e e m e nt. T hi s 
all o w s t h e S p o n s or t o pr ot e ct pr o pri 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.
T h e S p o n s or will c o m pl y wit h t h e 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. I n 
a c c or d a n c e wit h s t 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 I n 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 al E dit or s 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 c o ntri b uti o n of 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 I n 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 o n n el.
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 fr o m t hi s st u d y 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 an 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.
9. 5 
P R O T O C O L A M E N D M E N T S
A n y pr ot o c ol a m e n d m e nt s will b e pr e p ar e d b y t h e S p o n s or. I n v e sti g at or s ar e 
r e s p o n si bl e f or pr o m ptl y i nf or mi n g t h e I R B/I E C of a n y a m e n d m e nt s t o t h e pr ot o c ol. 
A p pr o v al m u st b e o bt ai n e d fr o m t h e I R B/I E C b ef or e i m pl e m e nt ati o n of a n y c h a n g e s, 
e x c e pt 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 p ati e nt s or 
c h a n g e s t h at i n v ol v e l o gi sti c al or a d mi ni str ati v e a s p e ct s o nl y ( e. g. , c h a n g e i n M e di c al 
E x p ert or c o nt a ct i nf or m ati o n) .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 1 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
1 0. 
R E F E R E N C E S
Ar a ki M, Ar a n a mi T, M at s u o k a T et al. Cli ni c al i m pr o v e m e nt i n a p ati e nt wit h 
n e ur o m y eliti s o pti c a f oll o wi n g t h er a p y wit h t h e a nti -I L-6 r e c e pt or m o n o cl o n al 
a nti b o d y t o cili z u m a b. M o d R h e u m at ol 2 0 1 2; e p u b a h e a d of pri nt.
A y z e n b er g I, Kl eit er I, S c hr o d er , et al. I nt erl e u ki n 6 r e c e pt or bl o c k a d e i n p ati e nt s wit h 
n e ur o m y eliti s o pti c a n o nr e s p o n si v e t o a nti -C D 2 0 t h er a p y. J A M A N e ur ol 
2 0 1 3; 7 0: 3 9 4 -7.
C a m m A J a n d R eiff el J A. D efi ni n g e n d p oi nt s i n cli ni c al tri al s o n atri al fi brill ati o n. E ur 
H e art J 2 0 0 8; 1 0 s u p p H: H 5 5 -H 5 8.
C hi h ar a N, Ar a n a mi T, S at o W et al. I nt erl e u ki n 6 si g n ali n g pr o m ot e s a nti -a q u a p ori n 4 
a ut o a nti b o d y pr o d u cti o n fr o m pl a s m a bl a st s i n n e ur o m y eliti s o pti c a. Pr o c N atl 
A c a d S ci U S A 2 0 1 1; 1 0 8: 3 7 0 1 -6.
C o h e n J A, B ar k h of F, C o mi G et al. Or al fi n g oli m o d or i ntr a m u s c ul ar i nt erf er o n f or 
r el a p si n g m ulti pl e s cl er o si s. N e w E n gl J M e d 2 0 1 0; 3 6 2: 4 0 2-1 5.
C oll o n g u e s N, M ari g ni er R, Z e p hir H et al. L o n g -t er m f oll o w-u p of n e ur o m y eliti s o pti c a 
wit h a p e di atri c o n s et. N e ur ol o g y 2 0 1 0; 7 5: 1 0 8 4 -8 8.
C o s s b ur n M, T a c kl e y G, B a k er K et al. T h e pr e v al e n c e of n e ur o m y eliti s o pti c a i n 
S o ut h E a st W al e s. E ur J N e ur ol 2 0 1 2; 1 9: 6 5 5 -9.
E ur o p e a n U ni o n. Et hi c al c o n si d er ati o n s f or cli ni c al tri al s o n m e di ci n al pr o d u ct s 
c o n d u ct e d wit h t h e p a e di atri c p o p ul ati o n . E u dr a L e x V ol u m e 1 0 Cli ni c al tri al s 
g ui d eli n e s 2 0 0 8: C h a pt er V.
Gi o v a n n o ni G, C o mi G, C o o k S et al. A pl a c e b o -c o ntr oll e d tri al of or al cl a dri bi n e f or 
r el a p si n g m ulti pl e s cl er o si s. N e w E n gl J M e d 2 0 1 0; 3 6 2: 4 1 6-2 6.
G ol d R , K a p p o s L, Ar n ol d D L et al. Pl a c e b o-c o ntr oll e d p h a s e 3 st u d y of or al B G -1 2 f or 
r el a p si n g m ulti pl e s cl er o si s. N E n gl J M e d 2 0 1 2; 3 6 7: 1 0 9 8-1 0 7.
J a c o b A, M c K e o n A, N a k a s hi m a I et al. C urr e nt c o n c e pt of n e ur o m y eliti s o pti c a ( N M O) 
a n d N M O s p e ctr u m di s or d er s. J N e ur ol N e ur o s ur g P s y c hi atr y 2 0 1 2; e p u b a h e a d 
of  pri nt.
J ari u s S, R u pr e c ht K, Wi l d e m a n n B et al. C o ntr a sti n g di s e a s e p att er n s i n s er o p o siti v e 
a n d s er o n e g ati v e n e ur o m y eliti s o pti c a: A m ulti c e ntr e st u d y of 1 7 5 p ati e nt s. 
J N e ur oi nfl a m m ati o n 2 0 1 2; 9: 1 4.
K a p p o s L, R a d u e E W,  O' C o n n or P et al. A pl a c e b o -c o ntr oll e d tri al of or al fi n g oli m o d i n 
r el a p si n g m ulti pl e s cl er o si s. N E n gl J M e d 2 0 1 0; 3 6 2: 3 8 7-4 0 1.
K et el sl e g er s I A. I n ci d e n c e of a c q uir e d d e m y eli n ati n g s y n dr o m e s of t h e C N S i n D ut c h 
c hil dr e n: a n ati o n wi d e st u d y. J N e ur ol 2 0 1 2 ;2 5 9: 1 9 2 9 -3 5.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 1 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
Ki e s ei er B C, St u v e O, D e h m el T, et al. Di s e a s e a m eli or ati o n wit h t o cili z u m a b i n a 
tr e at m e nt-r e si st a nt p ati e nt wit h n e ur o m y eliti s o pti c a: i m pli c ati o n f or c ell ul ar 
i m m u n e r e s p o n s e s. J A M A N e ur ol 2 0 1 3; 7 0: 3 9 0-3.
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st at u s s c al e ( E D S S). N e ur ol o g y 1 9 8 3; 3 3: 1 4 4 4 -5 2.
L a n g er -G o ul d A, Z h a n g J L. I n ci d e n c e of a c q uir e d C N S d e m y eli n ati n g s y n dr o m e s i n a 
m ulti -et h ni c c o h ort of c hil dr e n. N e ur ol o g y 2 0 1 1 ;7 7: 1 1 4 3 -8.
L e n n o n V A, Kr y z er T J, Pitt o c k S J et al. I g G m ar k er of o pti c -s pi n al c or d m ulti pl e 
s cl er o si s bi n d s t o t h e a q u a p ori n -4 w at er c h a n n el. J E x p. M e d 2 0 0 5; 2 0 2: 4 7 3 -7.
L e n n o n V A, Wi n g er c h u k D M, Kr y z er T J et al. A s er u m a ut o a nti b o d y m ar k er of 
n e ur o m y eliti s o pti c a: di sti n cti o n fr o m m ulti pl e s cl er o si s. L a n c et 2 0 0 4; 3 6 4: 2 1 0 6 -
1 2.
L ot z e T E, N ort hr o p J L, H utt o n G J et al. S p e ctr u m of P e di atri c N e ur o m y eliti s O pti c a. 
P e di atri c s 2 0 0 8 ;1 2 2: e 1 0 3 9 -4 7.
M ari g ni er R, B er n ar d -V al n et R, Gir a u d o n P et al. A q u a p ori n -4 a nti b o d y -n e g ati v e 
n e ur o m y eliti s o pti c a: Di sti n ct a s s a y s e n siti vit y -d e p e n d e nt e ntit y. N e ur ol o g y 
2 0 1 3; 8 0: 2 1 9 4 -2 0 0.
O’ C o n n or P, W oli n s k y J, C o nf a cr e u x C et al. R a n d o mi z e d tri al of or al t erifl u n o mi d e f or 
r el a p si n g m ulti pl e s cl er o si s. N e w E n gl J M e d 2 0 1 1; 3 6 5: 1 2 9 3-3 0 3.
O h J, L e v y M.  N e ur o m y eliti s o pti c a: a n a nti b o d y-m e di at e d di s or d er of t h e c e ntr al 
n er v o u s s y st e m. N e ur ol R e s I nt 2 0 1 2 p u bli s h e d o nli n e.
S a m p s o n H A, M u ñ o z -F url o n g A, C a m p b ell R L et al. S e c o n d s y m p o si u m o n t h e 
d ef i niti o n a n d m a n a g e m e nt of a n a p h yl a xi s: s u m m ar y r e p ort--S e c o n d N ati o n al 
I n stit ut e of All er g y a n d I nf e cti o u s Di s e a s e/ F o o d All er g y a n d A n a p h yl a xi s 
N et w or k s y m p o si u m. J All er g y Cli n I m m u n ol 2 0 0 6; 1 1 7: 3 9 1 -7.
S ell n er J, B o g gil d M, Cl a n et M et al. E F N S g ui d eli n e s o n di a g n o si s a n d m a n a g e m e nt 
of  n e ur o m y eliti s o pti c a. E ur J N e ur ol 2 0 1 0; 1 7: 1 0 1 9 -3 2.
S or m a ni M P, Si g n ori A, Siri P et al. Ti m e t o fir st r el a p s e a s a n e n d p oi nt i n m ulti pl e 
s cl er o si s tri al s. M ult S cl er 2 0 1 3; 1 9: 4 6 6 -7 4.
T a k a h a s hi T, F uji h ar a K, N a k a s hi m a I et al. A nti -a q u a p ori n -4 a nti b o d y i s i n v ol v e d i n 
t h e p at h o g e n esi s of N M O: a st u d y o n a nti b o d y titr e. Br ai n 2 0 0 7; 1 3 0: 1 2 3 5 -4 3.
Till e m a J. M, M c K e o n A. T h e S p e ctr u m of N e ur o m y eliti s O pti c a ( N M O) i n C hil d h o o d. 
J o ur n al of C hil d N e ur ol o g y 2 0 1 2 ;2 7: 1 4 3 7 -4 7.
C e nt er s f or Di s e a s e C o ntr ol a n d Pr e v e nti o n . A nt hr o p o m etri c r ef er e n c e d at a f or 
c hil dr e n a n d a d ult s: U S 2 0 0 7 -2 0 1 0. 
htt p:// w w w. c d c. g o v/ n c h s/ d at a/ s eri e s/ sr _ 1 1/ sr 1 1 _ 2 5 2. p df


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 1 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
W e b st er K, C ell a D, Y o st K. T h e f u n cti o n al a s s e s s m e nt of c hr o ni c ill n e s s t h er a p y 
( F A CI T) m e a s ur e m e nt s y st e m: pr o p erti e s, a p pli c ati o n s, a n d i nt er pr et ati o n. 
H e alt h Q u al Lif e O ut c o m e s 2 0 0 3; 1: 7 9.
W e i n s h e n k er B G. N e ur o m y eliti s o pti c a i s di sti n ct fr o m m ulti pl e s cl er o si s. Ar c h N e ur ol 
2 0 0 7; 6 4: 8 9 9 -9 0 1.
Wi n gerc h u k D M, B a n well B, Be n nett J L et al. I nter n ati o n al c o nse ns us di a g n ostic 
criteri a f or ne ur o m yelitis o pti c a s pectr u m dis or ders. Ne ur ol o g y 2 0 1 5; 8 5: 1 7 7-8 9.
Wi n g er c h u k D M, L e n n o n V A, Pitt o c k S J, et al. R e vi s e d di a g n o sti c crit eri a f or 
n e ur o m y eliti s o pti c a. N e ur ol o g y 2 0 0 6; 6 6: 1 4 8 5 -9.
Wi n g er c h u k D M, L e n n o n V A, L u c c hi n etti C F, et al. T h e s p e ctr u m of n e ur o m y eliti s 
o pti c a . L a n c et N e ur ol 2 0 0 7; 6: 8 0 5-1 5. 
Z arit S H, R e e v er K E, B a c h -P et er s o n J. R el ati v e s of t h e i m p air e d el d erl y: c orr el at e s of 
f e eli n g s of b ur d e n. G er o nt ol o gi st 1 9 8 0; 2 0: 6 4 9-5 5 .






A p p e n di x 1:
S c h e d ul e of A cti viti e s ( c o nt.)
T a bl e 6 :  O b s er v ati o n a n d T e st S c h e d ul e i n t h e S cr e e ni n g P eri o d a n d t h e D o u bl e -Bli n d P eri o d ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 1 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
e) O nl y  E D S S i s c o n d u ct e d.
f) Bl o o d s a m pl e f or pl a s m a bl a st s will b e c oll e ct e d i n U nit e d Ki n g d o m, Fr a n c e, G er m a n y, J a p a n a n d T ai w a n .
g) F or f e m al e s of c hil d -b e ari n g p ot e nti al. S er u m β -h C G m u st b e p erf or m e d at s cr e e ni n g. D uri n g t h e st u d y, s er u m or uri n e [ s e n siti vit y of at l e a st 
2 5 mI U/ m L] β -h C G will b e p erf or m e d. F or p ati e nt s a g e d 1 2 t o 1 7 at t h e ti m e of i nf or m e d c o n s e nt, uri n e β -h C G will b e r e c o m m e n d e d ( s e e 
A p p e n di x 1 3 ).
h) P ati e nt s w h o ar e cl a s sifi e d a s P M L or M S m u st b e e x cl u d e d. If P M L c a n n ot b e r ul e d o ut, J C vir u s i n t h e c er e br o s pi n al fl ui d ( C S F) will b e 
m e a s ur e d.
i) W B C, A N C, A L C, P L T, A S T, A L T.
j) B o d y t e m p er at ur e, s y st oli c a n d di a st oli c bl o o d pr e s s ur e a n d p ul s e r at e ar e m e a s ur e d j u st b ef or e d o si n g a n d 1 5 mi n ( ± 5 mi n) a n d 6 0 mi n ( ± 5 
mi n) aft er d o si n g i n c a s e of st u d y dr u g i nj e cti o n vi sit.
k) T B t e st ( e. g., t u b er c uli n t e st a n d/ or Q u a ntif er o nt e st) s h o ul d b e c o n d u ct e d a c c or di n g a s l o c al g ui d a n c e.
l) T h e c o pi e s of E C G c h art s h o ul d b e c oll e ct e d f or o nl y  p ati e nt s w h o o bt ai n e d i nf or m e d c o n s e nt t o a d diti o n al P K s a m pli n g.
m) Vi s u al f u n cti o n t e sti n g i s n ot r e q uir e d if it i s i m pl e m e nt e d wit h F S S a s s e s s m e nt.
n) E C G s h o ul d b e p erf or m e d pri or t o bl o o d dr a w s.
o) Wi n d o w i n d a y s i s wit hi n ± 2 8 d a y s.
p) Z BI i s o pti o n al a n d will b e p erf or m e d f or c ar e gi v er w h o si g n e d i nf or m e d c o n s e nt t o c ar e gi v er b ur d e n a s s e s s m e nt.
q) H e p atiti s B vir al D N A m u st b e m e a s ur e d i n p a ti e nt s f or w h o m a p o siti v e r e s ult f or H B s A b i s n ot cl e arl y a s s o ci at e d wit h v a c ci n ati o n a g ai n st 
h e p atiti s B vir u s or w h o m H B c A b i s p o siti v e at s cr e e ni n g.
r) H e p atiti s B vir al D N A m u st b e m o nit or e d i n p ati e nt s f or w h o m a p o siti v e r e s ult f or H B s A b i s n ot cl e a rl y a s s o ci at e d wit h v a c ci n ati o n a g ai n st 
h e p atiti s B vir u s a n d H B V D N A i s n e g ati v e at s cr e e ni n g or w h o m H B c A b i s p o siti v e a n d H B V D N A i s n e g ati v e at s cr e e ni n g.
s) A nti -A Q P 4 a nti b o d y at s cr e e ni n g will b e m e a s ur e d o nl y b y  E LI S A a s an e x pl or at or y  bi o mar k er. Ot h er p oi nt s will b e m e a s ur e d b y c ell -b a s e d 
a s s a y a n d/ o r E LI S A a s a P D m ar k er .
t) F or p ati e nt s a g e d 1 2 t o 1 7 at t h e ti m e of i nf or m e d c o n s e nt, t h e g ui d a n c e pr o vi d e d i n A p p e n di x 1 3 s h o ul d b e c o n si d er e d.
u) I nf or m e d c o n s e nt m u st b e o bt ai n e d pri or t o fir st s cr e e ni n g a s s e s s m e nt, b ut if i nf or m e d c o n s e nt i s o bt ai n e d b ef or e t h e 2 8-d a y s cr e e ni n g 
p eri o d (i. e. , b ef or e D a y -2 7), all s cr e e ni n g a s s e s s m e nt s m u st b e c o m pl et e d wit hi n 2 8 d a y s pri or t o b a s eli n e (i. e. , fr o m D a y -2 7 t o 0). If fir st 
s cr e e ni n g a s s e s s m e nt i s n ot p erf or m e d wit hi n 3 m o nt h s fr o m t h e d a y i nf or m e d c o n s e nt i s o bt ai n e d, r e -c o n s e nt i s n e e d e d pri or t o all 
s cr e e ni n g a s s e s s m e nt.






A p p e n di x 1:
S c h e d ul e of A cti viti e s ( c o nt.)
T a bl e 6 :  O b s er v ati o n a n d T e st S c h e d ul e i n t h e S cr e e ni n g P eri o d a n d t h e D o u bl e -Bli n d P eri o d ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 2 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
n) H e p atiti s B vir al D N A m u st b e m o nit or e d i n p ati e nt s f or w h o m a p o siti v e r e s ult f or H B s A b i s n ot cl e arl y a s s o ci at e d wit h v a c ci n ati o n a g ai n st 
h e p atiti s B vir u s a n d H B V D N A i s n e g ati v e at s cr e e ni n g or w h o m H B c A b i s p o siti v e a n d H B V D N A i s n e g ati v e at s cr e e ni n g.
o) E v er y 1 2 w e e k s.
p) F or p ati e nt s a g e d 1 2 t o 1 7 at t h e ti m e of i nf or m e d c o n s e nt, t h e g ui d a n c e pr o vi d e d i n A p p e n di x 1 3 s h o ul d b e c o n si d er e d.
q) I n t h e e v e nt t h at t h e st u d y dr u g i s n ot a d mi ni st er e d wit hi n t h e s c h e d ul e d vi sit wi n d o w a n d i s s u b s e q u e ntl y a d mi ni st er e d o ut si d e t h e vi sit 
wi n d o w . Mi ni mu m  d o si n g i nt er v al s h o ul d b e 1 4 d a ys.
r) 
For p ati e nt s a g e d 1 2 t o 1 7 y e ar s at t h e ti m e of i nf or m e d c o n s e nt w h o wit h dr a w fr o m t h e st u d y , F oll o w-U p A s s e s s m e nt f or A d ol e s c e nt s
( F U A A) wi ll b e c o n d u ct e d at 1 2 ( WD vi sit), 2 4 a n d 4 8 w e e k s aft er t h e l a st d o s e of st u d y dr u g.






A p p e n di x 1:
S c h e d ul e of A cti viti e s ( c o nt.)
T a bl e 7:  O b s er v ati o n a n d T e st S c h e d ul e i n t h e E xt e n si o n P eri o d ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 2 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
e) F or p ati e nt s w h o wit h dr a w fr o m t h e st u d y. E v er y eff ort s h o ul d b e m a d e t o c o n d u ct t h e vi sit at 1 2 w e e k s aft er t h e l a st d o s e of s atr ali z u m a b .
P ati e nt s a g e d 1 2 t o 1 7 y e ar s at t h e ti m e of i nf or m e d c o n s e nt w h o wit h dr a w fr o m t h e st u d y  will att e n d WD vi sit at 1 2 w e e k s ( ± 7 d a y s) aft e r 
l a st d o s e of s atr ali z u m a b f or F U A A.
f) Wi n d o w i n d a y s i s wit hi n ± 2 8 d a y s.
g) Vi s u al f u n cti o n t e sti n g i s n ot r e q uir e d if it i s i m p l e m e nt e d wit h F S S a s s e s s m e nt.
h) E C G s h o ul d b e p erf or m e d pri or t o bl o o d dr a w s.
i) F or t h e p ati e nt s w h o will e nt er t h e e xt e n si o n p eri o d ( s e e S e cti o n 4. 3. 2. 2 ), t h e pati e nt s w h o ar e tr e at e d r e s c u e t h er a p y i n t h e d o u bl e-bli n d 
p eri o d c a n e nt er t h e e xt e n si o n p eri o d aft er r e s c u e t h er a p y f or r el a p s e, b et w e e n D a y 3 1 t o D a y 6 0, d efi ni n g t h e d a y of o n s et of  r el a p s e i n t h e 
d o u bl e -bli n d p eri o d a s D a y 1. T h e p ati e nt s w h o ar e n ot tr e at e d wit h r e s c u e t h er a p y d uri n g t h e d o u bl e -bli n d p eri o d c a n e nt er t h e e xt e n si o n 
p eri o d aft er 4 w e e k s ( ± 7 d a y s) fr o m t h e l a st d o si n g i n t h e d o u bl e-bli n d p eri o d. F or a d ol e s c e nt s w h o ar e e nr oll e d i nt o t h e e xt e n si o n p eri od 
af t er t h e e n d of t h e d o u bl e-bli n d p eri o d, t hi s vi sit i s b a s eli n e.
j) Z BI i s o pti o n al a n d will b e p erf or m e d f or c ar e gi v er w h o si g n e d i nf or m e d c o n s e nt t o c ar e gi v er b ur d e n a s s e s s m e nt.
k) B o d y t e m p er at ur e, s y st oli c a n d di a st oli c bl o o d pr e s s ur e a n d p ul s e r at e ar e m e a s ur e d j u st b ef or e d o si n g a n d 1 5 mi n ( ± 5 mi n) a n d 6 0 mi n ( ± 5 
mi n) aft er d o si n g i n c a s e of st u d y dr u g i nj e cti o n vi sit.
l) H e p atiti s B vir al D N A m u st b e m o nit or e d i n p ati e nt s f or w h o m a p o siti v e r e s ult f or H B s A b i s n ot cl e arl y a s s o ci at e d wit h v a c ci n ati o n a g ai n st 
h e p atiti s B vir u s a n d H B V D N A i s n e g ati v e at s cr e e ni n g or w h o m H B c A b i s p o siti v e a n d H B V D N A i s n e g ati v e at s cr e e ni n g.
m) E v er y 1 2 w e e k s.
n) F or p ati e nt s a g e d 1 2 t o 1 7 at t h e ti m e of i nf or m e d c o n s e nt, t h e g ui d a n c e pr o vi d e d i n A p p e n di x 1 3 s h o ul d b e c o n si d er e d .
o) I n t h e e v e nt t h at t h e st u d y dr u g i s n ot a d mi ni st er e d wit hi n t h e s c h e d ul e d vi sit wi n d o w a n d i s s u b s e q u e ntl y a d mi ni st er e d o ut si d e t h e vi sit 
wi n d o w. Mi ni m u m  d o si n g i nt er v al s h o ul d b e 1 4 d a ys.
p) F or p ati e nt s a g e d 1 2 t o 1 7 y e ar s at t h e ti m e of i nf or m e d c o n s e nt w h o wit h dr a w fr o m t h e st u d y or c o m pl et e e xt e n si o n p eri o d, F U A A wi ll b e 
c o n d u ct e d at 1 2 ( W D vi sit f or p ati e nt wit h dr a w n), 2 4 a n d 4 8 w e e k s aft er t h e l a st d o s e of s atr ali z u m a b .
q) U ntil w e e k 4 8 .
r) Af t er w e e k 4 8.
s) O nl y  f or a d ol e s c e nt s w h o ar e e nr oll e d i nt o t h e e xt e n si o n p eri o d af t er t h e e n d of t h e d o u bl e-bli n d p eri o d .
t) O nl y  f or p ati e nt s w h o e x p eri e n c e a r el a p s e w hi c h i s tr e at e d wit h r e s c u e t h er a p y a n d/ or a pr ot o c ol -d efi n e d r el a p s e w hi c h i s a dj u di c at e d b y 
C E C i n t h e d o u bl e -bli n d p eri o d or w h o c o m pl et e t h e d o u bl e -bli n d p eri o d .
u) Wi n d o w i n d a y s i s wit hi n ± 2 8 d a y s f or p ati e nt s w h o e x p eri e n c e a r el a p s e, w hi c h i s tr e at e d wit h r e s c u e t h er a p y , a n d/ or a pr ot o c ol -d efi n e d 
r el a p s e, w hi c h i s a dj u di c at e d b y C E C i n t h e d o u bl e -bli n d p eri o d or w h o c o m pl et e t h e d o u bl e -bli n d p eri o d.
v)
I n t he O L E peri o d after Wee k 4 8, i n a c c or d a n ce wit h l o c al re g ul ati o ns, a d mi nistr ati o n of s atr ali z u m a b prefille d s yri n ges o utsi de of t he 
st u d y site (e. g., self -a d mi nistr ati o n or a d mi nistr ati o n b y a c are gi ver after c o m pleti n g tr ai ni n g, a d mi nistr ati o n b y t he p atie nt’s [l o c al] 


A p p e n di x 1:
S c h e d ul e of A cti viti e s ( c o nt.)
T a bl e 7:  O b s er v ati o n a n d T e st S c h e d ul e i n t h e E xt e n si o n P eri o d ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 2 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
ge ner al p h ysi ci a n, or h o me a d mi nistr ati o n b y a m o bile n urse) will be all o we d i n e mer ge n c y sit u ati o ns s u c h as t he S A R S -C o V -2 ( C O VI D 
1 9) p a n de mi c.
w) If p atie nts c a n n ot p h ysi c all y atte n d a visit at t he st u d y site i n e mer ge n c y sit u ati o ns s u c h as t he S A R S -C o V -2 ( C O VI D -1 9) p a n de mi c, all 
eff orts s h o ul d be m a de t o f oll o w u p w it h p atie nts ar o u n d t he ti me of t he s c he d ule d visit b y p h o ne t o c olle ct a n y i nf or m ati o n o n s afet y 
a n d/ or ne ur ol o gi c al w orse ni n g t he p atie nt mi g ht e x perie n ce a n d t o c o nfir m p atie nt c o m pli a n ce wit h st u d y tre at me nt.  A n y iss ue s 
o c c urri n g d uri n g t he d osi n g per i o d o utsi de of t he st u d y site s h o ul d be re p orte d.
x) F oll o wi n g t he i m ple me nt ati o n of Pr ot o c ol Versi o n 1 1 a n d i n a c c or d a n ce wit h l o c al re g ul ati o ns, a d mi nistr ati o n of s atr ali z u m a b o utsi de of 
t he st u d y site c a n be i m ple me nte d.  P atie nts will be f oll o we d u p b y st u d y site pers o n nel t hr o u g h p h o ne c alls t o m o nit or c o m pli a n ce a n d 
perf or m s afet y assess me nts.
A b br e vi ati o n s: 
A L P al k ali n e p h o s p h at a s e: A L T al a ni n e a m i n otr a n sf er a s e; A N Ca b s ol ut e n e utr o p hil c o u nt; A Q P 4 A q u a p ori n -4; A S T A s p art at e 
a m i n otr a n sf er a s e; B LB a s eli n e; B U N bl o o d ur e a nitr o g e n; C K cr e ati n e ki n a s e; C- S S R S C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e ; 
D B P di a st oli c bl o o d pr e s s ur e; D N A d e o x y ri b o n u cl ei c a ci d; DO W d o s e o ut si d e t h e vi sit wi n d o w ; E C Gel e ctr o c ar di o gr a 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 CI T F u n cti o n al A s s e s s m e nt of C hr o ni c Ill n e s s T h er a p y; F S S f u n cti o n al st at u s s c al e; F U A A F oll o w -U p 
A s s e s s m e nt f or A d ol e s c e nt s ; γ- G T P g a m m a gl ut a m yl tr a n s p e pti d a s e; H b h e m o gl o bi n; h C G H u m a n c h ori o ni c g o n a d otr o pi n; H C T h e m at o crit ; 
H B s A g H e p atiti s B s urf a c e a nti g e n; H B c A b T ot al h e p atiti s B c or e a nti b o d y; H B s A b A nti b o d y t o 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 C V A b H e p atiti s C a nti b o d y; H D L hi g h -d e n sit y  li p o pr ot ei n; h s C R Phi g h -s e n siti vit y C- r e a cti v e pr ot ei n; I L- 6 I nt erl e u ki n-6; 
I N Ri nt er n ati o n al n or m ali z e d r ati o; I UI nt er n ati o n al U nit s; L D H l a ct at e d e h y dr o g e n a s e; L D Ll o w-d e n sit y li p o pr ot ei n; M RI m a g n eti c 
r e s o n a n c e i ma gi n g; m R S m o difi e d R a n ki n S c al e; N M O n e ur o m y e liti s o pti c a; N M O S Dn e ur o m y e liti s o pti c a s p e ctr u m di s or d er; 
P K p h ar m a c o ki n eti c s; P L T pl at el et; sI L -6 R s ol u bl e I L -6 r e c e pt or; S B P s y st oli c bl o o d pr e s s ur e; S C s u b c ut a n e o u s; S F -3 6 S h ort F or m 
g e n eri c h e alt h s ur v e y; S F U S af et y  f oll o w-u p; T B t u b er c ul o si s; V A Svi s u al a n al o g u e s c al e; W B C W h it e bl o o d c ell; WD Wi t h dr a w al; 
Z BI Z arit B ur d e n I nt er vi e w .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 2 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 2
E D S S/ F S S A s s e s s m e nt F or m
 
  
  
  
  
 
 
 
  
  
  
    
  
  
  
  
 
 
  
  
  
    
  
  
  
    
 
  
  
  
    
  
  
  
  
  
   
 
    
 
  
    
  
  
  
  
  
      
 
 
  
  
  
  
  
  
 
 
        
 
  
    
 
 
  
  
 
 
   
  
 
  
    
 
 
 
 
 
 
  
  
    
        
  
 
 
 
 
  
  
  
  
    
  
  
  
    
  
 
 
  
 
   
 
 
 
    
       
 
  
    
        
 
 
  
  
 
  
  
  
  
  
  
    
  
 
  
  
  
 
 
 
 
    
   
   
 
 
 
  
  
  
 
 
  
  
 
 
  
  
    
  
  
 
 
 
 
  
  
  
  
  
  
 
 
  
  
 
 
    
  
  
 
  
  
  
 
 
  
    
  
 
 
 
  
  
  
  
  
 
 
  
  
    
   
 
 
 
 
  
  
  
 
 
  
  
    
  
  
 
  
  
  
  
 
 
  
  
 
 
  
  
  
  
  
  
  
    
 
  
  
  
 
 
    
  
  
  
 
  
  
 
  
  
  
    
  
   
  
 
 
 
  
  
 
 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
    
  
 
  
  
  
 
  
  
  
    
  
   
  
 
 
 
  
  
  
  
  
  
  
 
 
    
  
  
  
  
  
  
    
  
 
  
  
    
  
  
 
 
  
 
  
  
  
 
  
  
  
  


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 2 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
  
  
  
  
  
  
    
  
 
 
 
  
  
 
 
  
 
  
  
  
  
 
 
 
 
 
    
  
 
    
  
  
  
  
  
   
  
 
   
  
  
  
  
  
  
  
   
  
  
  
    
  
  
 
  
 
  
  
  
 
  
  
  
  
  
  
  
    
 
 
    
  
  
    
  
  
   
  
  
  
    
 
  
  
  
  
 
 
  
 
    
  
  
  
  
 
  
  
 
  
 
  
  
  
  
 
 
  
 
 
  
    
 
 
 
 
   
  
  
 
 
 
 
  
  
 
 
  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
 
  
  
 
 
 
  
 
 
  
    
  
 
 
  
  
  
  
 
 
  
  
 
  
  
 
 
  
 
  
  
  
 
 
 
  
  
  
 
  
  
  
  
 
  
 
  
  
  
 
 
  
  
  
  
 
 
  
   
  
  
 
  
 
  
    
  
 
 
  
 
 
 
  
  
  
   
    
  
  
    
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
  
  
  
    
  
  
  
 
 
   
  
  
 
    
  
  
  
 
 
 
 
  
  
  
  
  
  
  
  
 
   
    
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
 
    
  
  
  
  
  
  
  
 
  
 
  
 
  
  
  
  
  
 
 
  
  
  
  
  
  
  
 
  
   
 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 2 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
 
 
 
 
  
  
  
 
  
 
 
 
  
  
  
 
  
  
 
    
 
   
 
  
  
  
 
  
  
  
  
  
    
  
 
  
 
  
 
 
 
 
  
    
  
 
 
    
  
  
 
 
  
  
  
   
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
 
  
  
  
 
 
 
  
  
  
 
  
 
 
  
 
 
  
  
    
 
  
  
  
 
 
  
 
  
  
  
  
  
 
 
  
 
  
    
 
 
  
  
 
 
 
 
  
  
  
  
  
   
 
  
  
  
  
 
 
  
 
 
  
  
 
 
 
 
  
  
 
 
  
 
  
    
  
 
 
 
  
 
  
    
  
  
 
  
  
 
 
 
 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
 
  
 
 
   
  
  
    
 
 
  
 
  
    
    
    
  
  
  
  
   
    
 
 
  
    
  
  
  
  
  
  
 
 
  
 
 
  
  
    
 
 
  
  
  
  
 
    
 
 
  
    
  
  
    
  
  
 
     
  
    
 
 
  
 
  
  
    
 
 
    
 
 
  
    
 
 
    
  
 
 
  
    
    
  
  
 
  
    
  
  
  
 
 
 
 
  
    
  
 
 
  
  
 
  
  
  
 
 
  
  
 
 
  
  
  
  
 
 
  
  
  
  
  
 
 
  
  
  
 
 
 
  
 
 
  
  
  
  
 
 
 
 
  
  
  
  
 
 
 
  
   
  
 
 
    
 
 
  
 
 
 
  
 
    
 
 
 
  
 
 
 
  
  
 
 
 
 
 
  
 
  
  
  
 
 
   
  
 
  
 
 
  
 
  
 
 
  
  
  
 
 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T h e a ct u al f or m s will b e pr o vi d e d t o t h e sit e s a n d s h o ul d b e u s e d f or a s s e s s m e nt .
 
 
 
  
 
 
 
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
 
 
 
  
  
  
  
 
 
  
    
  
  
  
 
  
 
 
 
 
  
  
  
  
 
 
  
  
  
  
  
 
 
 
 
  
  
  
 
 
  
 
 
 
  
 
 
  
  
  
  
  
 
  
  
 
 
  
 
  
 
 
  
 
 
 
 
 
  
  
  
  
 
 
  
 
 
 
  
 
 
 
 
 
  
  
  
  
 
 
  
 
 
 
  
 
 
 
 
  
  
  
  
  
  
 
  
  
  
 
 
  
  
 
  
    
  
  
 
 
    
  
 
 
 
 
 
   
  
  
 
 
    
  
  
  
  
  
  
 
 
  
 
  
 
 
  
  
  
  
  
    
 
 
  
 
 
  
 
  
  
  
 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 3
S F -3 6 Q u e sti o n n air e
T hi s s ur v e y a s k s f or y o ur vi e w s a b o ut y o ur h e alt h. T hi s i nf or m ati o n will h el p k e e p 
tr a c k of h o w y o u f e el a n d h o w w ell y o u ar e a bl e t o d o y o ur u s u al a cti viti e s. T h a n k y o u 
f or c o m pl eti n g t hi s s ur v e y!
F or e a c h of t h e f oll o wi n g q u e sti o n s, pl e a s e ti c k t h e o n e b o x t h at b e st d e s cri b e s y o ur 
a n s w er.
1.
I n g e n er al, w o ul d y o u s a y y o ur h e alt h i s:
2.
C o m p ar e d t o o n e y e ar a g o, h o w w o ul d y o u r at e y o ur h e alt h i n g e n er al n o w ?
3.
T h e f oll o wi n g q u e sti o n s ar e a b o ut a cti viti e s y o u mi g ht d o d uri n g a t y pi c al d a y.
D o e s y o ur h e alt h n o w li mit y o u i n t h e s e a cti viti e s ? If s o, h o w m u c h ?
4.
D uri n g t h e p a st 4 w e e k s, h o w m u c h of t h e ti m e h a v e y o u h a d a n y of t h e f oll o wi n g 
pr o bl e m s wit h y o ur w or k or ot h er r e g ul ar d ail y a cti viti e s a s a r e s ult of y o ur p h y si c al 
h e alt h
5.
D uri n g t h e p a st 4 w e e k s , h o w m u c h of t h e ti m e h a v e y o u h a d a n y of t h e f oll o wi n g 
pr o bl e m s wit h y o ur w or k or ot h er r e g ul ar d ail y a cti viti e s a s a r e s ult of a n y 
e m oti o n al pr o bl e m s ( s u c h a s f e eli n g d e pr e s s e d or a n xi o u s) ?
6.
D uri n g t h e p a st 4 w e e k s, t o w h at e xt e nt h a s y o ur p h y si c al h e alt h or e m oti o n al 
pr o bl e m s i nt erf er e d wit h y o ur n or m al s o ci al a cti viti e s wit h f a mil y, fri e n d s, 
n ei g h b o ur s or gr o u p s ?
7.
H o w m u c h b o dil y p ai n h a v e y o u h a d d uri n g t h e p a st 4 w e e k s ?
8.
D uri n g t h e p a st 4 w e e k s, h o w m u c h di d p ai n i nt erf er e wit h y o ur n or m al w or k 
(i n cl u din g b ot h w or k o ut si d e t h e h o m e a n d h o u s e w or k) ?
9.
T h e s e q u e sti o n s ar e a b o ut h o w y o u f e el a n d h o w t hi n g s h a v e b e e n wit h y o u 
d uri n g t h e p a st 4 w e e k s. F or e a c h q u e sti o n, pl e a s e gi v e t h e o n e a n s w er t h at 
c o m e s cl o s e st t o t h e w a y y o u h a v e b e e n f e eli n g. H o w m u c h of t h e ti m e d uri n g t h e 
p a st 4 w e e k s …
1 0. D uri n g t h e p a st 4 w e e k s, h o w m u c h of t h e ti m e h a s y o ur p h y si c al h e alt h or 
e m oti o n al pr o bl e m s i nt erf er e d wit h y o ur s o ci al a cti viti e s (li k e vi siti n g wit h fri e n d s, 
r el ati v e s, et c.) ?
1 1. H o w T R U E or F A L S E i s e a c h of t h e f oll o wi n g s t at e m e nt s f or y o u ?
T h e a ct u al f or m s will b e pr o vi d e d t o t h e sit e s a n d s h o ul d b e u s e d f or a s s e s s m e nt .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 4
Vi s u al A n al o g u e S c al e f or P ai n
T h e a ct u al f or m s will b e pr o vi d e d t o t h e sit e s a n d s h o ul d b e u s e d f or a s s e s s m e nt .




S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 6
M o difi e d R a n ki n S c al e
T h e a ct u al f or m s will b e pr o vi d e d t o t h e sit e s a n d s h o ul d b e u s e d f or a s s e s s m e nt .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 7
Z arit B ur d e n I nt er vi e w
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


A p p e n di x 7:
Z arit B ur d e n I nt er vi e w ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T h e a ct u al f or m s will b e pr o vi d e d t o t h e sit e s a n d s h o ul d b e u s e d f or a s s e s s m e nt .


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 8
E ur o Q ol -5 D (E Q -5 D )
 
 
 
  
  
  
 
 
  
  
 
 
 
 
  
    
 
 
 
 


A p p e n di x 8:
E ur o Q ol -5 D ( E Q -5 D) ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 3 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
    
 
 
  
 
 
  
  
  
  
  
  
 
  
  
 
 
  
 
 
 
  
  
  
    
  
 
  
  
  
    
  
 
  
  
    
 
 
  
  
  
  
  
 
  
  
  
  
 
 
  
 
  
  
    
 
 
  
 
  
  
  
   
 
  
 
 
  
 
 
 
 
 
 
 
  
  
  
  
 
  
  
  
 
 
  
  
  
  
  
  
  
  
 
 
  
  
    
  
  
  
 
 
 
  
  
  
 
 
 
  
  
  
    
 
  
  
  
    
 
 
  
  
  
    
 
  
 
  
    
 
  
  
  
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 








S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 4 3 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 1 0
C- S S R S at B a s eli n e
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
  
 
 
  
  
  
  
  
 
 
  
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
   
 
 
   
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
  
   
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
    
 
 
   
 
 
 
    
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
  
  
 
 


A p p e n di x 1 0:   C- S S R S at B a s eli n e ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 4 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
  
  
 
 
 
 
   
 
  
 
   
     
  
 
 
   
 
  
    
  
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
  
 
 
  
 
 
  
  
 
 
  
  
 
 
 
 
 
  
 
 
   
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
      
 
 
 
 
  
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
   
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
   
  
 
 
 
  
 
 


A p p e n di x 1 0:   C- S S R S at B a s eli n e ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 4 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T h e a ct u al f or m s will b e pr o vi d e d t o t h e sit e s a n d s h o ul d b e u s e d f or a s s e s s m e nt .
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
    
 
 
  
 
 
 
   
   
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
   
 
 
 
  
 
 
  
 
  
    
  
  
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
   
 
 
 
 
   
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
   
 
 
 
 
  
 
  
 
 
 
   
  
  
 
 
 
 
 
 
 
 
 
 
 
    
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
  
 
 
  
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
   
  
  
 
 
  
  
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
  
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 4 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 1 1
C- S S R S s i n c e L a st V i sit
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
  
  
 
 
  
   
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
   
   
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
 
  
  
 
 
 
  
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 


A p p e n di x 1 1:   C- S S R S si n c e L a st Vi sit ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 4 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
 
  
  
   
 
 
 
  
 
 
   
 
  
 
  
      
  
  
 
 
  
  
  
 
 
 
 
 
 
  
  
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
  
   
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
  
 
   
  
 
  
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
   
    
  
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 


A p p e n di x 1 1:   C- S S R S si n c e L a st Vi sit ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 4 8 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T h e a ct u al f or m s will b e pr o vi d e d t o t h e sit e s a n d s h o ul d b e u s e d f or a s s e s s m e nt .
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
  
 
 
   
  
 
  
 
  
  
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
   
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
   
 
 
  
 
 
  
  
 
 
 
  
 
 
 
 
 
 
     
 
 
 
 
 
 
 
   
 
 
  
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
  
 
   
 
 
  
   
 
  
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
  
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
  
 
   
 
   
 
 
 
 
 
  
 
 
   
 
 


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 4 9 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 1 2
C- S S R S A lr e a d y Enr oll e d S u bj e ct s
 
 
 
 
 
  
  
 
  
 
    
  
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
    
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
    
 
 
   
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 


A p p e n di x 1 2:   C- S S R S Al r e a d y E nr oll e d S u bj e ct s ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 5 0 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1


A p p e n di x 1 2:   C- S S R S Al r e a d y E nr oll e d S u bj e ct s ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 5 1 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T h e a ct u al f or m s will b e pr o vi d e d t o t h e sit e s a n d s h o ul d b e u s e d f or a s s e s s m e nt.


S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 5 2 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 1 3
T h e G ui d a n c e f or B l o o d S a m pli n g
F or p ati e nt s a g e d 1 2 t o 1 7 at t h e ti m e of i nf or m e d c o n s e nt, bl o o d s a m pli n g 
s h o ul d b e p erf or m e d i n a c c or d a n c e wit h t h e f oll o wi n g  E M A  g ui d eli n e s - Et hi c al 
c o n si d er ati o n s f or Cli ni c al Tri al s o n M e di ci n al pr o d u ct s c o n d u ct e d wit h t h e 
P a e di atri c p o p ul ati o n, 2 0 0 8.
A s p er t h e a b o v e g ui d eli n e, t h e t ot al bl o o d l o s s p er i n di vi d u al at a n y si n gl e ti m e 
s h o ul d n ot e x c e e d 1 % of t h e t ot al bl o o d v ol u m e, w h er e t ot al bl o o d v ol u m e i s 
e sti m at e d at 8 0 t o 9 0 m L / k g b o d y w ei g ht. I n a d diti o n, t ot al bl o o d v ol u m e wit h dr a w n 
o v er a p eri o d of f o ur w e e k s s h o ul d n ot e x c e e d 3 % of t ot al bl o o d v ol u m e, w hi c h 
e sti m at e s t o 2. 4 m L
bl o o d p er k g of b o d y w ei g ht.
Bl o o d s a m pli n g at e a c h si n gl e vi sit
T ot al bl o o d v ol u m e t a k e n at e a c h si n gl e vi sit i s r e c o m m e n d e d t o b e s ati sf i e d wit h t h e 
f oll o wi n g crit erio n.
T ot al bl o o d v ol u m e at e a c h si n gl e vi sit ( m L) ≤ B o d y  w ei g ht ( k g) × 0. 8 ( m L/ k g)
F or e x a m pl e, if t h e b o d y w ei g ht i s 4 0 k g, t h e t ot al a m o u nt of bl o o d wit h dr a w al at a n y 
si n gl e vi sit s h o ul d n ot e x c e e d 3 2 m L.
Bl o o d s a m pli n g f or 4 w e e k s
T ot al bl o o d v ol u m e t a k e n f or 4 w e e k s i s r e c o m m e n d e d t o b e s ati sfi e d wit h t h e 
f oll o wi n g crit erio n .
T ot al bl o o d v ol u m e f or 4 w e e k s ( m L) ≤ B o d y w ei g ht ( k g) × 2. 4 ( m L/ k g)
F or e x a m pl e, if t h e b o d y w ei g ht i s 4 0 k g, t h e t ot al a m o u nt of bl o o d wit h dr a w al f or
4 w e e k s s h o ul d n ot e x c e e d 9 6 m L.
If t h e t ot al a m o u nt of bl o o d wit h dr a w al r e q uir e d i s m or e t h a n t h e p er mi s si bl e v ol u m e
s h o w n a b o v e , t h e n t h e bl o o d s a m pl e c oll e cti o n s h o ul d b e a dj u st e d a s p er t h e 
f oll o wi n g re c o m m e n d e d or d e r of pri orit y a c c or di n g l y i n a n a s c e n di n g or d er of t h e 
n u m b er (i. e. , “i” s h o ul d b e c on si d er e d fir st ).




S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 5 4 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
A p p e n di x 1 4
In str u cti o n f or T u b er c ul o si s ( T B) Scr e e ni n g a n d T r e at m e nt
I nt er pr et ati o n of T B s cr e e ni n g r e s ult s
I m m u n o s u p pr e s s a nt bi ol o gi c tr e at m e nt s h a v e b e e n s h o w n t o i n cr e a s e t h e ri s k of 
t u b er c ul o si s ( T B) i nf e cti o n or t o c a u s e c o n v er si o n fr o m l at e nt t o a cti v e T B i n s o m e 
cir c u m st a n c e s. B e c a u s e of t hi s, p ati e nt s m u st b e s cr e e n e d f or a cti v e or l at e nt T B pri or 
t o e ntr y t o t hi s st u d y.
D efi niti o n s
A cti v e T B i s a di s e a s e c a u s e d b y M y c o b a ct eri u m t u b er c ul o si s
i n a n y p art of t h e b o d y 
a n d t h at i s i n a n a cti v e st at e a s d et er mi n e d b y eit h er a s m e ar or c ult ur e t a k e n fr o m 
a n y s o ur c e w hi c h t e st s p o siti v e f or T B or if t h er e i s r a di o gr a p hi c e vi d e n c e of T B. 
I n di vi d u al s wit h a cti v e T B ar e s y m pt o m ati c, d e p e n di n g u p o n t h e l o c ati o n of t h e 
di s e a s e ( m o st c o m m o nl y i n t h e l u n g s b ut al s o p o s si bl y i n t h e br ai n , ki d n e y s, s pi n e or 
el s e w h er e) a n d c a n s pr e a d t h e i nf e cti o n t o ot h er s. 
L at e nt T B i s s ai d t o e xi st w h e n a n i n di vi d u al i s i nf e ct e d wit h M y c o b a ct eri u m 
t u b er c ul o si s, a s e vi d e n c e d b y a p o siti v e T u b er c uli n S ki n T e st ( T S T) or I nt erf er o n 
G a m m a R el e a s e A s s a y (I G R A - s u c h a s Q u a ntif er o n -T B G ol d) b ut i s a s y m pt o m ati c 
a n d h a s n o e vi d e n c e of a cti v e i nf e cti o n o n s cr e e ni n g p at h ol o g y or r a di o gr a p hi c t e st s. 
S u c h i n di vi d u al s d o n ot p a s s t h e di s e a s e t o ot h er s . A p pr o pri at e a nti -m y c o b a ct eri al 
t h er a p y m u st st art f or s u c h i n di vi d u al s at l e a st 3 w e e k s b ef or e i niti ati n g st u d y dr u g
a d mi ni str ati o n i n t hi s st u d y , b e c a u s e t h e eff e ct of a nti-m y c o b a ct eri al t h er a p y m a y n ot 
a p p e ar i m m e di at el y aft er i niti ati n g .
T B s cr e e ni n g 
T B s cr e e ni n g m u st b e p erf or m e d pri or t o i niti ati o n of st u d y dr u g t r e at m e nt. T B 
s cr e e ni n g s h o ul d b e c o n d u ct e d p er l o c al g ui d a n c e ( or t h e t a bl e d e s cri b e d b el o w if 
n o n e e xi st). F or r ef er e n c e, t h e U S C D C n ot e s o n T B t e sti n g m a y b e f o u n d at
htt p:// w w w. c d c. g o v/ T B/ T O PI C/t e sti n g/ d ef a ult. ht m .
 
A s p art of r e c or di n g t h e p ati e nt' s m e di c al hi st or y, t h e p ati e nt will b e a s k e d if t h e y 
h a v e h a d eit h er a cti v e or l at e nt T B i n t h e p a st a n d w h et h er t h e y h a v e r e c ei v e d a 
B C G v a c ci n ati o n. T h e y will al s o b e a s k e d if t h e y h a v e b e e n i n c o nt a ct wit h a n y 
i n di vi d u als k n o w n t o h a v e a cti v e T B.
 
T B t e st ( e. g. , T S T [ P P D, P urifi e d Pr ot ei n D eri v ati v e] a n d/ or I G R A 
[e. g. , Q u a ntif er o n -T B G ol d ]) i s r e q uir e d at s cr e e ni n g. 
 
A c h e st X -r a y i s r e q uir e d at s cr e e ni n g a n d i s r e c o m m e n d e d t o b e p erf or m e d a n d 
r e p ort e d b y a q u alifi e d r a di o l o gi st. 


A p p e n di x 1 4:   I n str u cti o n f or T u b er c ul o si s ( T B) S cr e e ni n g a n d Tr e at m e nt ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 5 5 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
N ot e:
1)
T h e T S T m a y b e p o siti v e if t h e p ati e nt h a s h a d a B C G v a c ci n ati o n or h a s b e e n 
i nf e ct e d wit h T B i n t h e p a st; I G R A r e s ult s m a y al s o b e p o siti v e i n s o m e c a s e s of 
p a st i nf e cti o n.
2)
P o siti v e r e s ult s of t h e T S T a n d I G R A t e st m a y b e r e d u c e d b y i m m u n e s u p pr e s si o n.
3)
L o c al g ui d a n c e m a y v ar y d e p e n di n g u p o n t h e s e n siti vit y of str ai n s of 
M y c o b a ct eri u m t u b er c ul o si s pr e s e nt l o c all y.
I n c a s e of a n y d o u bt a s t o t h e di a g n o si s of l at e nt T B, it i s a d vi s e d t h at a l o c al 
p h y si ci a n wit h e x p erti s e i n t h e tr e at m e nt of T B or t h e M e di c al M o nit or
i s c o n s ult e d.
A c o m bi n ati o n of t h e m e di c al hi st or y, t h e r e s ult s of t h e T S T t e st, t h e I G R A t e st, c h e st 
X- r a y a n d a n y ot h er i n v e sti g ati o n s d e e m e d a p pr o pri at e b y t h e I n v e sti g at or b a s e d o n 
cli ni c al si g n s a n d s y m pt o m s i n di c ati v e of T B i nf e cti o n el s e w h er e i n t h e b o d y will b e 
u s e d b y t h e In v e sti g at or t o d et er mi n e st u d y eli gi bilit y at s cr e e ni n g f or t h i s st u d y a s 
f oll o w s:
T S T or I G R A
r e s ult
C h e st X -r a y
I nt er pr et ati o n/A c ti o n
E vi d e n c e of 
c urr e nt, 
a cti v e T B
E vi d e n c e of
ol d T B 
a) 
P o siti v e T S T or 
I G R A
P o siti v e 
P o siti v e or 
n e g ati v e
A cti v e T B pr e s e nt. I n eli gi bl e f or e ntr y 
t o st u d y. 
b) 
P o siti v e T S T 
N e g ati v e 
P o siti v e or 
n e g ati v e
C o ul d b e eit h er i) pri or B C G v a c ci n e ,
ii) p a st hi st or y of T B, iii) l at e nt T B or 
i v) e xtr a-p ul m o n ar y a cti v e T B. 
P erf or m I G R A t e st t o e x cl u d e i) t h e n 
f oll o w i n str u cti o n s i n s e cti o n c) b el o w .
c) 
P o siti v e I G R A 
N e g ati v e 
P o siti v e or 
n e g ati v e
P o s si bl e l at e nt T B or e xtr a -p ul m o n ar y 
T B pr e s e nt. E x cl u d e e xtr a -p ul m o n ar y 
T B u si n g f urt h er i n v e sti g ati o n s 
a p pr o pri at e t o a n y si g n/ s y m pt o m s. 
O n c e e xtr a -p ul m o n ar y T B h a s b e e n 
e x cl u d e d p ati e nt i s o nl y eli gi bl e f or 
st u d y e ntr y aft er at l e a st 3 w e e k s of 
pr o p h yl a cti c a nti -m y c o b a ct eri al 
t h er a p y pri or t o i niti ati n g st u d y dr u g
a d m i ni str ati o n a n d if c o m mitt e d t o 
c o m pl eti n g t hi s c o ur s e of tr e at m e nt , 
b e c a u s e t h e eff e ct of a nti -
m y c o b a ct eri al t h er a p y m a y n ot 
a p p e ar i m m e di at el y aft er i niti ati n g .


A p p e n di x 1 4:   I n str u cti o n f or T u b er c ul o si s ( T B) S cr e e ni n g a n d Tr e at m e nt ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 5 6 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
T S T or I G R A
r e s ult
C h e st X -r a y
I nt er pr et ati o n/A c ti o n
E vi d e n c e of 
c urr e nt, 
a cti v e T B
E vi d e n c e of
ol d T B 
d) 
N e g ati v e T S T 
or I G R A
P o siti v e 
P o siti v e or 
n e g ati v e
Li k el y a n o m al o u s T S T/I G R A r e s ult. 
R e p e at T S T/I G R A t e st if i n d o u bt. 
I n eli gi bl e f or e ntr y t o st u d y. 
e) 
N e g ati v e T S T 
or I G R A
N e g ati v e  
P o siti v e 
Pr o p h yl a cti c a nti -m y c o b a ct eri al 
t h er a p y s h o ul d b e c o n si d er e d, 
a c c or di n g t o l o c al g ui d eli n e s (if s u c h 
e xi st) b e c a u s e t h er e m a y  b e a f al s e 
n e g ati v e T S T or I G R A if t h e p ati e nt 
h a s b e e n o n pri or 
i m m u n o s u p pr e s s a nt s. S u c h 
pr o p h yl a cti c t h er a p y i s n ot 
c o m p ul s or y b ut i s at t h e I n v e sti g at or' s 
di s cr eti o n. T h e p ati e nt m a y b e eli gi bl e 
f or st u d y e ntr y wit h or wit h o ut 
pr o p h yl a cti c a nti -m y c o b a ct eri al 
tr e at m e nt.
(If i n d o u bt a b o ut T S T/I G R A r e s ult, 
r e p e at t e st s.)
f) 
N e g ati v e T S T 
or I G R A
N e g ati v e   
N e g ati v e 
Eli gi bl e f or st u d y e ntr y .
g) 
I n d et er mi n at e 
T S T or I G R A
P o siti v e 
P o siti v e or 
n e g ati v e
Li k el y a n o m al o u s T S T/I G R A r e s ult. 
R e p e at T S T/I G R A t e st if i n d o u bt. 
I n eli gi bl e f or e ntr y t o st u d y.
h) 
I n d et er mi n at e 
T S T or I G R A
N e g ati v e 
P o siti v e or 
n e g ati v e
P o s si bl e a n o m al o u s T S T/I G R A r e s ult 
or l at e nt T B. R e p e at I G R A t e st. If 
r e s ult still i n d et er mi n at e, a n d t h er e 
ar e n o si g n s/ s y m pt o m s of e xtr a -
p ul m o n ar y , f oll o w i n str u cti o n s i n 
s e cti o n e ) or f) a b o v e.
If r e s ult of r e p e at I G R A n e g ati v e, 
f oll o w i n str u cti o n s i n s e cti o n e) or f) 
a b o v e.
T B Tr e at m e nt 
If t h e p ati e nt i s p o siti v e f or l at e nt T B , t h e n a p pr o pri at e a nti-m y c o b a ct eri al t h er a p y 
m u st st art f or t h e p ati e nt at l e a st 3 w e e k s b ef or e i niti ati n g st u d y dr u g a d mi ni str ati o n i n 
t hi s st u d y, b e c a u s e t h e eff e ct of a nti-m y c o b a ct eri al t h er a p y m a y n ot
a p p e ar 
i m m e di at el y aft er i niti ati n g. Tr e at m e nt r e gi m e n s s h o ul d b e f oll o w e d b y t h e l o c al 


A p p e n di x 1 4:   I n str u cti o n f or T u b er c ul o si s ( T B) S cr e e ni n g a n d Tr e at m e nt ( c o nt.)
S atr ali z u m a b ( S A 2 3 7) — F. H off m a n n -L a R o c h e Lt d
1 5 7 /Pr ot o c ol B N 4 0 8 9 8 ( S A -3 0 7 J G), V er si o n 1 1
g ui d a n c e. If n o l o c al g ui d a n c e e xi st s f or tr e at m e nt of  i m m u no c o m pr o mi s e d i n di vi d u al s, 
t h e n t h e U S C D C m u st b e f oll o w e d 
(htt p:// w w w. c d c. g o v/ T B/ p u bli c ati o n s/ L T BI/ d ef a ult. ht m ).
I n c a s e of a n y d o u bt a s t o t h e a p pr o pri at e c o ur s e of a nti-m y c o b a ct eri al t h er a p y of
l at e nt T B, it i s a d vi s e d t h at a l o c al p h y si ci a n wit h e x p erti s e i n t h e tr e at m e nt of T B or 
t h e M e di c al M o nit or
i s c o n s ulte d.
M a n a g e m e nt of si g n s/ s y m pt o m s of T B d uri n g t h e st u d y
If n e w si g n s/ s y m pt o m s of T B i nf e cti o n d e v el o p d uri n g t h e st u d y, p erf or m di a g n o sti c 
t e st s a s a b o v e. If T B i nf e cti o n i s di a g n o s e d, i nt err u pt st u d y dr u g a n d c o n s ult t h e 
M e di c al M o nit or. R e p ort T B i nf e cti o n a s a " S el e ct e d A d v er s e E v e nt" ( s e e pr ot o c ol 
S e cti o n 5. 2. 4 ).

SAP_001.pdf: 
 
Official Title: 
A Multicenter, Randomized, Addition to Baseline Treatment, 
Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the 
Efficacy and Safety of Satralizumab (SA237) in Patients With 
Neuromyelitis Optica (NMO) and NMO Spectrum Disorder 
(NMOSD) 
NCT Number: 
NCT02028884 
Document Date: 
SAP Version 9: 20-April-18 
 
 
 
 


TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 1 of 58 
 
 
 
 
Chugai Pharmaceutical Co. Ltd. 
SA-307JG 
A multicenter, randomized, addition to baseline treatment, double-blind, placebo-
controlled, phase 3 study to evaluate the efficacy and safety of SA237 in patients with 
neuromyelitis optica (NMO) and NMO spectrum disorder (NMOSD) 
Statistical Analysis Plan 
PAREXEL Project Number: 211853 
Version 9.0 [Final]  
Date: 20 April 2018
 




Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 3 of 58 
TABLE OF CONTENTS 
1 
AMENDMENTS FROM PREVIOUS VERSION .................................................................. 7 
2 
INTRODUCTION ................................................................................................................... 7 
3 
STUDY OBJECTIVES ............................................................................................................ 7 
4 
INVESTIGATIONAL PLAN .................................................................................................. 7 
4.1 Overall Study Design and Plan ....................................................................................... 7 
4.2 Efficacy and Safety Variables ......................................................................................... 9 
4.2.1 Efficacy Variables.................................................................................................. 9 
4.2.2 Safety Variables ..................................................................................................... 9 
5 
STATISTICAL METHODS .................................................................................................... 9 
5.1 Data Quality Assurance .................................................................................................. 9 
5.2 General Presentation Considerations .............................................................................. 9 
5.3 Handling of Missing data .............................................................................................. 12 
5.4 Study Subjects ............................................................................................................... 12 
5.4.1 Disposition of Subjects ........................................................................................ 12 
5.4.2 Protocol Deviations.............................................................................................. 13 
5.5 Analysis Populations ..................................................................................................... 13 
5.6 Demographic and Other Baseline Characteristics......................................................... 14 
5.7 Medical History ............................................................................................................ 15 
5.8 Prior and Concomitant Medications ............................................................................. 15 
5.9 Treatment Compliance .................................................................................................. 16 
5.10 Efficacy Evaluation ....................................................................................................... 16 
5.10.1 
Analysis and Data Conventions .................................................................. 17 
5.10.1.1 Multi-center Studies ............................................................................... 17 
5.10.1.2 Adjustments for Covariates.................................................................... 17 
5.10.1.3 Handling of Missing Data ...................................................................... 17 
5.10.1.4 Multiple Comparisons/Multiplicity ....................................................... 18 
5.10.1.5 Examination of Subgroups ..................................................................... 18 
5.10.1.6 EQ-5D Scoring Algorithm ..................................................................... 18 
5.10.1.7 SF-36 Scoring Algorithm ....................................................................... 18 
5.10.1.8 FACIT-Fatigue Scale Scoring Algorithm .............................................. 19 
5.10.1.9 EDSS Scoring ........................................................................................ 20 
5.10.1.10 mRS Scoring ........................................................................................ 20 
5.10.1.11 ZBI Scoring .......................................................................................... 20 
5.10.1.12 Visual acuity function (Snellen chart) ................................................. 21 
5.10.2 
Primary Efficacy Variable ........................................................................... 22 
5.10.3 
Secondary Efficacy Variables ..................................................................... 24 
5.11 Safety Evaluation .......................................................................................................... 27 
5.11.1 
Extent of Exposure ...................................................................................... 27 
5.11.2 
Adverse Events ........................................................................................... 27 
5.11.3 
Serious Adverse Events and Death ............................................................. 27 
5.11.4 
AESI: ALT/AST, Infection Agent Transmission and Selected AEs ........... 28 
5.11.5 
Infections, Serious Infection, Opportunistic Infection  ............................... 28 
5.11.6 
Anaphylaxis ................................................................................................ 29 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 4 of 58 
5.11.7 
IRR and ISR ................................................................................................ 29 
5.11.8 
Safety evalutions for the Adolescent population ......................................... 29 
5.11.9 
Clinical Laboratory Evaluation ................................................................... 30 
5.11.10 
Electrocardiograms ..................................................................................... 31 
5.11.11 
Vital Signs, Physical Findings and Other Observations Related to Safety . 32 
5.12 Pharmacokinetics and Pharmacodynamics ................................................................... 32 
5.13 Immunogenicity ............................................................................................................ 35 
5.14 Determination of Sample Size ...................................................................................... 36 
6 REFERENCES ........................................................................................................................... 38 
7 
APPENDIX ............................................................................................................................ 39 
7.1 Laboratory Data Conversion and Transformation Rules .............................................. 39 
7.2 MedDRA basket ............................................................................................................. 43 
7.3 EQ-5D Scoring Algorithm: ............................................................................................. 47 
7.4 Step to identify the Day of baseline treatment increase/change: .................................. 55 
7.5 Procedure to identify the clinical relapse of optic neuritis occurred in the double-blind 
period: ........................................................................................................................... 56 
7.6 Rule for summary of titer for anti AQP4 antibody status ............................................. 57 
7.7 SAS Codes: ..................................................................................................................... 57 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 5 of 58 
LIST OF ABBREVIATIONS 
ADA 
Anti-SA237 antibody 
AE(s) 
Adverse event(s) 
ALQ 
Above the upper limit of quantification 
ANCOVA 
Analysis of covariance 
AQP4 
Aquaporin-4 
ARR 
Annualized relapse rate 
ATC 
Anatomical Therapeutic and Chemical 
BLQ 
below the limit of quantification 
BOCF 
baseline observation carried forward 
CEC 
Clinical Endpoint Committee 
CI 
Confidence interval 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
eCRF  
Electronic Case Report form 
ECG  
Electrocardiogram 
EDSS 
Expanded Disability Status Scale 
EU 
European Union 
FACIT 
Functional Assessment Of Chronic Illness Therapy 
FPI 
First patient in 
GEE 
Generalized Estimating Equation 
IDMC 
Independent Data Monitoring Committee 
ITT 
Intent-to-treat 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measures 
mRS 
Modified Rankin Scale 
N.C. 
Not calculated 
NMO 
Neuromyelitis optica 
NMOSD 
NMO spectrum disorder 
PD 
Pharmacodynamics 
PK  
Pharmacokinetics 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PPS 
Per-Protocol Set 


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PT 
Preferred term 
Q4W 
Every 4 Weeks 
SAE(s)  
Serious adverse event(s) 
SAP 
Statistical analysis plan  
SC 
Subcutaneously 
SD  
Standard deviation 
SF-36 
Short Form Generic Health Survey 
SF-MPQ 
Short Form McGill Pain Questionnaire 
SFU 
Safety Follow-Up 
SOC 
System organ class 
SAF 
Safety Set 
TFR 
Time to first relapse 
VAS 
Visual Analogue Scale 
WHO-DD 
World Health Organization Drug Dictionary 
ZBI 
Zarit Burden Interview 
 


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1 
AMENDMENTS FROM PREVIOUS VERSION 
 
The following changes were made in this SAP from the previous version of SAP due 
to the amendment to the protocol. 
• Adolescents population was added based on the protocol amendment (Protocol 
version 8.0) 
• 
Only treatment-emergent adverse events are collected in this study. Previously 
the SAP contained summaries of adverse events and treatment-emergent 
adverse events, the latter were removed to avoid redundancy.   
• Detailed description on the identification of the following adverse event were 
added: serious infections, opportunistic infections, anaphylaxis, injection 
related reactions and injection site reactions.  
• Detailed description of the following efficacy evaluation were added: EQ-5D 
Scoring and Visual acuity function. 
• Detailed description of the immunogenicity and immunogenicity analyses were 
added. 
• 
The analysis of relapse-free subjects using logistic regression will not be 
conducted because of a lot of early events.  
• Clarify the definition of baseline ARR. 
• Resolve inconsistencies mainly for scope of analysis in SAP. 
2 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides details of the summaries and analyses to be 
performed to report the results of the study. It should be read in conjunction with 
following documents: 
• 
Study Protocol, Version 8.0, 17th April 2017 
• 
Electronic Case Report Form (eCRF), Version 10.0, 30th June, 2017 
3 
STUDY OBJECTIVES 
The objective of this study is to evaluate the efficacy and safety of SA237 in subjects 
with neuromyelitis optica (NMO) and NMO spectrum disorder (NMOSD). 
 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This is a multicenter, randomized, addition-to-baseline treatment, double-blind, 
placebo-controlled, parallel assignment study followed by an open-label extension period. 
Subjects will be randomized to either SA237 120 mg or placebo. Blinded study drug will 
be administered subcutaneously (SC) at Weeks 0, 2 and 4, and thereafter every 4 weeks 
(Q4W) in combination with one of the following baseline maintenance treatments: 
azathioprine, mycophenolate mofetil or oral corticosteroids (treatment with both oral 




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Subjects who withdraw from the study in the double blind period due to clinical relapse 
should be asked to continue Safety Follow-Up (SFU) for a period of 24 weeks from the 
last dose of study drug. 
4.2 
Efficacy and Safety Variables 
4.2.1 Efficacy Variables 
The primary efficacy variable is the TFR based on protocol-defined relapses with CEC 
evaluations. TFR is defined as the time from the date of the randomization until the first 
occurrence of relapse throughout the double-blind period. 
The secondary efficacy variables include change in Visual Analogue Scale (VAS) for pain 
score, change in Functional Assessment Of Chronic Illness Therapy (FACIT) fatigue scale 
score, change in Short Form generic health survey (SF-36) PCS and MCS scores, change 
in EQ-5D score , annualized relapse rate (ARR), the proportion of relapse-free subjects, 
change in modified Rankin Scale (mRS) score, change in Zarit Burden Interview (ZBI) 
score, change in Expanded Disability Status Scale (EDSS) score and change in visual 
acuity (Snellen chart) score. 
4.2.2 Safety Variables 
The safety variables are incidence and severity of adverse reactions, adverse events (AEs), 
adverse events of special interest (AESIs), serious AEs (SAEs), selected AEs (including 
infusion/injection related reactions), injection site reactions (ISRs), subject withdrawals 
due to AEs, vital signs (temperature, systolic blood pressure [SBP], diastolic blood pressure 
[DBP], and pulse rate), physical examination, clinical laboratory tests (hematology, 
chemistry, and urinalysis), 12-lead ECG, and suicidality (Columbia-Suicide Severity 
Rating Scale [C-SSRS]). 
5 
STATISTICAL METHODS 
5.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently 
checked for consistency, integrity and in accordance with standard PAREXEL procedures. 
5.2 
General Presentation Considerations  
Unless otherwise specified, Week 0 (Day 1) visit, which in most cases should correspond 
to the date of first dose, will be the baseline in the double-blind period, in which the 
baseline measurements will be collected at Day 1 prior to the first injection.  
 
The date of first SA237 dose will be the baseline in the All-Subjects-Treated (All SA237) 
population analyses, in which the baseline measurements will be collected on the day of 
the first dose, prior to the study drug injection. 
 
The definition of each duration for analysis is as follows:   
• Double blind period for efficacy analysis 
- 
Double-blind period starts on the day of the randomization. The double-blind period 
ends on the earliest day of 1) clinical cutoff date (CCOD), 2) the day before the first 


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treatment in the extension period, 3) the end of the study, or 4) last contact for 
patients lost to follow up.  
 
• Double blind period for safety analysis 
- 
Double blind period starts on the day of first dose of study drug. The double-blind 
period ends on the same day as efficacy analysis..  
 
• SA237 exposure duration for safety analysis (for All SA237 analysis) 
- 
SA237 exposure duration starts on the day of first dose of SA237. SA237 exposure 
duration ends on the earliest day of 1) CCOD, 2) the end of the study, or 3) last 
contact for patients lost to follow up. 
 
The definition of summaries by visit is as follows: 
• Summaries by visit for double blind period 
- 
Baseline is defined as the latest data before the date of first administration for all data. 
Summarized visits except for baseline are defined as follows. Irregular visits such as 
unscheduled visit between week X, dose outside the visit window (DOW), extra visit 
at relapsing, and the end of the study are out of scope. Week X visits are directly 
used for categories of time. In other words, time window is not applied. If there are 
the same visits data, one representative assessment nearest to the scheduled visit day 
will be summarized. 
 
• Summaries by visit for All SA237 analysis 
- 
Baseline is defined as the latest data before the date of first administration of SA237 
for all data. Summarized visits except for baseline are defined as follows. Irregular 
visits such as unscheduled visit between week X, dose outside the visit window 
(DOW), extra visit at relapsing, and the end of the study are out of scope. Time 
window is applied as if visit schedules continue in the double blind period. Middle 
of each specified day of visit will be used for the range of time window of each visit. 
One representative assessment nearest to the specified day of visit in time window 
of each visit will be summarized. 
 
Continuous data will be summarized in terms of the mean, standard deviation (SD), 
median, minimum, maximum and number of observations, unless otherwise stated.  The 
minimum and maximum will be reported to the same number of decimal places as the raw 
data recorded in the database.  The mean, median and SD will be reported to one more 
decimal place than the raw data recorded in the database.  In general, the maximum number 
of decimal places reported shall be four for any summary statistics. If the data contains 
inequality signs, use the number on the end (i.e. treat “<= 0.02” as “0.02”) in analysis for 
calculation of representative value to be presented in the summaries. 
For categorical parameters, the number and percentages of subjects in each category will 
be presented at the relevant time point. The denominator for percentage will be based on 


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the number of subjects appropriate for the purpose of analysis. Unless otherwise noted, 
percentages will be presented to one decimal place. Percentages will not be presented for 
zero counts and 100% will be presented as an integer. The denominator for all percentages 
will be the number of subjects in that treatment group within the population of interest, 
unless otherwise noted. Missing category will only be displayed when there are missing 
data.  
For pharmacokinetic endpoint, concentrations will be analyzed using all reported decimal 
places, and displayed to the same number of decimal places as they are recorded in the 
database. If any samples are collected outside of the protocol defined time window 
(Appendix 1 in the protocol), the relevant values will be excluded for the calculation of 
descriptive statistics. Furthermore, if the samples are collected more than 6 weeks after the 
last administration, the relevant values will be excluded for the calculation of descriptive 
statistics considering the half-life of IgG.  Descriptive statistics will include number of the 
subjects, geometric mean, geometric CV and the 95% confidence interval for the geometric 
mean for the concentrations, as well as arithmetic mean, SD, median, minimum, and 
maximum of SA237 concentrations will be calculated by visit and per defined time window 
post-dose for the Pharmacokinetics Per-Protocol Set (PK-PPS). The CV will be presented 
with 1 decimal place. For the calculation of descriptive statistics, a serum concentration 
below limit of quantification will be substituted by half of lower limit of quantification (i.e. 
LLOQ/2) If more than half of the measured values are BLQ at any blood sampling time 
point, the statistics will not be tabulated for that time point and will be shown as “N.C.”. 
 
For immunogenicity, below rules will be applied to neutralizing antibody. 
➢ Neutralinzing antibody will be only assessed if anti- SA237 antibody is positive. 
➢ If SA237 concentration is over 1 ug/mL, the data of the neutralizing antibody 
will be excluded for the calculation of descriptive statistics. This is because 
neutralizing antibody analysis may be false negative or false positive affected 
by SA237.  
 
Changes from baseline in categorical data will be summarized using shift tables where 
appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal 
places.  However, if a p-value is only presented to four decimal places (by SAS) it will not 
be rounded again, but will be presented to four decimal places. P-values less than 0.001 
will be presented as “<0.001”. 
Confidence intervals (CIs) will be presented to one more decimal place than the raw data. 
The confidence interval for hazard ratio will be calculated based on the Wald type and the 
relapse rate confidence interval will be provided using Kaplan Meier method with a 
LOGLOG transformation. 
All report outputs will be produced using SAS® version 9.2 or a later version in a secure 
and validated environment. 


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5.3 
Handling of Missing data  
Medications with a missing start date and whose stop date is either unknown or after the 
date of the first dose of study drug, will be considered concomitant. Medications with a 
missing start date and whose stop date is prior to the date of the first dose of study drug, 
will be considered as prior medications. 
Where the adverse events start dates of year part are missing then the value will not be 
imputed. For the partial missing situation (month or day missing), the value will be imputed 
for the analysis purpose. 
Missing pattern 
Start Date / Pre-Dosing  
End Date / Post-Dosing 
completely missing 
leave missing 
missing year 
leave missing 
missing month 
set to ‘JAN’ 
set to ‘DEC’ 
missing day 
set to ‘01’ 
set to last day of the month 
missing month and day set to ‘01JAN’  
set to ‘31DEC’ 
missing time 
(concomitant 
medication) 
set to ‘00:00:00’ 
missing hours: 0 
missing minutes: 0 
missing seconds: 0 
set to ‘23:59:59’ 
missing hours: 23 
missing minutes: 59 
missing seconds: 59 
missing time 
(adverse event) 
set to ‘23:59:59’ 
missing hours: 23 
missing minutes: 59 
missing seconds: 59 
These rules apply to AE and concomitant medication. For AE, beginning/end date of AE, 
first date of study treatment and date of death are considered to avoid inconsistency. 
For Visit data other than efficacy, only missing time rules apply. For efficacy visit data, no 
imputation is made. For birth date, set missing month to '06' and/or set missing day to '15'. 
5.4 
Study Subjects 
5.4.1 Disposition of Subjects 
Summary tables of subject disposition will be provided as follows: 
• 
A summary table of the number of subjects who were randomized to study treatment, 
number of subjects receiving at least one dose of study drug, number of subjects ending 
the double-blind period, number of withdrawal from the double-blind period, reason 
for withdrawal in the double-blind period, number of subjects entering the safety 
follow-up after double-blind period, number of subjects finishing the safety follow-up 
after double-blind period, number of subjects entering the open-label extension period, 
number of withdrawal from the extension period, reason for withdrawal in the 
extension period, number of subjects conducting last observation visit or withdrawal 
visit will be provided by treatment group and overall for both the blinded period and 
the open label extension. 
• 
A by-subject listing of disposition status, including the date of informed consent, date 
of treatment with study drug and study completing/withdrawal, and reason for 
withdrawal from treatment and from study. 


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5.4.2 Protocol Deviations 
Major protocol deviations are defined as those deviations from the protocol that are likely 
to have an impact on the subject’s rights, safety, well-being, and/or on the validity of the 
data for analysis. The impact of major protocol deviations on the efficacy results will be 
investigated by assessing the robustness of the study results and conclusions to the choice 
of analysis population (see Section 5.5), both including and excluding data potentially 
affected by major protocol deviations. 
A summary table and listing of protocol deviations will be provided as follows: 
• 
The number and percentage of subjects without any deviation, without any major 
deviation, with at least 1 major deviation, type of major deviations will be summarized 
by randomized treatment group, overall and by site. 
• 
A by-subject listing of protocol deviations will be presented. 
5.5 
Analysis Populations 
The intent-to-treat (ITT) population will serve as the primary population for the analysis 
of efficacy, which consists of all randomized subjects. Subjects will be analyzed as 
randomized for analysis purposes. In case even a subject is incorrectly stratified at time of 
randomization, the analysis will be performed using the stratification for randomization. 
The Per-Protocol Set population (PPS) will include all subjects in the ITT population who 
received at least 3 doses of study drug, and without any major protocol deviations which 
are considered to have an impact on efficacy. Subjects will be analyzed as treated for 
analysis purposes in the PPS. 
The Safety Set (SAF) population will include all randomized subjects who have received 
at least one dose of active study drug or placebo.  Subject will be included in the treatment 
group corresponding to the trial treatment they actually received for the analysis of safety 
data using the SAF population, i.e. patients who received at least one dose of SA237 will 
be assigned to the SA237 treatment arm, irrespective of randomized arm. . 
 
The All-Subjects-Treated (All SA237) population will be defined as all enrolled subjects 
who took at least one dose of active study drug at any time.  Date of the first active study 
drug administration will be defined as Day 1 for All SA237 analysis (i.e. Day 1 of subjects 
allocated in placebo group is redefined on the day of first dose of SA237 when entering 
extension period. 
The Pharmacokinetics Per-Protocol Set (PK-PPS) and immunogenicity (anti-SA237 
antibody; ADA) will include all subjects in the SAF with at least 1 valid post-dose 
concentration result with a dosing record and sampling time. Pharmacodynamics variables 
will be analyzed using the SAF population. 
The Adolescents population will be defined as all enrolled subjects from 12 to 17 years old 
(< 18 years) at the first informed consent. After the total number of protocol-defined 
relapses judged by the CEC reaches 26, the recruitment period for the adolescents may be 
continued in the extension period until a minimum of 8 adolescents are enrolled into the 
study. 


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The following summary and listing will be provided:  
• A summary of analysis populations, including the number and percentage of subjects in 
the defined analysis sets by treatment group and overall. 
• A by-subject listing of analysis population (ITT, PPS, SAF, All SA237, PK-PPS, 
Adolescents Population, and PK-Adolescents Population) information will be provided. 
This listing should include: subject number, inclusion/exclusion flag for each population 
and reason for exclusion from each population. 
Subgroup analysis will be conducted based on the following variables: 
- 
Age category (<18, 18 years ) 
- 
NMO/NMOSD and AQP4 Status at screening (5 categories: NMO, NMOSD, NMO 
and AQP4 positive, NMO and AQP4 negative, and NMO/NMOSD and AQP4 
positive ) 
- 
Baseline treatment (azathioprine, mycophenolate mofetil, oral corticosteroids, 
azathioprine + oral corticosteroids, mycophenolate mofetil + oral corticosteroids) 
- 
Baseline ARR (1,  >1) based on the last two years before screening 
- 
Geographic region (Asia, Europe/other) 
- 
Japanese, Non-Japanese subjects 
- 
ADA status (ADA negative subjects, ADA unaffected subjects, Treatment-boosted 
ADA subjects, Treatment-induced ADA subjects) (see Section 5.13) 
For safety analyses, baseline weight (<median, median) will be included in addition. 
5.6 
Demographic and Other Baseline Characteristics 
Summary tables and listing will be provided as follows for ITT, PK-PPS and SAF: 
• 
Demographics will be summarized as collected at screening or baseline visit before 
administration of first dose of study drug and will include gender, race (American 
Indian/Alaska Native, Asian [Japanese], Asian [Non-Japanese], Black/African 
American, Native Hawaiian/other Pacific Islander, White and Other), Geographic 
region (Asia, Europe/other), age (years), age category (<18, 18 ), ethnicity, racial 
subgroup, height, body weight (the first and the third quartiles of body weight will be 
presented), body mass index (BMI, kg/m2), BMI category (<18.5, ≥18.5 to <25, ≥25 
to <30, and ≥30 kg/m2), Baseline ARR (1,  >1) , AQP4 status at screening (positive, 
negative), Diagnosis (NMO, NMOSD) and Baseline treatment (azathioprine, 
mycophenolate mofetil, oral corticosteroids, azathioprine + oral corticosteroids, 
mycophenolate mofetil + oral corticosteroids) by treatment group and overall. 
• 
A by-subject listing of demographic data. 
Age will be calculated as the number of complete years between a subject's birth date 
and the date of the first informed consent. 
The subgroup summary tables will be presented for ITT and SAF by the defined variables 
with the exception of ADA status (See section 5.5). 


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5.7 
Medical History 
Medical history will be classified according to the terminology of the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA). 
Medical conditions are categorized as past or concomitant as follows: 
• 
Past diseases: Medical conditions which are specified as start date is before Day 1 Visit 
date with no ongoing status or the stop date is prior to Day 1 Visit date 
• 
Baseline  diseases: Medical conditions which are specified as start date is before Day 
1 Visit date with ongoing status or the stop date is on or after Day 1 Visit date. 
The following summaries will be provided by treatment group and overall, based on the 
SAF. 
• 
A summary table of past diseases will be presented by system organ class (SOC) and 
preferred term (PT). 
• 
A summary table of concomitant diseases will be presented by SOC and PT, by 
treatment group and overall. 
• 
A by-subject listing of medical history data will be provided. 
5.8 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHO-DD). 
Medication start and stop dates will be compared to the date of the first dose of randomized 
study drug and thus the medications will be classified as Prior or Concomitant. 
Medications that start and stop prior to the date of first dose of study drug will be classified 
as Prior medications.  Medications taken on or after (including ongoing) the first dose of 
study drug will be classified as Concomitant medication. If a medication starts before the 
date of first dose of study drug and stops on or after the date of first dose of study drug then 
the medication will be classified as both Prior and Concomitant medication. 
NMO/NMOSD pain drugs will be reported as collected on the CRF. 
The following summaries will be provided by treatment group and overall, based on the 
Safety population. 
• 
A summary table of Prior Medications (other treatments than NMO/NMOSD) will be 
provided by anatomical therapeutic chemical (ATC) and PT.  
• 
A summary table of Concomitant Medications (other treatments than NMO/NMOSD) 
will be provided by ATC and PT. 
• 
A summary table of Prior NMO/NMOSD drugs for relapse prevention will be provided 
by ATC and PT. 
• 
A summary table of Concomitant NMO/NMOSD drugs for relapse prevention will be 
provided by ATC and PT. 
• 
A summary table of Prior NMO/NMOSD drugs for relapse/rescue therapy will be 
provided by ATC and PT. 


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• 
A summary table of Concomitant NMO/NMOSD drugs for relapse/rescue therapy will 
be provided by ATC and PT. 
• 
A summary table of Prior NMO/NMOSD pain drugs will be provided by ATC and PT. 
• 
A summary table of Concomitant NMO/NMOSD pain drugs will be provided by ATC 
and PT. 
• 
A summary table of Prior other NMO/NMOSD drugs will be provided by ATC and PT. 
• 
A summary table of Concomitant other NMO/NMOSD drugs will be provided by ATC 
and PT. 
• 
A by-subject listing of Prior medication data will be provided for NMO/NMOSD pain 
drugs and others separately. 
• 
A by-subject listing of concomitant medication data will be provided. 
5.9 
Treatment Compliance 
Compliance will be computed by determining the number of SC injections relative to the 
number of SC injections that should have been administered. The compliance will be 
evaluated during the double-blind period. If a subject who experience a relapse which is 
treated with rescue therapy and/or a protocol-defined relapse which is adjudicated by CEC 
or early discontinued from study treatment, the number of planned and actual SC will be 
counted based on the visits before the discontinuation. Treatment compliance will be 
summarized in terms of compliance based on the Safety population. Administration using 
prefilled syringe will be flagged in the listing of administration. 
Compliance will be calculated using the following formula: 
Compliance 
(%)   
= 
Number of SC injections during the double-blind period 
x 100 
Number of planned SC injections during the double-
blind period 
The following summaries and listings will be provided: 
• 
A summary table of compliance will be presented by treatment group, and overall. The 
number and percentage of treatment compliance will also be presented by categorized 
compliance as: <80%, 80%-100%, >100%,  
• 
A by-subject listing of study drug administration as well as overall compliance during 
the double blind and whole period. 
5.10 Efficacy Evaluation 
For the definition of the double-blind period for efficacy evaluations see section 5.2. See 
Appendix 7.7 how to descrive models with SAS code. 


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5.10.1 Analysis and Data Conventions 
This study is designed to assess the efficacy of SA237 over placebo on the treatment of 
NMO/NMO-SD. The null hypothesis for primary endpoint will be that there is no 
difference on the TFR between SA237 and placebo during double-blinded period. The 
alternative hypothesis will be that there is a difference in TFR during double-blinded 
period. 
A two-sided stratified log-rank test at 5% level will be used to test this hypothesis. 
5.10.1.1 Multi-center Studies 
For the purpose of the summaries and analyses, the term ‘Center’ will be used to define 
each site. 
All centers will be pooled by country for the purpose of analysis. 
Descriptive summaries will not be presented by individual center. Subject data listing will 
be provided by individual center. 
5.10.1.2 Adjustments for Covariates 
The primary efficacy analysis will be adjusted for the following baseline covariates: 
• 
Baseline ARR: one or more than one based on the last two years before screening 
• 
Geographic region: Asia and EU/Other. 
In addition, for each covariate, a statistical test for the presence of a treatment-by-covariate 
interaction will be performed, by including the interaction term in the secondary analysis 
model. Subgroup analyses will be performed to explore the treatment-by-covariate 
interactions. If any of the treatment-by-covariate are found to be statistically significant, 
conclusions based on the secondary analysis (no interaction) will be interpreted with 
caution. 
In addition, a Mixed-effect model repeated measures (MMRM) for secondary endpoints 
will be adjusted for Baseline ARR and Geographical region (stratification factors). 
5.10.1.3 Handling of Missing Data 
For details on censoring rule for the primary endpoint, see section 5.10.2. 
For secondary continuous endpoints, a Mixed-effects model repeated measures (MMRM) 
analysis incorporating all data in double blind period will be used to utilize all the data 
collected over time with consideration of the variance-covariance matrix of the repeated 
measures. This method allows a general unstructured variance-covariance matrix and will 
include data from subjects with incomplete data from some scheduled time points. 
For FACIT fatigue questionnaire, if there are less than 7 responses recorded, then the total 
fatigue score will be considered missing. If there are 7 or more responses recorded, then 
the total fatigue score for that questionnaire will be calculated as the average of the non-
missing scores multiplied by 13. 


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5.10.1.4 Multiple Comparisons/Multiplicity 
The serial gatekeeping methodology will be employed to control the rate of false positive 
for the primary endpoint (TFR based on protocol-defined relapses) and key secondary 
endpoints (change in VAS for pain at week 24 and change in the FACIT fatigue scale at 
week 24). The 3 efficacy endpoints will be analyzed in hierarchical order, beginning with 
the TFR based on protocol-defined relapses, followed by the VAS for pain, and ending 
with FACIT fatigue. A fixed-sequence approach will be applied to control the overall 
significance level at 0.05. An initial null hypothesis will be tested for the first hierarchical 
primary efficacy endpoint, the TFR based on protocol-defined relapses. If this is 
significant, then a repeat of the aforementioned testing procedure for the second 
hierarchical key secondary end point, the VAS for pain will be done. This will be repeated 
a third time for the FACIT fatigue if the VAS for pain showed a significant difference. 
5.10.1.5 Examination of Subgroups 
Descriptive statistics by subgroup for the demographic data, primary efficacy and key 
secondary variables will be presented by the defined variables in Section 5.5. 
Additionally, main safety data will be presented by Japanese/Non-Japanese subgroup. 
5.10.1.6 EQ-5D Scoring Algorithm 
The EQ-5D 3 level version (EQ-5D 3L) descriptive system comprises the following 5 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  
Each dimension has 3 levels: no problem, some problems, and extreme problems.  The 
scoring algorithm (US) as described in appendix 7.3 will be used but other norms may be 
explored for sensitivity analysis. 
The EQ-5D index score will be missing in case any answer to one of the five EQ-5D 
dimensions is missing. 
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale 
ranging from 0 to 100 where the endpoints are labelled ‘Best imaginable health state’ and 
‘Worst imaginable health state’. 
5.10.1.7 SF-36 Scoring Algorithm 
The SF-36 is a multi-purpose, short form health survey with 36 questions. It yields an 8 
scale profile (vitality, physical functioning, bodily pain, general health, role-physical, role-
emotional, social role functioning and mental health) of functional health and well-being 
scores as well as physical and mental health component summary measures (PCS and 
MCS). 
The SF36 will be scored using the Quality Metric proprietary scoring system (version 4.5). 
Component and domain scores are transformed to a 0-100 scale based on the 2009 US 
Normative population. Higher scores are indicative of better health related quality of life 
and a score of 50 is average for the US population. 


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For the SF-36, missing data rules will be applied according to the proprietary scoring 
software provided by the license holder (Maruish et al. 2011 p57 and p60). 
 
5.10.1.8 FACIT-Fatigue Scale Scoring Algorithm 
The FACIT Fatigue scale is a 13-item questionnaire that assesses self-reported fatigue and 
its impact upon daily activities and function over the past 7 days.  As each of the 13 items 
of the scale ranges from 0-4, the range of possible scores is 0-52, which 0 being the worst 
possible score and 52 the best.  Items are scored as follows: 0 = Not at all; 1= A little bit; 
2= Somewhat; 3= Quite a bit; 4= Very much. All items are reverse scored except item An5 
(I have energy) and An7 (I am able to do my usual activities). See Table 5-1 for further 
guidance. 
When there are missing data, a total score is prorated from the score of the answered items, 
as long as more than 50% of the items are answered (i.e. a minimum of 7 of 13 items). The 
prorated score is calculated as the average of the non-missing scores multiplied by 13.  
 
 


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Table 5-1: FACIT scoring 
Item code 
Reverse item 
Item response 
Item score 
HI7 
4 
- 
  = 
 
HI12 
4 
- 
  = 
 
An1 
4 
- 
  = 
 
An2 
4 
- 
  = 
 
An3 
4 
- 
  = 
 
An4 
4 
- 
  = 
 
An5 
0 
+ 
  = 
 
An7 
0 
+ 
  = 
 
An8 
4 
- 
  = 
 
An12 
4 
- 
  = 
 
An14 
4 
- 
  = 
 
An15 
4 
- 
  = 
 
An16 
4 
- 
  = 
 
 
 
 
 
 
 
 
Sum individual item scores:
 
 
 
Multiply by 13: 
 
 
 
Divide by number of items answered:________=FACIT 
score 
5.10.1.9 EDSS Scoring 
The EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological exam) to 
10 (death due to NMO) in 0.5 unit increments that represent higher levels of disability.   
The EDSS scoring will be based on the score recorded on CRF. 
5.10.1.10 mRS Scoring  
The mRS is a 7-point disability scale that assesses the degree of disability in subjects with 
neurological impairment. Possible scores range from 0 (no symptom at all) up to 6 (death).  
The higher scores reflect increased disability. The mRS scoring will be based on the score 
recorded on CRF. 
5.10.1.11 ZBI Scoring 
The ZBI is the measurement to assess caregiver burden. The 22 items ask for the strain 
caregivers perceive.  Responses range from 0 (never) to 4 (nearly always) with maximum 
score of 88. The higher the total score, the heavier the perceived burden. The ZBI scoring 
will be based on the score recorded on CRF.  For summary tables, only questionnaire with 
responses to 17 or more out of 22 questions (>= 75% valid response) are used. 
The ZBI can be scored if 17 or more items are completed. Interpretation approach can be 
used if at least 75% of the items have been completed: 
1. Sum the items that were answered. 
2. Divide the sum by the number of items that were answered to yield the mean 
response per item. 
3. Multiply the mean response per item by 22 (the total items in the scale). 


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5.10.1.12 Visual acuity function (Snellen chart) 
Visual acuity will be measured by a Snellen 20-foot wall chart. The test will be performed 
monocularly and subjects may use their habitual distance glasses or contact lenses. If visual 
acuity is less than 20/200, these data will be recorded on CRF as below: 
・ If the subject can count fingers, this is recorded as “20/300” (CF). 
・ If the subject can see finger movements, this is recorded as “20/400” (HM). 
・ If the subject can perceive the flashlight, this is recorded as “20/500” (LP). 
・ If the subject cannot perceive the flashlight, this is recorded as “20/600” (NLP). 
・  
In order to calculate change from baseline, visual acuity scores will be converted to 
logMAR visual acuity scoring. Transformation of scores will be conducted based on the 
following table. If the record of visual acuity score (Snellen chart) is worse than 20/200 
(i.e. CF, HM, LP or NLP in this study), the score will be converted to logMAR 1.85, 
logMAR 2.00, logMAR 2.70 and logMAR 3.00, respectively. If score which is not in the 
table is recorded, it would adjust to the following lower one (e.g. 20/27 will be converted 
to 20/30). 
Table 5-2: logMAR visual acuity scoring 
Snellen chart 
LogMAR 
20/10 
-0.30 
20/12.5 
-0.20 
20/15 
-0.12 
20/16 
-0.10 
20/20 
0.00 
20/25 
0.10 
20/30 
0.18 
20/32 
0.20 
20/40 
0.30 
20/50 
0.40 
20/60 
0.48 
20/63 
0.50 
20/70 
0.54 
20/80 
0.60 
20/100 
0.70 
20/114 
0.76 
20/125 
0.80 
20/150 
0.88 
20/160 
0.90 
20/200 
1.00 
CF 
1.85 
HM 
2.00 
LP 
2.70 
NLP 
3.00 


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5.10.2 Primary Efficacy Variable 
The primary efficacy analyses will be based on the ITT population. Supportive evaluations 
will be performed using the PPS population. 
The primary efficacy endpoint is TFR based on protocol-defined relapses confirmed by the 
CEC with EDSS/FSS assessment performed by the examining assessor within 7 days after 
relapse symptoms were reported to site by the subject. TFR is defined as the time from the 
date of the randomization until the first occurrence of relapse throughout the study. Time 
point of relapse onset is defined as time at which the subject experiences any new or 
worsening neurological NMO representing clinical relapse(s) which is later confirmed by 
the CEC as protocol-defined.  
Censor is defined as the earliest day of 1) the end of double blind period for efficacy 
analysis, 2) switching or increasing the baseline treatment (for details on the identification 
of the switch and increase in baseline therapy see appendix 7.4), or 3) receiving rescue 
therapy for clinical relapse. 
The primary analysis of the study is to test the equality of the TFR distribution based on 
protocol-defined relapse in the SA237 + baseline treatment (SA237) and Placebo + 
baseline treatment (placebo) arms: 
H0: TFRSA237 = TFRplacebo versus H1: TFRSA237 ≠ TFRplacebo 
A stratified two-sided log-rank test using strata of baseline ARR (one vs. more than one) 
and geographical region (Asia and EU/Other) will be used.  
The Kaplan-Meier method will be used to estimate the TFR based on protocol-defined 
relapses distribution for each treatment group. The Kaplan-Meier curve will provide a 
visual description of the differences across treatment groups. In addition, estimates of the 
treatment effect will be expressed as hazard ratio and 95% CIs using a stratified (baseline 
ARR and geographical region) Cox proportional-hazards model (Exact method will be 
used for tie data). Treatment by covariate interactions will be assessed by including the 
pairwise interaction terms in the Cox proportional-hazards model. 
The following summary tables, figures and analysis will be provided for the ITT and PPS: 
• 
A summary table of Kaplan-Meier estimate of TFR (protocol-defined relapse) will be 
presented by treatment group. 
• 
A figure of Kaplan-Meier estimate of TFR (protocol-defined relapse) will be presented 
by treatment group. 
• 
Analysis of TFR (protocol-defined relapse) will be performed using the stratified log-
rank test. 
• 
Analysis of TFR (protocol-defined relapse) will be performed using the stratified Cox 
regression. 
The subgroup forest plot of HR of TFR (protocol-defined relapse) will be presented by the 
defined variables in Section 5.5. 
Additionally, summary tables of sensitivity analysis of TFR (clinical relapse), TFR (treated 
clinical relapse), TFR (treated clinical relapse: optic neuritis) , protocol-defined relapse 


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based on CEC adjudication (regardless of assessment limit of 7 days) and protocol-defined 
relapse based on EDSS/FSS increase relative to baseline will be conducted for ITT as 
follows. All relapses reported by investigators will be handled as events for TFR (clinical 
relapse). Relapses treated with rescue therapy will be handled as events in addition to 
protocol-defined relapses for TFR (treated clinical relapse). Relapses treated with rescue 
therapy and judged optic neuritis by investigator will be handled as events in addition to 
protocol-defined relapses for TFR (treated clinical relapse: optic neuritis). Optic neuritis 
will be identified via relapse assessment form before data base lock (for details see appendix 
7.4).. The same censoring rules as for the primary endpoint will be applied, except for the 
specific event of interest.  
 
• 
A summary table of Kaplan-Meier estimate of TFR (clinical relapse) will be presented 
by treatment arm. 
• 
A summary table of Kaplan-Meier estimate of TFR (treated clinical relapse) will be 
presented by treatment arm. 
• 
A summary table of Kaplan-Meier estimate of TFR (treated clinical relapse: optic 
neuritis) will be presented by treatment arm. 
• 
A summary table of Kaplan-Meier estimate of TFR (protocol-defined relapse based on 
CEC adjudication (regardless of assessment limit of 7 days)) will be presented by 
treatment arm. 
• 
A summary table of Kaplan-Meier estimate of TFR (protocol-defined relapse based on 
EDSS/FSS increase relative to baseline) will be presented by treatment arm. 
• 
A figure of Kaplan-Meier estimate of TFR (clinical relapse) will be presented by 
treatment group. 
• 
A figure of Kaplan-Meier estimate of TFR (treated clinical relapse) will be presented 
by treatment group. 
• 
A figure of Kaplan-Meier estimate of TFR (treated clinical relapse: optic neuritis) will 
be presented by treatment group. 
• 
Analysis of TFR (clinical relapse) will be performed using the stratified log-rank test. 
• 
Analysis of TFR (treated clinical relapse) will be performed using the stratified log-
rank test. 
• 
Analysis of TFR (treated clinical relapse: optic neuritis) will be performed using the 
stratified log-rank test. 
• 
Analysis of TFR (clinical relapse) will be performed using the stratified Cox regression. 
• 
Analysis of TFR (treated clinical relapse) will be performed using the stratified Cox 
regression. 
• 
Analysis of TFR (treated clinical relapse: optic neuritis) will be performed using the 
stratified Cox regression. 


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• 
Analysis of TFR (protocol-defined relapse based on CEC adjudication (regardless of 
assessment limit of 7 days)) will be performed using the stratified Cox regression. 
• 
Analysis of TFR (protocol-defined relapse based on EDSS/FSS increase relative to 
baseline) will be performed using the stratified Cox regression. 
• 
TFR (clinical relapse) is defined if the relapse will be reported in eCRF. TFR (treated 
clinical relapse) is defined if the subject received rescue therapy for clinical relapse. 
• 
A by-subject listing of TFR, which also includes clinical relapse, treated clinical 
relapse, treated clinical relapse: optic neuritis, will be provided. 
5.10.3 Secondary Efficacy Variables 
The key secondary efficacy endpoints are change from baseline in VAS for pain score and 
the FACIT fatigue scale score at week 24. All efficacy analyses will be based on the ITT 
population in double-blind period. 
5.10.3.1 Key Secondary Endpoints 
• 
Analysis of change in VAS for pain score from baseline at week 24 using ANCOVA. 
• 
Analysis of change in FACIT fatigue scale score from baseline at week 24 using 
ANCOVA. 
The ANCOVA will include treatment group as fixed effect; the baseline measurements and 
stratification factors as covariates.  
The missing data will be imputed by baseline observation carried forward (BOCF) method.  
For sensitivity analysis, random hot deck multiple imputation method using a regression 
based approach will be conducted. In this imputation method, missing values will be 
replaced with values from a similar responding unit. Uncertainty with this imputation will 
be considered via Multiple Imputations (MI) combining rules (Rubin, 1987; Little, 1988).  
• 
Analysis of change in VAS for pain score from baseline at week 24 using ANCOVA 
by hot deck multiple imputation method. 
• 
Analysis of change in FACIT fatigue scale score from baseline at week 24 using 
ANCOVA by hot deck multiple imputation method. 
The imputation for FACIT fatigue questionnaire written in Section 5.10.1.8 will be applied 
before conducting multiple imputations. 
The following summary tables and analyses will also be provided: 
• 
A summary table of change in VAS for pain score from baseline to every 24 weeks.  
• 
A summary table of change in FACIT fatigue scale score from baseline to every 24 
weeks.  
• 
Analysis of change in VAS for pain score from baseline to every 24 weeks using 
MMRM analysis.  
• 
Analysis of change in FACIT fatigue scale score from baseline to every 24 weeks using 
MMRM analysis.  


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The MMRM will include treatment group, protocol-specified visit, treatment-by-visit 
interaction as fixed effects; the baseline measurements and stratification factors as a 
covariate; and visit as a repeated measure. The unstructured covariance matrix will be 
assumed in the model.  
If the unstructured covariance matrix does not converge, other covariance structure will be 
used. If treatment-by-visit interaction is not statistically significant, the full model will be 
kept. 
If the normality assumption for the key secondary variable does not hold, GEE or 
Generalized Linear Mixed-effect model analysis will be used. The assessment will be 
performed prior to unblinding. 
5.10.3.2 Other Secondary Endpoints 
The following summary tables, figures and analysis will be provided for the ITT: 
• 
A summary table of change in SF-36 domain scores from baseline to every 24 weeks. 
• 
A summary table of change in SF-36 summary score (physical and mental) from 
baseline to every 24 weeks. 
• 
A summary table of change in EQ-5D scores from baseline to every 24 weeks. 
• 
A summary table of the proportion of relapse-free subjects. 
• 
A summary table of ARR (protocol-defined relapse). 
The ARR is calculated as the total number of relapses experienced divided by the 
person-years at risk. The 95% CI will be presented based on the Poisson distribution. 
ARR based on the person-years at risk on the total study period will also be provided. 
In order to account for different study treatment exposure durations among subjects, 
log-transformed exposure time will be included in the model as an “offset” variable for 
appropriate computation of ARR. 
• 
A summary table of ARR (clinical relapse). 
• 
A summary table of ARR (treated clinical relapse). 
• 
Analysis of ARR will be performed using negative binomial regression model 
(protocol-defined relapse). 
For comparing the difference between 2 treatment arms, relapse number will be the 
response variable; treatment group, baseline ARR and geographic region as covariates 
Log-transformed exposure time will be included in the model as an “offset” variable. 
• 
 summary table of change in mRS scores from baseline to every 24 weeks. 
• 
A summary table of change in ZBI scores from baseline to every 24 weeks. 
• 
A summary table of change in EDSS scores from baseline to every 24 weeks. 
• 
A summary table of change in visual acuity (Snellen chart) scores from baseline to 
every 24 weeks. 


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• 
Analysis of change in SF-36 domain scores from baseline to every 24 weeks using 
MMRM analysis. 
• 
Analysis of change in SF-36 components (physical and mental) from baseline to every 
24 weeks using MMRM analysis. 
• 
Analysis of change in EQ-5D scores from baseline to every 24 weeks using MMRM 
analysis. 
• 
Analysis of change in mRS scores from baseline to every 24 weeks using MMRM 
analysis. 
• 
Analysis of change in ZBI scores from baseline to every 24 weeks using MMRM 
analysis. 
• 
Analysis of change in EDSS scores from baseline to every 24 weeks using MMRM 
analysis.  
The MMRM will include treatment group, protocol-specified visit, treatment-by-visit 
interaction as fixed effects; the baseline measurements and stratification factors as 
covariates; and visit as a repeated measure. The unstructured covariance matrix will be 
assumed in the model. 
If the unstructured covariance matrix does not converge, compound symmetric structure 
will be used. If treatment-by-visit interaction is not statistically significant, the full model 
will be kept. 
If the normality assumption for other secondary variables does not hold, GEE or 
Generalized Linear Mixed-effect model analysis will be used. The assessment will be 
performed prior to unblinding. 
5.10.3.3 Examination of Adolescents 
The following endpoints will be presented for the adolescent population in listings:  
• 
TFR (protocol-defined relapse). 
• 
EDSS scores. 
• 
Visual acuity (Snellen chart) scores. 
• 
SF-36 domain scores. 
• 
SF-36 summary score (physical and mental). 
• 
VAS for pain score. 
• 
FACIT fatigue scale score. 
• 
EQ-5D scores. 
• 
mRS scores. 
• 
ZBI scores. 


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5.11 Safety Evaluation 
Unless otherwise specified, all safety analyses will be based upon the SAF for double blind 
period and All SA237 for overall period as defined in Section 5.5.  
Subgroup population was defined in Section 5.5. 
If we have low numbers of AEs only listings may be provided. 
5.11.1 Extent of Exposure  
Duration of exposure to study drug (days) is defined as date of last dose - date of first dose 
+ 1, and will be summarized.  
Number of doses and total cumulative dose of study drug will be summarized. Descriptive 
statistics will be presented by treatment group.  
5.11.2 Adverse Events 
Adverse events will be coded using most recent version of MedDRA. All summaries will 
be sorted alphabetically by System Organ Class (SOC) and preferred term (PT), starting 
with the most frequent event. All adverse events reported in whole study will be reported 
in listings. For AEs, if the AE intensity is missing, the worst case (severe) will be assumed. 
If the drug relationship is missing, the worst case (drug related) will be assumed. In 
summaries, multiple occurrences of the same PT event in one individual counted only once.  
The following summary tables of AEs will be provided:  
• An overall summary of AEs will be presented. It will include the number and percentage 
of subjects with at least 1 AE, serious AE, AE leading to early discontinuation of 
treatment, and severe AE and number of death. 
• A summary of AEs by SOC and PT.  
• A summary of AEs by Intensity, SOC and PT. 
• A summary of AEs leading to discontinuations of treatment. 
• 
A summary of AEs leading to drug interruption. 
• A summary of adverse drug reactions (ADRs) by SOC and PT. 
• A by-subject listing of all AEs. 
• A by-subject listing of all AEs leading to treatment discontinuation. 
• A by-subject listing of all AEs leading to drug interruption. 
• A by-subject listing of all ADRs. 
5.11.3 Serious Adverse Events and Death 
SAE will be provided by treatment group. SAE will be provided by subgroups defined in 
Section 5.5. As for C-SSRS, scores reported in Baseline and Prior to study page of CRF 
will be handled as baseline score. Scores reported in Since Last Visit and Since Study Start 


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page of CRF will be summarized by visit when the data is recorded. The following 
summary tables of SAEs will be provided: 
• 
A summary of incidence of serious AEs (SAEs) by SOC and PT. 
• 
A summary of incidence of SAEs leading to discontinuation by SOC and PT. 
• 
A by-subject listing for all deaths. 
• 
A summary of C-SSRS. 
• 
A by-subject listing of C-SSRS. 
5.11.4 AESI: ALT/AST, Infection Agent Transmission and Selected AEs 
AESI are defined in the protocol as follows and collected in the eCRF using a specific 
question. The following summary tables and listings will be provided: 
• A summary of AESI by SOC and PT. 
• Suspected transmission of an infectious agent by the study drug. 
• A by-subject listing of all AESI. 
• 
A by-subject listing for infection (SOC: Infections and infestations) medicated by IV 
treatment. 
• 
A by-subject listing for opportunistic infection (defined by MedDRA basket in 
Appendix) medicated by PO treatment. 
AST and ALT will be categorized into four group (>3-5 xULN, 6-10 xULN, 11-20 xULN 
and 21- xULN) based on maximum post-baseline levels within baseline and post-baseline 
respectively for each test by maximum post-baseline levels for total bilirubin and alkaline 
phosphatase (total bilirubin <= 2xULN, total bilirubin > 2xULN, total bilirubin > 2xULN 
and alkaline phosphatase < 2xULN, total bilirubin > 2xULN and alkaline phosphatase <= 
5xULN). The denominator is the number of subjects with any valid assessment at baseline 
and post-baseline respectively. Subjects with AST or ALT results fulfilling criteria for 
more than one category are counted only once, in the category indicating the highest 
elevation level within baseline and post-baseline. 
• Summary of AST and ALT Results. 
5.11.5 Infections, Serious Infection, Opportunistic Infection  
• Serious adverse event in “SOC: Infections and infestations” will be summarized. 
Opportunistic infections are defined by MedDRA basket in Appendix.. Serious 
infection will be provided per 100 subject-year by treatment group during the double 
blind period. The patient-years will be based on the double blind period for safety 
analysis (see section 5.2). The rate per 100 subject-years by treatment group (along with 
the 95% CI) will be calculated for serious infections.  
The number of serious infections per 100 subject-years is calculated as:  
Total number of serious infections / Total number of subject-years ×100  
 


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The 95% CI for the number of serious infections per 100 subject-years is calculated as 
follows:  
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 serious infections, T is total number of subject-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 serious infections is zero.   
The following summary tables will be provided. 
• A summary of serious infection by SOC and PT. 
• Rates of serious infections by 100 patient-years. 
• A by-subject listing of Infections. 
• A by-subject listing of Opportunistic Infections. 
5.11.6 Anaphylaxis 
Anaphylaxis is defined by MedDRA SMQ “Anaphylactic reaction - Narrow” and will 
be listed.  
• A by-subject listing of Anaphylaxis. 
5.11.7 IRR and ISR 
IRR in CRF selected AE (IRR) page will be summarized. ISR flagged as “Injection site 
reaction” in CRF selected AE (IRR) or general AE page will be summarized. The following 
summary tables will be provided:  
• 
A summary of IRRs. 
• 
A summary of ISRs by SOC and PT. 
• 
A by-subject listing of all IRRs.  
• 
A by-subject listing of all ISRs. 
 
5.11.8 Safety evalutions for the Adolescent population 
The following analyses will be provided for the Adolescent population: 
• A by-subject listing of all AESI. 
• A by-subject listing of all SAE. 
• A by-subject listing of all IRRs. 
• A by-subject listing of all Infections. 
• A by-subject listing of C-SSRS. 
 


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5.11.9 Clinical Laboratory Evaluation 
For continuous laboratory measurements including hematology, clinical chemistry, and 
urinalysis, summary using descriptive statistics of the actual values and their change from 
baseline will be presented by treatment group at each visit. The laboratory tests to be 
performed are presented in Table 4-4. 
When analyzing categorical data, the number and percentage of subjects in each category 
will be presented. In addition, shift tables may be used to evaluate the number and 
percentage of subjects having a different post-baseline status when compared to their 
baseline status. 
A subject data listing will be provided for all laboratory data. Values outside the normal 
range will be flagged within the listing. A subject data listing will also be provided for all 
treatment emergent marked laboratory abnormalities (see Section 7.1). 
The following summaries, listings and figures will be provided: 
• 
A summary of each laboratory parameter in Table 4-4 and change from baseline will 
be provided by visit. 
• 
A shift table based on the normal range for each laboratory parameter will be presented 
by double-blind period endpoint value relative to baseline by treatment group. 
• 
A by-subject listing of laboratory parameters. 
The summaries above will be provided by treatment group. 
Table 4-4 
Laboratory measurements 
Hematology 
Clinical chemistry 
Urinalysis 
Complement 
Hematocrit 
Hemoglobin 
International 
normalized ratio 
Platelet count  
Red blood cell 
(RBC) count WBC 
count 
Absolute 
differential count 
(neutrophils, 
eosinophils, 
lymphocytes, 
monocytes, 
basophils, other 
cells) 
Calcium 
Phosphorus 
Serum electrolytes 
(sodium, potassium, 
chloride) 
Ferritin 
Albumin 
Total serum protein 
Blood urea nitrogen 
(BUN) 
Creatinine 
Uric acid  
Alkaline 
phosphatase 
AST 
ALT 
GGT 
Total bilirubin 
Fibrinogen 
Glucose 
Protein 
Urinary occult 
blood 
Urobilinogen 
Complement tests 
(C3, C4 and CH50) 


Chugai Pharmaceutical co. Ltd. 
 
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Lactate 
dehydrogenase 
(LDH) 
Total cholesterol 
Low density 
lipoprotein (LDL) 
cholesterol 
High density 
lipoprotein (HDL) 
cholesterol 
Triglycerides 
Creatine kinase 
(CK) 
 
5.11.10 
Electrocardiograms 
For quantitative ECG measurements (heart rate, PR interval, QRS duration, QT interval, 
and corrected QT intervals using Bazett and Fridericia correction methods), values during 
the double-blind period will be presented by treatment group for all visits. 
The Bazett corrected QT (QTcB) will be calculated as 
QTcB=QT/RR0.5, where RR = 60/HR. 
The Fridericia corrected QT (QTcF) will be calculated as 
QTcF=QT/RR0.33, where RR = 60/HR. 
The following summaries and listings will be provided: 
• 
A summary of 12-lead by treatment group at each specified visit. 
• 
The number and percentage of subjects with a QTc (using Bazett and Fridericia 
corrected) of 450ms, >450 to 480ms, >480 to 500ms, and >500ms will be 
summarized by treatment group at each specified visit. 
• 
The number and percentage of subjects with a QTc (using Bazett and Fridericia 
corrected) of an increase from baseline of >0 to 30ms, >30 to 60ms, and >60ms will 
be summarized by treatment group at each specified visit. 
• 
The number and percentage of subjects with PR interval values 120ms, >120 to 
220ms, and >220ms, and the number and percentage of subjects with QRS interval 
values 60ms, >60 to 120ms, and >120ms will be presented by treatment group at 
each specified visit. 
• 
The number and percentage of subjects with abnormal ECG findings at Visit 1, and the 
number and percentage of subjects in the SAF with an abnormal ECG after the start of 
dose of study medication drug will be summarized by visit and treatment group in 
separate tables. Subjects with a clinically relevant abnormal ECG as determined by the 
investigator will be listed. 


Chugai Pharmaceutical co. Ltd. 
 
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• 
A summary of incidence of treatment-emergent abnormality 12-lead ECG findings 
after start of study drug by treatment group. 
• 
A by-subject listing of abnormal 12-lead ECG data will be provided. 
5.11.11 
Vital Signs, Physical Findings and Other Observations Related to 
Safety 
Noninvasive pulse rate, temperature, systolic blood pressure (SBP) and diastolic blood 
pressure (DBP) will be measured at visits with the subject in a sitting position after at least 
10 minutes at rest, according to the tabular schedule of study procedures in the protocol. 
Summary statistics of the actual measurement and their changes from baseline will be 
presented by treatment group at each specified visit. 
In addition, summary statistics for the actual value and change from baseline will be 
presented by treatment group for all visits during the double-blind period. 
Abnormal vital signs will be summarized by treatment group for double-blind and 
extension period. 
 
Abnormal vital sign criteria as follows: 
- 
 diastolic blood pressure [DBP]: <50, >90, >100 mmHg 
- 
 systolic blood pressure [SBP]: <90, >140, >160 mmHg 
- 
 pulse rate [PR]: <60, >100 bpm 
- 
 Temperature: <36.0, >38.0 
The following summaries and listings will be provided: 
• 
A summary of pulse rates, temperature, blood pressure and change from baseline by 
treatment group and visit. 
• 
The number and percentage of subjects with abnormal vital signs during double-blind 
period and extension period by treatment group. 
• 
A by-subject listing of vital signs. 
5.12 Pharmacokinetics and Pharmacodynamics 
The serum SA237 concentrations will be reported using the PK-PPS. The PD variables (IL-
6, sIL-6R, hsCRP, anti-AQP4Ab, plasmablast) will be reported using the SAF population. 
To determine the concentrations of SA237, serum samples will be drawn at various time 
points throughout the study. At Week 0, blood specimens for PK and PD samples will be 
collected prior to first dose administration of study drug (blank value). At other visits, PK 
and PD samples will be collected along with hematology samples at any time prior to study 
drug administration according to the Schedule of Study assessments. 
 To support the Japanese BLA, the following reports will be produced. Concentration for 
SA237 and PD variables in serum will be listed and summarized using descriptive statistics 
(including geometric mean and CV%, arithmetic mean and SD, median, observed 
maximums and minimums, and sample size). Arithmetic mean ±  SD serum concentration-


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
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time profile and combined all subjects serum concentration-time profiles (spaghetti plot) 
will be plotted using linear and semi-log scale. In addition, individual serum concentration-
time profile will be plotted for each subjects using linear and semi-log scale. 
Concentration for SA237 and PD variables (absolute values as well as change from 
baseline) in serum will be summarized using descriptive statistics and arithmetic mean ±  
SD serum concentration-time profile will be plotted by following subgroup using linear 
scale. 
Samples that were excluded from the summary statistics will be marked in the listing. 
Summary tables, figures, and listings of SA237 concentration and PD variables will be 
provided as follows: 
• 
Summaries of concentrations of SA237 by visit will be presented by age category, 
Japanese/non-Japanese, relapse/no-relapse, ADA status, and overall. 
• 
Summary of concentration of IL-6, sIL-6R, and hsCRP by visit will be presented by 
age category, Japanese/non-Japanese, relapse/no-relapse and overall in each of 
treatment group. 
• 
Summary of titer for anti AQP4 antibody status, Plasmablast (Plasmablasts/CD19+ (%), 
Plasmablasts/CD45+ (%), and Plasmablasts (cells/uL)), and CD19+ cells 
(CD19+/CD45+ (%) and CD19+ (cells/uL)) by visit will be presented by 
NMO/NMOSD and AQP4 Status, relapse/no-relapse and overall in each of treatment 
group. 
*Plasmablast and CD19+ cells will be calculated by following equation 
➢ Plasmablasts (cells/uL) = CD45+Abs * Plasmablasts/CD45+ (%) 
➢ CD19+ (cells/uL) = CD45+Abs * CD19+/CD45+ (%) 
• 
A by-subject listing of concentration for SA237 in serum. 
• 
A by-subject listing of IL-6, sIL-6R, and hsCRP 
• 
A by-subject listing of anti-AQP4 antibody (positive/negative and titer) 
• 
Plasmablast (Plasmablasts/CD19+(%), Plasmablasts/CD45+(%), and Plasmablast 
(cells/uL)), and CD19+ cells (CD19+/CD45+(%) and CD 19+ (cells/uL)) 
• 
A by-subject spaghetti plot of concentration for SA237 in serum by subgroup (age 
category, Japanese/non-Japanese, relapse/no-relapse, ADA status) using linear scale 
and overall using linear and semi log scale. 
• 
A by-subject spaghetti plot of the absolute value and the change from baseline for 
concentration of IL-6, sIL-6R, and hsCRP by treatment group using linear and semi log 
scale. 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
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Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 34 of 58 
• 
A by-subject spaghetti plot of the absolute value for concentration of IL-6, sIL-6R, and 
hsCRP by subgroup (age category, Japanese/non-Japanese, relapse/no-relapse, ADA 
status) in each of treatment group using linear scale 
• 
A by-subject spaghetti plot of the absolute value for concentration of IL-6, sIL-6R, and 
hsCRP by treatment group in each subgroup (age category, Japanese/non-Japanese, 
relapse/no-relapse, ADA status) using linear scale 
• 
A by-subject spaghetti plot of the absolute value and the change from baseline for  titer 
of anti-AQP4 antibody, Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ 
(%), and Plasmablasts (cells/uL)), and CD19+ cells (CD19+/CD45+ (%), and CD19+ 
(cells/uL)) by treatment group using linear and semi-log scale 
• 
A by-subject spaghetti plot of the absolute value for titer of anti-AQP4 antibody, 
Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ (%), and Plasmablasts 
(cells/uL)), and CD19+ cells (CD19+/CD45+ (%), and CD19+ (cells/uL)) by subgroup 
(NMO/NMOSD and AQP4 Status, relapse/no-relapse) in each of treatment group using 
linear scale. 
• 
A by-subject spaghetti plot of the absolute value for titer of anti-AQP4 antibody, 
Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ (%), and Plasmablasts 
(cells/uL)), and CD19+ cells (CD19+/CD45+ (%), and CD19+ (cells/uL)) by treatment 
group in each subgroup (NMO/NMOSD and AQP4 Status, relapse/no-relapse) using 
linear scale. 
• 
An Arithmetic mean ±  SD plot of concentration for SA237 in serum by subgroup (age 
category, Japanese/non-Japanese, relapse/no-relapse, ADA status) using linear scale 
and overall using linear and semi log scale. 
• 
An Arithmetic mean ±  SD plot of the absolute value and the change from baseline for 
concentration of IL-6, sIL-6R, and hsCRP by treatment group using linear and semi-
log scale. 
• 
An Arithmetic mean ±  SD plot of the absolute value for concentration of IL-6, sIL-
6R, and hsCRP by subgroup (age category, Japanese/non-Japanese, relapse/no-relapse, 
ADA status) in each of treatment group using linear scale. 
• 
An Arithmetic mean ±  SD plot of the absolute value for concentration of IL-6, sIL-
6R, and hsCRP by treatment group in each subgroup (age category, Japanese/non-
Japanese, relapse/no-relapse, ADA status) using linear scale 
• 
An Arithmetic mean ±  SD plot of the absolute value and the change from baseline for 
titer 
of 
anti-AQP4 
antibody, 
Plasmablast 
(Plasmablasts/CD19+ 
(%), 
Plasmablasts/CD45+ (%), Plasmablasts (cells/uL)), and CD19+ cells (CD19+/CD45+ 
(%) and CD19+ (cells/uL)) by treatment group using linear and semi-log scale 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 35 of 58 
• 
An Arithmetic mean ±  SD plot of the absolute value for titer of anti-AQP4 antibody, 
Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ (%), Plasmablasts 
(cells/uL)), and CD19+ cells (CD19+/CD45+ (%) and CD19+ (cells/uL)) by subgroup 
(NMO/NMOSD and AQP4 Status, relapse/no-relapse) in each of treatment group using 
linear scale 
• 
An Arithmetic mean ±  SD plot of the absolute value for titer of anti-AQP4 antibody, 
Plasmablast (Plasmablasts/CD19+ (%), Plasmablasts/CD45+ (%), Plasmablasts 
(cells/uL)), and CD19+ cells (CD19+/CD45+ (%) and CD19+ (cells/uL)) by treatment 
group in each subgroup (NMO/NMOSD and AQP4 Status, relapse/no-relapse) using 
linear scale. 
• 
A by-subject listing of actual doses, date and time of sampling, visit, relative day, and 
the accession number.  
• 
Scatter plot of anti-AQP4 antibody titer versus plasmablast (Plasmablasts/CD19+ (%), 
Plasmablasts/CD45+ (%), Plasmablasts (cells/uL)) will be presented at Weeks 0, 2 and 
4, 8, 12, 24, and Q24W. When the data of anti-AQP4 antibody is negative, put “1” as 
a titer for negative samples and replace to “BLQ”. 
• 
Scatter plots of serum SA237 concentration versus body weight at weeks 2, 4, Q4W 
respectively. 
5.13 Immunogenicity 
ADA subgroup using confirmatory sample status are defined as below. 
➢ ADA negative subjects: subjects without positive ADA during study. If sample at 
baseline is missing and no sample after the the baseline  is positive, the subject is 
defined as ” ADA negative subjects”. 
➢ ADA unaffected subjects: subjects who have pre-existing ADA (POSITIVE at 
baseline) that was NOT boosted to a higher level after the post dose. “NOT boosted 
to a higher level” means that ADA titer after the baseline is <fourfold than the ADA 
titer at baseline. 
➢ Treatment-boosted ADA subjects: subjects who have pre-existing ADA that was 
boosted to a higher level at least one time point after baseline “Boosted to a higher 
level” means  as follow 
1) ADA titer after the baseline is greater fourfold than the ADA titer at baseline  
➢ Treatment-induced ADA subjects: subjects who have positive ADA not at baseline 
but after the baseline. If sample at baseline is missing and at least one sample after the 
baseline is positive, the subject is defined as ” Treatment-induced ADA subjects” 
The immunogenicity will be analyzed using the SAF population. 
• 
The numbers and proportions of subjects with positive ADA at baseline will be 
presented by treatment group and overall. 
• 
The numbers and proportions of ADA negative subjects, ADA unaffected subjects, 
treatment-boosted ADA subjects, and treatment-induced ADA subjects will be 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
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Related to: SOP-GRO-WW-019 
 
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summarized. The numbers and proportions of transient ADA and persistent ADA will 
be summarized in the treatment-induced ADA subjects. 
Transient ADA: 1) Treatment-induced ADA detected only at one sampling time point 
(excluding the last sampling time point) during the study or 2) treatment-induced ADA 
detected at two or more sampling time points during the study, where the period between 
first and last ADA-positive sampling time points is less than 16 weeks, and the subject’s 
last sampling time point is ADA-negative. 
Persistent ADA: 1) Treatment-induced ADA detected at two or more sampling time points 
during the study, where the period between first and last ADA-positive sampling time 
points is 16 weeks or longer or 2) where the period between first and last ADA-positive 
sampling time points is less than 16 weeks, and the subject’s last sampling time point is 
ADA-positive or 3) treatment-induced ADA detected only at the last sampling time point.  
➢ The numbers and proportions of patients with positive/negativeanti-SA237 
antibody and neutralizing antibody will be presented at Week 0 and Q4W in SA237 
group by visit. 
➢ A by-subject 
listing of anti-SA237 antibody (confirmatory judgment 
(positive/negative), titer, ratio of peak titer/baseline titer, and ADA subgroup), 
neutralizing judgment (positive/negative)), and adverse events in the subject having 
anti-SA237 antibody at least once at any point in time. 
5.14 Determination of Sample Size 
Approximately 70 subjects need to be recruited and randomized in a 1:1 ratio to the two 
treatment groups (SA237 and placebo). The sample size considerations are based on the 
following assumptions: 
• 
A two-sided log-rank test 
• 
80% power at the 5% significance level 
• 
A 66.5% reduction in the risk of relapse, i.e. the TFR hazard ratio of SA237 over 
placebo is 0.335 
• 
TFR in the placebo arm following an exponential distribution, with hazard rate for one 
year h(t) = 0.4184 
• 
A 2-year dropout rate of 10% 
Based on the assumptions, 26 TFR events are needed for the primary analysis. TFR events 
are defined as protocol-defined relapses confirmed by the CEC with EDSS/FSS assessment 
performed by the examining assessor within 7 days after relapse symptoms were reported 
to site by the subject. The maximum accrual rate is estimated to be approximately 8 subjects 
per month, after the FPI plus 8 months of ramp up. The 70 subjects enrolled over one year 
and followed for an additional one and a half year will provide 26 TFR events. The primary 
analysis will be performed once 26 TFR events have been observed. Sponsor will conduct 
blind review during the double-blind period and might take appropriate action based on 
blind review. 


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Since the annualized relapse rate (ARR) is the number of relapse counts observed when 
every subject is observed for a year and suppose that the distribution follows a Gamma-
Poisson distribution and that the mean and variance ratio (variance / mean) is a constant 
value of √2. The ratio was estimated using MS trials’ data1, 2) because there are no approved 
medications for NMO. 
Because the mean ARR of NMO subjects is estimated at 0.7533) and eligibility criterion 2 
says more than one ARR subjects are selected, we calculate the zero-truncated mean of the 
Gamma-Poisson distribution with the mean of 0.75 and the mean and variance ratio of √2, 
then the baseline ARR is estimated at 1.6. The two phase III MS trials above reported that 
pre- and post- baseline ARR in the placebo group were 1.4 and 0.4, so the post-baseline 
ARR in placebo group in this trial is estimated at 0.5. 
Using the proportion of zero under supposed ARR distribution, we estimate the relapse-free 
rate at a year in placebo group at 65.8%. The relapse-free rate is assumed to follow the 
exponential distribution with a constant hazard, and then we set the hazard for one year of 
0.4184 in placebo group. 
According to tocilizumab case report in NMO subjects, the pre- and post- baseline relapse 
counts were reduced from total 4 counts per 6 months to 1 count per 6 months. Then the 
pre- and post- baseline ratio of 0.25 is used as the estimation of the mean ARR ratio of 
tocilizumab compared with placebo. Moreover, the azathioprine’s data showed the pre- 
and post- baseline mean ARR ratio was 0.33 (= 0.77/2.32, the mean ARR were estimated 
from the median ARR and the distribution supposition above) and the rituximab data 
showed the pre- and post- baseline mean ARR ratio was 0.125 (= 0.3/2.4), then we estimate 
the rituximab mean ARR ratio compared with azathioprine at 0.38 (= 0.125/0.33). 
Under the assumption of ARR and relapse-free rate distribution above, the mean ARR ratio 
is coincided with the hazard ratio. Tocilizumab hazard ratio data (0.25) could have a 
possibility of overestimation because of the case report with only three subjects and the 
hazard ratio between rituximab and azathioprine (0.38) is the comparison with an active 
control, then we consider the SA237 hazard ratio compared to placebo should exist 
between 0.25 and 0.38. So we have set the SA237 hazard ratio compared with placebo at 
0.335. 
 
 


Chugai Pharmaceutical co. Ltd. 
 
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 6 REFERENCES  
[1] Maruish ME. User’s manual for the SF-36v2 Health Survey (3rd ed.). Lincoln, RI: 
QualityMetric Incorporated. 2011. 
[2] Rubin, DB. Multiple Imputation for Nonresponse in Surveys. New York: Wiley; 1987. 
[3] Little RJA. Missing-data adjustments in large surveys. J Buss Econ Stat. 1988; 6:287–
296. 
[4] Gold R, Kappos L, Arnold DL et al. Placebo-controlled phase 3 study of oral BG-12 
for relapsing multiple sclerosis. N Engl J Med. 2012; 367: 1098-107. 
[5] Kappos L, Radue EW, O'Connor P et al. A placebo-controlled trial of oral fingolimod 
in relapsing multiple sclerosis. N Engl J Med. 2010; 362: 387-401. 
[6] Cossburn M, Tackley G, Baker K et al. The prevalence of neuromyelitis optica in South 
East Wales. Eur J Neurol. 2012; 19: 655-9.  
 
 


Chugai Pharmaceutical co. Ltd. 
 
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Version Date: 20Apr18 
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Page 39 of 58 
7 
APPENDIX 
7.1 Laboratory Data Conversion and Transformation Rules 
 
Conversion to Système International (SI) Units 
Laboratory data should be stored on the database in the units in which they were originally 
delivered by the laboratory.  
For analysis and reporting purposes, the data will be converted to SI units to allow the 
comparison of data delivered in different original units.  
Results that include inequality sign will be converted into a numeric form removing 
inequality sign. 
Results that cannot be converted into an expected numeric form nor interpreted, such as 
alphabetic entries like “adequate”, will usually not be further processed, but displayed in 
patient listings. 
 
 
Marked Laboratory Abnormalities 
For each laboratory test, a Marked Abnormality Range has been defined. A value outside of 
this range is considered to be potentially clinically relevant. This Marked Abnormality 
Range is wider than the Reference Range.  
In addition, for each laboratory test, a percentage change, as an increase and/or decrease, has 
been defined which represents a clinically relevant change from baseline. 
A Marked Abnormality is therefore defined as a test result: 
which is outside of the Marked Abnormality Range,  
and 
which also represents a clinically relevant change from baseline of at least the designated 
amount  
during or within 30 days after end of trial treatment.  
Baseline is taken as the last valid value before starting treatment. If no baseline is available, 
the midpoint of the Reference Range will be substituted for processing purposes for 
determination of Marked Abnormalities.  
For urinalysis a missing baseline value will be replaced by 0 (zero).  
NOTE: For calculating means and mean changes over time, missing values will not be 
included. If no baseline is available, no change from baseline will be calculated. 
Values above and below the Reference Range are flagged on the listing by H and L, 
respectively. Marked Abnormalities are flagged by HH or LL. 
 
 


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 
Reference Ranges 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
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Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 41 of 58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
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Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
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 
Formula for Linear Transformation 
RT = SL + [(RU - IL) / (IH - IL)]*(SH - SL) 
RT : transformed value 
RU : untransformed value 
IL : IH investigator limits, low and high 
SL : SH reference limits, low and high 
For female to male transformation replace IL, IH by the reference limits for female, and SL, SH 
by the reference limits for male. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
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7.2 MedDRA basket 
Opportunistic infections 
Meningomyelitis 
herpes 
Capnocytophaga 
test positive 
Eye infection 
toxoplasmal 
Histoplasmosis 
disseminated 
Mycobacterium 
ulcerans 
infection 
Pulmonary 
trichosporonosis 
Abscess fungal 
Central nervous 
system fungal 
infection 
Eye infection 
viral 
Human 
anaplasmosis 
Mycotic corneal 
ulcer 
Pulmonary 
tuberculoma 
Acid fast bacilli 
infection 
Central nervous 
system viral 
infection 
Female genital 
tract tuberculosis 
Human 
bocavirus 
infection 
Mycotic 
endophthalmitis 
Pulmonary 
tuberculosis 
Acinetobacter 
bacteraemia 
Cerebral 
aspergillosis 
Flavobacterium 
infection 
Human 
ehrlichiosis 
Myocarditis 
mycotic 
Pyelonephritis 
fungal 
Acinetobacter 
infection 
Cerebral 
candidiasis 
Focal epithelial 
hyperplasia 
Human 
herpesvirus 8 
infection 
Myocarditis 
toxoplasmal 
Q fever 
Acute 
haemorrhagic 
conjunctivitis 
Cerebral fungal 
infection 
Fungaemia 
Indeterminate 
leprosy 
Nasal herpes 
Raoultella 
ornithinolytica 
infection 
Acute hepatitis B 
Cerebral 
toxoplasmosis 
Fungal abscess 
central nervous 
system 
Infection in an 
immunocompro
mised host 
Necrotising 
fasciitis fungal 
Renal 
tuberculosis 
Acute hepatitis C 
Cervix warts 
Fungal cystitis 
Intestinal 
tuberculosis 
Necrotising 
herpetic 
retinopathy 
Respiratory 
moniliasis 
Acute pulmonary 
histoplasmosis 
Chromoblastomy
cosis 
Fungal 
endocarditis 
Isosporiasis 
Neurocryptococc
osis 
Respiratory tract 
infection fungal 
Adrenal gland 
tuberculosis 
Chronic 
pulmonary 
histoplasmosis 
Fungal 
labyrinthitis 
JC virus granule 
cell 
neuronopathy 
Neutropenic 
infection 
Retinitis 
histoplasma 
Aeromonas 
infection 
Coccidioides 
encephalitis 
Fungal 
oesophagitis 
JC virus 
infection 
Neutropenic 
sepsis 
Retinitis viral 
Aeromonas test 
positive 
Coccidioidomyc
osis 
Fungal 
peritonitis 
JC virus test 
Nocardia sepsis 
Rhodococcus 
infection 
Alcaligenes 
infection 
Colitis herpes 
Fungal 
pharyngitis 
JC virus test 
positive 
Nocardia test 
positive 
Rhodococcus 
test positive 
Allescheriosis 
Conjunctivitis 
tuberculous 
Fungal retinitis 
Joint 
tuberculosis 
Nocardiosis 
Salpingitis 
tuberculous 
Alternaria 
infection 
Coxiella 
infection 
Fungal sepsis 
Kaposi's sarcoma 
Oesophageal 
candidiasis 
Scedosporium 
infection 
Amoebiasis 
Creutzfeldt-
Jakob disease 
Fungal tracheitis 
Kaposi's sarcoma 
AIDS related 
Oesophageal 
tuberculosis 
Sepsis 
pasteurella 
Amoebic brain 
abscess 
Cronobacter 
infection 
Fusarium 
infection 
Kaposi's 
varicelliform 
eruption 
Ophthalmic 
herpes simplex 
Shewanella algae 
bacteraemia 
Amoebic colitis 
Cronobacter 
necrotising 
enterocolitis 
Gastritis fungal 
Keratitis fungal 
Ophthalmic 
herpes zoster 
Sinusitis 
aspergillus 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 44 of 58 
Amoebic 
dysentery 
Cryptococcal 
cutaneous 
infection 
Gastritis herpes 
Keratitis viral 
Opportunistic 
infection 
Sinusitis fungal 
Amoebic lung 
abscess 
Cryptococcal 
fungaemia 
Gastroenteritis 
cryptococcal 
Keratouveitis 
Oral candidiasis 
Sphingomonas 
paucimobilis 
infection 
Amoebic skin 
ulcer 
Cryptococcosis 
Gastroenteritis 
cryptosporidial 
Laryngitis fungal 
Oral fungal 
infection 
Spleen 
tuberculosis 
Anal fungal 
infection 
Cryptococcus 
test 
Gastrointestinal 
candidiasis 
Legionella 
infection 
Oral hairy 
leukoplakia 
Splenic 
candidiasis 
Angina 
gangrenous 
Cryptococcus 
test positive 
Gastrointestinal 
fungal infection 
Lepromatous 
leprosy 
Oral herpes 
Splenic infection 
fungal 
Angiostrongylus 
infection 
Cryptosporidiosi
s infection 
Genital herpes 
Leprosy 
Oral tuberculosis 
Stenotrophomon
as infection 
Anogenital warts 
Cutaneous 
coccidioidomyco
sis 
Genital herpes 
simplex 
Leptotrichia 
infection 
Oro-pharyngeal 
aspergillosis 
Stenotrophomon
as sepsis 
Anorectal human 
papilloma virus 
infection 
Cutaneous 
tuberculosis 
Genital herpes 
zoster 
Leuconostoc 
infection 
Oropharyngeal 
candidiasis 
Stomatococcal 
infection 
Anti-JC virus 
antibody index 
Cytomegalovirus 
chorioretinitis 
Granulicatella 
bacteraemia 
Listeria 
encephalitis 
Oropharyngitis 
fungal 
Stomatococcus 
test positive 
Arthritis fungal 
Cytomegalovirus 
colitis 
Granulicatella 
infection 
Listeria sepsis 
Orthopox virus 
infection 
Strongyloidiasis 
Aspergilloma 
Cytomegalovirus 
duodenitis 
Hepatic 
candidiasis 
Listeria test 
positive 
Osteomyelitis 
blastomyces 
Superinfection 
fungal 
Aspergillosis 
oral 
Cytomegalovirus 
enteritis 
Hepatic infection 
fungal 
Listeriosis 
Osteomyelitis 
fungal 
Superinfection 
mycobacterial 
Aspergillus 
infection 
Cytomegalovirus 
enterocolitis 
Hepatitis B 
Lower 
respiratory tract 
herpes infection 
Otitis media 
fungal 
Systemic 
candida 
Aspergillus test 
Cytomegalovirus 
gastritis 
Hepatitis C 
Lower 
respiratory tract 
infection fungal 
Pancreatitis 
fungal 
Systemic 
mycosis 
Aspergillus test 
positive 
Cytomegalovirus 
gastroenteritis 
Hepatitis 
toxoplasmal 
Lower 
respiratory tract 
infection viral 
Pantoea 
agglomerans 
infection 
Thyroid 
tuberculosis 
Atypical 
mycobacterial 
infection 
Cytomegalovirus 
gastrointestinal 
infection 
Hepatosplenic 
candidiasis 
Lupus vulgaris 
Paracoccidioides 
infection 
Tonsillitis fungal 
Atypical 
mycobacterial 
lower respiratory 
tract infection 
Cytomegalovirus 
gastrointestinal 
ulcer 
Herpes 
oesophagitis 
Lymph node 
tuberculosis 
Parasitic 
encephalitis 
Toxoplasmosis 
Atypical 
mycobacterial 
lymphadenitis 
Cytomegalovirus 
hepatitis 
Herpes 
ophthalmic 
Lymphadenitis 
fungal 
Parvimonas 
infection 
Tuberculoid 
leprosy 
Atypical 
mycobacterial 
pneumonia 
Cytomegalovirus 
infection 
Herpes 
pharyngitis 
Male genital 
tract tuberculosis 
Parvimonas 
micra infection 
Tuberculoma of 
central nervous 
system 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 45 of 58 
Atypical 
mycobacterium 
pericarditis 
Cytomegalovirus 
mucocutaneous 
ulcer 
Herpes sepsis 
Meningitis 
aspergillus 
Peliosis hepatis 
Tuberculosis 
Atypical 
pneumonia 
Cytomegalovirus 
myelomeningora
diculitis 
Herpes simplex 
Meningitis 
candida 
Penicillium 
infection 
Tuberculosis 
bladder 
Babesiosis 
Cytomegalovirus 
myocarditis 
Herpes simplex 
cervicitis 
Meningitis 
coccidioides 
Pericarditis 
fungal 
Tuberculosis 
gastrointestinal 
Bacillary 
angiomatosis 
Cytomegalovirus 
oesophagitis 
Herpes simplex 
colitis 
Meningitis 
cronobacter 
Pericarditis 
histoplasma 
Tuberculosis 
liver 
Balamuthia 
infection 
Cytomegalovirus 
pancreatitis 
Herpes simplex 
encephalitis 
Meningitis 
cryptococcal 
Pericarditis 
tuberculous 
Tuberculosis of 
central nervous 
system 
BK virus 
infection 
Cytomegalovirus 
pericarditis 
Herpes simplex 
gastritis 
Meningitis 
exserohilum 
Peritoneal 
candidiasis 
Tuberculosis of 
eye 
Blastocystis 
infection 
Cytomegalovirus 
syndrome 
Herpes simplex 
hepatitis 
Meningitis 
fungal 
Peritoneal 
tuberculosis 
Tuberculosis of 
genitourinary 
system 
Blastomycosis 
Cytomegalovirus 
test 
Herpes simplex 
meningitis 
Meningitis 
herpes 
Phaehyphomyco
sis 
Tuberculosis of 
intrathoracic 
lymph nodes 
Bone 
tuberculosis 
Cytomegalovirus 
test positive 
Herpes simplex 
meningoencepha
litis 
Meningitis 
histoplasma 
Pharyngeal 
abscess 
Tuberculosis of 
peripheral lymph 
nodes 
Borderline 
leprosy 
Cytomegalovirus 
urinary tract 
infection 
Herpes simplex 
meningomyelitis 
Meningitis 
listeria 
Pneumocystis 
jirovecii 
infection 
Tuberculosis 
ureter 
Botryomycosis 
Cytomegalovirus 
viraemia 
Herpes simplex 
necrotising 
retinopathy 
Meningitis 
toxoplasmal 
Pneumocystis 
jirovecii 
pneumonia 
Tuberculous 
abscess central 
nervous system 
Bovine 
tuberculosis 
Dengue fever 
Herpes simplex 
oesophagitis 
Meningitis 
tuberculous 
Pneumocystis 
test positive 
Tuberculous 
endometritis 
Brachyspira 
infection 
Disseminated 
Bacillus 
Calmette-Guerin 
infection 
Herpes simplex 
otitis externa 
Meningoencepha
litis herpes 
simplex neonatal 
Pneumonia 
blastomyces 
Tuberculous 
laryngitis 
Brevibacterium 
infection 
Disseminated 
cryptococcosis 
Herpes simplex 
pharyngitis 
Meningoencepha
litis herpetic 
Pneumonia 
cryptococcal 
Tuberculous 
pleurisy 
Bronchitis fungal 
Disseminated 
cytomegaloviral 
infection 
Herpes simplex 
pneumonia 
Meningoencepha
litis viral 
Pneumonia 
cytomegaloviral 
Tuberculous 
tenosynovitis 
Bronchopulmona
ry aspergillosis 
Disseminated 
tuberculosis 
Herpes simplex 
sepsis 
Methylobacteriu
m infection 
Pneumonia 
fungal 
Upper 
respiratory 
fungal infection 
Burkholderia 
cepacia complex 
infection 
Disseminated 
varicella zoster 
vaccine virus 
infection 
Herpes simplex 
visceral 
Microsporidia 
infection 
Pneumonia 
herpes viral 
Urinary tract 
infection fungal 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 46 of 58 
Burkholderia 
cepacia complex 
sepsis 
Ear tuberculosis 
Herpes virus 
infection 
Miliary 
pneumonia 
Pneumonia 
legionella 
Variant 
Creutzfeldt-
Jakob disease 
Burkholderia 
gladioli infection 
Encephalitis 
cytomegalovirus 
Herpes zoster 
Mucocutaneous 
candidiasis 
Pneumonia 
toxoplasmal 
Varicella 
Burkholderia 
infection 
Encephalitis 
fungal 
Herpes zoster 
cutaneous 
disseminated 
Mucormycosis 
Polyomavirus-
associated 
nephropathy 
Varicella 
keratitis 
Burkholderia 
mallei infection 
Encephalitis post 
varicella 
Herpes zoster 
disseminated 
Mycetoma 
mycotic 
Porphyromonas 
infection 
Varicella zoster 
gastritis 
Burkholderia 
pseudomallei 
infection 
Endocarditis 
candida 
Herpes zoster 
infection 
neurological 
Mycobacterial 
infection 
Presumed ocular 
histoplasmosis 
syndrome 
Varicella zoster 
oesophagitis 
Burkholderia test 
positive 
Endocarditis 
histoplasma 
Herpes zoster 
meningitis 
Mycobacterial 
peritonitis 
Progressive 
multifocal 
leukoencephalop
athy 
Varicella zoster 
pneumonia 
Candida 
endophthalmitis 
Endocarditis Q 
fever 
Herpes zoster 
meningoencepha
litis 
Mycobacterium 
abscessus 
infection 
Progressive 
vaccinia 
Varicella zoster 
virus infection 
Candida 
infection 
Enterocolitis 
fungal 
Herpes zoster 
meningomyelitis 
Mycobacterium 
avium complex 
immune 
restoration 
disease 
Prostatitis 
tuberculous 
Viral 
keratouveitis 
Candida 
osteomyelitis 
Epididymitis 
blastomyces 
Herpes zoster 
necrotising 
retinopathy 
Mycobacterium 
avium complex 
infection 
Pseudallescheria 
infection 
Viral myelitis 
Candida 
pneumonia 
Epididymitis 
tuberculous 
Herpes zoster 
oticus 
Mycobacterium 
chelonae 
infection 
Pseudallescheria 
sepsis 
Viral 
oesophagitis 
Candida retinitis 
Exserohilum 
infection 
Herpes zoster 
pharyngitis 
Mycobacterium 
fortuitum 
infection 
Pseudomonal 
sepsis 
Viral sepsis 
Candida sepsis 
Extrapulmonary 
tuberculosis 
Histoplasmosis 
Mycobacterium 
kansasii 
infection 
Pseudomonas 
aeruginosa 
meningitis 
Viral uveitis 
Capnocytophaga 
infection 
Eye infection 
fungal 
Histoplasmosis 
cutaneous 
Mycobacterium 
marinum 
infection 
Pulmonary 
mycosis 
Yersinia sepsis 
 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 47 of 58 
7.3 EQ-5D Scoring Algorithm: 
 
This program computes the U.S. preference-weighted index score using self-reported EQ-5D data.  
It is presumed that the data set includes the following 5 variables: 
Dimension               Variable Name     Range 
Mobility                       MO                  1-3 
Self-care                      SC                  1-3 
Usual activities             UA                  1-3 
Pain/discomfort            PD                  1-3 
Anxiety/depression       AD                  1-3 
Where a 1 indicates no problems, a 2 indicates moderate problems, and a 3 indicates severe problems. 
To get U.S. EQ-5D index scores, paste data to the first 5 columns and read values from the last colomn. 
The index score will not be generated when responses are missing for 1 or more of the 5 dimensions.  
If there are more than 5,000 respondents, apply the algorithms for all the variables excepte the first 5 to more lines.  
MO 
SC 
UA 
PD 
AD 
m1 
s1 
u1 
p1 
a1 
m2 
s2 
u2 
p2 
a2 
d1 
i2 
i22 
i3 
i32 
pred 
full health 
EQ-5D 
index(US_D1) 
  
3 
3 
3 
3 
3 
0 
0 
0 
0 
0 
1 
1 
1 
1 
1 
4 
0 
0 
4 
16 
-0.1090707 
-0.109 
-0.1090707 
 
3 
3 
2 
3 
3 
0 
0 
1 
0 
0 
1 
1 
0 
1 
1 
4 
0 
0 
3 
9 
-0.0996728 
-0.100 
-0.0996728 
 
3 
3 
1 
3 
3 
0 
0 
0 
0 
0 
1 
1 
0 
1 
1 
3 
0 
0 
3 
9 
-0.0995382 
-0.100 
-0.0995382 
 
3 
3 
3 
3 
2 
0 
0 
0 
0 
1 
1 
1 
1 
1 
0 
4 
0 
0 
3 
9 
-0.0402381 
-0.040 
-0.0402381 
 
3 
2 
3 
3 
3 
0 
1 
0 
0 
0 
1 
0 
1 
1 
1 
4 
0 
0 
3 
9 
-0.0383556 
-0.038 
-0.0383556 
 
3 
3 
3 
3 
1 
0 
0 
0 
0 
0 
1 
1 
1 
1 
0 
3 
0 
0 
3 
9 
-0.02361 
-0.024 
-0.02361 
 
3 
3 
2 
3 
2 
0 
0 
1 
0 
1 
1 
1 
0 
1 
0 
4 
1 
1 
2 
4 
-0.0119344 
-0.012 
-0.0119344 
 
3 
2 
2 
3 
3 
0 
1 
1 
0 
0 
1 
0 
0 
1 
1 
4 
1 
1 
2 
4 
-0.0100519 
-0.010 
-0.0100519 
 
3 
1 
3 
3 
3 
0 
0 
0 
0 
0 
1 
0 
1 
1 
1 
3 
0 
0 
3 
9 
-0.002608 
-0.003 
-0.002608 
 
3 
3 
1 
3 
2 
0 
0 
0 
0 
1 
1 
1 
0 
1 
0 
3 
0 
0 
2 
4 
-0.001113 
-0.001 
-0.001113 
 
3 
2 
1 
3 
3 
0 
1 
0 
0 
0 
1 
0 
0 
1 
1 
3 
0 
0 
2 
4 
0.0007695 
0.001 
0.0007695 
 
3 
3 
2 
3 
1 
0 
0 
1 
0 
0 
1 
1 
0 
1 
0 
3 
0 
0 
2 
4 
0.0153805 
0.015 
0.0153805 
 
3 
3 
1 
3 
1 
0 
0 
0 
0 
0 
1 
1 
0 
1 
0 
2 
0 
0 
2 
4 
0.0155151 
0.016 
0.0155151 
 
3 
3 
3 
2 
3 
0 
0 
0 
1 
0 
1 
1 
1 
0 
1 
4 
0 
0 
3 
9 
0.0300077 
0.030 
0.0300077 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 48 of 58 
3 
1 
2 
3 
3 
0 
0 
1 
0 
0 
1 
0 
0 
1 
1 
3 
0 
0 
2 
4 
0.0363825 
0.036 
0.0363825 
 
3 
1 
1 
3 
3 
0 
0 
0 
0 
0 
1 
0 
0 
1 
1 
2 
0 
0 
2 
4 
0.0365171 
0.037 
0.0365171 
 
3 
2 
3 
3 
2 
0 
1 
0 
0 
1 
1 
0 
1 
1 
0 
4 
1 
1 
2 
4 
0.0493828 
0.049 
0.0493828 
 
3 
3 
2 
2 
3 
0 
0 
1 
1 
0 
1 
1 
0 
0 
1 
4 
1 
1 
2 
4 
0.0583114 
0.058 
0.0583114 
 
3 
3 
3 
1 
3 
0 
0 
0 
0 
0 
1 
1 
1 
0 
1 
3 
0 
0 
3 
9 
0.0633035 
0.063 
0.0633035 
 
3 
3 
1 
2 
3 
0 
0 
0 
1 
0 
1 
1 
0 
0 
1 
3 
0 
0 
2 
4 
0.0691328 
0.069 
0.0691328 
 
3 
2 
3 
3 
1 
0 
1 
0 
0 
0 
1 
0 
1 
1 
0 
3 
0 
0 
2 
4 
0.0766977 
0.077 
0.0766977 
 
2 
3 
3 
3 
3 
1 
0 
0 
0 
0 
0 
1 
1 
1 
1 
4 
0 
0 
3 
9 
0.0774663 
0.077 
0.0774663 
 
1 
3 
3 
3 
3 
0 
0 
0 
0 
0 
0 
1 
1 
1 
1 
3 
0 
0 
3 
9 
0.0838874 
0.084 
0.0838874 
 
3 
2 
2 
3 
2 
0 
1 
1 
0 
1 
1 
0 
0 
1 
0 
4 
2 
4 
1 
1 
0.0859055 
0.086 
0.0859055 
 
3 
1 
3 
3 
2 
0 
0 
0 
0 
1 
1 
0 
1 
1 
0 
3 
0 
0 
2 
4 
0.0958172 
0.096 
0.0958172 
 
3 
3 
2 
1 
3 
0 
0 
1 
0 
0 
1 
1 
0 
0 
1 
3 
0 
0 
2 
4 
0.102294 
0.102 
0.102294 
 
3 
3 
1 
1 
3 
0 
0 
0 
0 
0 
1 
1 
0 
0 
1 
2 
0 
0 
2 
4 
0.1024286 
0.102 
0.1024286 
 
2 
3 
2 
3 
3 
1 
0 
1 
0 
0 
0 
1 
0 
1 
1 
4 
1 
1 
2 
4 
0.10577 
0.106 
0.10577 
 
3 
1 
3 
3 
1 
0 
0 
0 
0 
0 
1 
0 
1 
1 
0 
2 
0 
0 
2 
4 
0.1124453 
0.112 
0.1124453 
 
2 
3 
1 
3 
3 
1 
0 
0 
0 
0 
0 
1 
0 
1 
1 
3 
0 
0 
2 
4 
0.1165914 
0.117 
0.1165914 
 
3 
3 
3 
2 
2 
0 
0 
0 
1 
1 
1 
1 
1 
0 
0 
4 
1 
1 
2 
4 
0.1177461 
0.118 
0.1177461 
 
3 
2 
1 
3 
2 
0 
1 
0 
0 
1 
1 
0 
0 
1 
0 
3 
1 
1 
1 
1 
0.1181005 
0.118 
0.1181005 
 
3 
2 
3 
2 
3 
0 
1 
0 
1 
0 
1 
0 
1 
0 
1 
4 
1 
1 
2 
4 
0.1196286 
0.120 
0.1196286 
 
1 
3 
2 
3 
3 
0 
0 
1 
0 
0 
0 
1 
0 
1 
1 
3 
0 
0 
2 
4 
0.1228779 
0.123 
0.1228779 
 
1 
3 
1 
3 
3 
0 
0 
0 
0 
0 
0 
1 
0 
1 
1 
2 
0 
0 
2 
4 
0.1230125 
0.123 
0.1230125 
 
3 
2 
2 
3 
1 
0 
1 
1 
0 
0 
1 
0 
0 
1 
0 
3 
1 
1 
1 
1 
0.134594 
0.135 
0.134594 
 
3 
3 
3 
2 
1 
0 
0 
0 
1 
0 
1 
1 
1 
0 
0 
3 
0 
0 
2 
4 
0.145061 
0.145 
0.145061 
 
3 
2 
1 
3 
1 
0 
1 
0 
0 
0 
1 
0 
0 
1 
0 
2 
0 
0 
1 
1 
0.1454154 
0.145 
0.1454154 
 
3 
1 
2 
3 
2 
0 
0 
1 
0 
1 
1 
0 
0 
1 
0 
3 
1 
1 
1 
1 
0.1537135 
0.154 
0.1537135 
 
3 
3 
2 
2 
2 
0 
0 
1 
1 
1 
1 
1 
0 
0 
0 
4 
2 
4 
1 
1 
0.1542688 
0.154 
0.1542688 
 
3 
2 
2 
2 
3 
0 
1 
1 
1 
0 
1 
0 
0 
0 
1 
4 
2 
4 
1 
1 
0.1561513 
0.156 
0.1561513 
 
3 
3 
3 
1 
2 
0 
0 
0 
0 
1 
1 
1 
1 
0 
0 
3 
0 
0 
2 
4 
0.1617287 
0.162 
0.1617287 
 
3 
2 
3 
1 
3 
0 
1 
0 
0 
0 
1 
0 
1 
0 
1 
3 
0 
0 
2 
4 
0.1636112 
0.164 
0.1636112 
 
3 
1 
1 
3 
2 
0 
0 
0 
0 
1 
1 
0 
0 
1 
0 
2 
0 
0 
1 
1 
0.1645349 
0.165 
0.1645349 
 
2 
3 
3 
3 
2 
1 
0 
0 
0 
1 
0 
1 
1 
1 
0 
4 
1 
1 
2 
4 
0.1652047 
0.165 
0.1652047 
 
3 
1 
3 
2 
3 
0 
0 
0 
1 
0 
1 
0 
1 
0 
1 
3 
0 
0 
2 
4 
0.166063 
0.166 
0.166063 
 
2 
2 
3 
3 
3 
1 
1 
0 
0 
0 
0 
0 
1 
1 
1 
4 
1 
1 
2 
4 
0.1670872 
0.167 
0.1670872 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 49 of 58 
3 
3 
3 
1 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
2 
0 
0 
2 
4 
0.1783568 
0.178 
0.1783568 
 
3 
1 
2 
3 
1 
0 
0 
1 
0 
0 
1 
0 
0 
1 
0 
2 
0 
0 
1 
1 
0.1810284 
0.181 
0.1810284 
 
3 
1 
1 
3 
1 
0 
0 
0 
0 
0 
1 
0 
0 
1 
0 
1 
0 
0 
1 
1 
0.181163 
0.181 
0.181163 
 
1 
3 
3 
3 
2 
0 
0 
0 
0 
1 
0 
1 
1 
1 
0 
3 
0 
0 
2 
4 
0.1823126 
0.182 
0.1823126 
 
1 
2 
3 
3 
3 
0 
1 
0 
0 
0 
0 
0 
1 
1 
1 
3 
0 
0 
2 
4 
0.1841951 
0.184 
0.1841951 
 
3 
3 
1 
2 
2 
0 
0 
0 
1 
1 
1 
1 
0 
0 
0 
3 
1 
1 
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1 
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0.186 
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1 
2 
3 
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0 
1 
0 
1 
0 
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1 
1 
1 
1 
0.1883463 
0.188 
0.1883463 
 
2 
3 
3 
3 
1 
1 
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0 
0 
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1 
1 
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4 
0.1925196 
0.193 
0.1925196 
 
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4 
0.1989407 
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0.1993588 
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1 
0.2017274 
0.202 
0.2017274 
 
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1 
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1 
1 
1 
1 
0.2029573 
0.203 
0.2029573 
 
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2 
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1 
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1 
1 
0.2036099 
0.204 
0.2036099 
 
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0.2135216 
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1 
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1 
1 
0.215586 
0.216 
0.215586 
 
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3 
2 
1 
2 
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1 
0 
1 
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1 
1 
1 
1 
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0.220 
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1 
1 
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1 
1 
2 
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4 
0.2199427 
0.220 
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2 
1 
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1 
1 
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1 
3 
1 
1 
1 
1 
0.2215075 
0.222 
0.2215075 
 
3 
1 
2 
2 
3 
0 
0 
1 
1 
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1 
1 
1 
1 
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3 
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1 
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1 
1 
0 
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0 
2 
0 
0 
1 
1 
0.2304464 
0.230 
0.2304464 
 
3 
2 
1 
1 
3 
0 
1 
0 
0 
0 
1 
0 
0 
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1 
2 
0 
0 
1 
1 
0.2323289 
0.232 
0.2323289 
 
2 
3 
1 
3 
2 
1 
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0 
0 
1 
0 
1 
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3 
1 
1 
1 
1 
0.2339224 
0.234 
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1 
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0 
1 
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2 
0 
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1 
1 
0.2347807 
0.235 
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3 
3 
2 
3 
1 
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1 
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1 
1 
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1 
4 
1 
1 
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4 
0.2354505 
0.235 
0.2354505 
 
2 
2 
1 
3 
3 
1 
1 
0 
0 
0 
0 
0 
0 
1 
1 
3 
1 
1 
1 
1 
0.2358049 
0.236 
0.2358049 
 
1 
3 
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3 
2 
0 
0 
1 
0 
1 
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1 
0 
1 
0 
3 
1 
1 
1 
1 
0.2402089 
0.240 
0.2402089 
 
1 
2 
2 
3 
3 
0 
1 
1 
0 
0 
0 
0 
0 
1 
1 
3 
1 
1 
1 
1 
0.2420914 
0.242 
0.2420914 
 
3 
3 
2 
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1 
0 
0 
1 
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0 
1 
1 
0 
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0 
1 
1 
0.2469399 
0.247 
0.2469399 
 
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1 
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1 
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0.2470745 
 
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3 
1 
1 
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1 
0 
0 
0 
1 
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3 
1 
1 
1 
1 
0.2504159 
0.250 
0.2504159 
 
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3 
1 
3 
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2 
0 
0 
1 
1 
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0.251 
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1 
3 
3 
2 
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1 
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0 
1 
1 
0 
1 
3 
0 
0 
2 
4 
0.2525584 
0.253 
0.2525584 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 50 of 58 
1 
2 
1 
3 
3 
0 
1 
0 
0 
0 
0 
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1 
1 
2 
0 
0 
1 
1 
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0.253 
0.2529128 
 
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2 
2 
2 
2 
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1 
1 
1 
1 
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4 
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0 
0.2603277 
0.260 
0.2603277 
 
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3 
1 
3 
1 
1 
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0 
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1 
0.2612373 
0.261 
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2 
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3 
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2 
1 
1 
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0 
1 
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1 
1 
0 
4 
2 
4 
1 
1 
0.2630446 
0.263 
0.2630446 
 
3 
2 
3 
2 
1 
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1 
0 
1 
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1 
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3 
1 
1 
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1 
0.2642745 
0.264 
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3 
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1 
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1 
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1 
0.2676584 
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1 
0.2679419 
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1 
0.2680765 
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0.2680765 
 
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1 
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1 
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3 
1 
1 
1 
1 
0.2714179 
0.271 
0.2714179 
 
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3 
2 
2 
3 
1 
0 
1 
1 
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1 
4 
2 
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1 
1 
0.2719732 
0.272 
0.2719732 
 
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3 
3 
1 
3 
1 
0 
0 
0 
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1 
3 
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0 
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4 
0.2794331 
0.279 
0.2794331 
 
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3 
1 
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1 
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1 
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0.2809422 
 
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1 
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1 
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1 
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1 
1 
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1 
1 
1 
1 
0.283394 
0.283 
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3 
3 
1 
3 
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4 
0.2858542 
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1 
1 
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1 
1 
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1 
1 
0.2885258 
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1 
1 
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3 
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1 
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0.2886604 
 
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3 
2 
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1 
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1 
1 
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3 
1 
1 
1 
1 
0.3015261 
0.302 
0.3015261 
 
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3 
1 
2 
3 
1 
0 
0 
1 
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1 
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0 
1 
3 
1 
1 
1 
1 
0.3041682 
0.304 
0.3041682 
 
2 
2 
2 
3 
2 
1 
1 
1 
0 
1 
0 
0 
0 
1 
0 
4 
3 
9 
0 
0 
0.3077863 
0.308 
0.3077863 
 
3 
2 
3 
1 
1 
0 
1 
0 
0 
0 
1 
0 
1 
0 
0 
2 
0 
0 
1 
1 
0.3082571 
0.308 
0.3082571 
 
1 
3 
2 
2 
3 
0 
0 
1 
1 
0 
0 
1 
0 
0 
1 
3 
1 
1 
1 
1 
0.3104547 
0.310 
0.3104547 
 
3 
1 
3 
2 
1 
0 
0 
0 
1 
0 
1 
0 
1 
0 
0 
2 
0 
0 
1 
1 
0.3107089 
0.311 
0.3107089 
 
2 
2 
3 
3 
1 
1 
1 
0 
0 
0 
0 
0 
1 
1 
0 
3 
1 
1 
1 
1 
0.3117331 
0.312 
0.3117331 
 
3 
2 
1 
2 
2 
0 
1 
0 
1 
1 
1 
0 
0 
0 
0 
3 
2 
4 
0 
0 
0.3138963 
0.314 
0.3138963 
 
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3 
1 
2 
3 
0 
0 
0 
1 
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1 
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1 
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0 
1 
1 
0.3212761 
0.321 
0.3212761 
 
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1 
3 
1 
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0 
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1 
1 
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1 
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0 
1 
1 
0.3273766 
0.327 
0.3273766 
 
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2 
3 
3 
1 
0 
1 
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0 
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1 
0.328841 
0.329 
0.328841 
 
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2 
2 
2 
1 
0 
1 
1 
1 
0 
1 
0 
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2 
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0 
0.3303898 
0.330 
0.3303898 
 
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1 
3 
3 
2 
1 
0 
0 
0 
1 
0 
0 
1 
1 
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3 
1 
1 
1 
1 
0.3308526 
0.331 
0.3308526 
 
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3 
3 
2 
2 
1 
0 
0 
1 
1 
0 
1 
1 
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0 
4 
2 
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1 
1 
0.3314079 
0.331 
0.3314079 
 
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2 
3 
2 
3 
1 
1 
0 
1 
0 
0 
0 
1 
0 
1 
4 
2 
4 
1 
1 
0.3332904 
0.333 
0.3332904 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 51 of 58 
2 
3 
2 
1 
3 
1 
0 
1 
0 
0 
0 
1 
0 
0 
1 
3 
1 
1 
1 
1 
0.3373294 
0.337 
0.3373294 
 
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1 
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0.344 
0.3440047 
 
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1 
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0.3470575 
0.347 
0.3470575 
 
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1 
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0.3479605 
0.348 
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1 
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0.348 
0.3481508 
 
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1 
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2 
2 
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1 
1 
1 
1 
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0 
0.3495093 
0.350 
0.3495093 
 
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3 
2 
1 
3 
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1 
1 
0.3544373 
0.354 
0.3544373 
 
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3 
1 
1 
3 
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1 
1 
0.3545719 
0.355 
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1 
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3 
1 
1 
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1 
0.3581675 
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0.3581675 
 
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2 
1 
3 
2 
1 
1 
0 
0 
1 
0 
0 
0 
1 
0 
3 
2 
4 
0 
0 
0.3613549 
0.361 
0.3613549 
 
3 
2 
1 
2 
1 
0 
1 
0 
1 
0 
1 
0 
0 
0 
0 
2 
1 
1 
0 
0 
0.3625848 
0.363 
0.3625848 
 
1 
1 
3 
3 
1 
0 
0 
0 
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1 
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1 
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0 
1 
1 
0.3645886 
0.365 
0.3645886 
 
1 
2 
2 
3 
2 
0 
1 
1 
0 
1 
0 
0 
0 
1 
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3 
2 
4 
0 
0 
0.3676414 
0.368 
0.3676414 
 
1 
3 
3 
2 
2 
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0 
0 
1 
1 
0 
1 
1 
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3 
1 
1 
1 
1 
0.3698894 
0.370 
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2 
3 
2 
3 
0 
1 
0 
1 
0 
0 
0 
1 
0 
1 
3 
1 
1 
1 
1 
0.3717719 
0.372 
0.3717719 
 
2 
3 
2 
2 
2 
1 
0 
1 
1 
1 
0 
1 
0 
0 
0 
4 
3 
9 
0 
0 
0.3761496 
0.376 
0.3761496 
 
2 
2 
2 
3 
1 
1 
1 
1 
0 
0 
0 
0 
0 
1 
0 
3 
2 
4 
0 
0 
0.3778484 
0.378 
0.3778484 
 
2 
2 
2 
2 
3 
1 
1 
1 
1 
0 
0 
0 
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1 
4 
3 
9 
0 
0 
0.3780321 
0.378 
0.3780321 
 
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2 
1 
1 
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1 
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1 
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1 
1 
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0.3792525 
0.379 
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2 
3 
3 
2 
1 
1 
0 
0 
1 
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1 
1 
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3 
1 
1 
1 
1 
0.3800964 
0.380 
0.3800964 
 
3 
1 
1 
2 
2 
0 
0 
0 
1 
1 
1 
0 
0 
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2 
1 
1 
0 
0 
0.3817043 
0.382 
0.3817043 
 
3 
2 
2 
1 
1 
0 
1 
1 
0 
0 
1 
0 
0 
0 
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2 
1 
1 
0 
0 
0.395746 
0.396 
0.395746 
 
2 
3 
3 
1 
2 
1 
0 
0 
0 
1 
0 
1 
1 
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0 
3 
1 
1 
1 
1 
0.3967641 
0.397 
0.3967641 
 
2 
1 
2 
3 
2 
1 
0 
1 
0 
1 
0 
0 
0 
1 
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3 
2 
4 
0 
0 
0.3969679 
0.397 
0.3969679 
 
1 
3 
3 
2 
1 
0 
0 
0 
1 
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0 
1 
1 
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2 
0 
0 
1 
1 
0.3972043 
0.397 
0.3972043 
 
3 
1 
2 
2 
1 
0 
0 
1 
1 
0 
1 
0 
0 
0 
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2 
1 
1 
0 
0 
0.3981978 
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0.3981978 
 
2 
2 
3 
1 
3 
1 
1 
0 
0 
0 
0 
0 
1 
0 
1 
3 
1 
1 
1 
1 
0.3986466 
0.399 
0.3986466 
 
1 
2 
1 
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1 
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1 
1 
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0.3998364 
0.400 
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1 
3 
2 
3 
1 
0 
0 
1 
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0 
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3 
1 
1 
1 
1 
0.4010984 
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2 
1 
1 
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1 
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1 
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1 
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0.4065674 
0.407 
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1 
1 
2 
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0 
1 
0 
1 
0 
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0 
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1 
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0 
0 
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0.4090192 
0.409 
0.4090192 
 
2 
2 
1 
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1 
1 
1 
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0 
0 
0 
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1 
1 
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0.4100434 
0.410 
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1 
3 
3 
1 
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0 
0 
0 
0 
1 
0 
1 
1 
0 
0 
2 
0 
0 
1 
1 
0.413872 
0.414 
0.413872 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 52 of 58 
3 
1 
2 
1 
2 
0 
0 
1 
0 
1 
1 
0 
0 
0 
0 
2 
1 
1 
0 
0 
0.4148655 
0.415 
0.4148655 
 
1 
2 
3 
1 
3 
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1 
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0 
0 
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1 
0 
1 
2 
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0 
1 
1 
0.4157545 
0.416 
0.4157545 
 
1 
2 
2 
3 
1 
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1 
1 
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0 
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1 
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1 
1 
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0.4163299 
0.416 
0.4163299 
 
1 
1 
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1 
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1 
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1 
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1 
1 
0.4182063 
0.418 
0.4182063 
 
2 
3 
3 
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1 
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1 
1 
0.424079 
0.424 
0.424079 
 
3 
1 
1 
1 
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1 
1 
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0 
0 
0 
0.4256869 
0.426 
0.4256869 
 
1 
2 
1 
3 
1 
0 
1 
0 
0 
0 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0.4271513 
0.427 
0.4271513 
 
2 
1 
1 
3 
2 
1 
0 
0 
0 
1 
0 
0 
0 
1 
0 
2 
1 
1 
0 
0 
0.4291629 
0.429 
0.4291629 
 
2 
3 
1 
2 
2 
1 
0 
0 
1 
1 
0 
1 
0 
0 
0 
3 
2 
4 
0 
0 
0.4297182 
0.430 
0.4297182 
 
1 
3 
3 
1 
1 
0 
0 
0 
0 
0 
0 
1 
1 
0 
0 
1 
0 
0 
1 
1 
0.4305001 
0.431 
0.4305001 
 
2 
2 
1 
2 
3 
1 
1 
0 
1 
0 
0 
0 
0 
0 
1 
3 
2 
4 
0 
0 
0.4316007 
0.432 
0.4316007 
 
1 
1 
2 
3 
2 
0 
0 
1 
0 
1 
0 
0 
0 
1 
0 
2 
1 
1 
0 
0 
0.4354494 
0.435 
0.4354494 
 
1 
3 
2 
2 
2 
0 
0 
1 
1 
1 
0 
1 
0 
0 
0 
3 
2 
4 
0 
0 
0.4360047 
0.436 
0.4360047 
 
2 
2 
3 
2 
2 
1 
1 
0 
1 
1 
0 
0 
1 
0 
0 
4 
3 
9 
0 
0 
0.4374668 
0.437 
0.4374668 
 
1 
2 
2 
2 
3 
0 
1 
1 
1 
0 
0 
0 
0 
0 
1 
3 
2 
4 
0 
0 
0.4378872 
0.438 
0.4378872 
 
3 
1 
2 
1 
1 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0.4421804 
0.442 
0.4421804 
 
3 
1 
1 
1 
1 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.442315 
0.442 
0.442315 
 
2 
1 
3 
1 
3 
1 
0 
0 
0 
0 
0 
0 
1 
0 
1 
2 
0 
0 
1 
1 
0.445081 
0.445 
0.445081 
 
2 
1 
2 
3 
1 
1 
0 
1 
0 
0 
0 
0 
0 
1 
0 
2 
1 
1 
0 
0 
0.4456564 
0.446 
0.4456564 
 
2 
3 
2 
2 
1 
1 
0 
1 
1 
0 
0 
1 
0 
0 
0 
3 
2 
4 
0 
0 
0.4462117 
0.446 
0.4462117 
 
1 
1 
1 
3 
2 
0 
0 
0 
0 
1 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0.4462708 
0.446 
0.4462708 
 
1 
1 
3 
1 
3 
0 
0 
0 
0 
0 
0 
0 
1 
0 
1 
1 
0 
0 
1 
1 
0.4515021 
0.452 
0.4515021 
 
2 
1 
1 
3 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0.4564778 
0.456 
0.4564778 
 
1 
1 
2 
3 
1 
0 
0 
1 
0 
0 
0 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0.4627643 
0.463 
0.4627643 
 
2 
3 
2 
1 
2 
1 
0 
1 
0 
1 
0 
1 
0 
0 
0 
3 
2 
4 
0 
0 
0.4628794 
0.463 
0.4628794 
 
1 
1 
1 
3 
1 
0 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0.4628989 
0.463 
0.4628989 
 
2 
2 
2 
1 
3 
1 
1 
1 
0 
0 
0 
0 
0 
0 
1 
3 
2 
4 
0 
0 
0.4647619 
0.465 
0.4647619 
 
2 
1 
2 
2 
3 
1 
0 
1 
1 
0 
0 
0 
0 
0 
1 
3 
2 
4 
0 
0 
0.4672137 
0.467 
0.4672137 
 
1 
3 
1 
2 
2 
0 
0 
0 
1 
1 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.4681997 
0.468 
0.4681997 
 
1 
2 
1 
2 
3 
0 
1 
0 
1 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.4700822 
0.470 
0.4700822 
 
2 
3 
1 
2 
1 
1 
0 
0 
1 
0 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.4784067 
0.478 
0.4784067 
 
1 
3 
2 
2 
1 
0 
0 
1 
1 
0 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.4846932 
0.485 
0.4846932 
 
2 
3 
1 
1 
2 
1 
0 
0 
0 
1 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.4950744 
0.495 
0.4950744 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 53 of 58 
1 
3 
1 
2 
1 
0 
0 
0 
1 
0 
0 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0.4955146 
0.496 
0.4955146 
 
2 
2 
1 
1 
3 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.4969569 
0.497 
0.4969569 
 
1 
2 
3 
2 
2 
0 
1 
0 
1 
1 
0 
0 
1 
0 
0 
3 
2 
4 
0 
0 
0.4973219 
0.497 
0.4973219 
 
2 
1 
1 
2 
3 
1 
0 
0 
1 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.4994087 
0.499 
0.4994087 
 
1 
3 
2 
1 
2 
0 
0 
1 
0 
1 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.5013609 
0.501 
0.5013609 
 
1 
2 
2 
1 
3 
0 
1 
1 
0 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.5032434 
0.503 
0.5032434 
 
1 
1 
2 
2 
3 
0 
0 
1 
1 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.5056952 
0.506 
0.5056952 
 
2 
2 
3 
2 
1 
1 
1 
0 
1 
0 
0 
0 
1 
0 
0 
3 
2 
4 
0 
0 
0.5075289 
0.508 
0.5075289 
 
2 
3 
2 
1 
1 
1 
0 
1 
0 
0 
0 
1 
0 
0 
0 
2 
1 
1 
0 
0 
0.5115679 
0.512 
0.5115679 
 
1 
3 
1 
1 
2 
0 
0 
0 
0 
1 
0 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0.5121823 
0.512 
0.5121823 
 
1 
2 
1 
1 
3 
0 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0.5140648 
0.514 
0.5140648 
 
1 
1 
1 
2 
3 
0 
0 
0 
1 
0 
0 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0.5165166 
0.517 
0.5165166 
 
2 
3 
1 
1 
1 
1 
0 
0 
0 
0 
0 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0.5223893 
0.522 
0.5223893 
 
2 
2 
3 
1 
2 
1 
1 
0 
0 
1 
0 
0 
1 
0 
0 
3 
2 
4 
0 
0 
0.5241966 
0.524 
0.5241966 
 
2 
1 
3 
2 
2 
1 
0 
0 
1 
1 
0 
0 
1 
0 
0 
3 
2 
4 
0 
0 
0.5266484 
0.527 
0.5266484 
 
1 
3 
2 
1 
1 
0 
0 
1 
0 
0 
0 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0.5286758 
0.529 
0.5286758 
 
1 
3 
1 
1 
1 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0.5288104 
0.529 
0.5288104 
 
2 
1 
2 
1 
3 
1 
0 
1 
0 
0 
0 
0 
0 
0 
1 
2 
1 
1 
0 
0 
0.5325699 
0.533 
0.5325699 
 
2 
1 
1 
1 
3 
1 
0 
0 
0 
0 
0 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0.5433913 
0.543 
0.5433913 
 
1 
2 
3 
2 
1 
0 
1 
0 
1 
0 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5460104 
0.546 
0.5460104 
 
1 
1 
2 
1 
3 
0 
0 
1 
0 
0 
0 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0.5496778 
0.550 
0.5496778 
 
1 
1 
1 
1 
3 
0 
0 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0.5498124 
0.550 
0.5498124 
 
1 
2 
3 
1 
2 
0 
1 
0 
0 
1 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5626781 
0.563 
0.5626781 
 
1 
1 
3 
2 
2 
0 
0 
0 
1 
1 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5651299 
0.565 
0.5651299 
 
2 
2 
3 
1 
1 
1 
1 
0 
0 
0 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5728851 
0.573 
0.5728851 
 
2 
1 
3 
2 
1 
1 
0 
0 
1 
0 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5753369 
0.575 
0.5753369 
 
1 
2 
3 
1 
1 
0 
1 
0 
0 
0 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0.589993 
0.590 
0.589993 
 
2 
1 
3 
1 
2 
1 
0 
0 
0 
1 
0 
0 
1 
0 
0 
2 
1 
1 
0 
0 
0.5920046 
0.592 
0.5920046 
 
1 
1 
3 
2 
1 
0 
0 
0 
1 
0 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0.5924448 
0.592 
0.5924448 
 
2 
2 
2 
2 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
4 
4 
16 
0 
0 
0.5971891 
0.597 
0.5971891 
 
1 
1 
3 
1 
2 
0 
0 
0 
0 
1 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0.6091125 
0.609 
0.6091125 
 
2 
1 
3 
1 
1 
1 
0 
0 
0 
0 
0 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0.6193195 
0.619 
0.6193195 
 
1 
1 
3 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0.6257406 
0.626 
0.6257406 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 54 of 58 
2 
2 
1 
2 
2 
1 
1 
0 
1 
1 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.6721313 
0.672 
0.6721313 
 
1 
2 
2 
2 
2 
0 
1 
1 
1 
1 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.6784178 
0.678 
0.6784178 
 
2 
2 
2 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.6886248 
0.689 
0.6886248 
 
2 
2 
2 
1 
2 
1 
1 
1 
0 
1 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.7052925 
0.705 
0.7052925 
 
2 
1 
2 
2 
2 
1 
0 
1 
1 
1 
0 
0 
0 
0 
0 
3 
3 
9 
0 
0 
0.7077443 
0.708 
0.7077443 
 
1 
2 
1 
2 
2 
0 
1 
0 
1 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7319864 
0.732 
0.7319864 
 
2 
2 
1 
2 
1 
1 
1 
0 
1 
0 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7421934 
0.742 
0.7421934 
 
1 
2 
2 
2 
1 
0 
1 
1 
1 
0 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7484799 
0.748 
0.7484799 
 
2 
2 
1 
1 
2 
1 
1 
0 
0 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7588611 
0.759 
0.7588611 
 
2 
1 
1 
2 
2 
1 
0 
0 
1 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7613129 
0.761 
0.7613129 
 
1 
2 
2 
1 
2 
0 
1 
1 
0 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7651476 
0.765 
0.7651476 
 
1 
1 
2 
2 
2 
0 
0 
1 
1 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7675994 
0.768 
0.7675994 
 
2 
2 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7753546 
0.775 
0.7753546 
 
2 
1 
2 
2 
1 
1 
0 
1 
1 
0 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7778064 
0.778 
0.7778064 
 
1 
2 
1 
2 
1 
0 
1 
0 
1 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.7806749 
0.781 
0.7806749 
 
2 
1 
2 
1 
2 
1 
0 
1 
0 
1 
0 
0 
0 
0 
0 
2 
2 
4 
0 
0 
0.7944741 
0.794 
0.7944741 
 
1 
2 
1 
1 
2 
0 
1 
0 
0 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.7973426 
0.797 
0.7973426 
 
1 
1 
1 
2 
2 
0 
0 
0 
1 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.7997944 
0.800 
0.7997944 
 
2 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8075496 
0.808 
0.8075496 
 
2 
1 
1 
2 
1 
1 
0 
0 
1 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8100014 
0.810 
0.8100014 
 
1 
2 
2 
1 
1 
0 
1 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8138361 
0.814 
0.8138361 
 
1 
1 
2 
2 
1 
0 
0 
1 
1 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8162879 
0.816 
0.8162879 
 
1 
2 
1 
1 
1 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.8246575 
0.825 
0.8246575 
 
2 
1 
1 
1 
2 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8266691 
0.827 
0.8266691 
 
1 
1 
1 
2 
1 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.8271093 
0.827 
0.8271093 
 
1 
1 
2 
1 
2 
0 
0 
1 
0 
1 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8329556 
0.833 
0.8329556 
 
2 
1 
2 
1 
1 
1 
0 
1 
0 
0 
0 
0 
0 
0 
0 
1 
1 
1 
0 
0 
0.8431626 
0.843 
0.8431626 
 
1 
1 
1 
1 
2 
0 
0 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.843777 
0.844 
0.843777 
 
2 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.853984 
0.854 
0.853984 
 
1 
1 
2 
1 
1 
0 
0 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0.8602705 
0.860 
0.8602705 
 
1 
1 
1 
1 
1 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
-1 
0 
0 
0 
0 
0.8604051 
1.000 
1 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 55 of 58 
7.4 Step to identify the Day of baseline treatment increase/change: 
[Step] 
1. 
Identify “Relapse prevention therapy used at BL (i.e. Drug A)”. 
2. 
Identify “Relapse prevention therapy* newly used from BL by the potential censored Day** 
other than the Day of increase/change of BL treatment (i.e. Drug B)”. 
✓ 
End if there is no Drug B. 
3. 
Scientifically/medically evaluate if any of following information of Drug A are different from 
those of Drug B: 
i. 
Dose regimen 
ii. 
Drug name 
✓ 
End if not different. 
✓ 
If different, the earliest start Day of Drug B is the Day of dose increase/change of baseline 
treatment. 
 
*; Including immunosuppressants and corticosteroids which were not used for relapse prevention (i.e. 
the indication is AE or Medical History etc). For them, route and duration of administration etc. will 
also be considered in step No.3 (e.g. temporal local administration will not be considered as 
increase/change of Drug A). 
 
**; Including following days; 
a. 1st Day of rescue therapy started in the double-blind period for this patient (if any) 
b. The relapse onset Day of the event*** for this patient (if any) 
c. Clinical cut-off Day (CCOD): the relapse onset day of the event*** with the 26th earliest onset date 
d. Day of discontinuation from the double-blind period for this patient (e.g. Day of WD visit, Day of 
consent withdrawal) (if any) 
 
***; the relapse adjudicated as protocol-defined relapse by Clinical Endpoint Committee (CEC) and 
EDSS/FSS assessed within 7 days from the date when the patient first reported symptoms to the site. 
 
[Note] 
- 
Day 1 = Baseline in the double blind period 
- 
There may be more than one Drug B. 
- 
Drug A must meet both of followings: 
✓ 
“Day of medication started” =< 1 
✓ 
“Day of medication stop” >= 1 
- 
Drug B must meet both of followings: 
✓ 
“Day of medication started” >= 1 
✓ 
“Day of medication started” < “potential censored Day**” 
 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 56 of 58 
7.5 Procedure to identify the clinical relapse of optic neuritis occurred in the double-
blind period: 
The clinical relapse of optic neuritis occurred in the double-blind period of SA-307JG study will be 
identified by satisfying with either or both of followings. The Relapse Assessment Form (RAF) 
completed by study sites will be used for the identification. 
- 
Lower box “New or worsening neurological symptoms relating to this functional area reported by 
the patient at this visit. Please describe:” is ticked in the Section A-1 “Visual (optic) functions: 
Symptoms” of the RAF, and then the information is described per the instruction. 
- 
The information on new or worsening neurological symptoms in visual (optic) functions are 
described in section B of RAF. 
 
[Reference: Section A-1 of RAF] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 57 of 58 
7.6 Rule for summary of titer for anti AQP4 antibody status 
Titer for anti AQP4 antibody status except screening visit will be replaced by 
following rule. This rule will apply to throughout TFL. 
- 
If value is “<16”, value will be replaced as 4.  
- 
If titer is character (eg. “>16384”, “>65536” except “<16”) or titer is numeric more than 16384 
(eg. “65536”, “262144”), value will be replaced as 65536. 
7.7 SAS Codes: 
Log-rank test: 
proc lifetest data=final; 
time DURATION*STATUS (0); 
strata ARR REGEON / group=TREATMENT; 
ods output test=_logrank; 
run; 
Cox Regression Model: 
proc phreg data=final; 
class TREATMENT/descending; 
Model DURATION*STATUS(0)=TREATMENT / ties=exact rl; 
strata ARR REGION; 
ods output parameterEstimates=est; 
run; 
 
Mixed effect Model Repeat Measurement (MMRM) 
proc mixed data=VAS method=REML; 
class REGION TREATMENT VISIT USUBJIDARR; 
model CHG = BASE TREATMENT REGION VISIT ARR  
TREATMENT*VISIT/ddfm=KR; 
repeated VISIT / type=un subject = USUBJID; 
lsmeans TREATMENT*VISIT / pdiff cl; 


Chugai Pharmaceutical co. Ltd. 
 
SA-307JG 
Statistical Analysis Plan 
TP-GRO-WW-016-03 
Confidential 
Version 9.0 [Final]  
Effective Date: 18 Dec 12 
 
Version Date: 20Apr18 
Related to: SOP-GRO-WW-019 
 
Page 58 of 58 
ods output lsmeans = lsm; * contains the adjusted means;  
ods output diffs = dif; * contains treatment differences; 
run; 
 
 
ANCOVA; 
proc mixed data=; 
class TREATMENT ARR REGION; 
model CHG_BL=TREATMENT BASELINE ARR REGION; 
lsmeans TREATMENT / pdiff cl; 
run;