OPV116910: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Investigate the Efficacy and Safety of Ofatumumab Injection for Subcutaneous Use in Subjects With Pemphigus Vulgaris
Phase: PHASE3
Conditions: Pemphigus Vulgaris
Sponsor: Novartis Pharmaceuticals

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TI T L E P A G E
I nf or m ati o n T y pe: Cli nical Pr ot oc ol A me n d me nt
Title:
A Ra n d o mize d, D o u ble -Bli n d, Place b o - Co ntr olle d, Parallel -
G r o u p St u d y t o I n vesti gate t he Efficac y a n d Safet y of 
Ofat u m u ma b I njecti o n f or S u bc uta ne o u s Use i n S u bjects 
wit h Pe m p hi g us V ul garis
Cl i nic al St u d y I de ntifier:
G S K st u d y  O P V 1 1 6 9 1 0 (als o k n o w n as N o vartis 
St u d y  C O M B 1 5 7J 2 3 0 1 ) / N C T 0 1 9 2 0 4 7 7
C o m p o u n d N u m ber:
G S K 1 8 4 1 1 5 7 (als o k n o w n as O M B 1 5 7)
De vel o p me nt P h ase :
III
Effecti ve D ate:
0 5- Se p- 2 0 1 6
Pr ot oc ol A me n d me nt N u m ber: 8
Descri pti o n :  Ofat u m u ma b is a n o vel h u ma n I g G 1 k l ytic m o n ocl o nal a nti b o d y t hat 
s pecifically bi n ds t o t he h u ma n C D 2 0 a nti ge n, w hic h is e x presse d o nl y i n B l ym p h oc y tes 
fr o m t he pre– B- cell sta ge t o t he plas mac yt oi d i m m u n o blast sta ge.
T his gl o bal st u d y will i n vesti gate t he efficac y, safet y, a n d t olera bilit y of ofat u m u ma b 
i njecti o n f or s u bc uta ne o us ( S C) use i n t he treat me nt of s u bjects wit h pe m p hi g us v ul garis. 
T he pri mar y  o bjecti ve of t he st u d y is t o deter mi ne t he efficac y, base d o n disease 
re missi o n, of ofat u m u ma b S C at a d ose of 2 0 m g a dmi nistere d e ver y  4 wee ks ( wit h a n 
a d diti o nal 2 0-m g ‘l oa di n g’ d ose [ie, 4 0 m g t otal] at b ot h Wee k
0 a n d Wee k 4) i n s u bjects 
wit h pe m p hi g us v ul garis .  Ot her o bjecti ves i ncl u de e val uati o n of safety, t olera bilit y, 
B- cell de pleti o n a n d re pleti o n, a nti-des m o glei n a nti b o d y le vels, i m m u n o ge nicit y,
p har mac o ki netics, a n d ot her cli nical a n d q ualit y of life e n d p oi nts.
S u bject: 
pe m p hi g us v ul garis , ofat u m u ma b, m o n ocl o nal a nti b o d y
A ut h or s:
 
C o p y ri g ht 2 0 16 N o vartis P har ma A G .  All ri g hts reser ve d.  U na ut h orize d c o p yi n g or use 
of t his i nf or mati o n is pr o hi bite d.

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Re visi o n C hr o n ol o g y
Gl a x o S mit h Kli ne 
D oc u me nt N u m ber
D ate
Versi o n
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2 0 1 3 -A P R - 2 3
Ori gi nal
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2 0 1 3 -J U N- 2 1
A me n d me nt N o. 1
I m pr o ve clarit y, a dj ust ti mi n g of s o me assess me nts, a n d a d dress q uesti o ns/c o m me nts 
fr o m t he U S F D A.
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2 0 1 3 -S E P - 2 6
A me n d me nt N o. 2
I m pr o ve clarit y a n d a d dress q uesti o ns/c o m me nts fr om t he U S F D A.
T his a me n d me nt was s u perse de d b y Pr ot oc ol A me n d me nt 3 bef ore i m ple me ntati o n at 
a n y st u d y ce nter.
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2 0 1 4 -M A R - 1 3
A me n d me nt N o. 3
C ha n ge d ose, d osi n g re gi me n, a n d ass ociate d assess me nt ti me p oi nts.
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2 0 1 4 -S E P - 1 8
A me n d me nt N o. 4
A d diti o n of cr oss -refere nce t o A p pe n di x 2 f or c o u ntr y -s pecific re q uire me nts.
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2 0 1 5 -A P R - 0 2
A me n d me nt N o. 5
Mi n or i ncl usi o n criteria c ha n ges, c orrecti o ns a n d clarificati o ns f or c o nsiste nc y  
t hr o u g h o ut pr ot oc ol, a n d i ncl usi o n of c ou ntr y -s pecific re q uire me nts f or Ja pa n.
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2 0 1 5 -S E P - 2 8
A me n d me nt N o. 6
I ncl usi o n a n d e xcl usi o n criteria c ha n ges (I ncl usi o n # 3, I ncl usi o n # 5, E xcl usi o n # 4, a n d 
E xcl usi o n # 8), c ha n ges t o t he I n di vi d ualize d F oll o w - u p Peri o d, a d diti o n of a n o bjecti ve 
a n d t hree e n d p oi nts f or t he I n di vi d ualize d F oll o w -u p Peri o d, a d diti o n of c o u ntr y -s pecific 
re q uire me nts f or K orea, re m o val of refere nces t o t he dil uti o n met h o d of st u d y  treat me nt 
pre parati o n, c orrecti o ns a n d clarificati o ns f or c o nsiste nc y  t hr o u g h o ut t he pr ot oc ol.
O P V 1 1 6 9 1 0 Pr ot oc ol A me n d me nt 6 s u p p orte d a c ha n ge at t he e n d of t he treat me nt 
peri o d t o all o w s u bjects w h o c o m plete d treat me nt a n d were ot her wise eli gi ble t o r oll -o ver 
i nt o a n o pe n-la bel e xte nsi o n st u d y ( O P V 1 1 7 0 5 9). O nl y  sites i n t he U S A ha d s ubjects 
near c o m pleti o n of t he treat me nt peri o d; t heref ore, A me n d me nt 6 was o nl y s u b mitte d t o 
t he U S A F D A at t he ti me of fi nalizati o n a n d t he c ha n ges i n st u d y c o n d uct detaile d i n 
A me n d me nt 6 were o nl y  i m ple me nte d i n st u d y ce nters i n t he U S A.

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A me n d me nt N o. 7
S u bjects are re q uire d t o sta y  in t he I n di vi d ualize d F oll o w - u p Peri o d u ntil b ot h t heir I g G 
le vels A N D t heir C D 1 9 + B-cell c o u nts are ≥L L N or baseli ne le vels (if < L L N) or u p t o 
2 ye ars after t he last d ose of i n vesti gati o nal pr o d u ct ( w hic he ver c o mes first).
S u bjects are n o l o n ger re q uire d t o sta y  i n I n di vi d ualize d F oll o w-u p f or a mi ni m u m of 
1 ye ar.
D ue t o t he fact t hat A me n d me nt 6 was o nl y  s u b mitte d i n t he U S A, st u d y c o n d uct 
tra nsiti o ne d fr o m A me n d me nt 6 t o A me n d me nt 7 f or st u d y centers i n t he U S A a n d fr o m 
A me n d me nt 5 t o A me n d me nt 7 f or st u d y  ce nters i n all ot her c o u ntries.
D ate
Versi o n
2 0 1 6 - Se p- 0 1
A me n d me nt N o. 8
S p o ns or tra nsiti o n fr o m G S K t o N o vartis , i ncl u di n g a d diti o n of N o vartis st u d y IDs ( G S K 
st u d y O P V 1 1 6 9 1 0 n o w als o k n o w n as N o vartis st u d y  CO M B 1 5 7J 2 3 0 1 a n d G S K st u d y  
O P V 1 1 7 0 5 9 n o w als o k n o w n as N o vartis st u d y C O M B 1 5 7J 2 3 0 1 E 1 ) a n d c ha n ges of 
S p o ns or c o m pa n y  na me, a d dresses, a n d pers o n nel details.
Pre g na nc y  re p orti n g peri o d a me n de d t o 2 4 h o urs.
Pr ot oc ol A me n d me nt 7 i nc or p orat e d i n t he f ull pr ot oc ol d oc u me nt.

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S P O N S O R SI G N A T O R Y :
, M D, P h D
N o vartis P har ma A G
D ate

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S P O N S O R I N F O R M A TI O N P A G E
Cli nical St u d y  Ide ntifier: 
O P V 1 1 6 9 1 0 (als o k n o w n as C O M B 1 5 7J 23 0 1)
S p o ns or Le g al Re gistere d A d dress:
N o vartis P har ma A G
Lic htstrasse 3 5 , 4 0 5 6 Basel
S witzerla n d
S p o ns or C o nt act A d dress:
N o vartis A G
N o vartis Ca m p us
Fa bri kstrasse 2, 4 0 5 6 Basel
S witzerla n d
I n s o me c o u ntries, t he cli nical st u d y S p o ns or ma y  be t he l ocal N o vartis affiliate c o m pa n y 
( or desi g nee). W here a p plica ble, t he details of t he S p o ns or a n d c o ntact pers o n will be 
pr o vi de d t o t he rele va nt re g ulat or y  a ut h ority as part of t he cli nical st u d y s u b missi o n.
Me dic al M o nit or C o nt act I nf or m ati o n:
U nite d 
St ates
Me dical M o nit or
P h o ne:
Fa x: 
E mail:
E ur o pe
Me dical M o nit or
P h o ne:
Fa x:
E mail: 
Asi a 
P acific
Me dical M o nit or
P h o ne:
Fa x: 
E mail: 
Seri o us A d verse E ve nts ( S A E s) C o nt act I nf or m ati o n:
: U S Tele p h o ne
U S Fa x L i ne 
Re g ul at or y A ge nc y Ide ntif y i n g N u m bers: U S I N D 1 1 6 3 0 1 ; E u dra C T 2 0 1 3 - 0 0 1 3 7 0- 2 0

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I N V E S TI G AT O R P R O T O C O L A G R E E M E N T P A G E
 
I c o nfir m a gree me nt t o c o n d uct t he st u d y  i n c o m plia nce wit h t he pr ot oc ol.
 
I ac k n o wle d ge t hat I a m res p o nsi ble f or o verall st u d y  c o n d uct. I a gree t o 
pers o nall y c o n d uct or s u per vise t he descri be d cli nical st u d y.
 
I a gree t o e ns ure t hat all ass ociates, c ollea g ues, a n d e m pl o yees assisti n g i n t he 
c o n d uct of t he st u d y are i nf or me d a b o ut t heir o bli gati o ns. Mec ha nis ms are i n 
place t o e ns ure t hat site staff recei ve s t he a p pr o priate i nf or mati o n t hr o u g h o ut t he 
st u d y.
I n vesti gat or Na me:
I n vesti gat or A d dress:
I n vesti gat or P h o ne N u m ber:
I n vesti gat or Si g nat ure:
Date :

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T A B L E O F C O N T E N T S
P A G E
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 ...........................................................1 2
P R O T O C O L S U M M A R Y ...............................................................................................1 5
1. 
I N T R O D U C TI O N....................................................................................................2 0
1. 1. 
Di s e a s e B a c k gr o u n d ...................................................................................2 0
1. 2. 
C urr e nt Tr e at m e nt s .....................................................................................2 0
1. 3. 
Of at u m u m a b ...............................................................................................2 1
1. 4. 
R ati o n al e ....................................................................................................2 1
2. 
O B J E C TI V E( S) ......................................................................................................2 2
2. 1. 
Pri m ar y O bj e cti v e .......................................................................................2 2
2. 2. 
S e c o n d ar y O bj e cti v e s .................................................................................2 2
2 2
3. 
I N V E S TI G A TI O N A L P L A N.....................................................................................2 2
3. 1. 
St u d y D e si g n ..............................................................................................2 2
3. 1. 1. 
S cr e e ni n g P eri o d .........................................................................2 7
3. 1. 2. 
Tr e at m e nt P eri o d .........................................................................2 8
3. 1. 3. 
F oll o w -u p P eri o d ..........................................................................2 9
3. 1. 4. 
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 u b st u d y ............................3 0
3. 2. 
Di s c u s si o n of D e si g n ..................................................................................3 0
3. 3. 
D o s e R ati o n al e ...........................................................................................3 1
4. 
S U B J E C T S E L E C TI O N A N D W I T H D R A WA L C RI T E RI A .......................................3 4
4. 1. 
N u m b er of S u bj e ct s ....................................................................................3 4
4. 2. 
I n cl u si o n Crit eri a.........................................................................................3 4
4. 3. 
E x cl u si o n Crit eri a ........................................................................................3 6
4. 4. 
Wi t hdr a w al Crit eri a .....................................................................................3 8
4. 4. 1. 
D o s e -h ol di n g Crit eri a ...................................................................3 8
4. 4. 2.   
Di s c o nti n u ati o n of I n v e sti g ati o n al Pr o d u ct ....................................3 9
4. 4. 3. 
Wi t h dr a w al fr o m t h e St u d y...........................................................3 9
5. 
S T U D Y T R E A T M E N T S ..........................................................................................3 9
5. 1. 
I n v e sti g ati o n al Pr o d u ct a n d Ot h er St u d y Tr e at m e nt....................................3 9
5. 1. 1. 
I n v e sti g ati o n al Pr o d u ct.................................................................3 9
5. 1. 2.   
Ot h er St u d y Tr e at m e nt s ...............................................................4 1
5. 2. 
Tr e at m e nt A s si g n m e nt ................................................................................4 1
5. 3. 
Bli n di n g .......................................................................................................4 2
5. 4. 
Pr o d u ct A c c o u nt a bilit y ................................................................................4 3
5. 5. 
Tr e at m e nt C o m pli a n c e ................................................................................4 3
5. 6. 
C o n c o mit a nt M e di c ati o n s a n d N o n -Dr u g T h er a pi e s ....................................4 3
5. 6. 1. 
P er mitt e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s ..........................4 3
5. 6. 2. 
Pr o hi bit e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s .........................4 3
5. 6. 3. 
I m m u ni z ati o n s .............................................................................4 4
5. 7. 
Tr e at m e nt aft er t h e E n d of t h e St u d y ..........................................................4 4
5. 8. 
Tr e at m e nt of I n v e sti g ati o n al Pr o d u ct O v er d o s e ..........................................4 5
6. 
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S .....................................................4 5

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6. 1. 
Criti c al B a s eli n e A s s e s s m e nt s ....................................................................5 1
6. 1. 1.   
M e di c al Hi st or y ............................................................................5 1
6. 1. 2. 
P e m p hi g u s V ul g ari s Hi st or y .........................................................5 1
6. 2. 
Effi c a c y .......................................................................................................5 2
6. 2. 1.  
Pri m ar y Effi c a c y E n d p oi nt s ..........................................................5 2
6. 2. 2. 
S e c o n d ar y Effi c a c y E n d p oi nt s .....................................................5 2
5 3
5 3
6. 3. 
S af e t y .........................................................................................................5 4
6. 3. 1. 
Li v er C h e mi str y St o p pi n g a n d F oll o w -u p Crit eri a .........................5 5
6. 3. 2. 
A d v er s e E v e nt s ............................................................................5 6
6. 3. 2. 1. 
D efi niti o n of a n A E ......................................................5 6
6. 3. 2. 2. 
D efi ni ti o n of a n S A E ...................................................5 7
6. 3. 2. 3. 
A d v er s e E v e nt s of S p e ci al I nt er e st .............................5 8
6. 3. 3. 
L a b or at or y a n d Ot h er S af et y A s s e s s m e nt A b n or m aliti e s 
R e p ort e d a s A E s a n d S A E s .........................................................5 9
6. 3. 4. 
C ar di o v a s c ul ar E v e nt s .................................................................5 9
6. 3. 5. 
D e at h E v e nt s ...............................................................................5 9
6. 3. 6. 
Pr e g n a n c y ...................................................................................6 0
6. 3. 7. 
Ti m e P eri o d a n d Fr e q u e n c y of D et e cti n g A E s a n d S A E s .............6 0
6. 3. 8. 
M et h o d of D et e cti n g A E s a n d S A E s .............................................6 0
6. 3. 9. 
Pr o m pt R e p orti n g of S eri o u s A d v er s e E v e nt s a n d Ot h er 
E v e nt s t o N o v arti s ........................................................................6 1
6. 3. 1 0. 
L a b or at or y A s s e s s m e nt s .............................................................6 3
6. 3. 1 0. 1. 
Cli ni c al L a b or at or y D at a .............................................6 3
6. 3. 1 0. 2. 
H e p atiti s B S cr e e ni n g a n d M o nit ori n g .........................6 4
6. 3. 1 1. 
Ot h er S af et y O ut c o m e s ...............................................................6 5
6. 3. 1 1. 1. 
Vit al Si g n s ..................................................................6 5
6. 3. 1 1. 2. 
T w el v e -l e a d El e ctr o c ar di o gr a m ( E C G) .......................6 5
6. 3. 1 2. 
M e di c al D e vi c e I n ci d e nt s .............................................................6 6
6. 4. 
H e alt h O ut c o m e s ........................................................................................6 6
6. 5. 
P h ar m a c o ki n eti c s .......................................................................................6 7
6. 6. 
P h ar m a c o d y n a mi c s ....................................................................................6 7
6. 7. 
P h ar m a c o g e n eti c s ( P G x) ............................................................................6 7
7. 
D A T A M A N A G E M E N T ...........................................................................................6 8
8.  
D A T A A N A L Y SI S A N D S T A TI S TI C A L C O N SI D E R A TI O N S ...................................6 8
8. 1. 
H y p ot h e s e s .................................................................................................6 8
8. 2. 
St u d y D e si g n C o n si d er ati o n s ......................................................................6 8
8. 2. 1. 
S a m pl e Si z e A s s u m pti o n s ...........................................................6 8
8. 2. 2. 
S a m pl e Si z e S e n siti vit y ................................................................6 9
8. 2. 3. 
Bli n d e d S a m pl e Si z e R e - esti m ati o n .............................................7 0
8. 3. 
D at a A n al y si s C o n si d er ati o n s .....................................................................7 0
8. 3. 1. 
A n al y si s P o p ul ati o n s ....................................................................7 0
8. 3. 2.  
A n al y si s D at a S et s .......................................................................7 0
8. 3. 3. 
Tr e at m e nt C o m p ari s o n s ..............................................................7 1
8. 3. 3. 1. 
Pri m ar y C o m p ari s o n s of I nt er e st ................................7 1
8. 3. 3. 2. 
Ot h er C o m p ari s o n s of I nt er e st ....................................7 1
8. 3. 4. 
I nt eri m A n al y si s ...........................................................................7 1
8. 3. 5. 
R e p orti n g Ti m e P oi nt s .................................................................7 2
8. 3. 6. 
K e y El e m e nt s of A n al y si s Pl a n ....................................................7 2

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8. 3. 6. 1.   
Mi s si n g D at a ...............................................................7 2
8. 3. 6. 2. 
D eri v e d a n d Tr a n sf or m e d D at a ...................................7 3
8. 3. 6. 3. 
A s s e s s m e nt Wi n d o w s ................................................7 3
8. 3. 6. 4. 
R a n d o mi z ati o n a n d Str atifi c ati o n ................................7 3
8. 3. 6. 5. 
Effi c a c y A n al y s e s .......................................................7 3
8. 3. 6. 6. 
P h ar m a c o ki n eti c A n al y s e s ..........................................7 5
8. 3. 6. 7. 
P h ar m a c o d y n a mi c A n al y s e s ......................................7 5
8. 3. 6. 8. 
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 n al y s e s ...........7 5
8. 3. 6. 9. 
S af et y A n al y s e s ..........................................................7 6
8. 3. 6. 1 0. 
Cli ni c al M e a s ur e s .......................................................7 6
9. 
S T U D Y C O N D U C T C O N SI D E R A TI O N S ...............................................................7 7
9. 1. 
P o sti n g of I nf or m ati o n o n P u bli cl y A v ail a bl e Cli ni c al Tri al R e gi st er s ............7 7
9. 2. 
R e g ul at or y a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e I nf or m e d 
C o n s e nt Pr o c e s s ........................................................................................7 7
9. 3. 
Q u alit y C o ntr ol ( St u d y M o nit ori n g) ..............................................................7 7
9. 4. 
Q u alit y A s s ur a n c e .......................................................................................7 8
9. 5. 
St u d y a n d Sit e Cl o s ur e ...............................................................................7 8
9. 6. 
R e c or d s R et e nti o n ......................................................................................7 9
9. 7. 
Pr o vi si o n of St u d y R e s ult s t o I n v e sti g at or s, P o sti n g of I nf or m ati o n 
o n P u bli cl y A v ail a bl e Cli ni c al Tri al s R e gi st er s a n d P u bli c ati o n ....................7 9
9. 8. 
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e (I D M C) .......................................8 0
9. 9. 
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) A dj u di c ati o n ..............8 0
1 0.
R E F E R E N C E S .......................................................................................................8 1
1 1.
A P P E N DI C E S ........................................................................................................8 4
1 1. 1. 
A p p e n di x 1 – P h ar m a c o g e n eti c R e s e ar c h ..................................................8 4
1 1. 2. 
A p p e n di x 2 – C o u ntr y S p e cifi c R e q uir e m e nt s .............................................8 9
1 1. 2. 1. 
A p p e n di x 2 – C o u ntr y -S p e cifi c R e q uir e m e nt s: J a p a n ..................9 0
1 1. 3. 
A p p e n di x 3 – Li v er C h e mi str y St o p pi n g a n d F oll o w -u p Crit eri a ...................9 5
1 1. 4. 
A p p e n di x 4 – Al g orit h m f or P M L M o nit ori n g ................................................9 8
1 1. 5. 
A p p e n di x 5 – N e ur ol o gi c al S y m pt o m s Q u e sti o n n air e ...............................1 0 0
1 0 1
1 0 2
1 0 3
1 0 4
1 0 6
1 0 9
1 1 2
1 1. 1 3. A p p e n di x 1 3 – C e ntr al L a b or at or y R ef er e n c e R a n g e s ..............................1 1 6
1 1. 1 4. A p p e n di x 1 4 – P h o n e Vi sit Q u e sti o n n air e .................................................1 3 3
1 1. 1 5. A p p e n di x 1 5 – Pr ot o c ol C h a n g e s ..............................................................1 3 4

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0
LI S T O F T A B L E S
P A G E
T a bl e 3- 1 
St u d y O bj e cti v e s a n d E n d p oi nt s .............................................................2 6
T a bl e 3- 2 
Or al Pr e d ni s o n e/ Pr e d ni s ol o n e D o s e -t ap er S c h e d ul e .............................2 9
T a bl e 5 - 1  
Pr e- a n d P o sti nj e cti o n M e di c ati o n s ........................................................4 1
T a bl e 5 - 2 
Pr o hi bit e d M e di c ati o n s
a n d N o n -Dr u g T h er a pi e s ...................................4 4
T a bl e 6- 1 
Ti m e a n d E v e nt s T a bl e ..........................................................................4 7
T a bl e 6- 2 
Ti m e a n d E v e nt s T a bl e: I n di vi d u ali z e d F oll o w -u p P eri o d ........................4 9
T a bl e 6- 3 
Ti m e a n d E v e nt s T a bl e: 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 u b st u d y ................................................................................................5 0
T a bl e 6- 4 
R e p orti n g of S eri o u s A d v er s e E v e nt s a n d Ot h er E v e nt s t o 
N o v arti s ..................................................................................................6 2
T a bl e 6- 5 
L a b or at or y T e sti n g .................................................................................6 4
T a bl e 6 - 6 
H e p atiti s B Vir u s T e st R e s ult S c e n ari o s f or S u bj e ct Eli gi bilit y .................6 5
T a bl e 8- 1 
S a m pl e Si z e S e n siti vit y ..........................................................................6 9
T a bl e 8- 2 
O v er all P o w er f or t h e C o -pri m ar y E n d p oi nt s ..........................................7 0

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1
LI S T O F FI G U R E S
P A G E
Fi g ur e 3 - 1 
St u d y S c h e m a ........................................................................................2 4
F i g ur e 3- 2 
St u d y Fl o w c h art .....................................................................................2 5
Fi g ur e 3 - 3 
O b s er v e d M e di a n a n d I nt er -d e cil e R a n g e B -c ell D e pl eti o n f or 
Of at u m u m a b S C i n St u d y O M S 1 1 2 8 3 1 ..................................................3 2
Fi g ur e 3- 4 
Pr e di ct e d M e di a n a n d I nt er -d e cil e R a n g e B -c ell D e pl eti o n wit h 
Of at u m u m a b S C 4 0 m g A d mi ni st er e d at W e e k s 0 a n d 4, t h e n 2 0 
m g A d mi ni st er e d E v er y 4
W e e k s T hr o u g h W e e k 5 6 ..............................3 3
Fi g ur e 3- 5 
Pr e di ct e d M e di a n a n d I nt er -d e cil e R a n g e B -c ell P er c e nt 
I n hi biti o n wit h Of at u m u m a b S C 4 0 m g A d m i ni st er e d at We e k s 0 
a n d 4, t h e n 2 0 m g A d mi ni st er e d E v er y 4
W e e k s T hr o u g h 
W e e k 5 6 .................................................................................................3 3
Fi g ur e 6 - 1 
R el ati v e Ti mi n g of K e y A cti viti e s o n Of at u m u m a b S C D o si n g 
D a y s .......................................................................................................4 6
Fi g ur e 6- 2 
Li v er C h e mi str y St o p pi n g a n d I n cr e a s e d M o nit ori n g Al g orit h m ...............5 5
Fi g ur e 6 - 3 
Li v er C h e mi str y I n cr e a s e d M o nit ori n g Al g orit h m wit h C o nti n u e d 
T h er a p y f or A L T 3 x U L N b ut < 8 x U L N ...................................................5 6
Fi g ur e 1 1 - 1 
Al g orit h m f or P M L M o nit ori n g .................................................................9 9

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2
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
A b br e vi ati o n s
A E
a d verse e ve nt
A L T
ala ni ne a mi n otra nsferase
A N C O V A
a nal ys is of c o varia nce
a nti-H Bc ( or H Bc A b)
he patitis B c ore a nti b o d y
A S T
as partate a mi n otra nsferase
C M H
C oc hra n – Ma ntel – Hae nszel
C R F
case re p ort f or m
Ds g
des m o glei n
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m
F D A
F o o d a n d Dr u g A d mi n istrati o n
F S H
f ollicle-sti m ulati n g h or m o ne
g
gra m(s)
G C P
G o o d Cli nical Practice
G S K
Gla x o S mit h Kli ne
H A H A
h u ma n a nti -h u ma n a nti b o d y
H B V
he patitis B vir us
H Bs A b
he patitis B s urface a nti b o d y
H Bs A g
he patitis B s urface a nti ge n
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I D M C
in de pe n de nt data m o nit ori n g c o m mittee
I E C
in de pe n de nt et hics c o m mittee
I g
i m m u n o gl o b uli n 
I N R
i nter nati o nal n or malize d rati o
I RB
instit uti o nal re vie w b oar d
I T T
i nte nt t o treat ( p o p ulati o n)
I V
i ntra ve n o us
I V R
interacti ve v oic e res p o ns e
J C V
J C vir us
L L N
l o wer li mit of n or mal (refere nce ra n ge)
m g
milli gra m(s)
m L
milliliter(s)
P C R
p ol y merase c hai n reacti o n
P G x
p har mac o ge netic(s)
P M D A
P har mace uticals a n d Me dical De vices A ge nc y
P M L
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y
P P
per pr ot oc ol ( p o p ulati o n)
P V
pe m p hi g us v ul garis
Q Tc
c orrecte d Q T i nter val

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3
R A P
re p orti n g a n d a nal ys is pla n
R B C
re d bl o o d cell
R R M S
rela psi n g-re mitti n g m ulti ple scler osis
S A E
seri o us a d verse e ve nt
S C
s u bc uta ne o us(ly)
S P M
st u d y pr oce d ures ma n ual
S R
s ustai ne d re missi o n
T B
t u berc ul osis 
U L N
u p per li mit of n or mal (refere nce ra n ge)
W B C
w hite bl o o d cell
Pr ot o c ol- S p e cifi c D efi niti o n s
St u d y Peri o ds:
C ore St u dy Peri o d 
T he C ore St u d y  Peri o d i ncl u des t he 5 6-wee k d o u ble -bli n d 
Treat me nt Peri o d a n d 4 -wee k F oll o w -u p Visit (at Wee k 6 0).
I n divi d u alize d F oll o w- u p 
Peri o d
If B-cell c o u nts ha ve n ot rec o vere d by t he Wee k 6 0 visit , 
s u bjects n ot e nteri n g t he e xte nsi o n st u d y will re mai n i n a n 
I n di vi d ualize d F oll o w-u p Peri o d u ntil b ot h t he C D 1 9 + B-cell 
c o u nts a n d circ ulati n g I g G le vels are ≥L L N or basel i ne 
le vels (if < L L N) or u ntil 2 years after t he last d ose of 
i n vesti gati o nal pr o d uct ( w hic he ver c o mes first).  S u bjects 
w h o wit h dra w fr o m treat me nt will als o e nter t he 
I n di vi d ualize d F oll o w-u p Peri o d.
Scree ni n g Peri o d 
A Scree ni n g Peri o d of 2 t o 1 2 wee ks will occ ur pri or t o 
ra n d o mizati o n t o all o w s u bjects t o ac hie ve disease c o ntr ol 
usi n g a sta ble oral d ose of pre d nis o ne/ pre d nis ol o ne.  
M ulti ple visits t o t he cli nic are per mitte d d uri n g t his ti me t o 
assess disease stat us a n d t o a dj ust t he oral 
pre d nis o ne/ pre d nis ol o ne d ose. 
Cli nic al Defi niti o ns: 
Di d n ot fl are/rel a pse 
Ac hie ve d re missi o n o n mi ni mal ster oi d t hera p y  a n d di d n ot 
s u bse q ue ntl y ha ve a flare/rela pse of disease b y Wee k 6 0
Dise ase c o ntr ol
N o ne w lesi o ns f or 2 wee ks
Dise ase fl are /rel a pse
A p peara nce of ≥3 ne w lesi o ns wit hi n 1 m o nt h t hat d o n ot 
heal s p o nta ne o usl y wit hi n 1 wee k, or w he n t here is a n 
e xte nsi o n ( w orse ni n g) of lesi o ns t hat were prese nt at t he 
ra n d o mizati o n visit ( N ote: t he a p pe ar a nce of 1 or 2 ne w 
lesi o ns is n ot c o nsi dere d a fl are/rel a pse)
D ur ati o n of re missi o n o n 
mi ni m al ster oi d t her a py
T otal ti me (s u m) of all peri o ds of re missi o n w hile o n 
mi ni mal ster oi d t hera p y  (oral pre d nis o ne/ pre d nis ol o ne d ose 
≤1 0 m g/ da y ) u p t o Wee k 6 0

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4
Eli mi n ate d use of 
syste mic ster oi ds
A n oral pre d nis o ne/ pre d nis ol o ne d ose of 0 m g/ da y f or 
2 wee ks
Mi ni m al ster oi d t her a py 
A n oral pre d nis o ne/ pre d nis ol o ne d ose of ≤1 0 m g/ da y
Re missi o n
A bse nce of ne w or n o n heali n g (esta blis he d) lesi o ns f or 
8 wee ks ( N ote: S u bjects wit h existi n g, he ali n g lesi o ns m ay
be c o nsi dere d i n re missi o n if ot her criteri a are met.)
Re missi o n o n mi ni m al 
ster oi d t her a py
A bse nce of ne w or n o n heali n g (esta blis he d) lesi o ns w hile o n 
a n oral pre d nis o ne/ pre d nis ol o ne d ose of ≤1 0 m g/ da y  f or 
8 wee ks
S ust ai ne d re missi o n ( S R) 
T he a bse nce of ne w or n o n heali n g (esta blis he d) lesi o ns f or 
8 wee ks t hat is s ustai ne d u ntil Wee k 6 0
Ti me t o re missi o n off 
ster oi d t her a py
Ti me fr o m ra n d o mizati o n t o t he ti me t he s u bject i nitiall y  
ta pere d off all ster oi ds f or 8 wee ks wit h a n a bse nc e of ne w 
or n o n heali n g (esta blis he d) lesi o ns b y  Wee k 6 0
Ti me t o re missi o n o n 
mi ni m al ster oi d t her a py
Ti me fr o m ra n d o mizati o n t o t he ti me t he s u bject i nitiall y  
ta pere d his/ her oral pre d nis o ne/ pre d nis ol o ne d ose t o 
≤1 0 m g/ da y  a n d mai ntai ne d ≤1 0 m g/ da y  of oral 
pre d nis o ne/ pre d nis ol o ne wit h n o ne w or n o n heali n g 
(esta blis he d) lesi o ns f or 8 wee ks b y Wee k 6 0
Ti me t o i niti al 
fl are/rel a pse
Ti me fr o m ra n d o mizati o n t o t he ti me of a p p eara nce of
≥3 ne w lesi o ns wit hi n 1 m o nt h t hat d o n ot heal 
s p o nta ne o usl y wit hi n 1 wee k, or t o t he ti me w he n t here is a n 
e xte nsi o n of lesi o ns t hat were prese nt at t he ra n d o mizati o n 
visit
Ti me t o s ust ai ne d 
re missi o n o n mi ni m al 
ster oi d t her a py
Ti me fr o m ra n d o mizati o n t o t he ti me t he s u bject i nitiall y  
ta pere d his/ her oral pre d nis o ne/ pre d nis ol o ne d ose t o 
≤1 0 m g/ da y  a n d mai ntai ne d ≤1 0 m g/ da y  of oral 
pre d nis o ne/ pre d nis ol o ne wit h n o ne w or n o n heali n g 
(esta blis he d) lesi o ns f or 8 wee ks A N D mai ntai ne d t hat 
stat us u nt il Wee k 6 0

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5
P R O T O C O L S U M M A R Y
R ati o n al e
Pe m p hi g us v ul garis ( P V ) is a n ac q uire d, rare, c hr o nic, de bilitati n g, a n d p ote ntiall y 
life-t hreate ni n g a ut oi m m u ne vesic ul o b ull o us dis or der t hat is c haracterize d b y 
m uc oc uta ne o us blisters.  Wit h o ut treat me nt,
s uc h blisteri n g e ve nt uall y lea ds t o er osi o ns 
i n t he s ki n, res ulti n g i n si g nifica nt m ortalit y.
S y ste mic gl uc oc ortic oi ds ha ve bee n t he c or nerst o ne of ma na ge me nt, re d uci n g m ortalit y 
fr o m 7 0 % t o less t ha n 2 0 % [Cars o n , 1 9 9 6; La n g a n, 2 0 0 8]. I n t he U nite d States, vari o us 
ster oi d pre parati o ns are a p pr o ve d f or treat me nt of pe m p hi g us.  I n E ur o pe, b ot h ster oi ds 
a n d azat hi o pri ne are a p pr o ve d f or pe m p hi g us or P V.  U nf ort u natel y, c hr o nic treat me nt 
wit h hi g h -d ose c ortic oster oi ds ca uses si g nifica nt m or bi dit y .  A rece nt C oc hra ne re p ort 
[Marti n , 2 0 1 1] i de ntifie d o nl y 1 1 ra n d o mize d c o ntr olle d st u dies assessi n g pe m p hi g us 
i nter ve nti o ns, a n d c o ncl u de d t hat t he o pti mal t hera pe utic strate g y re mai ns u nclear.  
I ntra ve n o us (IV) rit u xi ma b, a c hi meric i m m u n o gl o b uli n (I g) G 1 m o n ocl o nal a nti b o d y  
tar geti n g t he B-cell s pecific C D 2 0 a nti ge n, has bee n re p orte d t o s uccessf ull y treat P V i n 
case-series re p orts i n se vere or refract or y disease [A h me d , 2 0 0 6; Cia nc hi ni , 2 0 0 7;
J ol y, 2 0 0 7; E mi n g , 2 0 0 8; Ki m , 2 0 1 1; Kas per kie wics , 2 0 1 2; Les he m , 2 0 13 ; 
L u nar d o n , 2 0 1 2], a n d i n a si n gle case re p ort as a first-li ne t hera py [ Cra y th or ne , 2 0 1 1].  
T he re d ucti o n of pat h o ge nic a nti b o dies via tar gete d B- cell de pleti o n f or ms t he basis f or 
t he use of rit u xi ma b i n t he treat me nt of P V, a n d cli nical res p o nse t o rit u xi ma b has 
c orrelate d wit h B -cell de pleti o n [M o u q uet , 2 0 0 8; E mi n g , 2 0 0 8; C olli o u , 2 0 1 3].  Use of 
rit u xi ma b f or P V treat me nt re mai ns li mite d b y t he nee d f or i nf usi o n s uites f or dr u g 
a d mi nis trati o n a nd t he lac k of a n y ra n d o mize d pr os pecti ve cli nical st u dies e val uati n g its 
efficac y a n d safety.  Rit u xi ma b is n ot a n a p pr o ve d treat me nt f or P V.  
Ofat u m u ma b is a m o n ocl o nal a nti b o d y  t hat tar gets t he C D 2 0 a nti ge n o n B-cells.  T he 
acti o ns of ofat u m u ma b o n B-cells are si milar t o rit u xi ma b; h o we ver, ofat u m u ma b bi n ds 
t o a differe nt e pit o pe o n t he C D 2 0 m olec ule a n d has de m o nstrate d s u peri or i n vitr o Fc 
effect or f u ncti o ns (c o m ple me nt -de pe n de nt a n d a nti b o d y -de pe n de nt cell ular c y t ot o xicit y).  
B- cell de pleti o n has bee n d oc u me nte d wit h I V a d mi nistrati o n of ofat u m u ma b i n s u bjects 
wit h r he u mat oi d art hritis a n d m ulti ple scler osis, a n d wit h s u bc uta ne o us ( SC ) 
a d mi nistrati o n of ofat u m u ma b i n s u bjects wit h r he u mat oi d art hritis (Gla x o S mit h Kli ne 
St u d y  O F A 1 1 0 8 6 7).  T here f ore, ofat u m u ma b i njecti o n f or S C use ( ofat u m u ma b S C) has 
t he p ote ntial t o re d uce disease acti vit y i n patie nts wit h P V, a p ote ntiall y life-t hreate ni n g 
c o n diti o n .
O bj e cti v e s
Pri m ar y  O bj e cti v e
T o deter mi ne t he efficac y, base d o n disease re missi o n, of ofat u m u ma b S C at a d ose of 
2 0 m g a d mi nistere d e ver y 4 wee ks ( wit h a n a d diti o nal 2 0 -m g l oa di n g d ose [ie, 4 0 m g
t otal] at b ot h Wee k 0 a n d Wee k 4) i n s u bjects wit h P V.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6
S e c o n d ar y  O bj e cti v e s
 
T o e val uate t he safet y a n d t olera bilit y of ofat u m u ma b S C .
 
T o e val uate disease flare/rela pse d uri n g treat me nt wit h ofat u m u ma b S C.
 
T o e val uate re d ucti o ns i n ster oi d d ose w hile mai ntai ni n g disease c o ntr ol.
 
T o assess p o p ulati o n p har mac o d y na mics a n d t he e xte nt of B-cell de pleti o n a n d 
re pleti o n f oll o wi n g ofat u m u ma b S C.
 
T o e val uate t he i m m u n o ge nicit y  of ofat u m u ma b S C.
 
T o assess t he p o p ulati o n p ha r mac o ki netics of ofat u m u ma b S C.
St u d y D e si g n
T his is a gl o bal, m ultice nter, ra n d o mize d, d o u ble- bli n d, place b o -c o ntr olle d, 
parallel -gr o u p st u d y t o assess t he efficac y, safet y, a n d t olera bilit y of ofat u m u ma b S C i n 
s u bjects wit h P V, w h o ha ve faile d a pre vi o us atte m pt t o ta per ster oi d d osi n g  (ie, ha d a 
disease flare d uri n g t he ta per atte m pt).  T he st u d y i ncl u des a Scree ni n g Peri o d, a 5 6- wee k 
Treat me nt Peri o d, a n d a 4-wee k F oll o w -u p visit .  S u bjects will visit t he c li nic d uri n g 
Scree ni n g ; at Baseli ne ( Wee k 0) ; at Wee ks 2, 4, 6, a n d 8 ; a n d t he n e ver y 4 wee ks fr o m 
Wee k
8 t hr o u g h Wee k 6 0 .  S u bjects will als o ha ve str uct ure d p h o ne visits bet wee n eac h 
of t he cli nic visits fr o m Wee k 1 0 t hr o u g h Wee k
2 2.  It is a ntici pate d that t otal d urati o n of 
partici pati o n i n t his st u d y  will be a p pr o xi matel y 7 2 wee ks.
A S cree ni n g P eri o d of 2 t o 1 2 wee ks will occ ur pri or t o ra n d o mizati o n t o all o w s u bjects 
t o ac hie ve disease c o ntr ol ( n o ne w lesi o ns f or 2 wee ks) usi n g a sta ble oral d ose of 
p re d nis o ne/ pre d nis ol o ne ( 2 0 m g/ d a y  u p t o 1 2 0 m g/ da y  or 1. 5 m g/ k g/ da y  [ w hic he ver is 
hi g her] f or 2 wee ks ). M ulti ple visits t o t he cli nic are per mitte d d uri n g t he S cree ni n g 
P eri o d t o assess disease stat us a n d t o a dj ust t he oral ster oi d d ose. O nce disease c o ntr ol is 
ac hie ve d, s u bjects w ho c o nti n ue t o meet all i ncl usi o n a n d e xcl usi o n criteria ma y  be 
ra n d o mize d. All scree ni n g pr oce d ures s h o ul d be c o m plete d wit hi n 1 2 wee ks of i nf or me d 
c o nse nt bei n g gi ve n. 
At t he Baseli ne Visit ( Da y 0), a p pr o xi matel y  1 3 6 eli gi ble s u bjects will be ce ntrall y 
ra n d o mize d 1: 1 acr oss 2 strata ( disease d urati o n [1 ye ar, > 1 ye ar] a n d baseli ne 
pre d nis o ne d ose [< 6 0 m g / da y, 6 0 m g / da y]) t o recei ve S C a d mi nistrati o n of ofat u m u ma b 
2 0 m g or place b o o nce e ver y  4 wee ks ( wit h a n a d diti o nal 2 0 - m g ‘l oa di n g’ d ose at b ot h 
Wee k
0 a n d Wee k 4) f or a t otal of 5 6 wee ks ( t otal of 1 7 i njecti o ns acr oss 1 5 m o nt hl y  
d os i n g visits). T w o wee ks after t he first d ose of ofat u m u ma b S C or place b o (ie, Wee k
2), 
t he oral ster oi d d ose will be gra d ually re d uce d acc or di n g t o a fi xe d d ose -ta per sc he d ule 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
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wit h a g oal of re d uci n g (ie, t o 1 0 m g/ da y ) or eli mi nati n g t he d ose of 
pre d nis o ne/ pre d nis ol o ne. 
After t he last d ose of ofat u m u ma b S C or place b o at Wee k 5 6 , su bjects will be 
f oll o we d-u p f or a mi ni m u m of 4 wee ks , wit h a visi t sc he d ule d at Wee k 6 0.  As t he 
ofat u m u m a b de vel o p me nt pr o gra m i n t he i n dicati o n P V has bee n ter mi nate d, s u bjects 
c o m pleti n g t he st u d y will n o l o n ger be eli gi ble t o partici pate i n t he e xte nsi o n st u d y 
( OP V 1 1 7 0 5 9 [als o k n o w n as C O M B 1 5 7J 2 3 0 1 E 1] ).  S u bjects w h o were e nr olle d i n t he 
e xte nsi o n st u d y pri or t o pr o gra m ter mi nati o n ma y re mai n i n t he e xte nsi o n st u d y u ntil e xit 
criteria are met.  S u bjects w h o d o n ot partici pate i n t he pla n ne d e xte nsi o n st u d y  will n ot 
recei ve a ny a d diti o nal treat me nt after c o m pleti o n of t his st u d y.
If B-cell c o u nts ha ve n ot rec o vere d by t he Wee k 6 0
visit, s u bjects n ot e nteri n g t he 
e xte nsi o n st u d y will re mai n i n a n I n di vi d ualize d F oll o w-u p Peri o d u ntil b ot h t he C D 1 9 + 
B- cell c o u nts a n d circ ulati n g I g G le vels are ≥l o wer li mit of n or mal (L L N ) or baseli ne 
le vels (if < L L N) or u ntil 2 years after t he last d ose of i n vesti gati o nal pr o d uct ( w hic he ver 
c o mes first).  I n di vi d ualize d F oll o w -u p visits will be sc he d ule d e ver y  1 2 wee ks.   S u bjects 
w h o wit h dra w fr o m treat me nt will als o e nter t he I n di vi d ualize d F oll o w -u p Peri o d.
St u d y P o p ul ati o n
A p pr o xi matel y 1 3 6 s u bjects will be ra n d o mize d i nt o t he st u d y. 
St u d y E n d p oi nt s/ A s s e s s m e nt s
C o -Pri m ar y E n d p oi nt s *:
 
T i me t o s ustai ne d re missi o n o n mi ni mal ster oi d thera p y.
 
D urati o n of remissi o n o n mi ni mal ster oi d t hera p y .
S e c o n d ar y E n d p oi nt s *:
 
Pr o p orti o n of s u bjects ac hie vi n g re missi o n o n m i ni mal ster oi d thera p y at Wee k 6 0 .
 
Ti me t o re missi o n w hile o n mi ni mal ster oi d t hera p y b y  Wee k 6 0 .
 
Ti me t o i nitial flare /rela pse b y  Wee k 6 0 .
 
Pr o p orti o n of s u bjects w h o di d n ot flare/rela pse b y  Wee k 6 0 .
 
Ti me t o re missi o n off ster oi d t hera p y b y  Wee k 6 0 .
 
Pr o p orti o n of s u bjects ac hie vi n g re missi o n w hile off ster oi d t hera p y b y Wee k 6 0 .
 
N u m ber of da y s a s u bject mai ntai ne d mi ni mal ster oi d t hera py b y Wee k 6 0 .
 
C u m ulati ve d ose of c ortic oster oi ds.
* N ote: defi niti o ns are pr ovi de d wit h t he list of a b brevi ati o ns a n d i n Secti o n 6. 2 .

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S af et y : 
 
A d verse e ve nts ( A Es).
 
A d verse e ve nt fre q ue nc y, se verity, a n d relati o ns hi p t o i n vesti gati o nal pr o d uct.
 
F re q ue nc y a n d se verit y of i nfecti o ns.
 
F re q ue nc y of seri o us A Es.
 
Fre q ue nc y  of wit h dra w als d ue t o treat me nt-relate d A Es .
 
Fre q ue nc y  of A Es lea di n g t o per ma ne nt disc o nti n uati o n of i n vesti gati o nal pr o d uct.
 
Fre q ue nc y  of A Es of s pecial i nterest, p osti njecti o n s yste mic reacti o ns, a n d i njecti o n 
site reacti o ns.
 
C ha n ge fr o m baseli ne i n vital si g ns .
 
F re q ue nc y of vital si g ns of cli nical c o ncer n.
 
C ha n ge fr o m baseli ne i n la b orat or y (he mat ol o g y , c he mistr y, a n d uri nalys is)
para meters .
 
F re q ue nc y of la b orat or y (he mat ol o g y , c he mistr y, a n d uri nalys is) res ults of p ote ntial 
cli nical c o ncer n .
 
I m m u n o ge nicity as meas ure d b y t he i nci de nce, titer, a n d t y pe of h u ma n a nti-h u ma n 
a nti b o d y i m m u ne res p o nse.

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P h ar m a c o ki n eti c E n d p oi nt s:
 
Plas ma (tr o u g h) c o nce ntrati o ns of ofat u m u ma b .
 
E x p os ure -res p o nse relati o ns hi p.
 
F or s u bjects i n t he p h ar m ac oki netic-p h ar m ac o dy n a mic s u bst u dy : Ma xi m u m 
ofat u m u ma b c o nce ntrati o n; ti me of ma xi m u m c o nce ntrati o n; a n d area u n der t he ti me 
c o nce ntrati o n c ur ve.
 
Effect of de m o gra p hic fact ors, i ncl u di n g baseli ne c o variates, o n p har mac o ki netic 
e n d p oi nts.
P h ar m a c o d y n a mi c E n d p oi nt s:
 
C ha n ge fr o m baseli ne i n B -l ym p h oc y te c o u nts i n peri p heral bl o o d.
 
Ti me t o re pleti o n of C D 1 9 + B- cells t o eit her ≥ t he baseli ne le vel or ≥L L N ra n ge, 
w hic he ver is l o wer.
 
B- cell de pleti o n a n d re pleti o n as meas ure d by C D 1 9 + peri p heral bl o o d 
B- l ym p h oc y te c o u nt via r o uti ne fl u oresce nt acti vate d cell s orti n g a nalys is.
 
F or s u bjects i n t he p h ar m ac oki netic -p h ar m ac o dy n a mic s u bst u dy: C D 1 9 + peri p heral 
bl o o d B -l ym p h oc y te c o u nt via r o uti ne fl u oresce nt acti vate d cell s orti n g a nal ysis wit h 
s u bsets i ncl u di n g, b ut n ot restricte d t o, naï ve a n d me m or y  p he n ot y pes .

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1. 
I N T R O D U C TI O N
1. 1. 
Di s e a s e B a c k gr o u n d
Pe m p hi g us v ul garis ( P V) is a n ac q uire d, rare, c hr o nic, de bilitati n g, a n d p ote ntiall y  
life-t hreate ni n g a ut oi m m u ne vesic ul o b ull o us dis or der t hat is c haracterize d b y 
m uc oc uta ne o us er osi o ns or blisters. T he ter m “ pe m p hi g us” i ncl u des P V, pe m p hi g us 
f oliace us, a n d para ne o plastic pe m p hi g us, wit h P V bei n g t he m ost wi del y dia g n ose d f or m 
of pe m p hi g us . 
Pe m p hi g us v ul garis prese nts wit h pea k fre q ue nc y ge nerall y occ urri n g at 3 0 t o 6 0 ye ars of 
a ge a n d ol der, wit h a n i nci de nce of a p pr o xi matel y 7 per milli o n w o rl d wi de a nd a 
m ortalit y  rate of <2 0 % . T he disease is ca use d b y pat h o ge nic a nti b o d ies directe d a gai nst 
des m o glei n (Ds g ) 1 a n d 3, w hic h are me m bers of t he des m os o mal ca d heri n fa mil y . T he 
i n viv o bi n di n g of t hese a nti-Ds g a ut oa nti b o dies ( mai nl y i m m u n o gl o b uli n [I g] G 4 a n d 
I g G 1) ca uses a l oss of a d hesi o n bet wee n kerati n oc ytes, a n d t he res ulta nt f or mati o n of 
i ntra-e pi der mal blisters [A ma gai , 1 9 9 5]. T hese blisters e ve nt uall y lea d t o er osi o ns i n t he 
s ki n w hic h, pri or to t he c ortic oster oi d era, fre q ue ntl y res ulte d i n m ortality.
1. 2. 
C urr e nt Tr e at m e nt s
S y ste mic gl uc oc ortic oi ds ha ve bee n t he c or nerst o ne of ma na ge me nt f or P V, re d uci n g 
m ortalit y  fr o m 7 0 % t o less t ha n 2 0 % [ Cars o n , 1 9 9 6; La n ga n , 2 0 0 8]. I n t he U nite d States,
ster oi ds are i n dicate d f or t he treat me nt of pe m p hi g us; i n s o me E ur o pea n c o u ntries, 
ster oi ds a n d azat hi o pri ne are la bele d f or use i n patie nts wit h pe m p hi g us or P V.  C hr o nic 
hi g h - d ose ster oi d treat me nt, h o we ver, ca uses si g nifica nt m or bi dit y, res ulti n g i n patie nts 
bei n g a d diti o nall y treate d wit h vari o us a dj u va nt me dicati o ns wit h t he i nte nti o n of 
mi ni mizi n g ster oi dal si de effects (e g, i ncrease d bl o o d press ure, h yper gl yc e mia, 
ne ur o ps yc h iatric c ha n ges, a n d b o ne de mi neralizati o n). A n o pti mal ster oi d – s pari n g a ge nt 
has n ot y et bee n i de ntifie d, d ue i n part t o t he pa ucit y  of ra n d o mize d c o ntr olle d st u dies
c o n d ucte d t o date .  A rece nt C oc hra ne re p ort [Marti n , 2 0 1 1] i de ntifie d o nl y  
1 1 ra n d o mize d, c o ntr olle d st u dies assessi n g pe m p hi g us i nter ve nti o ns, a n d c o ncl u de d t hat 
t he o pti mal t hera pe utic strate g y re mai ns u nclear.
I ntra ve n o us (IV) rit u xi ma b, a c hi meric I g G 1 m o n ocl o nal a nti b o d y t hat de pletes B- cells 
b y  tar geti n g t he B- cell-s pecific C D 2 0 a nti ge n, was i de ntifie d i n case -series re p orts as a 
s uccessf ul treat me nt f or se vere or refract or y P V [A h me d , 2 0 0 6; Cia nc hi ni , 2 0 0 7;
J ol y, 2 0 0 7; E mi n g , 2 0 0 8; Ki m , 2 0 1 1; Kas per kie wics , 2 0 1 2; Les he m , 2 0 13 ; 
L u nar d o n , 2 0 1 2], a n d i n a si n gle case re p ort as a first- li ne t hera py  [Cra y th or ne , 2 0 1 1].  
T he re d ucti o n of pat h o ge nic a nti b o dies via tar gete d B- cell de pleti o n f or ms t he basis f or 
t he use of ritu xi ma b i n t he treat me nt of P V, a n d cli nical res p o nse t o rit u xi ma b has 
c orrelate d wit h B -cell de pleti o n [M o u q uet , 2 0 0 8; E mi n g , 2 0 0 8; C olli o u , 2 0 1 3].  
Rit u xi ma b, w hic h is n ot a p pr o ve d f or use i n P V, has n ot bee n e val uate d f or t he treat me nt 
of P V i n ra n d o mize d pr os pecti ve cli nical st u dies, a n d its use re mai ns li mite d gi ve n t he 
nee d f or i nf usi o n s uites f or dr u g a d mi nist rati o n.

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1. 3. 
Of at u m u m a b
Ofat u m u ma b is a m o n ocl o nal a nti b o d y  t hat tar gets t he C D 2 0 a nti ge n o n B-cells.  It is 
c urre ntl y a p pr o ve d a n d mar kete d ( A R Z E R R A™) f or t he treat me nt of patie nts wit h
c hr o nic l y m p h oc y tic le u ke mia refract or y t o fl u dara bi ne a n d ale mt uz u ma b.  
A d mi nistrati o n of A R Z E R R A is via I V i nf usi o n, wit h 1 2 d oses o ver 3 0 wee ks ( 3 0 0 m g 
i nitial d ose, f oll o we d b y 2 0 0 0 m g wee kl y f or 7 d oses, t he n 2 0 0 0 m g e ver y  4 wee ks f or 
4 d oses).  I n a d diti o n, ofat u m u ma b has bee n i n vesti gate d as a n I V i nf usi o n f or ot her 
o nc ol o g y  i n dicati o ns, a n d as a n I V i nf usi o n a n d as a s u bc uta ne o us ( S C) i njecti o n f or 
a ut oi m m u ne dis or ders (ie, rela psi n g-re mitti n g m ulti ple scler osis [ R R M S] a n d r he u mat oi d 
art hritis).
T he acti o ns of ofat u m u ma b o n B -cells are si milar t o rit u xi ma b; h o we ver, ofat u m u ma b 
bi n ds t o a differe nt e pit o pe o n t he C D 2 0 m olec ule a n d has de m o nstrate d s u peri or i n vitr o
Fc effect or f u ncti o ns ( c o m ple me nt -de pe n de nt a n d a nti b o d y -de pe n de nt cell ular 
c yt ot o xicit y).  R o b ust B- cell de pleti o n has bee n d oc u me nte d f oll o wi n g I V a d mi nistrati o n 
of ofat u m u ma b t o s u bjects wit h a ut oi m m u ne c o n diti o ns ( r he u mat oi d art hritis a n d R R M S ).  
B- cell de pleti o n wit h ofat u m u ma b S C has als o bee n d oc u me nte d f oll o wi n g si n gle-d ose 
a d mi nistrati o n t o s u bjects wit h r he u mat oi d art hritis (Gla x o S mit h Kli ne 
[G S K ] St u d y O F A 1 1 0 8 6 7) a n d re peat -d ose a d mi nistrati o n t o s u bjects wit h R R M S 
(G S K S t u d y O M S 1 1 2 8 3 1).
A d diti o nal i nf or mati o n is pr o vi de d i n t he I n vesti gat or’s Br oc h ure
[Ofat u m u ma b/ O M B 1 5 7/ G S K 1 8 4 1 1 5 7 I nv esti gat or’s Br oc h ure , 2 0 1 6].
1. 4. 
R ati o n al e
Alt h o u g h n o c ure is c urre ntl y  a vaila ble f or P V, the efficac y  of s yste mic c ortic oster oi ds 
(ofte n a d mi nistere d at hi g h d oses a n d c o nc o mita ntl y wit h ot her i m m u n os u p pressi ve 
treat me nt) i n ma na gi n g P V has bee n well de m o nstrate d [ Har ma n , 2 0 0 3].  S yste mic 
cortic oster oi ds are c urre ntl y t he m ost c o m m o nl y utilize d t hera p y f or t he ma na ge me nt of 
P V . 
Multi ple si de -effects ass ociate d wit h hi g h - d ose c ortic oster oi ds, h o we ver, i ncrease 
m or bi dit y  a n d ma y necessitate t he use of a dj u va nt ster oi d-s pari n g t hera pies.
F or s u bjects faili n g P V treat me nt d ue t o a d verse e ve nts (A Es ) ass ociate d wit h hi g h -d ose 
ster oi d treat me nt or o t her i m m u n os u p pressa nts, or d ue t o d osi n g i nc o n ve nie nce (as i n t he 
case of rit u xi ma b wit h t he atte n da nt nee d f or a n i nf usi o n s uite), a d diti o nal t hera pe utic 
a p pr oac hes are nee de d t o a p pr o priatel y treat P V.
T he o bjecti ve of t his st u d y  is t o e val uate t he efficac y, t olera bilit y, a n d safet y of
ofat u m u ma b i njecti o n f or S C use ( ofat u m u ma b S C) at a d ose of 2 0 m g a d mi nistere d 
e ver y 4 wee ks ( wit h a n a d diti o nal 2 0 -m g l oa di n g d ose [ie, 4 0 m g t otal] at b ot h Wee k 0 
a n d Wee k 4) i n s u bjects wit h P V.  It is a ntici pate d t hat wit h sustai ne d B- cell de pleti o n i n 
t he prese nce of ofat u m u ma b S C , a n d t he res ulta nt re d ucti o n of pat h o ge nic a nti -Ds g
a ut oa nti b o dies i n P V , t hat cli nical re missi o n of t he disease will res ult.

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2. 
O B J E C TI V E( S)
2. 1. 
Pri m ar y  O bj e cti v e
T o deter mi ne t he efficac y, base d o n disease re missi o n, of ofat u m u ma b S C at a d ose of 
2 0 m g a d mi nistere d e ver y 4 wee ks ( wit h a n a d diti o nal 2 0-m g l oa di n g d ose [ie, 4 0 m g
t otal] at b ot h Wee k 0 a n d Wee k 4) i n s u bjects wit h P V.
2. 2. 
S e c o n d ar y  O bj e cti v e s
 
T o e val uate t he safet y a n d t olera bilit y of ofat u m u ma b S C .
 
T o e val uate disease flare/rela pse d uri n g treat me nt wit h ofat u m u ma b S C.
 
T o e val uate re d ucti o ns i n ster oi d d ose w hile mai ntai ni n g di sease c o ntr ol.
 
T o deter mi ne t he e xte nt of B -cell de pleti o n a n d re pleti o n f oll o wi n g ofat u m u ma b S C.
 
T o e val uate t he i m m u n o ge nicit y  of ofat u m u ma b S C.
 
T o assess t he p o p ulati o n p har mac o ki netics of ofat u m u ma b S C.
3. 
I N V E S TI G ATI O N A L P L A N
Pr ot oc ol wai vers or e xe m pti o ns are n ot all o we d wit h t he e xce pti o n of i m me diate safet y  
c o ncer ns. T heref ore, a d here nce t o t he st u d y  desi g n re q uire me nts, i ncl u di n g t h ose 
s pecifie d i n t he Ti me a n d E ve nts Ta ble (Ta ble 6- 1 ), are esse ntial a n d re q uire d f or st u d y 
c o n d uct.
* Refer t o A p pe n dix 2 f or a ny a d diti o n al a p plic a ble c o u ntry -s pecific re q uire me nts. *
3. 1. 
St u d y D e si g n
T his is a gl o bal, m ultice nter, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, 
parallel -gr o u p st u d y t o assess t he efficac y, safet y, a n d t olera bilit y of ofat u m u ma b S C i n 
s u bjects wit h P V , w h o ha ve faile d a pre vi o us atte m pt t o ta per ster oi d d osi n g   (ie, ha d a 
disease flare d uri n g t he ta per atte m pt) . T he st u d y i ncl u des a Scree ni n g Peri o d, a C ore 
St u d y  Peri o d (c o nsisti ng of t he 5 6 -wee k Treat me nt Peri o d a n d 4 -wee k F oll o w -u p visit), 
a n d a n I n di vi d ualize d F oll o w -u p Peri o d (as a p plica ble) .  
S u bjects will visit t he cli nic d uri n g Scree ni n g ; at Baseli ne ( Wee k 0 ); at Wee ks 2 , 4, 6, 
a n d 8 ; a n d t he n e ver y 4 wee ks fr o m Wee k 8 t hr o u g h Wee k 6 0 .  S u bjects will als o ha ve 

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str uct ure d p h o ne visits bet wee n eac h of t he cli nic visits fr o m Wee k 1 0 t hr o u g h Wee k
2 2
(see A p pe n di x 1 4 ).  It is a ntici pate d t hat t otal d urati o n of partici pati o n i n t he C ore St u d y 
Peri o d will be a p pr o xi matel y  7 2 wee ks.
A Scree ni n g Peri o d of 2 t o 1 2 wee ks will occ ur pri or t o ra n d o mizati o n t o all o w s u bjects 
t o ac hie ve disease c o ntr ol ( n o ne w lesi o ns f or 2 wee ks) [ M urrell , 2 0 0 8]) usi n g a sta ble 
oral d ose of pre d nis o ne/ pre d nis ol o ne ( 2 0 m g / da y u p t o 1 2 0 m g/ da y  or 1. 5 m g/ k g/ da y  
[ w hic he ver is hi g her] f or 2 wee ks) .
M ulti ple visits t o t he cli nic are per mitte d d uri n g t his 
Scree ni n g Peri o d t o assess disease stat us a n d t o a dj ust t he oral pre d nis o ne/ pre d nis ol o ne 
d ose. O nce disease c o ntr ol is ac hie ve d, s u bjects w h o c o nti n ue t o satisf y  t he eli gi bilit y 
criteria m a y be ra n d o mize d.   All scree ni n g pr oce d ures s h o ul d be c o m plete d wit hi n 
1 2 wee ks of i nf or me d c o nse nt bei n g gi ve n.
At t he Baseli ne Visit ( Da y 0), a p pr o xi matel y  1 3 6 eli gi ble s u bjects will be ce ntrall y 
ra n d o mize d 1: 1 acr oss 2 strata ( disease d urati o n [1 ye ar, > 1 ye ar] a n d baseli ne 
pre d nis o ne d ose [< 6 0 m g / da y, 6 0 m g / da y]) t o recei ve S C a d mi nistrati o n of ofat u mu ma b 
2 0 m g or place b o o nce e ver y  4 wee ks ( wit h a n a d diti o nal 2 0 -m g ‘l oa di n g’ d ose at b ot h 
Wee k
0 a n d Wee k 4) f or a t otal of 5 6 wee ks ( t otal of 1 7 i njecti o ns acr oss 1 5 m o nt hl y 
d osi n g visits ).
T w o wee ks after t he first d ose of ofat u m u ma b S C or place b o (ie, W ee k 2), t he oral 
ster oi d d ose will be gra d uall y re d uce d acc or di n g t o a fi xe d d ose-ta per sc he d ule wit h a 
g oal of re d uci n g (ie, t o 1 0 m g/ da y ) or eli mi nati n g t he d ose of pre d nis o ne/ pre d nis ol o ne
(see Ta ble 3- 2 ).
After t he last d ose of ofat u m u ma b S C or place b o at Wee k 5 6, s u bjects will be 
f oll o we d-u p f or a mi ni m u m of 4 wee ks, wit h a visit sc he d ule d at Wee k 6 0.  As t he 
ofat u m u m a b de vel o p me nt pr o gra m i n t he i n dicati o n P V has bee n ter mi nate d, s u bjects 
c o m pleti n g t he st u d y will n o l o n ger be eli gi ble t o partici pate i n t he e xte nsi o n st u d y 
( OP V 1 1 7 0 5 9 [als o k n o w n as C O M B 1 5 7J 2 3 0 1 E 1] ).  S u bjects w h o were e nr olle d i n t he 
e xte nsi o n st u d y pri or t o pr o gra m ter mi nati o n ma y re mai n i n t he e xte nsi o n st u d y u ntil e xit 
criteria are met.  S u b jects w h o d o n ot partici pate i n t he pla n ne d e xte nsi o n st u d y will n ot 
recei ve a ny a d diti o nal treat me nt after c o m pleti o n of t his st u d y .
If B-cell c o u nts ha ve n ot rec o vere d b y t he Wee k 6 0
visit, s u bjects n ot e nteri n g t he 
e xte nsi o n st u d y will re mai n i n a n I n divi d ualize d F oll o w -u p Peri o d u ntil b ot h t he C D 1 9 + 
B- cell c o u nts a n d circ ulati n g I g G le vels are ≥l o wer li mit of n or mal (L L N ) or basel i ne 
le vels (if < L L N) or u ntil 2 ye ars after t he last d ose of i n vesti gati o nal pr o d uct ( w hic he ver 
c o mes first) (see Fi g ure 3- 2 ).  I n di vi d ualize d F oll o w -u p visits will be sc he d ule d e ver y  
1 2 wee ks.   S u bjects w h o wit h dra w fr o m treat me nt will als o e nter t he I n di vi d ualize d 
F oll o w -u p Peri o d (as a p plica ble; g ui da nce will be pr o vi de d wit hi n t he  
 visit re p ort, 
la borat or y val ues will re mai n bli n de d).
A n i n de pe n de nt data m o nit ori n g c o m mittee (I D M C) will e val uate ris ks relati ve t o 
be nefits t hr o u g h re vie w of safet y a n d efficac y data o n a n o n g oi n g basis d uri n g t he st u d y.
A n y  case of s us pecte d or co nfir me d pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  ( P M L)
will g o t hr o u g h i n de pe n de nt P M L  a dj u dicati o n a n d a n o pi ni o n will be pr o vi de d t o t he 
S p o ns or.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
2 4
Fi g ur e 3- 1 
St u d y  S c h e m a
A b br evi ati o n: S C =s u bc ut a n e o us.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
2 5
Fi g ur e 3- 2 
St u d y  Fl o w c h art
A b br evi ati o ns: H B V = h e p atitis B vir us; I g =i m m u n o gl o b u li n; L L N =l o w er li mit of n or m al.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
2 6
T a bl e 3- 1 
St u d y  O bj e cti v e s a n d E n d p oi nt s
Pri m a r y O bj e cti v e
C o -Pri m ar y Effi c a c y E n d p oi nt s
T o d et er mi n e t h e effic acy, b as e d o n 
dis e as e r e missi o n, of of at u m u m a b S C 
at a d os e of 2 0 m g a d mi nist er e d ev ery 
4 w e eks ( wit h a n a d diti o n al 2 0-m g 
l o a di n g d os e [i e, 4 0 m g t ot al] at b ot h 
W e ek 0 a n d W e ek 4) i n s u bj ects wit h 
P V
 
Ti m e t o s ust ai n e d r e missi o n o n mi ni m al st er oi d t h er a py
 
D ur ati o n of r e missi o n o n mi ni m al st er oi d t h er a py
S e c o n d ar y Effi c a c y  E n d p oi nt s – s u p p orti n g pri m ar y o bj e cti v e
 
Pr o p orti o n of s u bj ects ac hi evi n g r e missi o n o n mi ni m al st er oi d t h er a py 
at W e ek 6 0
 
Ti m e t o r e missi o n w hil e o n mi ni m al st er oi d t h er a py 
 
Ti m e t o r e missi o n off st er oi d t h er a py by W e ek 6 0
 
Pr o p orti o n of s u bj ects ac hi evi n g r e missi o n w hil e off st er oi d t h er a py by 
W e ek 6 0
S e c o n d ar y O bj e cti v e s –
Effi c a c y a n d P h ar m a c o d y n a mi c
S e c o n d ar y E n d p oi n t s
T o ev al u at e dis e as e fl ar e/r el a ps e 
d uri n g tr e at m e nt wit h of at u m u m a b S C
 
Ti m e t o i niti al fl ar e/r el a ps e by W e ek 6 0
 
Pr o p orti o n of s u bj ects w h o di d n ot fl ar e/r el a ps e by W e ek 6 0
T o ev al u at e r e d ucti o ns i n st er oi d d os e 
w hil e m ai nt ai ni n g dis e as e c o ntr ol
 
N u m b er of d ays a s u bj ect m ai nt ai n e d mi ni m al st er oi d t h er a py t o 
W e ek 6 0
 
C u m ul ativ e d os e of c ortic ost er oi ds
T o d et er mi n e p o p ul ati o n 
p h ar m ac o dy n a mics a n d t h e ext e nt of 
B- c ell d e pl eti o n a n d r e pl eti o n f oll o wi n g 
of at u m u m a b S C
 
C h a n g e fr o m b as eli n e i n B -ly m p h ocyt e c o u nts i n p eri p h er al bl o o d 
 
Ti m e t o r e pl eti o n of C D 1 9 + B -c ells t o eith er ≥b as eli n e l ev el or ≥L L N, 
w hic h ev er is l o w er
 
B- c ell d e pl eti o n a n d r e pl eti o n as m e as ur e d by C D 1 9 + p eri p h er al bl o o d 
B ly m p h ocyt e c o u nt vi a r o uti n e fl u or esc e nt activ at e d c ell s orti n g 
a n alysis 
 
F or s u bj ects i n t h e p h ar m ac oki n etic -p h ar m ac o dy n a mic s u bst u dy:
C D 1 9 + p eri p h er al bl o o d B -ly m p h ocyt e c o u nt vi a r o uti n e fl u or esc e nt 
activ at e d c ell s orti n g a n alysis wit h s u bs ets i ncl u di n g, b ut n ot r estrict e d 
t o, n aïv e a n d m e m ory p h e n oty p es
S e c o n d ar y O bj e cti v e s –
P h ar m a c o ki n eti c
T o ass ess t h e p o p ul ati o n 
p h ar m ac oki n etics of of at u m u m a b S C   
 
Pl as m a (tr o u g h) c o nc e ntr ati o ns of of at u m u m a b
 
Ex p os ur e -r es p o ns e r el ati o ns hi p
 
F or s u bj ects i n t h e p h ar m ac oki n etic -p h ar m ac o dy n a mic s u bst u dy:
M axi m u m of at u m u m a b c o nc e ntr ati o n; ti m e of m axi m u m c o nc e ntr ati o n; 
a n d ar e a u n d er t h e ti m e -c o nc e ntr ati o n c urv e
 
Eff ect of d e m o gr a p hic f act ors, i ncl u di n g b as eli n e c ov ari at es, o n 
p h ar m ac oki n etic e n d p oi nts

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
2 7
S e c o n d ar y O bj e cti v e s – S af et y 
S af et y E n d p oi nt s
T o ev al u at e t h e i m m u n o g e nicity of 
of at u m u m a b S C i n s u bj ects wit h P V
 
I m m u n o g e nicity as m e as ur e d by t h e i ncid e nc e, tit er, a n d ty p e of 
h u m a n a nti -h u m a n a nti b o dy i m m u n e r es p o ns e
T o ev al u at e t h e s af ety a n d t ol er a bility 
of of at u m u m a b S C
 
A Es:
– Fr e q u e ncy, s ev erity, a n d r el ati o ns hi p t o i nv esti g ati o n al pr o d uct
– Fr e q u e ncy a n d s ev erity of i nf ecti o ns
– Fr e q u e ncy of s eri o us A E s
– Fr e q u e ncy of w it h dr a w als d u e t o tr e at m e nt-r el at e d A Es 
– Fr e q u e ncy of A Es l e a di n g t o p er m a n e nt disc o nti n u ati o n of 
i nv esti g ati o n al pr o d uct
– Fr e q u e ncy of A Es of s p eci al i nt er est , posti nj ecti o n syst e mic 
r e acti o ns, a n d inj ecti o n sit e r e acti o ns
 
C h a n g e fr o m b as el i n e i n vit al si g ns a n d fr e q u e ncy of vit al si g ns of 
cli nic al c o nc er n 
 
C h a n g e fr o m b as eli n e i n l a b or at ory ( h e m at ol o gy, c h e mistry, a n d 
uri n alysis) p ar a m et ers a n d fr e q u e ncy of l a b or at ory r es ults of p ot e nti al 
cli nic al c o nc er n
A b br evi ati o n s: A E = a dv ers e ev e nt; 
; 
; L L N =l o wer li mit of n or m al; 
P V = p e m p hi g us v ul g aris ; S C =s u bc ut a n e o us.
3. 1. 1. 
S cr e e ni n g P eri o d
Bef ore a n y st u d y- s pecific pr oce d ures are perf or me d, t he a p pr o priate writte n i nf or me d 
c o nse nt m ust be o btai ne d (see Secti o n 9. 2 ).
To assess s u bject eli gi bilit y , all scree ni n g 
assess me nts, as liste d i n t he Ti me a n d E ve nts Ta ble ( Ta ble 6 - 1), s h o ul d be c o m plete d. 
A Scree ni n g Peri o d of u p t o 1 2 wee ks will all o w s u bjects t o ac hie ve disease c o ntr ol 
(ie, n o ne w lesi o ns f or 2 wee ks) usi n g a sta ble d ose of 2 0 m g/ da y  u p t o 1 2 0 m g/ da y  (or 
1. 5 m g/ k g/ da y , w hic he ver is hi g her) of oral pre d nis o ne/ pre d nis ol o ne f or 2 wee ks .  Once 
disease c o ntr ol has bee n attai ne d, s u bjects m a y be ra n d o mize d t o treat me nt, pr o vi de d 
t he y c o nti n ue t o f ull y satisf y t he eli gi bilit y criteria.  Refer t o t he st u d y pr oce d ures ma n ual 
(S P M ) f or retesti n g a n d/ or rescree ni n g pr oce d ures.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
2 8
3. 1. 2. 
Tr e at m e nt P eri o d
S u bjects w h o meet all eli gi bilit y criteria will be ra n d o mize d 1: 1 t o recei ve eit her 
ofat u m u ma b S C or place b o ; all d oses of i n vesti gati o nal pr o d uct will be a d mi nistere d at 
t he st u d y ce nter o nce e ver y 4 wee ks u n der t he o bser vati o n of t he i n vesti gat or , wit h t he 
first d ose ( Wee k 0) si g nif yi n g t he start of t he 5 6 - wee k Tr eat me nt P eri o d. 
D uri n g t he 5 6- wee k Treat me nt P eri o d, site pers o n nel will a d mi nister all d oses of 
i n vesti gati o nal pr o d uct i n t he cli nic. S u bjects m ust be treate d wit h 
aceta mi n o p he n / paraceta m ol a n d a n a nti hista mi ne (cetirizi ne or e q ui vale nt) 1 t o 2 h o urs 
p ri or t o eac h a d mi nistrati o n of i n vesti gati o nal pr o d uct t o lesse n t he li keli h o o d of 
l ocalize d reacti o ns.
S u bjects will re mai n o n t he sta ble daily oral ster oi d d ose ac hie ve d d uri n g t he Scree ni n g 
Peri o d u ntil Wee k 2, w he n t he y  will be gi n ta peri n g t heir ster oid d ose wit h t he g oal of 
re d uci n g or eli mi nati n g t he dail y use of ster oi ds.  Su bjects ’ dail y oral ster oi d d ose will be 
re d uce d by 1 d ose le vel e ver y 2 wee ks ( as ill ustrate d i n Ta ble 3 - 2) until t he o nset of 
disease f lare/rela pse. F or a s u bject w h o e x perie nces disease flare /rela pse, t he 
pre d nis o ne / pre d nis ol o ne d ose will be i ncrease d b y 1 t o 4 le vels per wee k u ntil disease 
c o ntr ol is ac hie ve d (ie, n o ne w lesi o ns f or 2 wee ks) ; the pre d nis o ne/ pre d nis ol o ne ta per 
will t he n be rei nitiate d after a 2 - wee k peri o d of disease c o ntr ol.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
2 9
T a bl e 3- 2 
Or al P r e d ni s o n e/P r e d ni s ol o n e D o s e -ta p er S c h e d ul e
C urr e nt 
D o s e
N e xt T a p er 
D o s e a
( ev ery 2 w e eks)
I n cr e a s e D o s e f or Fl ar e/ R el a p s eb
(i ncr e as e by 1 t o 4 l ev els p er w e ek)
D o s e f or 
P o st -Fl ar e 
T a p er
1 l e v el 
2 l e v el s  
3 l e v el s  
4 l e v el s
1 6 0
1 4 0  
1 8 0  
2 0 0  
2 2 0  
2 4 0
D ecr e as e d os e 
by 1 l ev el aft er 
2 w e eks of 
dis e as e c o ntr ol, 
t h e n r et ur n t o 
st a n d ar d t a p er 
sc h e d ul e.
1 4 0
1 2 0  
1 6 0  
1 8 0  
2 0 0  
2 2 0
1 2 0
1 0 0  
1 4 0 
1 6 0  
1 8 0  
2 0 0
1 0 0
8 0  
1 2 0  
1 4 0  
1 6 0  
1 8 0
8 0
6 0  
1 0 0  
1 2 0  
1 4 0  
1 6 0
6 0
5 0  
8 0  
1 0 0  
1 2 0  
1 4 0
5 0
4 0  
6 0  
8 0  
1 0 0  
1 2 0
4 0
3 0  
5 0  
6 0  
8 0  
1 0 0
3 0
2 5  
4 0  
5 0  
6 0  
8 0
2 5
2 0  
3 0  
4 0  
5 0  
6 0
2 0
1 7. 5 
2 5  
3 0  
4 0  
5 0
1 7. 5
1 5  
2 0  
2 5  
3 0  
4 0
1 5
1 2. 5  
1 7. 5 
2 0  
2 5  
3 0
1 2. 5
1 0  
1 5 
1 7. 5 
2 0 
2 5
1 0 c
7. 5 
1 2. 5 
1 5 
1 7. 5 
2 0
7. 5
5
1 0 
1 2. 5 
1 5 
1 7. 5
5
2. 5  
7. 5 
1 0 
1 2. 5 
1 5
2. 5
0
5 
7. 5 
1 0 
1 2. 5
0
0 
2. 5 
5 
7. 5 
1 0
a. 
Pr e d nis o n e/ pr e d nis ol o n e is r e d uc e d by 1 d os e l ev el ev ery 2 w e eks, wit h t h e g o al b ei n g eli mi n ati o n of 
pr e d nis o n e/ pr e d nis ol o n e.  F or s u bj ects at a st arti n g d os e > 1 6 0 m g, t a p er d os e by 2 0 m g ev ery 2 w e eks u ntil 
t h e d os e is 1 6 0 m g, at w hic h p oi nt t h e d ecr e m e nts s h o w n o n t h e t a bl e a b ov e s h o ul d b e us e d.
b. 
S u bj ects will r e m ai n o n t h e st a n d ar diz e d or al pr e d nis o n e/ pr e d nis ol o n e t a p er sc h e d ul e u ntil d is e as e 
fl ar e/r el a ps e.  I n t h e ev e nt of dis e as e fl ar e/r el a ps e, or al pr e d nis o n e/ pr e d nis ol o n e will b e i ncr e as e d by a r at e of 
1 t o 4 l ev els p er w e ek u ntil dis e as e c o ntr ol is r e-est a blis h e d.  T h e or al pr e d nis o n e/ pr e d nis ol o n e t a p er will t h e n 
b e r ei niti at e d aft er dis e as e c o ntr ol is m ai nt ai n e d f or 2 w e eks.
c. 
O nc e t h e d os e is r e d uc e d t o 1 0 m g, a n att e m pt at r e d uci n g t h e st er oi d d os e f urt h er n e e d o nly b e att e m pt e d 
u ntil t h e first fl ar e/r el a ps e occ urs.  I n t h e ev e nt of a fl ar e/r el a ps e at a pr e d nis o n e/ pr e d nis ol o n e d os e o f 
≤1 0 m g/ d ay, t h e d os e will b e t e m p or ally i ncr e as e d i n or d er t o r e -est a blis h dis e as e c o ntr ol ( n o n e w l esi o ns f or 
> 2 w e eks); aft er dis e as e c o ntr ol is m ai nt ai n e d, f urt h er st er oi d t a p eri n g att e m pts t o < 1 0 m g will b e at t h e 
i nv esti g at or’s discr eti o n.
3. 1. 3. 
F oll o w -u p P eri o d
S u bjects will be f oll o we d -u p f or a mi ni m u m of 4 wee ks after t he last d ose of 
i n vesti gati o nal pr o d uct at t he Wee k 5 6 visit.  T he f oll o w - u p visit will i ncl u de B- cell 
c o u nts a n d ot her safet y , efficac y, a n d q uality of life assess me nts.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
3 0
If B-cell c o u nts ha ve n ot rec o vere d b y t he Wee k 6 0
visit, s u bjects n ot e nteri n g t he 
e xte nsi o n st u d y ( O P V 11 7 0 5 9) will re mai n i n I n di vi d ualize d F oll o w -u p u ntil :
 
C D 1 9 + B -cell c o u nts a n d circ ulati n g I g G le vels are ≥L L N or baseli ne le vels (if 
< L L N)
 
Ot her criteria f or st u d y wit h dra wal/e xit are met (see Secti o n 4. 4. 3 )
 
T w o ye ars after t he last d ose of i n vesti gati o nal pr o d uct ( w hic he ver c o mes first).  
T he I n di vi d ualize d F oll o w- u p assess me nts s h o ul d be sc he d ule d a p pr o xi matel y e ver y 
1 2 wee ks.   S u bjects w h o wit h dra w fr o m treat me nt will als o e nter t he I n di vi d ualize d 
F oll o w -u p Peri o d.
N ote: S u bjects w h o are he patitis B s urface a nti ge n (H Bs A g ) ne gati ve, h e patitis B c ore 
a nti b o d y (a nti-H Bc ) p ositi ve, a n d he patitis B vir us (H B V ) D N A ne gati ve ( or if i n Ja pa n 
a n d H Bs A g ne gati ve, a nti - H Bc ( H Bc A b) ne gati ve, b ut he patitis B s urface a nti b o d y  
[H Bs A b ] p ositi ve) m ust c o nti n ue H B V D N A p ol y merase c hai n reacti o n (P C R )
m o nit ori n g at a mi ni m u m of e ver y  1 2 wee ks f or 6 m o nt hs after t he last d ose of st u d y 
treat me nt.
F or s u bjects w h o partici pate i n t he e xte nsi o n st u d y, O P V 1 1 6 9 1 0 (als o k n o w n as 
C O M B 1 5 7J 2 3 0 1 ) Wee k 6 0 st u d y  assess me nts will be c o m plete d bef ore a n y st u d y-relate d 
assess me nts are perf or me d f or t he e xte nsi o n st u d y.
3. 1. 4. 
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 u b st u d y
T his pr ot oc ol i ncl u des a s u bst u d y t o deter mi ne t he p har mac o ki netics a n d 
p har mac o d y n a mics of ofat u m u ma b S C i n s u bjects wit h P V.  T he s u bst u d y  will be 
c o n d ucte d at sel ecte d st u d y ce nters a n d will e nr oll a p pr o xi matel y 2 5 s u bjects.  S u bject 
partici pati o n i n t he s u bst u d y  is o pti o nal a n d re q uires i nf or me d c o nse nt.  A s u bject ma y be 
e nr olle d i n t he pri mar y st u d y w het her or n ot he/s he c h o oses t o partici pate i n t he s u bst u d y. 
T he Ti me a n d E ve nts Ta ble f or t he s u bst u d y -s pecific visits a n d sa m pli n g ti me p oi nts is 
pr o vi de d i n Ta ble 6 - 3.  A n atte m pt s h o ul d be ma de t o dra w p har mac o ki netic sa m ples at 
t he sa me ti me of da y as a d mi nistrati o n of t he first d ose of i n vesti gati o nal pr o d uct .
3. 2. 
Di s c u s si o n of D e si g n
T he desi g n of t he st u d y has ta ke n i nt o acc o u nt t he l o w i nci de nce a n d c hr o nic rela psi n g 
nat ure of P V, a n d t he fact t hat t hera p y wit h c ortic oster oi ds — al beit ass ociate d wit h 
si g nifica nt si de effects— re prese nts t he sta n dar d of care f or ma na ge me nt of P V. T he 
st u d y is desi g ne d t o e val uate t he efficac y of ofat u m u ma b S C i n a n e n vir o n me nt w here a 
s u bject re q uiri n g c ortic oster oi ds is u n der g oi n g a ta per t o war ds mi ni mal treat me nt or, 
i deall y, n o treat me nt wit h s yste mic ster oi ds. F or t his reas o n, t he st u d y  has bee n desi g ne d 
t o a d d t he ra n d o mize d st u d y treat me nt (1 gr o u p recei vi n g ofat u m u ma b S C a n d t he ot her 
gr o u p recei vi n g place b o ) o ver a bac k gr o u n d of ta peri n g ster oi ds i n all s u bjects.
T he d osi n g d urati o n of 1 ye ar will all o w a de q uate ti me t o assess ti me t o re missi o n i n b ot h 
st u d y gr o u ps.  Hist orical data i n dicate t hat re missi o n ca n be e x pecte d i n a p pr o xi matel y 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
3 1
5 4 % of s u bjects i n t he place b o gr o u p ( wit h ster oi d d ose a dj ust me nt), a n d i n a b o ut 8 0 % of 
s u bjects i n t he ofat u m u ma b S C gr o u p [Beissert , 2 0 1 0 ].
W he n a d mi nistere d via I V i nf usi o n, ofat u m u ma b has bee n ass ociate d wit h i nf usi o n 
reacti o ns t hat ha ve occasi o nall y le d t o te m p orar y i nterr u pti o n or wit h dra wal of treat me nt.
T o re d uce s uc h reacti o ns, pre me dicati o n wit h aceta mi n o p he n/ paraceta m ol, oral or I V
a nti hista mi ne, a n d oral a n d/ or I V gl uc oc ortic oi ds has bee n use d i n cli nical st u dies 
i n v ol vi n g o nc ol o g y  a n d r he u mat oi d art hritis p o p ulati o ns . I n t he c urre nt st u d y, t o lesse n 
t he li keli h o o d of l ocalize d reacti o ns wit h a d mi nistrati o n of ofat u m u ma b S C , oral d oses of 
aceta mi n o p he n / paraceta m ol a n d a nti hista mi ne will be a d mi nistere d 1 t o 2 h o urs pri or t o 
t he a d mi nistrati o n of i n vesti gati o nal pr o d uct.   All s u bjects ( ofat u m u ma b SC a n d place b o 
gr o u ps) will be pre me dicate d i n or der t o mai ntai n bli n di n g a n d t o mi ni mize c o nf o u n di n g
varia bles o n d osi n g da y s.
Wit hi n t he pr ot oc ol, refere nce t o N o vartis is i ncl usi ve of tas ks a n d res p o nsi bilities t hat 
will be perf or me d b y a c o ntract resear c h or ga nizati o n ( e g, 
).
3. 3. 
D o s e R ati o n al e
F or St u d y  O PV 1 1 6 9 1 0, a n ofat u m u ma b S C d ose of 2 0 m g will be a d mi nistere d e ver y  
4 wee ks t hr o u g h Wee k 5 6 ( wit h a n a d diti o nal 20- m g ‘l oa di n g’ d ose [ie, 4 0 m g t otal] at 
b ot h Wee k 0 a n d Wee k 4) .  T his d ose was selecte d o n t he basis of t he f oll o wi n g fact ors: 
safety a n d t olera bilit y fr o m st u dies c o n d ucte d i n ot her a ut oi m m u ne i n dicati o ns 
(r he u mat oi d art hritis a n d R R M S), B-cell de pleti o n/re pleti o n data fr o m a si n gle S C d ose 
st u d y (G S K St u d y O F A 1 1 0 8 6 7; N = 6/ar m) i n s u bjects wi t h r he u mat oi d art hritis, ne wl y -
a vaila ble data fr o m a lar ge P hase II re peat -d ose ( u p t o 2 0 wee ks) st u d y i n s u bjects wit h 
R R M S ( G S K St u d y O M S 1 1 2 8 3 1; N = 2 3 2), a n d p har mac o metric m o deli n g.
T he ori gi nal d ose rati o nale pr o p ose d a n ofat u m u ma b S C d ose of 6 0 m g e ver y 1 2 wee ks; 
h o we ver, i n t he o n g oi n g P hase II R R M S st u d y  (G S K St u d y O M S 1 1 2 8 3 1), ofat u m u ma b 
S C d oses of 3 t o 6 0 m g e ver y  1 2 wee ks were n ot f o u n d t o c o m pletel y  s u p press B cells 
d uri n g t he i nter - d osi n g i nter val (Fi g ure 3- 3 ).  H o we ver, w he n d ose d e ver y  4 wee ks, 
ofat u m u ma b s u p presse d B cells t o bel o w t he li m it of q ua ntificati o n d uri n g t he i nter-
d osi n g i nter val i n m ore t ha n 9 0 % of s u bjects.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
3 2
Fi g ur e 3- 3 
O b s er v e d M e di a n a n d I nt er -d e cil e R a n g e B -c ell D e pl eti o n f or 
Of at u m u m a b S C i n G S K St u d y  O M S 1 1 2 8 3 1
A b br evi ati o ns: L L N =l o w er li mit of n or m al; L L Q =l o w er li mit of q u a ntit ati o n; S C =s u bc ut a n e o us.
Ac hie vi n g a de q uate B cell de pleti o n is vie we d as esse ntial f or mai nte na nce of efficac y  i n 
P V [ E mi n g , 2 0 0 8; M o u q uet , 2 0 0 8], alt h o u g h n o t hres h ol d f or B cell de pleti o n has bee n 
de m o nstrate d.  T his f act n ot wit hsta n di n g, s u p pressi o n of B cells t o le vels see n wit h 
off -la bel rit u xi ma b is desira ble t o e ns ure c o m para ble efficac y, partic ularly d uri n g a 
peri o d of ster oi d wit h dra wal.  O n t he basis of o bser ve d B -cell s u p pressi o n wit h d oses of 3, 
3 0, a n d 6 0 m g a n d p har mac o metric m o deli n g, d i vi di n g t he d ose t o a d mi nister 
ofat u m u ma b S C 2 0 m g e ver y  4 wee ks, rat her t ha n 6 0 m g e ver y  1 2 wee ks, is a ntici pate d 
t o ac hie ve t hat g oal.
T he pre dicte d me dia n B cell de pleti o n a n d t he pre dicte d me dia n perce nta ge B cell 
i n hi biti o n, c o m plete wit h i nter-decile ra n ges, are s h o w n i n Fi g ure 3 - 4 a n d Fi g ure 3- 5
( n = 1 0 0 0 per si m ulati o n), res pecti vely.  At stea d y- state ( Wee k 1 2), t he pre dicte d me dia n 
i n hi biti o n is 9 9 %, wit h 9 0 % of s u bjects ac hie vi n g B cell i n hi biti o n greater t ha n 9 7. 5%, as 
i n dicate d by t he s ha de d re gi o n.  T o hel p ac hie ve a ra pi d o nset of cli nical effect, l oa di n g 
d oses of 4 0 m g (as t w o 2 0 - m g S C i njecti o ns) will be a d mi nistere d at Wee ks 0 a n d 4.
T he c urre nt d osi n g re gi me n is e x pecte d t o ra pi dl y de plete B -cells a n d mai nta i n t he 
desire d le vel of s u p pressi o n d uri n g t he i nter- d osi n g i nter vals i n t he maj orit y  of s u bjects i n 
or der t o mai ntai n disease re missi o n o nce ac hie ve d.  Afte r d osi n g ceases, t he pre dicte d 
me dia n ti me t o re plete t o t he L L N ( 1 1 0 cells/u L ) i n s u bjects wit h P V is a p pr o xi matel y 
2 8 wee ks.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
3 3
Fi g ur e 3- 4 
Pr e di ct e d M e di a n a n d I nt er -d e cil e R a n g e B -c ell D e pl eti o n wit h 
Of at u m u m a b S C 4 0 m g A d mi ni st er e d at W e e k s 0 a n d 4, t h e n 2 0 m g 
A d mi ni st er e d E v er y  4 W e e k s T hr o u g h W e e k 5 6
A b br evi ati o ns: L L N =l o w er li mit of n or m al; L L Q =l o w er li mit of q u a ntit ati o n; S C =s u bc ut a n e o us .
Fi g ur e 3- 5 
Pr e di ct e d M e di a n a n d I nt er -d e cil e R a n g e B -c ell P er c e nt I n hi biti o n 
wit h Of at u m u m a b S C 4 0 m g A d mi ni st er e d a t W e e k s 0 a n d 4, t h e n 
2 0 m g A d mi ni st er e d E v er y  4 W e e k s T hr o u g h W e e k
5 6
A b br evi ati o n: S C =s u bc ut a n e o us.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
3 4
Wit h res pect t o safet y a n d t olera bilit y, all d oses i n G S K St u d y  O M S 1 1 2 8 3 1 were well 
t olerate d a n d t here were n o ne w or u ne x pecte d safet y fi n di n gs d uri n g t he Treat me nt 
Peri o d (f oll o w-u p was o n g oi n g a s of Ja n uar y 2 0 1 4).  A d mi nistrati o n of ofat u m u ma b S C 
i n s u bjects wit h P V is als o a ntici pate d t o be well-t olerate d.
I n s u m mar y, o n t he basis of res ults of t he re peat-d ose st u d y  i n s u bjects wit h R R M S a n d 
s u bse q uent d ose m o deli n g , a d mi nistrati o n of ofat u m u ma b S C 2 0 m g e ver y  4 wee ks ( wit h 
a n a d diti o nal d ose at Wee ks
0 a n d 4 i n or der t o reac h stea dy- state m ore q uic kl y d uri n g 
i nitial ster oi d-ta peri n g) s h o ul d pr o vi de m ore c o nsiste nt B-cell s u p pressi o n i n s u bjects 
wit h P V t ha n t he pre vi o usl y -pr o p o se d d ose re gi me n of 6 0 m g  a d mi nistere d e ver y 
1 2 wee ks.  
4. 
S U B J E C T S E L E C TI O N A N D WI T H D R A W A L C RI T E RI A
Bef ore s u bjects ma y  be e ntere d i nt o t he st u d y, N o vartis re q uires a c o py of t he site’s 
writte n instit uti o nal re vie w b oar d (I R B)/ i nde pe n de nt et hics co m mittee (I E C) a p pr o val of 
t he pr ot oc ol, i nf or me d c o nse nt f or m, a n d all ot her s u bject i nf or mati o n a n d/ or recr uit me nt 
material, if a p plica ble (see Secti o n 9. 2 ). All s u bjects m us t pers o nall y si g n a n d date t he 
c o nse nt f or m bef ore a n y s u bse q ue nt scree ni n g pr oce d ures ma y be perf or me d. 
A s u bject will be c o nsi dere d e nr olle d o nce a ra n d o mizati o n n u m ber is assi g ne d . A 
s u bject ma y o nly be ra n d o mize d o nce, a n d ea c h ra n d o mizati o n n u m ber m a y o nl y be 
assi g ne d t o 1 s u bject. 
4. 1. 
N u m b er of S u bj e ct s
A p pr o xi matel y  1 3 6 s u bjects ( 6 8 s u bjects per treat me nt gr o u p) will be e nr olle d i nt o t he 
st u d y, w hic h acc o u nts f or a dr o p- o ut rate of 1 3 % (see Secti o n 8. 2. 1 ).  A p pr o xi matel y  
4 8 sites i n a p pr o xi matel y 1 5 c o u ntries are e x pecte d t o partici pate i n t his st u d y .
4. 2. 
I n cl u si o n Crit eri a
S pecific i nf or mati o n re gar di n g war ni n gs, preca uti o ns, c o ntrai n dicati o ns, A Es, a n d ot her 
perti ne nt i nf or mati o n o n t he N o vart is i n vesti gati o nal pr o d uct or ot her st u d y  treat me nt t hat 
ma y  i m pact s u bject eli gi bilit y is pr o vi de d i n t he I n vesti gat or’s Br oc h ure
[Ofat u m u ma b/ O M B 1 5 7/ G S K 1 8 4 1 1 5 7 I nvesti gat or’s Br oc h ure , 2 0 1 6].
De viati o ns fr o m i ncl usi o n crit eria are n ot all o we d , as t he y ca n p ote ntially j e o par dize t he 
scie ntific i nte grit y of t he st u d y, re g ulat or y acce pta bilit y, or s u bject safet y.  T heref ore, 
a d here nce t o t he criteria as s pecifie d i n t he pr ot oc ol is esse ntial .  
It is t he i n vesti gat or’s res p o nsi bilit y t o c o nfir m t hat p ote ntial s u bjects are willi n g a n d a ble 
t o pr o vi de writte n i nf or me d c o nse nt, partici pate i n t he st u d y as a n o ut patie nt, ma ke 
fre q ue nt visits t o t he st u d y ce nter d uri n g t he Treat me nt a n d F oll o w -u p Peri o ds, a n d 
c o m pl y wit h all st u d y re q uire me nts i ncl u di n g restricti o ns o n usa ge of c o nc o mita nt 
me dicati o ns a n d ot her treat me nts.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
3 5
T o be e li gi ble f or e nr oll me nt i n t he st u d y, su bjects m ust meet all of t he f oll o wi n g criteria:
All S u bjects
1. 
A d ults ( 1 8 t hr o u g h 7 0 ye ars of a ge) wit h c li nicall y-d oc u me nte d dia g n osis of P V f or 
> 2 m o nt hs a n d < 1 0 ye ars .
2. 
Hist or y  of bi o psy c o nsiste nt wit h P V ( H a n d E stai ni n g a n d direct 
i m m u n ofl u oresce nce).  If n o hist or y, a bi o psy ma y be perf or me d d uri n g t he 
Scree ni n g Peri o d.
3. 
At least 1 pre vi o us e pis o de of a faile d ster oid ta per (ie, disease flare/rela pse) at a 
pre d nis o ne/ pre d nis ol o ne d ose > 1 0 m g / da y, wit h a Pe m p hi g us Se verity of Cli nical 
Disease sc ore of m o derate ( 2) or se vere ( 3) ( ma y be hist orical/retr os pecti ve 
assess me nt [see A p pe n di x 6 a n d S P M f or g ui da nce]), w here se verit y of disease at 
flare/rela pse necessitate d a n i ncrease of > 2 0 m g/ da y .  N ote: pre d nis o ne/ pre d nis ol o ne 
d ose s h o ul d n ot be i ncre ase d f or t he s ole p ur p ose of e ntry i nt o t his st u dy .
A d diti o nal Criteria Pri or t o Ra n d o mizati o n
4. 
Scree ni n g a nti -Ds g a nti b o dies c o nsiste nt wit h a dia g n osis of P V (ie, ele vate d 
a nti-Ds g 3 a nti b o dies) .
5. 
Has i nitiate d a n d recei ve d a sta ble d ose of pre d nis o ne/ pre d nis ol o ne fr o m a mi ni m u m 
of 2 0 m g/ da y  (e g, 0. 2 5 m g / k g/ da y f or a n 8 0-k g pers o n) u p t o a ma xi m u m of 
1 2 0 m g/ da y or 1. 5 m g / k g/ da y ( w hic he ver is hi g her) f or 2 wee ks pri or t o 
ra n d o mizati o n. (N ote: s u bjects w h o are o n every-ot her -d ay d osi n g re gi me ns nee d t o 
c h a n ge t o a d aily d os i n g re gi me n f or 2 weeks d uri n g t he Scree ni n g Peri o d i n or der 
t o q u alify.)
6. 
Has e x hi bite d P V disease c o ntr ol, defi ne d as n o ne w lesi o ns f or 2 wee ks.
A d diti o nal Criteria f or Fe male S u bjects
7. 
A fe male s u bject is eli gi ble t o e nter t he st u d y if s he:
a. 
Is of n o nc hil d beari n g p ote ntial , w h o is d oc u me nte d as eit her s ur gicall y  sterile 
(bilateral t u bal li gati o n, bilateral o o p h orect o m y , or p ost-h y sterect o m y) or is 
p ost me n o pa usal wit h o ut me nses f or > 2 ye ars. W o me n w h o are
< 2 ye ars 
p ost me n o pa usal are re q uire d t o ha ve me n o pa usal stat us c o nfir me d b y  f ollicle-
sti m ulati n g h or m o ne ( F S H) a n d estr a di ol le vels at t he scree ni n g e val uati o n. If 
F S H a n d estra di ol le vels d o n ot pr o vi de c o nfir mati o n of me n o pa use, s u bject will 
be c o nsi dere d t o be o f c hil d beari n g p ote ntial.
b.
I s of c hil d beari n g p ote ntial, defi ne d as a w o ma n w h o has f u ncti o nal o varies,
d ucts, a n d a uter us wit h n o d oc u me nte d i m pair me nt t hat w o ul d ca use sterilit y .  
T his incl u des w o me n wit h oli g o me n orr h ea (e ve n se vere), w o me n w h o are 
peri me n o pa usal , a n d w o me n w h o ha ve j ust be g u n t o me nstr uate. S u bject m ust:
-
Ha ve a ne gati ve ser u m pre g na nc y  test at scree ni n g
-
Agree t o t he c o nsiste nt a n d c orrect use of acce pta ble met h o d s of c o ntrace pti o n 
d uri n g heter ose x ual i nterc o urse, be gi n ni n g w he n t he s u bject pr o vi des 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
3 6
i nf or me d c o nse nt a n d lasti n g u ntil 1 2 m o nt hs after last d ose of i n vesti gati o nal 
pr o d uct . Acce pt a ble met h o ds of c o ntrace pti o n are li mite d t o t he f oll o wi n g:
 
O ral c o ntrace pti ves (eit her c o m bi ne d or pr o gester o ne o nl y)
 
Injecta ble pr o gester o ne
 
L e v o n or gestrel i m pla nts
 
Estr o ge nic va gi nal ri n g
 
P erc uta ne o us c o ntrace pti ve patc hes
 
Intra uteri ne de vice or i ntra ut eri ne s ys te m wit h a d oc u me nte d fail ure rate 
of < 1 % per ye ar
 
Male part ner sterilizati o n ( vasect o m y wit h d oc u me ntati o n of 
az o os per mia) pri or t o t he fe male s u bject’s e ntr y  i nt o t he st u d y; t his male 
m ust be t he s u bject’s s ole part ner
 
D o u ble- barrier met h o d: c o n d o m a n d a n occl usi ve ca p ( dia p hra g m or 
cer vical/ va ult ca ps) wit h a va gi nal s per mici dal a ge nt 
(f oa m/ gel/fil m/crea m/s u p p osit or y)
 
C o m plete a bsti ne nce fr o m heter ose x ual i nterc o urse, w he n t his is i n li ne 
wit h t he preferre d a n d us ual lifest y le of t he s u bject
 
* I n J a p a n , refer t o A p pe n dix 2 f or a p plic a ble c o u ntry-s pecific 
cl arific ati o ns re g ar di n g acce pt a ble met h o ds of c o ntr ace pti o n f or su bject 
i ncl usi o n i n t his st u dy.*
I n Fr a nce , a s u bject will be eli gi ble f or i ncl usi o n i n t his st u d y o nly if eit her affiliate d 
wit h, or a be neficiar y  of, a s ocial sec urit y cate g or y.
4. 3. 
E x cl u si o n Crit eri a
De viati o ns fr o m e xcl usi o n criteria are n ot all o we d beca use t he y  ca n p ote ntiall y 
je o par dize t he scie ntific i nte grity of t he st u d y, re g ulat or y acce pt a bilit y, or s u bject safet y.  
T heref ore, a d here nce t o t he criteria as s pecifie d i n t he pr ot oc ol is esse ntial. 
S u bjects meeti n g a n y of t he f oll o wi n g criteria will n ot be e nr olle d:
1. 
Dia g n osis of pe m p hi g us f oliace us, para ne o plastic pe m p hi g us , or ot her a ut oi m m u ne 
blisteri n g disease ( ot her t ha n P V ).
2. 
Past or c urre nt hist or y  of h yperse nsiti vit y  t o c o m p o ne nts of t he i n vesti gati o nal 
pr o d uct or me dicall y  si g nifica nt a d verse effects (i ncl u di n g aller gic reacti o ns) fr o m 
cetirizi ne ( or a nti hista mi ne e q ui vale nt) or paracet a m ol/aceta mi n o p he n.
3. 
Pri or treat me nt wit h rit u xi ma b wit h o ut ac hie vi n g disease c o ntr ol wit hi n 6 m o nt hs of 
i nitiati n g rit u xi ma b d osi n g.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
3 7
4. 
Pri or treat me nt wit h a n y of t he f oll o wi n g wit hi n t he s pecifie d peri o ds:
Me dic ati o n a n d Ot her Tre at me nt Restricti o ns Pri or t o R a n d o miz ati o n
A n y ti me 
6 w ee ks 
8 w ee ks a
6 m o nt hs 
1 8 m o nt hs
Ofat u m u ma b, 
t otal b o d y 
irra diati o n, 
b o ne marr o w 
tra ns pla ntati o n, 
a nti-C D 4
Li ve 
vacci ne
I m m u n os u p pressi ve 
or i m m u n o m o d ulat or y 
a ge nts, i ncl u di n g:
– azat hi o pri ne
– c ycl os p ori ne
– da ps o ne
– m yc o p he n olate 
– met h otre xate
– tacr oli m us
– c ycl o p h os p ha mi de 
– cla dri bi ne
– plas ma p heresis 
– i m m u n oa bs or pti o n or 
i m m u n o gl o b uli n t hera p y
– ale mt uz u ma b 
– mit o xa ntr o ne
Rit u xi ma b or 
ot her 
a nti-C D 2 0 
treat me nts
5. 
C o nfir me d P M L , or n e ur ol o gical fi n di n gs p ote ntiall y  c o nsiste nt wit h P M L (see 
A p pe n di x 4 a n d A p pe n di x 5 ).
6. 
E vi de nce or hist or y  of cli nicall y si g nifica nt i nfecti o n i ncl u di n g:
 
C hr o nic or o n g oi n g acti ve i nfecti o us disease re q uiri n g l o n g-ter m s yste mic 
treat me nt, i ncl u di n g, b ut n ot li mite d t o , c hr o nic re nal i nfecti o n, c hr o nic c hest 
i nfecti o n wit h br o nc hiectasis, or acti ve he patitis C.
 
P ositi ve test f or H Bs A g. F or H B s A g ne gati ve, b ut a nti-H Bc / H Bc A b p ositi ve 
(re gar dless of HB s A b stat us), a n H B V D N A test will be perf or me d a n d t he 
s u bject will be e xcl u de d if res ults are p ositi ve.   C o ns ult wit h a p h y sicia n 
e x perie nce d i n t he care a n d ma na ge me nt of s u bjects wit h he patitis B t o 
ma na ge/treat s u bjects w h o are a nti -H Bc p ositi ve .
 
Hist or y  of p ositi ve ser ol o g y f or h u ma n i m m u n o deficie nc y vir us.
 
Pre vi o us seri o us o p p ort u nistic or at y pical i nfecti o ns.
 
Pri or hist or y , or s us pici o n, of t u berc ul osis ( T B).
 
* I n J a p a n , refer t o A p pe n dix 2 f or a d diti o n al c o u ntry-s pecific scree ni n g 
pr oce d ures a n d excl usi o n criteri a f or T B, P ne u m ocystis p ne u m o ni a, a n d 
he p atitis B. *
7. 
Past or c urre nt mali g na nc y , e xce pt f or:
 
Cer vical carci n o ma Sta ge 1 B or less .
 
N o n i n vasi ve basal cell a n d s q ua m o us cell s ki n carci n o ma.
 
Ca ncer dia g n oses wit h a d urati o n of c o m plete res p o nse (re missi o n) > 5 ye ars.  
N ote : A hist or y of he mat ol o gic mali g na nc y e xcl u des a s u bject fr o m partici pati o n, 
re gar dless of res p o nse.
8. 
Si g nifica nt c o nc urre nt, u nc o ntr olle d me dical c o n diti o n t hat c o ul d affect t he s u bject’s 
safety, i m pair t he s u bject’s relia ble partici pati o n i n t he st u d y, i m pair t he e val uati o n 
of e n d p oi nts, or necessitate t he use of me dicati o n n ot all o we d b y t he pr ot oc ol.

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C O N FI D E N TI A L
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O P V 1 1 6 9 1 0
3 8
9. 
A n y  of t he f oll o wi n g scree ni n g la b orat or y val ues:
 
W hite bl o o d cells < 3. 8
GI/ L ( < 3 8 0 0/ m m3).
 
Ne utr o p hils < 2 GI / L ( < 2 0 0 0/ m m3).
 
Platelets < 1 3 0 GI / L ( < 13 0, 0 0 0/ m m 3).
 
Circ ulati n g I g G , Ig A, or I g M le vels < 1 0 % of t he L L N a n d re q uiri n g treat me nt i n 
t he o pi ni o n of t he i n vesti gat or.
 
Ala ni ne a mi n otra nsferase ( A L T) > 2. 0 ti mes t he u p per li mit of n or mal ( U L N).
 
As partate a m i n otra nsferase > 2. 0 U L N.
 
Al kali ne p h os p hatase > 1. 5 U L N.
 
Bilir u bi n > 1. 5 U L N (e xce pt i n cases of is olate d pre d o mi na ntl y i n direct 
h y per bilir u bi ne mia d ue t o Gil bert’s s y n dr o me) .
1 0. Use of a n i n vesti gati o nal dr u g or ot her e x peri me ntal t hera p y wit hi n 4 wee ks,
5 p har mac o ki netic half -li ves, or t he d urati o n of bi ol o gical effect ( w hic he ver is 
l o n ger) pri or t o Scree ni n g .
1 1. Electr ocar di o gra m ( E C G) s h o wi n g a cli nicall y si g nifica nt a b n or malit y or s h o wi n g a 
c orrecte d Q T i nter val ( Q Tc) ≥4 5 0 msec ( ≥4 8 0 msec f or s u bjects wit h a b u n dle 
b ra nc h b l oc k) (E C G t o be o btai ne d d uri n g Scree ni n g/ pri or t o recei vi n g t he first d ose 
of st u d y  dr u g). 
1 2. W o ma n w h o is breastfee di n g.
4. 4. 
Wit h dr a w al Crit eri a
4. 4. 1. 
D o s e -h ol di n g Crit eri a
I n vesti gati o nal pr o d uct d osi n g will be hel d i n t he f oll o wi n g sit uati o ns:
 
Ne utr o pe nia wit h a n a bs ol ute ne utr o p hil c o u nt < 1 GI / L ( < 1 0 0 0/ m m3; < 1. 0 x 1 09/ L) 
(ie, Gra de 3 a n d hi g her [C T C A E , 2 0 1 3]).
 
S us pecte d seri o us s ys te mic i nfecti o n.
 
P ositi ve s y m pt o ms o n ne ur o l o gical s ym pt o ms q uesti o n naire (see A p pe n di x 4 a n d 
A p pe n di x 5 ).
If t he c o n diti o n res ol ves wit hi n 1 wee k, a d mi nister t he hel d d ose a n d t he n ret ur n t o t he 
re g ular d osi n g sc he d ule.  I f t he c o n diti o n d oes n ot res ol ve wit hi n 1 wee k after a hel d d ose, 
s ki p t hat d ose; after t he c o n diti o n res ol ves, ret ur n t o t he re g ular d osi n g sc he d ule.  C o ns ult 
wit h t he me dical m o nit or if a s u bject misses 2 or m ore c o nsec uti ve d oses.

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4. 4. 2. 
Di s c o nti n u ati o n of I n v e sti g ati o n al Pr o d u ct
S u bjects m ust disc o nti n ue i n vesti gati o nal pr o d uct f or a n y of t he f oll o wi n g reas o ns: 
 
S p o ns or re q uest , f or reas o ns s uc h as si g nifica nt pr ot oc ol de viati o n (a n d after 
disc ussi o n wit h t he i n vesti gat or) .
 
St u d y  is ter mi nate d by t he S p o ns or .
 
S u bject meets P M L  disc o nti n uati o n criteria (see A p pe n di x 4 ).
 
S u bject de vel o ps a n y ot her seri o us o p p ort u nistic or at y pical i nfecti o n .
 
S u bject meets li ver c he mistr y  st o p pi n g criteria (see A p pe n di x 3 ).
 
S u bject i nitiates treat me nt wit h a pr o hi bite d P V disease -m o dif y i n g dr u g.
 
S u bject bec o mes pre g na nt .
 
S u bject e x perie nces a seri o us or life- t hreate ni n g car diac arr hyt h mia.
A n y  s u bject wh o disc o nti n ues fr o m t he Treat me nt Peri o d s h o ul d c o m plete a n Earl y 
Wit h dra wal Visit a n d tra nsiti o n i nt o t he I n di vi d ualize d F oll o w -u p Peri o d f or i m p orta nt 
safety  m o nit ori n g (as a p plica ble; see Secti o n 3. 1. 3 ), u nless he/s he meets a criteri o n f or 
ma n dat or y  wit h dra wal fr o m t he st u d y (see Secti o n 4. 4. 3 ).
4. 4. 3. 
Wit h dr a w al fr o m t h e St u d y
S u bjects m ust disc o nti n ue i n vesti gati o nal pr o d uct a n d be wit h dra w n fr o m t he st u d y  f or 
t he f oll o wi n g reas o ns: 
 
S u bject wit h dra ws c o nse nt .
 
S u bject i nitiates treat me nt wit h a pr o hi bite d P V disease -m o dif y i n g dr u g t hat de pletes 
B-cells (e g, rit u xi ma b).
 
S p o ns or re q uest (after disc ussi o n wit h t he i n vesti gat or).
* I n J a p a n , refer t o A p pe n dix 2 f or a p plic a ble c o u ntry-s pecific det ails. *
5. 
S T U D Y T R E A T M E N T S
5. 1. 
I n v e sti g ati o n al Pr o d uct a n d Ot h er St u d y  Tr e at m e nt
5. 1. 1. 
I n v e sti g ati o n al Pr o d u ct
Ofat u m u ma b S C ( G S K 1 8 4 1 1 5 7; h u ma n m A b ofat u m u ma b i njecti o n f or S C use) will be 
s u p plie d b y N o vartis as a li q ui d c o nce ntrate i n a pre fille d glass syri n ge wit h sta ke d
nee dle , st o p per, a n d pl u n ger, wit h a nee dle safety de vice . I nitially, s yri n ges c o ntai ni n g 
0. 6 m L  ( 6 0 m g ) of c o nce ntrati o n 1 0 0 m g/ m L dr u g pr o d uct will be pr o vi de d .
Place b o i n prefille d glass s y ri n ges t o matc h t he ofat u m u ma b s yri n ges, will be ma de a n d 
s u p plie d b y N o vartis , usi n g n or mal sali ne (sterile, p yr o ge n-free 0. 9 % Na Cl) a n d fille d t o 

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C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
4 0
0. 6 m L  i n a prefille d glass s y ri n ge wit h sta ked nee dle , st o p per, a n d pl u n ger, wit h a nee dle 
safety de vice . 
C o nte nts of t he la bel will be i n acc or da nce wit h all a p plica ble re g ulat or y  re q uire me nts.
F or st u d y ce nters i nitiate d usi n g t he dil uti o n met h o d f or st u d y treat me nt pre parati o n , a n 
u n bli n de d p har macist ( or a p pr o priately- q ualifie d desi g nee) at t he st u d y ce nter will 
pre pare eac h d ose via a dil uti o n pr ocess acc or di n g t o t he detaile d i nstr ucti o ns i n t he 
p har mac y ma n ual.  Briefl y , th e c o nte nts of 2 prefille d ( 0. 6 m L ) s yri n ges (eit her 
1 ofat u m u ma b 6 0 -m g  s yri n ge pl us 1 place b o s yri n ge or 2 place b o s yri n ges) will be 
i njecte d i nt o a sterile vial a n d 0. 4 m L  of t he res ulti n g s ol uti o n will be dra w n i nt o a ne w 
s yri n ge t o ac hie ve t he 2 0-m g of at u m u ma b (c o nce ntrati o n 5 0 m g/ m L) or place b o d ose.   
S ol uti o ns o btai ne d fr o m t he dil uti o n met h o d will be filtere d t hr o u g h Ke n dall 5 micr o n 
filter nee dles pri or t o i njecti o n.  T he i n-use ti me after t he dr u g pr o d uct is dra w n i nt o t he 
s yri n ge f or a d mi nistrati on s h o ul d n ot e xcee d 2 h o urs; h o we ver, it is rec o m me n de d t hat 
t he dr u g pr o d uct be a d mi nistere d i m me diatel y.
I n c o u ntries (i ncl u di n g Ja pa n) a n d/ or st u dy ce nters n ot usi n g t he dil uti o n met h o d t o 
pre pare st u d y  i njecti o ns, Ke n dall 5 micr o n filter nee dles will not be use d a n d t here is n o 
nee d t o desi g nate a n u n bli n de d p har macist ( or a p pr o priatel y- q ualifie d desi g nee) f or dr u g 
pre parati o n.
W he n a vaila ble, N o vartis will s u p pl y  ofat u m u ma b S C i n prefille d glass syri n ges 
c o ntai ni n g 0. 4 m L  ( 2 0 m g ) of c o nce ntrati o n 5 0 m g / m L dr u g pr o d uct a n d matc hi n g 
place b o prefille d glass s yri n ges c o ntai ni n g 0. 4 m L  of n or mal sali ne.  
Trai ne d site pers o n nel will a d mi nister 0. 4 m L  of i n vesti gati o nal pr o d uct via S C i njecti o n 
i nt o a vertical f ol d of a b d o mi nal s ki n a p pr o xi matel y 2 t o 4 i nc hes lateral of t he u m bilic us.  
T he i njecti o n site ma y  be a dj uste d at i n vesti gat or’s discreti o n if t here are e xte nsi ve 
a b d o mi nal lesi o ns prese nt.  S u bjects s h o ul d sta y  at t he cli nic f or a mi ni m u m of 4 h o urs 
after t he first d ose of i n vesti gati o nal pr o d uct t o b e m o nit ore d f or a n y i njecti o n -relate d 
A Es.  I t is rec o m me n de d t hat s u bjects sta y at t he cli nic f or a mi ni m u m of 1 h o ur, at t he 
i n vesti gat or’s discreti o n, after eac h s u bse q ue nt d ose.
Sites s h o ul d a d here t o d osi n g o n t he s pecific visit sc he d ule as s h o w n i n Ta ble 6 - 1. 
Pr otect i n vesti gati o nal pr o d ucts fr o m li g ht a n d st ore i n a refri gerat or at 2° t o 8° C ( 3 6° t o 
4 6° F); d o n ot freeze . St ore t he i n vesti gati o nal pr o d uct i n a sec ure area u n der a p pr o priate 
p h ys ical c o n diti o ns. Access t o a n d a d mi nistrati o n of t he i n vesti gati o nal pr o d uct is 
li mite d t o t he i n vesti gat or a n d a ut h orize d site staff. Dis pe nse or a d mi nister 
i n vesti gati o nal pr o d uct o nl y t o s u bjects e nr olle d i n t he st u d y a n d i n acc or da nce wit h t he 
pr ot oc ol . T he st u d y m o nit or will be res p o nsi ble f or re vie wi n g dr u g acc o u nta bilit y  of t he 
i n vesti gati o nal pr o d uct at t he site. Detaile d i nstr ucti o ns relate d t o t he destr ucti o n of 
u n use d materials are pr o vi de d i n t he p har mac y  ma n ual .
U n der n or mal c o n diti o ns of ha n dli n g a n d a d mi nistrati o n, i n vesti gati o nal pr o d uct is n ot 
e x pecte d t o p ose si g nifica nt safet y ris ks t o site staff.  A Material Safet y Data S heet 
descri bi n g t he occ u pati o nal hazar ds a n d rec o m me n de d ha n dli n g preca uti o ns will be 
pr o vi de d t o site staff i n the p har mac y  ma n ual.

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O P V 1 1 6 9 1 0
4 1
5. 1. 2. 
Ot h er St u d y  Tr e at m e nt s
Pr e - a n d P o sti nj e cti o n M e di c ati o n s
Pri or t o eac h S C i njecti o n of i n vesti gati o nal pr o d uct, all s u bjects are re q uire d t o recei ve 
pre me dicati o n wit h aceta mi n o p he n / paraceta m ol a n d a n a nti hista mi ne (see Ta ble 5- 1 ), 
w hic h will be a d mi nistere d at t he cli nic.  A p pr o xi matel y  4 h o urs after t he first i njecti o n, 
su bjects will recei ve a sec o n d d ose of aceta mi n o p he n/ paraceta m ol.  
A p pr o xi matel y  4 t o 6 h o urs after s u bse q ue nt i njecti o ns of i n vesti gati o nal pr o d uct, 
s u bjects ma y ta ke aceta mi n o p he n/ paraceta m ol if nee de d (t his d ose ma y be 
self-a d mi nistere d b y s u bjects after lea vi n g t he cli nic) .
T a bl e 5- 1 
Pr e - a n d P o sti nj e cti o n M e di c ati o n s
Ti m e r el ati v e t o S C i nj e cti o ns 
M e di c ati o n
D o s e 
R o ut e 
1 -2 h o urs b ef or e e ac h i nj ecti o n 
A nti hist a mi n e (c etirizi n e or e q uiv al e nt)
1 0 m g a
Or al 
1 -2 h o urs b ef or e e ac h i nj ecti o n 
Ac et a mi n o p h e n / p ar ac et a m ol 
1 g  
Or al
4 h o urs aft er first i nj ecti o n
Ac et a mi n o p h e n/ p ar ac et a m ol 
1 g 
Or al
4 -6 h o urs aft er s u bs e q u e nt i nj ecti o ns 
(if n e e d e d aft er cli nic visit)
Ac et a mi n o p h e n/ p ar ac et a m ol 
1 g 
Or al
A b br evi ati o n : S C =s u bc ut a n e o us.
d. 
If a n e q uiv al e nt a nti hist a mi n e is c h os e n, t h e d os e r a n g e s h o ul d b e acc or din g t o l oc ally -acc e pt e d pr actic e .
Pr e d ni s o n e/ Pr e d ni s ol o n e 
See Secti o n 3. 1. 2 .
5. 2. 
Tr e at m e nt A s si g n m e nt
St u d y  s u bjects w h o pr o vi de i nf or me d c o nse nt a n d u n der g o Scree ni n g assess me nts recei ve 
a u ni q ue s u bject n u m ber. T his assi g n me nt of s u bjec t n u m bers occ urs at t he Scree ni n g 
visit a n d ser ves t o i de ntif y s u bject data i n a n a n o n y m o us fas hi o n.
S u bject eli gi bilit y  will be esta blis he d at t he c o ncl usi o n of t he baseli ne e val uati o ns ( pri or 
t o ra n d o mizati o n a n d first d ose of i n vesti gati o nal pr o d uct at Wee k
0) ; s u bjects w h o meet 
all e ntr y criteria will t he n be ra n d o mize d i n a 1: 1 all ocati o n t o recei ve eit her 
ofat u m u ma b S C or place b o acc or di n g t o a ce ntral ra n d o mizati o n sc he d ule.
Assi g n me nt t o a treat me nt will be base d o n a c o m p uter- ge nerate d ra n d o mizati o n list
pre pare d b y N o vartis or a N o vartis -a p pr o ve d ve n d or ; a n interacti ve v oice res p o nse (I V R) 
s yste m ser ves as a ce ntral s yste m t o all ocate ra n d o mizati o n n u m bers t o eac h s u bject. T he 
s u bjects a n d t he i n vesti gati ve staff, e xce pt t he u n bli n de d p har macist, will b e bli n de d t o 
t he treat me nt assi g n me nt.
S u bjects w h o wit h dra w fr o m t he st u d y f oll o wi n g i nf or me d c o nse nt, b ut pri or t o 
ra n d o mizati o n t o st u d y treat me nt, will be classifie d as scree n fail ures.  I n or der t o e ns ure 
tra ns pare nt re p orti n g of scree n fail ure s u bjects, meet t he C o ns oli date d Sta n dar ds of 

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O P V 1 1 6 9 1 0
4 2
Re p orti n g Trials p u blis hi n g re q uire me nts, a n d res p o n d t o q ueries fr o m re g ulat or y  
a ut h orities, a mi ni mal set of scree n fail ure i nf or mati o n will be c ollecte d i n t he electr o nic 
case re p ort f or m ( e C R F), i ncl u di n g de m o gra ph y , scree n fail ure details, eli gi bilit y criteria, 
a n d a n y seri o us a d verse e ve nts (S A Es ).
5. 3. 
Bli n di n g
T his is a d o u ble -bli n d st u d y . Eac h site t hat pre pares st u d y i njecti o ns usi n g t he dil uti o n 
met h o d m ust desi g nate a n u n bli n de d p har macist ( or a p pr o priatel y-q ua lifie d desi g nee) f or 
dr u g pre parati o n . All ot her st u d y staff (i ncl u di n g t he i n vesti gat or, s u bi n vesti gat ors, ot her 
site staff, t he s u bject, a n d S p o ns or) will be bli n de d t o t he treat me nt all ocate d t o i n di vi d ual 
s u bjects. 
I n c o u ntries (i ncl u di n g Ja pa n) a n d/or st u d y  ce nters n ot usi n g t he dil uti o n met h o d t o 
pre pare st u d y  i njecti o ns, t here is n o nee d t o desi g nate a n u n bli n de d p har macist ( or 
a p pr o priatel y- q ualifie d desi g nee) f or dr u g pre parati o n.
T he bli n de d st u d y  treat me nt assi g n me nts f or i n di vi d ual s u bject will be mai ntai ne d b y a 
ce ntral I V R s ys te m.  E mer ge nc y u n bli n di n g will be a vaila ble via t he ce ntral I V R s yste m
(refer t o t he S P M a n d I V R s yste m g ui deli nes f or a p pr o priate pr oce d ures t o f oll o w) .
T he i n vesti gat or or treati n g p h ys icia n ma y u n bli n d a s u bject’s treat me nt assi g n me nt o nl y 
i n t he c ase of a n e mer ge nc y or i n t he e ve nt of a seri o us me dic al c o n diti o n , w he n 
k n o wle d ge of t he st u d y treat me nt is esse ntial f or t he a p pr o priate cli nical ma na ge me nt or 
welfare of t he s u bject, as j u d ge d b y t he i n vesti gat or . I n vesti gat ors ha ve direct access t o 
t he s u bject’s i n di vi d ual st u d y treat me nt.  It is preferre d ( b ut n ot re q uire d) t hat t he 
i n vesti gat or first c o ntacts t he me dical m o nit or or a p pr o priate st u d y pers o n nel t o disc uss 
o pti o ns bef ore u n bli n di n g t he s u bject’s treat me nt assi g n me nt.  If st u d y pers o n nel are n ot 
c o ntacte d bef ore t he u n bli n di n g, t he i n vesti gat or m ust n otif y t he me dical m o nit or as s o o n 
as p ossi ble after u n bli n di n g, b ut wit h o ut re veali n g t he treat me nt assi g n me nt of t he 
u n bli n de d s u bject, u nless t hat i nf or mati o n is i m p orta nt f or t he safet y of s u bjects c urre ntl y 
i n t he st u d y. T he date a n d reas o n f or t he u n bli n di n g m ust be f ully d oc u me nte d i n t he 
a p pr o priate data c ollecti o n t o ol.
N o vartis Gl o bal Cli nical Safet y  a n d P har mac o vi gila nce staff ma y u n bli n d t he treat me nt 
assi g n me nt f or a n y s u bject wit h a n S A E . If t he S A E re q uires t hat a n e x pe dite d re g ulat or y 
re p ort be se nt t o o ne or m ore re g ulat or y a ge ncies, a c o p y of t he re p ort, i de ntif yi n g t he 
s u bject’s treat me nt assi g n me nt, ma y be se nt t o cli nical i n vesti gat ors i n acc or da nce wit h 
l ocal re g ulati o ns a n d/ or N o vartis p olic y .
If t he treat me nt bli n d is br o ke n b y t he site f or a s u bject i n t he Treat me nt Peri o d, t he 
s u bject i n q uesti o n will be wit h dra w n fr o m t he Treat me nt Peri o d a n d m o ve d i nt o t he 
F oll o w -u p P eri o d.
D uri n g t he st u d y, i n vesti gat ors will n ot recei ve ce ntral la b orat or y data t hat ha ve t he 
p ote ntial t o u n bli n d a s u bject’s treat me nt assi g n me nt.  T his i ncl u des l y m p h oc y tes, 
B- l ym p h oc y te c he m o ki ne,   
 
, a n d h u ma n a nti -h u ma n 
a nti b o d y (H A H A ).  Refer t o t he  
 i n vesti gat or ma n ual f or a d diti o nal i nf or mati o n.
After t he Wee k 6 0
visit a n d eac h I n di vi d ualize d F oll o w-u p visit, t he ce ntral la b orat or y
( or desi g nee) will pr o vi de t he la b orat or y val ues a n d n otif y t he i n vesti gat or w het her or n ot 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
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4 3
a s u bject ne e ds t o re mai n i n foll o w - u p or if t he s u bject ma y  be disc har ge d fr o m t he stu d y  
( base d o n B-l ym p h oc y te c o u nts a n d I g G le vels).
S p o ns or u n bli n di n g f or a nal yses will occ ur after all s u bjects ha ve c o m plete d t he Wee k 6 0 
visit , bee n wit h dra w n fr o m t he treat me nt p eri o d, or t he st u d y has bee n ter mi nate d (see 
Secti o n 8. 3. 4 ).
5. 4. 
Pr o d u ct A c c o u nt a bilit y
I n acc or da nce wit h l ocal re g ulat or y re q uire me nts, t he i n vesti gat or, desi g nate d site staff, 
or hea d of t he me dical i nstit uti o n ( w here a p plica ble ) m ust d oc u me nt t he a m o u nt of 
i n vesti gati o nal pr o d uct a d mi nistere d t o st u d y s u bjects, a n d t he a m o u nt recei ve d fr o m a n d 
ret ur ne d t o N o vartis , w he n a p plica ble. Pr o d uct acc o u nta bilit y  rec or ds m ust be 
mai ntai ne d t hr o u g h o ut t he c o urse of t he st u d y .
T he desi g nate d p har macist m ust kee p dr u g i n ve nt or y  a n d acc o u nta bilit y l o gs. T he 
i n ve nt or y will i ncl u de details of ofat u m u ma b S C a n d place b o recei ve d a n d dis pe nse d 
(a d mi nistere d) t o s u bjects, batc h, a n d i de ntificati o n n u m bers . All u n use d prefille d 
s yri n ges (s u p plie d b y N o vartis ) m ust be ke pt u ntil rec o nciliati o n of deli ver y rec or ds wit h 
acc o u nta bilit y l o gs b y t he m o nit or. After t he m o nit or has perf or me d acc o u nta bilit y , t he 
site ma y destr oy t he s yri n ges, u nless ot her wise i nstr ucte d. A n acc o u nti n g m us t be ma de 
of a n y dr u g deli beratel y or acci de ntall y destr o ye d . Discre pa ncies bet wee n t he a m o u nt of 
ofat u m u ma b S C a n d place b o recei ve d a n d dis pe nse d m ust be rec o ncile d.
* I n J a p a n , u n use d i nvesti g ati o n al pr o d ucts will be c ollecte d at t he e n d of t he st u d y by
t he Sp o ns or or S p o ns or’s c o nsi g n or .
5. 5. 
Tr e at m e nt C o m pli a n c e
I n vesti gati o nal pr o d uct will o nl y be a d mi nistere d i n t he cli nic b y trai ne d site pers o n nel. 
Eac h d ose will be rec or de d i n t he e C R F.
5. 6. 
C o n c o mit a nt M e di c ati o n s a n d N o n -Dr u g T h er a pi e s
5. 6. 1. 
P er mitt e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s
S u bjects ma y  ta ke ot her me dicati o ns f or treat me nt of t he s ym pt o ms ass ociate d wit h P V ,
s o l o n g as t he y d o n ot fall i nt o a n y of t he pr o hi bite d me dicati o ns cate g ories
( Secti o n 5. 6. 2 ). T he a p peara nce of 1 or 2 ne w lesi o ns , n ot ot her wise meeti n g t he criteria 
f or disease flare/rela pse, ma y  be treate d wit h s u p p orti ve care, s uc h as t o pical pre parati o ns.
If t he i n vesti gat or is i n a n y d o u bt a b o ut w het her a c o nc o mita nt me dicati o n is per mitte d
d uri n g t he st u d y, he/s he s h o ul d disc uss it wit h t he me dical m o nit or.
5. 6. 2. 
Pr o hi bit e d M e di c ati o n s a n d N o n- Dr u g T h er a pi e s
T he me dicati o ns a n d t hera pies/treat me nts liste d i n T a ble 5 - 2 will n ot be all o we d d uri n g
t he st u d y (i ncl u di n g t he Scree ni n g, Treat me nt, a n d In di vi d ualize d F oll o w - u p Peri o ds ). 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
4 4
Use of pr o hi bite d me dicati o ns a n d t hera pies d uri n g t he st u d y  ma y res ult i n t he s u bject 
bei n g wit h dra w n fr o m st u d y treat me nt a n d p ote ntiall y wit h dra w n fr o m t he st u d y.
T a bl e 5- 2 
Pr o hi bit e d M e di c ati o n s
a n d N o n -Dr u g T h er a pi e s
M e di c ati o n or T h er a p y
W a s h o ut B ef or e
R a n d o miz ati o n
Ly m p h ocyt e -d e pl eti n g t h er a pi es , s uc h as:

I V of at u m u m a b ( A R Z E R R A)

a nti -C D 4, t ot al b o dy irr a di ati o n, b on e m arr o w tr a ns pl a nt ati o n

cycl o p h os p h a mi d e, cl a dri bi n e

al e mt uz u m a b ( C a m p at h) 

mit ox a ntr o n e

At a ny ti m e

At a ny ti m e

6 m o nt hs

6 m o nt hs

6 m o nt hs
Rit uxi m a b or ot h er a nti -C D 2 0 tr e at m e nts
1 8 m o nt hs
Ot h er m o n ocl o n al a nti b o di es
C o nt act m e dic al 
m o nit or
I m munoabsorption, plas ma exchange/plas mapheresis, i m munoglobulin therapy 
6 m o nt hs
I m m u n os u p pr essiv e or i m m u n o m o d ul at ory a g e nts, i ncl u di n g az at hi o pri n e, 
cycl os p ori n e, d a ps o n e, myc o p h e n ol at e, m et h otr ex at e, a n d t acr oli m us
8 w e eks
R ec eiv e d a liv e v acci n e
6 w e eks
I niti ati o n of st ati n t h er a py
A p plic a bl e d uri n g
t h e st u dy o nly
A b br evi ati o n: I V, i ntr av e n o us.
* I n J a p a n , ale mt uz u m a b ( C a m p at h) a n d a nti - C D 4 tre at me nts are n ot a p pr ove d.
5. 6. 3. 
I m m u ni z ati o n s
T he safet y of (a n d a bilit y t o ge nerate a pri mar y  or a na m nestic res p o nse t o) i m m u nizati o n 
wit h li ve atte n uate d or i nacti vate d vacci nes d uri n g ofat u m u ma b treat me nt has n ot bee n 
st u die d. T he res p o nse t o vacci nati o n c o ul d be i m paire d w he n B- cells are de plete d. 
It is rec o m me n de d t hat t he i n vesti gat or re vie w t he s u bject’s i m m u nizati o n hist or y as part 
of t he i nitial scree ni n g pr oce d ure f or a s u bject bei n g c o nsi dere d f or treat me nt wit h 
ofat u m u ma b S C . Vacci nati o n of t he s u bject, i n c o m plia nce wit h l ocal area vacci nati o n 
g ui deli nes f or t he patie nt p o p ulati o n bei n g treate d, is rec o m me n de d pri or t o 
a d mi nistrati o n of ofat u m u ma b S C . I n partic ular a n d per l ocal g ui deli nes, he patitis B 
vacci nati o n s h o ul d be c o nsi dere d f or s u bjects at ris k f or i nfecti o n wit h he patitis B ( or i n 
areas wit h a hi g h pre vale nce of he patitis B) . After treat me nt wi t h ofat u m u ma b S C , a v oi d 
a d mi nistrati o n of li ve atte n uate d vacci nes u ntil B- cell c o u nts ha ve n or malize d.
5. 7. 
Tr e at m e nt a ft er t h e E n d of t h e St u d y
As t he ofat u m u m a b de vel o p me nt pr o gra m i n t he i n dicati o n P V has bee n ter mi nate d, 
su bjects c o m pleti n g t he st u d y will n o l o n ger be eli gi ble t o partici pate i n t he e xte nsi o n 
st u d y ( OP V 1 1 7 0 5 9) .  S u bjects w h o were e nr olle d i n t he e xte nsi o n st u d y  pri or t o pr o gra m 
ter mi nati o n ma y re mai n i n t he e xte nsi o n st u d y u ntil e xit criteria are met.  S u bjects w h o 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
4 5
d o n ot partici pate i n t he pla n ne d e xte nsi o n st u d y will n ot recei ve a ny a d diti o nal treat me nt 
after c o m pleti o n of t his st u d y . 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat c o nsi derati o n has bee n gi ve n t o t he p ost 
st u d y care of t he s u bject’s me dical c o n diti o n, w het her or n ot N o va rtis is pr o vi di n g 
s pecific p ost st u d y treat me nt.
5. 8. 
Tr e at m e nt of I n ve sti g ati o n al Pr o d u ct O v er d o s e
If a n o ver d ose d oes occ ur, t here are n o rec o m me n de d me dicati o ns or n o n dr u g t hera pies 
f or treat me nt.
T he i n vesti gat or s h o ul d use his/ her cli nical j u d g me nt i n treati n g a n y 
o ver d ose . If a n o ver d ose d oes occ ur, i n di vi d uals s h o ul d be ma na ge d wit h a p pr o priate 
s u p p orti ve t hera py, as deter mi ne d b y t he i n vesti gat or i n c o ns ultati o n wit h t he me dical 
m o nit or . If t here are si g ns a n d s y m pt o ms ass ociate d wit h a n o ver d ose, t hese s h o ul d be 
re p orte d as a n A E/ S A E.
6. 
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S
Ta ble 6 - 1 prese nts t he sc he d ule of assess me nts f or t he st u d y . T he i n vesti gat or, or a 
me dicall y  q ualifie d desi g nee, is t o c o n d uct all st u d y assess me nts. T he i n vesti gat or or 
desi g nee m ust o btai n writte n i nf or me d c o nse nt pri or t o perf or mi n g a n y of t he 
assess me n ts. Rec or d st u d y  i nf or mati o n i n t he s o urce d oc u me nts a n d, w here a p pr o priate, 
t he e C R F.
T he Scree ni n g Peri o d be gi ns o nce t he s u bject has pr o vi de d writte n i nf or me d c o nse nt a n d 
lasts fr o m 2 t o 1 2 wee ks pri or t o ra n d o mizati o n.
If a visit ca n n ot be sc he d ule d o n t he a p pr o priate date, t he visit s h o ul d be re -sc he d ule d as 
cl ose as p ossi ble t o t he pla n ne d date, i deally wit hi n 3 da y s.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v ar ti s
O P V 1 1 6 9 1 0
4 6
Fi g ur e 6- 1 
R el ati v e Ti mi n g of K e y  Acti viti e s o n Of at u m u m a b S C D o si n g D a y s
A b br evi ati o n: S C =s u bc ut a n e o us.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
4 7
T a bl e 6- 1 
Ti m e a n d E v e nt s T a bl e
P eri o d:
S cr e e n
Core St udy Period (60 Weeks)
E arl y 
W D b
B L
Tr e at m e nt P eri o d ( 5 6 W e e k s)
F-up b
St u d y W e e k:
-2 t o -1 2 a
D ay 0 
2 
4 
6 
8 
1 0 
1 2 
1 4 
1 6 
1 8 
2 0 
2 2 
2 4 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8 
5 2 
5 6 
6 0 b
Cli ni c ( C) or P h o n e ( P ) Vi sit: 
C 
C 
C 
C 
C 
C 
P 
C 
P 
C 
P 
C 
P 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C
I nf or m e d c ons e nt
X
Eli gi bility crit eri a
X  
X
P hysic al ex a m, w ei g ht, & h ei g ht 
X
De mography; P V & medical history 
X
S m oki n g st at us
X  
X
X
X  
X
Vit al si g ns 
X  
X c
X c
X c
X c
X c
X c
X c
X c
X c
X c
X c
X c
X c
X c
X c
X  
X
El ectr oc ar di o gr a m
X
X  
X
A dv ers e ev e nts d
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
C o nc o mit a nt m e dic ati o ns
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P V l esi o n m a p pi n g
X  
X  
X  
X  
X  
X 
X 
X 
X 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
R a n d o miz ati o n
X
St u dy tr e at m e nt a d mi nistr ati o n e
X X 
X X 
X 
X 
X 
X 
X  
X  
X  
X  
X  
X  
X  
X  
X
D oc u m e nt st er oi d d os e
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
St er oi d t a p er 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
L a b or at ory f
X  
X 
H 
H 
X 
H 
H 
X  
H  
H  
X  
H  
H  
X  
H  
H  
X  
X
S er u m h C G ( w o m e n o nly)
X
X  
X
Uri n e h C G ( w o m e n o nly)
X 
X 
X 
X 
X 
X 
X  
X  
X  
X  
X  
X  
X  
X  
X
H A H A; hs C R P g
X
X
X
X
X  
X  
X  
X  
X
I g G, I g M, I g A
X  
X
X
X
X
X  
X  
X  
X  
X
P h ar m ac o dy n a mic m ark ers g
X  
X 
X 
X 
X 
X 
X 
X
X
X  
X  
X  
X  
X

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
4 8
P eri o d:
S cr e e n
Core St udy Period (60 Weeks)
E arl y 
W D b
B L
Tr e at m e nt P eri o d ( 5 6 W e e k s)
F-up b
St u d y W e e k:
-2 t o -1 2 a
D ay 0 
2 
4 
6 
8 
1 0 
1 2 
1 4 
1 6 
1 8 
2 0 
2 2 
2 4 
2 8 
3 2 
3 6 
4 0 
4 4 
4 8 
5 2 
5 6 
6 0 b
Cli ni c ( C) or P h o n e ( P ) Vi sit: 
C 
C 
C 
C 
C 
C 
P 
C 
P 
C 
P 
C 
P 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C 
C
P h ar m ac oki n etic s a m pl e g
X 
X 
X 
X 
X 
X 
X
X
X 
X  
X  
X
P h ar m ac o ki n etic s u bst u dy g, h,i
S e e T a bl e 6- 3 f or P K-P D s u bst u dy visits a n d s a m pl e c oll ecti o n ti m e p oi nts 
P h ar m ac o g e n etics s a m pl e g, h
X
Seru m banking for J C virus testing
X
Neurological sy mpto m questionnaire 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
A b br evi ati o n s: 
; a d mi n = a d mi nistr ati o n; 
; B L = B as eli n e; B L C = B-ly m p h ocyt e c h e m oki n e; C =cli nic 
visit; 
; F-u p =f oll o w -u p visit; H A H A = h u m a n a nti -h u m a n a nti b o dy; h C G = h u m a n c h ori o n ic g o n a d otr o pi n; hs C R P = h i g h s e nsitivity C-r e activ e pr ot ei n; 
I g =i m m u n o gl o b uli n; P = p h o n e visit; P D = p h ar m ac o dy n a mic; P K = p h ar m ac oki n etic; P V = p e m p hi g us v ul g aris; 
; 
W D = wit h dr a w al .
a. 
Scr e e ni n g m ay b e u p t o 1 2 w e eks f or dis e as e c o ns oli d ati o n/c o ntr ol a n d a dj ust m e nt/st a biliz ati o n of pr e d nis o n e/ pr e d nis ol o n e d os e.  M ulti pl e visits ( u ns c h e d ul e d) ar e p er mitt e d.
b. 
If s u bj ect is n ot e nt eri n g t h e ext e nsi o n st u dy a n d C D 1 9 + B c ell c o u nts a n d circ ul ati n g I g G l ev els ar e b el o w t h e l o w er li mit of n or m al at W e ek 6 0 ( or e arly wit h dr a w al visit), t h e 
s u bj ect will tr a nsiti o n i nt o I n divi d u aliz e d F oll o w -u p (s e e T a bl e 6- 2 ).  S u bj ects r e q uiri n g a d diti o n al h e p atitis B vir us t esti n g will als o r et ur n f or f oll o w-u p visits f or 6 m o nt hs aft er t h e 
l ast d os e.
c. 
Vit al si g ns s h o ul d b e t ak e n b ef or e e ac h i nj ecti o n of i nv esti g ati o n al pr o d uct, at a p pr oxi m at ely 4 h o urs aft er t h e first d os e, a n d at a p pr oxi m at ely 1 h o ur aft er s u bs e q u e nt d os es.
d. 
A dv ers e ev e nts ( A Es ) will b e c oll ect e d fr o m t h e st art of st u dy tr e at m e nt t hr o u g h t h e C or e St u dy P eri o d.  S eri o us A Es ass ess e d as r el at e d t o st u dy p artici p ati o n will b e c oll ect e d 
fr o m t h e ti m e a s u bj ect c o ns e nts t o p artici p at e i n t h e st udy u p t o a n d i ncl u di n g a ny f oll o w -u p c o nt act.
e. 
Pr e m e dic ati o n : E ac h d os e of st u dy tr e at m e nt will b e pr ec e d e d by ac et a mi n o p h e n/ p ar ac et a m ol a n d a n a nti hist a mi n e (s e e S ecti o n 5. 1. 2 ).  
P ost d os e o bs erv ati o n a n d m e dic ati o n : Aft er t h e first d os e, s u bj ects s h o u l d st ay at t h e cli nic t o b e m o nit or e d f or a ny i nj ecti o n-r el at e d A Es f or a mi ni m u m of 4 h o urs, wit h 
ac et a mi n o p h e n/ p ar ac et a m ol a d mi nist er e d a g ai n at 4 h o urs.  Aft er s u bs e q u e nt d os es, it is r ec o m m e n d e d t h at s u bj ects st ay at t h e cli nic f or a mi ni m u m of 1 h o ur, wit h 
ac et a mi n o p h e n/ p ar ac et a m ol s elf -a d mi nist er e d a p pr oxi m at ely 4 t o 6 h o urs aft er d osi n g if n e e d e d.
N ot e: A n a d diti o n al 2 0 -m g l o a di n g d os e (t ot al of t w o 2 0 -m g i nj ecti o ns) will b e a d mi nist er e d at W e ek 0 a n d W e ek 4.
f. 
L a b or at ory ass ess m e nts i ncl u d e h e m at ol o gy , cli nic al c h e mistry, a n d uri n alysis.  “ H” i n dic at es visits wit h o nly h e m at ol o gy.  
At Scr e e ni n g a n d W e ek 6 0/ e arly wit h dr a w al o nly — H e p atitis B, H e p atitis C, p n e u m oc occ al a nti b o dy ass ay, a n d t ox oi d a nti b o dy ass ay.
g. 
C oll ect s a m pl e pr e d os e o n d osi n g d ays.
h. 
I nf or m e d c o ns e nt m ust b e o bt ai n e d b ef or e c oll ecti n g s a m pl es f or o pti o n al t esti n g (i e, p h ar m ac o g e n etics r es e arc h a n d p h ar m ac oki n etic -p h ar m ac o dy n a mic s u bst u dy a n alys es).
i. 
O nly sit es pr ei d e ntifi e d t o p artici p at e i n p h ar m ac oki n etic -p h ar m ac o dy n a mic s u bst u dy.  S e e T a bl e 6- 3 f or t h e sc h e d ul e of visits f or s a m pl e c oll ecti o n.
N ot e: 
Visits fr o m W e ek 2 t hr o u g h W e ek 6 0 t o b e sc h e d ul e d wit hi n 3 d ay s of t h e s p ecifi e d ti m e p oi nt.  Visits d uri n g I n divi d u aliz e d F oll o w -u p t o b e sc h e d ul e d wit hi n 7 d ays.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
4 9
T a bl e 6- 2 
Ti m e a n d E v e nt s T a bl e: I n di vi d u ali z e d F oll o w- u p P eri o d
A s a p pli c a bl e a
E arl y 
W D
St u d y W e e k f or C or e St u d y C o m pl et er s: 
7 2  
8 4  
9 6  
1 0 8  
1 2 0  
1 3 2  
1 4 4  
1 5 6
St u d y W e e k f or E arl y Wit h dr a w a l s:
+ 1 2  
+ 2 4  
+ 3 6  
+ 4 8  
+ 6 0  
+ 7 2  
+ 8 4  
+ 9 6
A dv ers e ev e nts (i ncl u di n g S A Es a n d A Es of s p eci al i nt er est) b
X 
X 
X 
X 
X 
X 
X 
X 
X
C o nc o mit a nt m e dic ati o ns
X 
X 
X 
X 
X 
X 
X 
X 
X
D oc u m e nt st er oi d d os e
X 
X 
X 
X 
X 
X 
X 
X 
X
N e ur ol o gic al sy m pt o ms q u esti o n n air e ( P M L m o nit ori n g)
X 
X 
X 
X 
X 
X 
X 
X 
X
P V l esi o n m a p pi n g
X 
X 
X 
X 
X 
X 
X 
X 
X
Pr e g n a ncy t esti n g ( uri n e) ( w o m e n) – t est m o nt hly f or 1 2 m o nt hs 
aft er t h e l ast d os e of of at u m u m a b S C; s u bj ects m ay t est at h o m e 
d uri n g m o nt hs wit h o ut a cli nic visit
X  
X  
X  
X
X
H e m at ol o gy
X 
X 
X 
X 
X 
X 
X 
X 
X
Cli nic al c h e mistry
X 
X 
X 
X 
X 
X 
X 
X 
X
I g G, I g M, I g A
X 
X 
X 
X 
X 
X 
X 
X 
X
H u m a n a nti -h u m a n a nti b o dy
X
X
P h ar m ac o dy n a mic m ark ers (fl o w cyt o m etry)
X 
X 
X 
X 
X 
X 
X 
X 
X
H B V D N A – if a p plic a bl e, t est ev ery1 2 w e eks f or 6 m o nt hs aft er t h e 
l ast d os e of of at u m u m a b S C
P R N  
P R N
P R N
A b br evi ati o ns: A E = a dv ers e ev e nt; 
; H B V = h e p atitis B vir us; I g =i m m u n o gl o b uli n; P M L = pr o gr essiv e m ultif oc al l e uk o e nc e p h al o p at hy; P R N = as n e e d e d/ as i n dic at e d; 
P V = p e m p hi g us v ul g aris; S A E =s eri o us a dv ers e ev e nt; S C =s u bc ut a n e o us; W D = wit h dr a w al.
a. 
S u bj ects e nt eri n g t h e In divi d u aliz e d F oll o w -u p P eri o d will c o nti n u e t o b e m o nit or e d ev ery 1 2 w e eks, u ntil C D 1 9 + B -ly m p h ocyt e c o u nts a n d I g G r ec ov er t o ≥ l o w er li mit of n or m al 
(L L N ) or t o t h e s u bj ect’s B as eli n e v al u e (if < L L N) or if crit eri a f or st u dy wit h dr a w al ar e m et or f or a m axi m u m of 2 y e ars aft er t h e l ast d os e of of at u m u m a b S C.
b. 
A Es (i ncl u di n g A Es of s p eci al i nt er est) a n d S A Es will b e c oll ect e d d uri n g t h e first y e ar of t h e I n divi d u aliz e d F oll o w -u p P eri o d .  O nly S A Es a n d A Es of s p eci al i nt er est will b e 
c oll ect e d d uri n g t h e s ec o n d y e ar of t h e I n divi d u aliz e d F oll o w -u p P eri o d .  Any S A Es ass ess e d as r el at e d t o st u dy p artici p ati o n will b e c oll ect e d fr o m t h e ti m e a s u bj ect c o ns e nts 
t o p artici p at e i n t h e st u dy u p t o a n d i ncl u di n g a ny f oll o w-u p c o nt act.
N ot e: Visits d uri n g I n divi d u aliz e d F oll o w -u p t o b e sc h e d ul e d wit hi n ± 7 d ays.

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T a bl e 6- 3 
Ti m e a n d E v e nt s T a bl e: 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 u b st u d y
P eri o d : 
B a s eli n e
Tr e at m e nt P eri o d ( 5 6 W e e k s)
F -u p
E arl y 
W D
Vi sit Wi n d o w:
2 h o urs
3 d ays
Ti m e P oi nt:
D ay 0 
predose
D a y 0 
p ost d ose D a y 1 D a y 2 D a y 3 D a y 4
D a y 7/ 
W e e k 1
W e ek
2
W e ek
4
W e ek
8
W e ek 
1 2
W e ek 
1 6
W e ek
2 0
W e ek 
2 4
W e ek 
3 6
W e ek 
4 8
W e ek 
5 2
W e ek 
5 6
W e ek 
6 0
P h ar m ac oki n etic s a m pl e a –
r e g ul arly sc h e d ul e d visits
X a, b
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P h ar m ac oki n etic s a m pl e –
a d diti o n al visits
X b
X  
X  
X  
X  
X
P h ar m ac o dy n a mic  s a m pl e a –
B- ly m p h ocyt e s u bs et a n alys es
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
A dv ers e ev e nts
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
A b br evi ati o ns: F- u p =f oll o w -u p visit; W D = wit h dr a w al 
a. 
C oll ect s a m pl e pr e d os e o n d osi n g d ays.
b. 
D ay 0 bl o o d dr a ws will occ ur pr e d os e a n d 4 h o urs p ost d os e.
N ot e: fr o m D ay 1 t hr o u g h D ay 7, p h ar m ac oki n etic s a m pl es s h o ul d b e c oll ect e d at t h e s a m e ti m e of d ay ( 2 h o urs ) t h at t h e i niti al d os e of i nv esti g ati o n al pr o d uct w as a d mi nist er e d ; 
W e ek 2 t hr o u g h W e ek 6 0 visits s h o ul d b e sc h e d ul e d wit hi n 3 d ays of t h e s p ecifi e d ti m e p oi nt.
** R ef er t o t h e f ull Ti m e a n d E v e nt s t a bl e (T a bl e 6- 1 ) f or t h e c o m pl et e li st of a s s e s s m e nt s t o b e p erf or m e d at t h e r e g ul arl y s c h e d ul e d vi sit s**

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6. 1. 
Criti c al B a s eli n e A s s e s s m e nt s
I nf or mati o n c ollecte d d uri n g t he Scree ni n g P eri o d assess me nts descri be d bel o w 
re prese nts ke y data t hat i de ntifies a n d defi nes s u bject baseli ne stat us.  T his i nf or mati o n is 
critical f or t he e val uati o n a n d c o m paris o n of s u bse q ue nt meas ure me nts a n d 
deter mi nati o ns.
Car di o vasc ular me dical hist or y /ris k fact ors will be assesse d at Scree ni n g/ B aseli ne.
* I n J a p a n , refer t o A p pe n dix 2 f or a d diti o n al scree ni n g assess me nts f or T B, 
P ne u m ocystis p ne u m o ni a, a n d i nterstiti al p ne u m o ni a. *
6. 1. 1. 
M e di c al Hi st or y
A c o m plete me dical hist or y will be ta ke n at t he Scree ni n g Visit. I nf or mati o n fr o m t he 
me dical hist or y  is i m p orta nt t o esta blis h t he baseli ne c o n diti o n of t he s u bject, a n d will 
i m pact t he safety m o nit ori n g assess me nts d uri n g t he st u d y. A n y si g nifica nt m e dical 
c o n diti o ns affecti n g t he s u bject i n t he past 5 ye ars s h o ul d be rec or de d o n t he Me dical 
C o n diti o ns pa ge of t he e C R F. T he hist or y  s h o ul d i ncl u de t he f oll o wi n g:
 
A t h or o u g h re vie w of s ys te ms, i ncl u di n g a ny past or c urre nt c o n diti o ns
 
Pri or s ur gical pr oc e d ures
 
P har mac ot hera p y a n d c hr o nic or rece nt use of a n y me dicati o n
 
Pri or i m m u n os u p pressi ve t hera pies, i ncl u di n g t y p e, n u m ber, a n d d urati o n
 
Aller gies a n d si g nifica nt aller gic reacti o ns
 
Si g nifica nt i nfecti o ns, or hist or y  of rec urre nt i nfecti o n, i ncl u di n g urinar y  a n d 
res pirat or y tract i nfecti o ns
 
S m o ki n g hist or y  (c urre nt or pre vi o us s m o ker, n u m ber of pac ks a da y s m o ke d)
6. 1. 2. 
P e m p hi g u s V ul g ari s Hi st or y
D etails of t he s u bject’s P V hist or y  will be c ollecte d (e g, dates of s y m pt o m o nset, 
dia g n osis, a n d flares/rela pses) in t he e C R F. T hese data are critical f or esta blis hi n g 
s u bject eli gi bilit y, as well as esta blis hi n g a baseli ne f or s u bse q ue nt cli nical assess me nts.
T he date of eac h s u bject’s m ost rece nt faile d ster oi d ta per t hat res ulte d i n a disease 
flare/rela pse at a pre d nis o ne/ pre d nis ol o ne d ose > 1 0 m g/ da y will be c ollecte d i n t he e C R F .  
A d diti o nall y , a hist orical assess me nt of pe m p hi g us cli nical se verit y at t he ti me of t he 
faile d ster oi d ta per will be c ollecte d usi n g t he scale descri b e d i n A p pe n di x 6 .

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6. 2. 
Effi c a c y
6. 2. 1. 
Pri m ar y  Effi c a c y E n d p oi nts
T w o c o -pri mar y  efficac y e n d p oi nts will be e val uate d:
 
Ti me t o s ustai ne d re missi o n (S R ) o n mi ni mal ster oi d t hera p y ( defi ne d as ti me fr o m 
ra n d o mizati o n t o t he ti me t he s u bject i nitiall y ta pere d his/ her oral 
pre d nis o ne/ pre d nis ol o ne d ose t o ≤1 0 m g/ da y  a n d mai ntai ne d ≤1 0 m g/ da y  of oral 
pre d nis o ne/ pre d nis ol o ne wit h n o ne w or n o n heali n g lesi o ns f or ≥8 wee ks A N D 
mai ntai ne d t hat stat us u ntil Wee k 6 0 ).
 
D urati o n of re missi o n o n mi ni mal ster oi d t hera p y  (defi ne d as t otal ti me [s u m] of all 
peri o ds of re missi o n w hile o n mi ni mal ster oi d t hera p y [ oral pre d nis o ne/ pre d nis ol o ne 
d ose of ≤1 0 m g/ da y ] u p t o Wee k 6 0 ).
6. 2. 2. 
S e c o n d ar y  Effi c a c y E n d p oi nt s
 
Pr o p orti o n of s u bjects ac hie vi n g re missi o n o n m i ni mal ster oi d thera p y ( defi ne d as 
s ubjects w h o ha d a n a bse nce of ne w or n o n heali n g lesi o ns w hile o n an oral
pre d nis o ne / pre d nis ol o ne d ose of ≤1 0 m g/ da y  f or 8 wee ks) at Wee k 6 0 .
 
Ti me t o re missi o n w hile o n mi ni mal ster oi d t hera p y ( defi ne d as ti me fr o m 
ra n d o mizati o n t o t he ti me t he s u bject i nitiall y ta pere d his/ her oral
pre d nis o ne/ pre d nis ol o ne d o se t o ≤1 0 m g/ da y  a n d mai ntai ne d ≤1 0 m g/ da y  of oral 
pre d nis o ne/ pre d nis ol o ne wit h n o ne w or n o n heali n g lesi o ns f or ≥8 wee ks ) b y  
Wee k
6 0 .
 
Ti me t o i nitial flare /rela pse ( defi ne d as t he ti me fr o m ra n d o mizati on t o t he ti me t hat 
≥3 ne w lesi o ns wit hi n 1 m o nt h a p pear a n d d o n ot heal s p o nta ne o usl y wit hi n 1 wee k, 
or t o t he ti me w he n t here is a n e xte nsi o n of lesi o ns t hat were prese nt at t he 
ra n d o mizati o n visit) b y Wee k 6 0 .
 
Pr o p orti o n of s u bjects w h o di d n ot flare/rela pse ( defi ne d as s u bjects w h o ac hie ve d 
re missi o n o n mi ni mal ster oi d t hera p y a n d di d n ot s u bse q ue ntl y ha ve a flare of 
disease ) b y  Wee k 6 0 . A flare/rela pse is defi ne d as ne w lesi o ns t hat d o n ot heal 
s p o nta ne o usl y wit hi n 1 wee k, or w he n t here is a n e xte nsi o n of lesi o ns t hat were 
prese nt at t he ra n d o mizati o n visit .
 
Ti me t o re missi o n off ster oi d t hera p y b y Wee k 6 0
(defi ne d as t he ti me fr o m 
ra n d o mizati o n t o t he ti me t he s u bject i nitiall y ta pere d off all ster oi ds f or 8 wee ks 
wit h a n a bse nce of ne w or n o n heali n g lesi o ns).
 
Pr o p orti o n of s u bjects ac hie vi n g re missi o n w hile off ster oi d t hera p y b y Wee k 6 0 .
 
N u m ber of da y s a s u bject mai ntai ne d mi ni mal ster oi d t hera py (a n oral
pre d nis o ne/ pre d nis ol o ne d ose of ≤1 0 m g/ da y  i n t he a bse nce of ne w or n o n heali n g
lesi o ns) b y Wee k
6 0 .
 
C u m ulati ve d ose of c ortic oster oi ds.

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6. 3. 
S af et y
T he f oll o wi n g sa fety e n d p oi nts will be assesse d:
 
A d verse e ve nts
 
A d verse e ve nt fre q ue nc y, se verity, a n d relati o ns hi p t o i n vesti gati o nal pr o d uct
 
Fre q ue nc y  a n d se verit y of i nfecti o ns
 
Fre q ue nc y  of S A Es
 
Fre q ue nc y  of wit h dra w als d ue t o treat me nt-relate d A Es .
 
Fre q ue nc y  of A Es lea di n g t o per ma ne nt disc o nti n uati o n of i n vesti gati o nal pr o d uct.
 
Fre q ue nc y  of A Es of s pecial i nterest, p osti njecti o n s yste mic reacti o ns, a n d i njecti o n 
site reacti o ns. 
 
C ha n ge fr o m baseli ne i n vital si g ns .

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 
Fre q ue nc y  of vital si g ns of cli nical c o ncer n .
 
C ha n ge fr o m baseli ne i n la b orat or y (he mat ol o g y , c he mistr y, a n d uri nalys is)
para meters .
 
Fre q ue nc y  of la b orat or y (he mat ol o g y , c he mistr y, a n d uri nalys is) res ults of p ote ntial 
cli nical c o ncer n .
 
I m m u n o ge nicit y as meas ure d by t h e i nci de nce, titer, a n d ty pe of H A H A i m m u ne 
res p o nse.
6. 3. 1. 
Li v er C h e mi str y St o p pi n g a n d F oll o w -u p Crit eri a
Li ver c he mistr y  st o p pi n g a n d f oll o w- u p criteria ha ve bee n desi g ne d t o e ns ure s u bject 
safety a n d e val uate li ver e ve nt eti ol o g y (i n ali g n me nt wit h t he F o o d a n d Dr u g 
A d mi nistrati o n pre mar keti n g cli nical li ver safet y g ui da nce).   Li ver s afet y re q uire d acti o ns 
a n d foll o w - u p assess me nts ca n be f o u n d i n A p pe n di x 3 .
Fi g ur e 6- 2 
Li v er C h e mi str y  St o p pi n g a n d I n cr e a s e d M o nit ori n g Al g orit h m
C o nti n u e St u d y Tr e at m e nt  
Disc o nti n u e St u d y Tr eat m e nt  
Pl u s 
Bi lir ubi n > 2 x
U L N ( >3 5 %  
di r ect ) or  pl u s
I NR > 1. 5, if 
m e a s ur e d *
P o s si bl e  
H y ’ s L a w
A L T > 3 x U L N
A L T
> 8 x U L N
Pl u s
S y m pt o m s  of 
li ver  inj ur y
or  
h y p er s e n s iti vit y
N o
Y e s
Y e s
Y e s
N o
N o
N o
S e e al g or it h m 
f or co nt i nu e d  
t her a p y wit h  
i ncr e a s e d li ver  
c h e m i str y 
m o ni t ori ng
Y e s
*I NR v al u e n o t a p pli c a bl e t o s u bj e ct s o n  ant i c o a g ul ant s 
A L T 
> 3 x U L N 
b ut  
< 8 x U L N
Y e s
 M u st  ref er  to Li v e r Saf et y R e q ui r ed A ct i o n s an d F ol l o w u p A s s e s s m e n t s se ct i on i n t he A p p e n di x
 R e p or t a s a n S A E if po s si bl e H y ’ s L a w c a s e:  A L T > 3 x U L N a n d  Bilir u bi n > 2 x U L N ( > 35 % di r ect )  or 
I N R > 1. 5, if m e a s ur e d*
A b br evi ati o ns: A L T = al a ni n e a mi n otr a nsf er as e; I N R =i nt er n ati o n al n or m aliz e d r ati o; S A E =s eri o us a dv ers e ev e nt; 
U L N = u p p er li mit of n or m al.

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Fi g ur e 6- 3 
Li v er C h e mi str y  I n cr e a s e d M o nit ori n g Al g orit h m wit h C o nti n u e d 
T h er a p y  f or AL T 3 x U L N b ut < 8 x U L N
C o nt i n u e St u d y Tr e at m e nt   a n d   M o nit or Li ver  Ch e m istry
Dis c o nti n u e St u d y Tr e at m e nt 
AL T > 5 x UL N 
b ut < 8 x UL N
+ bili < 2 x UL N +
n o sym pt o ms
N o
 M u st  ref er  to Li v e r Saf et y R e q ui r ed A ct i on s  an d F ol l ow u p A s s e s s m e n t s se ct i o n in t he A p p e n di x
Y e s
AL T > 3 x UL N 
b ut < 5 x UL N
+ bili < 2 x UL N  +
n o sym pt o ms
A bl e t o 
m o nit or  
w e ek ly 
f or  ≥2 
w e ek s
P e rsists f or 
≥2 w e ek s  
or  ot her  
st op pi n g 
crit eri a  
m e t
N o
Y e s
Ye s
Y e s
N o
N o
A bl e t o 
m o nit or  
w e ek ly 
f or  ≥4 
w e ek s
P e rsists f or 
≥4 w e ek s  
or  ot her  
st op pi n g 
crit eri a  
m e t
N o
Y e s
Y e s
Y e s
Y e s
AL T > 5 x UL N 
AL T < 5 x UL N 
Y e s
Y e s
*I N R v alu e  not a p plic a bl e t o s u bjects o n a ntic o a g ul a nts 
 M u st  ref er  to Li v e r Saf et y R e q ui r ed A ct i on s  an d F ol l ow u p A s s e s s m e n t s se ct i o n in t he A p p e n di x
 R e p or t a s a n S A E if po s si bl e H y ’ s L a w c a s e:  A L T > 3 x U L N a n d  Bi lir ubi n > 2 x U L N  (> 3 5 % di r ect )  or  
I NR > 1. 5,  if m e a s ur e d*
A b br evi ati o ns: A L T = al a ni n e a mi n otr a nsf er as e; bili = bilir u bi n; I N R =i nt er n ati o n al n or m aliz e d r ati o; S A E =s eri o us a dv ers e 
ev e nt; U L N = u p p er li mit of n o r m al.
6. 3. 2. 
A d v er s e E v e nt s
T he i n vesti gat or or site staff will be res p o nsi ble f or detecti n g, d oc u me nti n g, an d re p orti n g 
e ve nts t hat meet t he defi niti o n of a n A E or S A E.
6. 3. 2. 1. 
D efi niti o n of a n A E
A n y  u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject, 
te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d 
relate d t o t he me dici nal pr o d uct.
N ote: A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g), sy m pt o m, or disease ( ne w or e xacer bate d) te m p orall y  
ass ociate d wit h t he use of a me dici nal pr o d uct .  F or mar kete d me dici nal pr o d ucts, t his 
als o i ncl u des fail ure t o pr o d uce e x pecte d be nefits ( ie, lac k of efficac y), a b use, or mis use.
E ve nts meeti n g t he defi niti o n of a n A E i ncl u d e:
 
E xacer bati o n of a c hr o nic or i nter mitte nt pre- e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncrease i n fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n
 
Ne w c o n diti o ns detecte d or dia g n ose d after st u d y treat me nt a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve bee n prese nt pri or t o t he start of t he st u d y

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 
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d i nteracti o n
 
S i g ns, s ym pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y 
treat me nt or a c o nc o mita nt me dicati o n ( o ver d ose per se will n ot be re p orte d as a n 
A E/ S A E) u nless t his is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self -
har mi n g i nte nt . T his s h o ul d be re p orte d re gar dless of se q uelae .
“ Lac k of efficac y” or “fail ure of e x pecte d p har mac ol o gical acti o n” per se will n o t be 
re p orte d as a n AE or S A E ; ho we ver, t he si g ns a n d s y m pt o ms a n d/ or cli nical se q uelae 
res ulti n g fr o m lac k of efficac y will be re p orte d if t he y f ulfill the defi niti o n of a n A E or 
S A E. 
E ve nts t hat d o n ot meet t he defi niti o n of a n A E i ncl u de:
 
Me dical or s ur gical pr oce d ure ( e g, e n d osc o p y, a p pe n dect o my); t he c o n diti o n t hat 
lea ds t o t he pr oce d ure is a n A E
 
Sit uati o ns w here a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital)
 
A ntici pate d da y -t o-d a y  fl uct uati o ns of pre-e xisti n g disease(s) o r c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n
 
T he disease/ dis or der bei n g st u die d, or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of 
t he disease/ dis or der bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he s u bject’s 
c o n diti o n
6. 3. 2. 2. 
D efi niti o n of a n S A E
A n S A E is a n y u nt o war d me dical occ urre nce t hat, at a n y d ose:
a. 
Res ults i n deat h
b. 
Is life-t hreate ni n g
N O T E:  T he ter m ‘life-t hreate ni n g’ i n t he defi niti o n of ‘seri o us’ refers t o a n e ve nt i n 
w hic h t he s u bject was at ris k of deat h at t he ti me of t he e ve nt.  It d oes n ot refer t o a n 
e ve nt, w hic h h y p ot heticall y  mi g ht ha ve ca use d deat h, if it were m ore se vere.
c. 
Re q uires h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n
N O T E:  I n ge neral, h os pitalizati o n si g nifies t hat t he s u bject has bee n detai ne d 
( us uall y i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or 
o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h y sicia n’s 
office or o ut patie nt setti n g .  C o m plicati o ns t hat occ ur d uri n g h os pital izati o n are A Es.  
If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he 
e ve nt is seri o us .  W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was 
necessar y , t he A E s h o ul d be c o nsi dere d seri o us.
H os pitalizati o n f or el ecti ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n 
fr o m baseli ne is n ot c o nsi dere d a n A E.
d. 
Res ults i n disa bilit y /i nca pacit y, or

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N O T E:  T he ter m disa bilit y  mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o 
c o n d uct n or mal life f u ncti o ns .  T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces 
of relati vel y mi n or me dical si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, 
v o miti n g, diarr hea, i nfl ue nza, a n d acci de ntal tra u ma ( e g, s prai ne d a n kle) w hic h ma y 
i nterfere or pre ve nt e ver y da y life fu ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial 
disr u pti o n.
e. 
Is a c o n ge nital a n o maly/ birt h defect
f. 
Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y  n ot be 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize 
t he s u bject or ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 1 of t he ot her 
o utc o mes liste d i n t he a b o ve defi niti o n .  T hese s h o ul d als o be c o nsi dere d seri o u s.  
E xa m ples of s uc h e ve nts are i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt i n a n 
e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d y scrasias, or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y  
or dr u g a b use.
g. 
All e ve nts of p ossi ble dr u g -i n d uce d li ver inj ur y  wit h h y per bilir u bi ne mia defi ne d as 
A L T 3 U L N a n d bilir u bi n 2 U L N ( > 3 5 % direct) ( or A L T 3 U L N a n d 
i nter nati o nal n or malize d rati o [I NR] > 1. 5, if I N R meas ure d) ter me d ‘ H y ’s La w’ 
e ve nts (I N R meas ure me nt is n ot re q uire d a n d t he t hres h ol d val ue state d will n ot 
a p pl y t o s u bjects recei vi n g a ntic oa g ulants).
N O T E: bilir u bi n fracti o nati o n is perf or me d if testi n g is a vaila ble .  If testi n g is 
u na vaila ble, rec or d prese nce of detecta ble uri nar y  bilir u bi n o n di pstick i n dicati n g 
direct bilir u bi n ele vati o ns a n d s u g gesti n g li ver i nj ur y . If testi n g is u na vaila ble a n d a 
s u bject meets t he criteri o n of t otal bilir u bi n 2 U L N , t he n t he e ve nt is still re p orte d 
as a n S A E. If I N R is o btai ne d, i ncl u de val ues o n t he S A E f or m.  I N R ele vati o ns 
> 1. 5 s u g gest se vere li ver i nj ur y . 
6. 3. 2. 3. 
A d v er s e E v e nt s of S p e ci al I nt er e st
T he me dical m o nit or s h o ul d be n otifie d of t he occ urre nce of t he f oll o wi n g A Es of s pecial 
i nterest:
 
A n y  o p p ort u nistic i nfecti o ns, s uc h as i nfecti o ns ca use d b y or ga nis ms t hat d o n ot 
ca use disease i n a pers o n wit h a healt h y i m m u ne s yste m, or t y pes of i nfecti o ns t hat 
d o n ot c o m m o nl y  occ ur i n s o me o ne wit h a healt h y i m m u ne s y ste m
(e g, P ne u m oc y stis p ne u m o nia, cr y pt oc occal me ni n gitis, m y c o bacteri u m i nfecti o ns, 
c yt o me gal o vir us reti nitis, s yste mic ca n di diasis).
 
S eri o us p osti njecti o n s yste mic reacti o ns: s u bjects ma y  be wit h dra w n fr o m 
i n vesti gati o nal pr o d uct a d mi nistrati o n at t he discreti o n of t he i n vesti gat or .
 
P M L : foll o w a n y cases of s us pecte d P M L as per t he al g orit h m i n A p pe n di x 4 .  
C o nfir me d P M L  is t o be re p orte d as a n S A E.
 
H B V reacti vati o n (see Secti o n 6. 3. 1 0. 2 ).
 
Se vere m uc oc uta ne o us reacti o ns (e g, t o xic epi der mal necr ol ys is a n d 
St e ve ns-J o h ns o n s yn dr o me) .

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 
C y t o pe nias.
 
Car di o vasc ular e ve nts (see Secti o n 6. 3. 4 ).
All i nfecti o ns a n d seri o us p osti njecti o n s yste mic reacti o ns s h o ul d be m o nit ore d cl osely 
t hr o u g h o ut t he st u dy a n d rec or de d o n t he A E / S A E f or ms as s o o n as p ossi ble. A s 
a p plica ble, t he i n vesti gat or m ust als o c o m plete t he res pecti ve ‘Se vere I nfecti o ns’ or 
‘P ost injecti o n S y ste mic Reacti o n’ e C R F pa ge.
Refer t o Secti o n 4. 4. 2 a n d Secti o n 4. 4. 3 f or disc o nti n uati o n a n d wit h dra wal criteria.
6. 3. 3. 
L a b or at or y  a n d Ot h er S af et y As s e s s m e nt A b n or m aliti e s
R e p ort e d a s A E s a n d S A E s
A n y  a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts ( e g, E C Gs, ra di ol o gical sca ns, vital si g ns meas ure me nts), 
i ncl u di n g t h ose t hat w orse n fr o m baseli ne, a n d felt t o be cli nicall y si g nifica nt i n t he 
me dical a n d scie ntific j u d g me nt of t he i n vesti gat or are t o be rec or de d as A Es or S A Es.
H o we ver, a n y cli nicall y s i g nifica nt safety assess me nts t hat are ass ociate d wit h t he 
u n derl y i n g disease, u nless j u d ge d b y t he i n vesti gat or t o be m ore se vere t ha n e x pecte d f or 
t he s u bject’s c o n diti o n, are n ot t o be re p orte d as A Es or S A Es.
6. 3. 4. 
C ar di o v a s c ul ar E v e nt s
I n vesti gat ors will be re q uire d t o fill o ut e ve nt s pecific data c ollecti o n t o ols f or t he 
f oll o wi n g A Es a n d S A Es:  
 
M y ocar dial i nfarcti o n/ u nsta ble a n gi na
 
C o n gesti ve heart fail ure
 
Arr h yt h mias
 
Val v ul o pat h y
 
P ul m o nar y  h yperte nsi o n
 
Cere br o vasc ular e ve nts/str o ke a n d tra nsie nt isc he mic attac k
 
Pe ri p heral arterial t hr o m b osis
 
Dee p v e n o us thr o m b osis
 
Re vasc ularizati o n
T his i nf or mati o n s h o ul d be rec or de d wit hi n 1 wee k of w he n t he A E/ S A E(s) are first 
re p orte d.
6. 3. 5. 
D e at h E v e nt s
I n a d diti o n, all deat hs, w het her or n ot t he y are c o nsi dere d S A Es, will re q uire a s pecific 
deat h data c ollecti o n t o ol t o be c o m plete d.  T he deat h data c ollecti o n t o ol i ncl u des 
q uesti o ns re gar di n g car di o vasc ular (i ncl u di n g s u d de n car diac deat h) a n d 
n o ncar di o vasc ular deat h.

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T his i nf or mati o n s h o ul d be rec or de d wit hi n 1 wee k of w he n t he dea t h is first re p orte d.
6. 3. 6. 
Pr e g n a n c y
Pre g na nc y  i nf or mati o n will be c ollecte d fr o m t he start of st u d y treat me nt t hr o u g h t he 
f oll o w-u p c o ntact.  A n y pre g na nc y  t hat occ urs d uri n g st u d y partici pati o n m ust be 
re p orte d usi n g a cli nical trial pre g na nc y f or m.  T o e ns ure s u bject safet y, eac h pre g na nc y 
m ust be re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre nce.  T he 
pre g na nc y  m ust be f oll o we d u p t o deter mi ne o utc o me (i ncl u di n g pre mat ure ter mi nati o n) 
a n d stat us of m ot her a n d c hil d.  Pre g na nc y c o m plicati o ns a n d electi ve ter mi nati o ns f or 
me dical reas o ns m ust be re p orte d as a n A E or S A E.   S p o nta ne o us a b orti o ns m ust be 
re p orte d as a n S A E.
A n y  S A E occ urri n g i n ass ociati o n wit h a pre g na nc y t hat is br o u g ht t o t he i n vesti gat or’s 
atte nti o n after t he s u bject has c o m pl ete d t he st u d y a n d is c o nsi dere d b y t he i n vesti gat or as 
p ossi bl y  relate d t o t he st u d y treat me nt m ust be pr o m ptl y  re p orte d t o N o vartis .
I n a d diti o n, t he i n vesti gat or m ust atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y fe male 
part ners of male st u d y  s u bjects w h o bec o me pre g na nt w hile t he s u bject is e nr olle d i n t he 
st u d y.  Pre g na nc y i nf or mati o n m ust be re p orte d t o N o vartis as descri be d a b o ve.
6. 3. 7. 
Ti m e P eri o d a n d Fr e q u e n c y  of D et e cti n g A E s a n d S A E s
T he i n vesti gat or or site staff is res p o nsi ble f or detecti n g, d oc u me nti n g , a n d re p orti n g 
e ve nts t hat meet t he defi niti o n of a n A E or S A E.
All A Es will be c ollecte d fr o m t he start of st u d y treat me nt t hr o u g h t he e n d of t he C ore 
St u d y  Peri o d.  S A Es a n d A Es of s pecial i nterest will c o nti n ue t o be c ollecte d d uri n g t he 
I n di vi d ualize d F oll o w-u p Peri o d .
S A Es will be c ollecte d o ver t he sa me ti me peri o d as state d a b o ve f or A Es. H o we ver, a n y 
S A Es assesse d as rel ate d t o st u d y partici pati o n (e g, st u d y treat me nt, pr ot oc ol -ma n date d 
pr oce d ures, i n vasi ve tests, or c ha n ge i n e xisti n g t hera p y) or relate d t o a N o vartis
c o nc o mita nt me dicati o n, will be rec or de d fr o m t he ti me a s u bject c o nse nts t o partici pate 
i n t he st u d y u p to a n d i ncl u di n g a n y f oll o w -u p c o ntact. All S A Es wi ll be re p orte d t o 
N o vartis wit hi n 2 4 h o urs, as i n dicate d i n Secti o n 6. 3. 9 .
6. 3. 8. 
M et h o d of D et e cti n g A E s a n d S A E s
Care m ust be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d S A Es.  O pe n -e n de d a n d 
n o nlea di n g ver bal q uesti o ni n g of t he s u bject is t he preferre d met h o d t o i n q uire a b o ut A E
occ urre nce.  A p pr o priate q uesti o ns i ncl u de t he f oll o wi n g:
 
“ H o w are y o u feeli n g?”
 
“ Ha ve y o u ha d a n y ( ot her) me dical pr o ble ms si nce yo ur last visit/c o ntact?”
 
“ Ha ve y o u ta ke n a n y ne w me dici nes, ot her t ha n t h ose pr o vi de d i n t his st u d y , si nce 
y o ur last visit/c o ntact?”

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6. 3. 9. 
Pr o m pt R e p orti n g of S eri o u s A d v er s e E v e nt s a n d Ot h er E v e nt s 
t o N o v arti s
I n vesti gat ors m ust re p ort all e ve nts meeti n g t he pr ot oc ol-defi ne d criteria f or S A Es, 
pre g na ncies , a n d li ver f u ncti o n a b n or malities t o N o vartis pr o m ptl y , as descri be d i n 
Ta ble 6- 4 , o nce t he i n vesti gat or deter mi nes t hat t he e ve nt meets t he defi niti o n.

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T a bl e 6- 4 
R e p orti n g of S eri o u s A d v er s e E v e nt s a n d Ot h er E v e nt s t o N o v arti s
I niti al R e p ort s
F oll o w -u p I nf or m ati o n o n a 
Pr e vi o u s R e p ort
T y p e of E v e nt
Ti m e 
Fr a m e
D o c u m e nt s
Ti m e 
Fr a m e
D o c u m e nt s
All S A Es 
2 4 h o urs 
“ S A E” d at a c oll ecti o n t o ol 
2 4 h o urs 
U p d at e d “ S A E” d at a 
c oll ecti o n t o ol
C ar di ov asc ul ar or 
D e at h ev e nt s: 
A d diti o n al i nf or m ati o n
1 w e ek 
“ C V ev e nts” a n d/ or “ D e at h” 
d at a c oll ecti o n t o ol(s)
1 w e ek 
U p d at e d “ C V ev e nts” 
a n d/ or “ D e at h” d at a 
c oll ecti o n t o ol(s)
Pr e g n a ncy 
2 4 h o urs 
“ Pr e g n a ncy N otific ati o n F or m” 
2 w e eks 
“ Pr e g n a ncy F oll o w-u p 
F or m”
N o n s eri o us a dv ers e 
ev e nts r el at e d t o st u dy 
tr e at m e nt
5 d ays 
(c al e n d ar)
“ A dv ers e R e acti o n” d at a 
c oll ecti o n t o ol
2 w e eks 
U p d at e d “ A dv ers e 
R e acti o n” d at a c oll ecti o n 
t o ol
A L T 3U L N a n d
bilir u bi n 2U L N ( > 3 5 % 
dir ect) ( or A L T 3U L N 
a n d I N R > 1. 5, if I N R 
m e as ur e d) a
2 4 h o urs b
“ S A E” d at a c oll ecti o n t o ol.  
“ Liv er Ev ent” D oc u m e nts 
(i e, “ Liv er Ev e nt C R F” a n d 
“ Liv er I m a gi n g” a n d/ or “ Liv er 
Bi o psy” C R Fs, if a p plic a bl e) c
2 4 h o urs 
U p d at e d “ S A E” d at a 
c oll ecti o n t o ol.  
U p d at e d “ Liv er Ev e nt” 
D oc u m e nts c
A L T 8U L N; 
A L T 3U L N wit h 
h e p atitis or r as h or 
3U L N a n d < 5 U L N 
t h at p ersists 4 w e eks
2 4 h o urs b
“ Liv er Ev e nt” D oc u m e nts c
2 4 h o urs 
U p d at e d “ Liv er Ev e nt” 
D oc u m e nts c
A L T 5U L N pl us 
bilir u bi n < 2 U L N
2 4 h o urs b “ Liv er Ev e nt” D oc u m e nts d o n ot 
n e e d c o m pl eti n g u nl ess 
el ev ati o ns p ersist f or 2 w e eks 
or s u bj ect c a n n ot b e m o nit or ed 
w e e kly f or 2 w e eks c
2 4 h o urs 
U p d at e d “ Liv er Ev e nt” 
D oc u m e nts, if a p plic a bl e c
A L T 5U L N a n d 
bilir u bi n < 2 U L N t h at 
p ersists 2 w e eks
2 4 h o urs b
“ Liv er Ev e nt” D oc u m e nts c
2 4 h o urs 
U p d at e d “ Liv er Ev e nt” 
D oc u m e nts c
A L T 3U L N a n d 
< 5x U L N a n d bilir u bi n 
< 2 U L N
2 4 h o urs b “ Liv er Ev e nt” D oc u m e nts d o n ot 
n e e d c o m pl eti n g u nl ess 
el ev ati o ns p ersist f or 4 w e eks 
or s u bj ect c a n n ot b e m o nit or e d 
w e ekly f or 4 w e eks c
2 4 h o urs 
U p d at e d “ Liv er Ev e nt” 
D oc u m e nts, if a p plic a bl e c
A b br evi ati o ns: A L T = al a ni n e a mi n otr a nsf er as e; A S T = as p a rt at e a mi n otr a nsf er as e; C R F =c as e r e p ort f or m; 
C V =c ar di ov asc ul ar; I N R =i nt er n ati o n al n or m aliz e d r ati o; S A E =s eri o us a dv ers e ev e nt; U L N = u p p er li mit of n or m al
a. 
I N R m e as ur e m e nt is n ot r e q uir e d; if m e as ur e d, t h e t hr es h ol d v al u e st at e d will n ot a p ply t o s u bj ects r ec eivi n g 
a ntic o a g ul a nts.
b. 
N ov artis m ust b e c o nt act e d at o ns et of liv er c h e mistry el ev ati o ns t o disc uss s u bj ect s af ety
c. 
Liv er Ev e nt D oc u m e nts ( i e, “ Liv er Ev e nt C R F” a n d “ Liv er I m a gi n g C R F” a n d/ or “ Liv er Bi o psy C R F,” as a p plic a bl e) 
s h o ul d b e c o m pl et e d as s o o n as p ossi bl e.
T he S P M pr o vi des directi o n re gar di n g t he rec or di n g, re p orti n g/tra ns mitti n g, a n d 
f oll o w-u p of S A Es .

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Pr o m pt n otificati o n of S A Es b y  t he i n vesti gat or t o N o vartis is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o wa r ds t he safet y of s u bjects are met.
N o vartis has a le gal res p o nsi bilit y  t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a ge ncies a b o ut t he safety of a pr o d uct u n der cli nical i n ves ti gati o n. N o vartis
will c o m pl y wit h c o u ntr y -s pecific re g ulat or y re q uire me nts relati n g t o safety re p orti n g t o 
t he re g ulat or y a ut h orit y, I RB/I E C, a n d i n vesti gat ors.
I n vesti gat or safet y re p orts are pre pare d f or s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns acc or di n g t o l ocal re g ulat or y re q uire me nts a n d N o vartis p olic y  a n d are
f or war de d t o i n vesti gat ors as necessar y.
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E(s) or ot her 
s pecific safety i nf or mati o n ( e g, s u m mar y or listi n g of S A Es) fr o m N o vartis will file it 
wit h t he I nv esti gat or’s Br oc h ure [Ofat u m u ma b/ O M B 1 5 7/ G S K 1 8 4 1 1 5 7 I nvesti gat or’s 
Br oc h ure , 2 0 1 6] a nd will n otif y  t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal 
re q uire me nts.
6. 3. 1 0. 
L a b or at or y  As s e s s m e nt s
6. 3. 1 0. 1. 
Cli ni c al L a b or at or y  D at a
All pr ot oc ol re q uire d la b orat or y  assess me nts liste d i n Ta ble 6- 5 m ust be perf or me d b y t he 
ce ntral la b orat or y ( u nless ot her wise s pecifie d).  La b orat or y assess me nts m ust be 
c o n d ucte d i n acc or da nce wit h t he  
 i n vesti gat or ma n ual a n d Pr ot oc ol Ti me a n d 
E ve n ts Sc he d ule (Ta ble 6- 1 ).  La b orat or y re q uisiti o n f or ms m ust be c o m plete d a n d 
sa m ples m ust be clearly l a bele d wit h t he s u bject n u m ber, pr ot oc ol n u m ber, site n u m ber, 
a n d visit date.  Details f or t he pre parati o n a n d s hi p me nt of sa m ples a n d refere nce ra n ges 
f or all safet y para meters will be pr o vi de d t o t he site b y  t he ce ntral la b orat or y.
If a d diti o nal la b orat or y assess me nts n ot s pecifie d i n t he pr ot oc ol are perf or me d at t he 
i nstit uti o n’s l ocal la b orat or y a n d res ult i n a c ha n ge i n s u bject ma na ge me nt or are 
c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or (e g, S A E or A E), t he e ve nt(s) m ust be 
rec or de d i n t he s u bject’s case re p ort f or m ( C R F ).  Refer t o t he  
 i n vesti gat or ma n ual 
f or a p pr o priate pr ocessi n g a n d ha n dli n g of sa m ples t o a v oi d d u plicate a n d/ or a d diti o nal 
bl o o d dra ws.

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T a bl e 6- 5 
L a b or at or y  T e sti n g
C h e mi str y
H e m at ol o g y 
Uri n al y si s
Ot h er
T ot al pr ot ei n 
Pl at el et c o u nt 
A p p e ar a nc e
H e p atitis B:
b
Al b u m i n
R B C c o u nt
S p ecific gr avity 
- H B V s urf ac e a nti g e n
A L T
H e m o gl o bi n
p H
- H B V s urf ac e a nti b o dy
A S T
H e m at ocrit
Pr ot ei n
- a nti -H Bc
Alk ali n e p h os p h at as e 
W B C c o u nt
Gl uc os e
- H B V D N A P C R
G a m m a -gl ut a myl 
tr a nsf er as e
W B C diff er e nti al 
( a ut o m at e d)
- N e utr o p hils
- Ly m p h ocyt es a
- M o n ocyt es a
- B a n ds
- E osi n o p hils a
- B as o p hils a
K et o n es
H e p atitis C a nti b o dy b
L e uk ocyt e est er as e 
(l e uk ocyt es)
I m m u n o gl o b uli ns I g G, I g A, I g Ma
T ot al bilir u bi n
P n e u m oc occ al a nti b o dy ass ay 
(Str e pt oc occ us p n e u m o ni a e
I g G a nti b o dy ass ay) a, b
Bl o o d ur e a nitr o g e n
H e m o gl o bi n ( R B Cs)
Cr e ati ni n e
Micr osc o py:
- R B C/ H P F
- W B C/ H P F
- E pit h eli al c ells
- Tric h o m o n as
- B act eri a
- Y e ast
- Cryst als
- A m m o ni u m ur at es
- M uc o us t hr e a ds
- A m or p h o us s e di m e nt
- C asts
Cr e ati ni n e cl e ar a nc e
(c alc ul at e d)
T ox oi d a nti b o dy ass ay 
( T et a n us t ox oi d I g G a nti b o dy 
ass ay) a, b
S o di u m
P ot assi u m
N ucl e at e d R B Cs
Hi g h s e nsitivity C -r e activ e 
pr ot ei n a
C hl ori d e
C D 1 9 + B -ly m p h ocyt e 
c o u nts a
C alci u m
B -ly m p h ocyt e c h e m oki n e a
Bic ar b o n at e
C D 3 a
Gl uc os e
C D 4 a
C D8
a
 
C D 4: C D 8 r ati o
a
Micr o al b u mi n 
H u m a n a nti -h u m a n a nti b o dy a
Cr e ati ni n e
Micr o al b u mi n: cr e ati ni n e 
r ati o
A b br evi ati o ns: A L T = al a ni n e a mi n otr a nsf er as e; a nti -H Bc = h e p atitis B c or e a nti b o dy; A S T = as p art at e a mi n otr a nsf er as e; 
; Bly S = B- ly m p h ocyt e sti m ul at or;
; H B V = h e p atitis B vir us; H P F = hi g h 
p o w er e d fi el d; I g =i m m u n o gl o b uli n; P C R = p oly m er as e c h ai n r e acti o n; R B C =r e d bl o o d c ell; W B C = w hit e bl o o d c ell .
a. 
T o m ai nt a i n st u dy bli n di n g, v al u es will n ot b e r e p ort e d t o i nv esti g at ors d uri n g t h e Tr e at m e nt or I n divi d u aliz e d 
F oll o w -u p P eri o ds.  Aft er t h e W e ek 6 0 visit a n d all I n divi d u aliz e d F oll o w -u p visits, t h e c e ntr al l a b or at ory ( or 
d esi g n e e) will pr ovi d e t h e l a b or at ory v alu es a n d n otify t h e i nv esti g at or w h et h er or n ot a s u bj ect n e e ds t o r e m ai n i n 
F oll o w -u p.
b. 
Scr e e ni n g a n d W e ek 6 0 / e arly wit h dr a w al o nly.
c. 
N ot e : R ef er t o t h e Ti m e a n d Ev e nts Sc h e d ul e (T a bl e 6- 1 ) a n d t h e  
 i nv esti g at or m a n u al f or s p ecific ti mi n g of 
i n divi d u al l a b or at ory ass ess m e nts.  L a b or at ory r ef er e nc e r a n g es ar e pr ovi d e d i n A p p e n dix 1 3 .
6. 3. 1 0. 2. 
H e p atiti s B S cr e e ni n g a n d M o nit ori n g
E xcl u de s u bjects w h o are H B s A g p ositi ve, re gar dless of ot her he patitis B ser ol o gies.  
If a s u bject is HB s A g ne gati ve a n d a nti-H Bc p ositi v e, perf or m H B V D N A .  Excl u de 
s u bjects w h o are H B V D N A p ositi ve.  
* I n J a p a n , if a s u bject is H Bs A g ne g ative, a nti-H Bc ( H Bc A b) ne g ative, b ut H Bs A b 
p ositive, a n H B V D N A test will be perf or me d a n d t he s u bject will be excl u de d if res ults 
are p ositive (refer t o A p pe n dix 2 ). *

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S u bjects w h o are H B s A g ne gati ve, a nti-H Bc p ositi ve , a n d H B V D N A ne gati ve ma y  be 
i ncl u de d i n t he st u d y, b ut m ust u n der g o H B V D N A P C R m o nit ori n g at a mi ni m u m of 
e ver y 1 2 wee ks d uri n g t he Treat me nt Peri o d a n d f or 6 m o nt hs after t he last d ose . C o ns ult 
wit h a p h y sicia n e x perie nce d i n t he care a n d ma na ge me nt of s u bjects wit h he patitis B t o 
ma na ge/treat s u bjects w h o are a nti -H Bc p ositi ve.  A nti viral t hera p y t o be i nitiate d if 
re q uire d.
T a bl e 6- 6 
H e p atiti s B Vir u s T e st R e s ult S c e n ari o s f or S u bj e ct Eli gi bilit y
H B s A g  
a nti -H B c 
( H Bc Ab)
H B s A b 
H B V D N A 
S u bj e ct Eli gi bilit y a n d M o nit ori n g
All s u bj e ct s:
+ / - 
+ / - 
+ / - 
p ositiv e  
Excl u d e s u bj ect if p ositiv e at scr e e ni n g; 
disc o nti n u e st u dy tr e at m e nt if p ositiv e d uri n g st u dy
p ositiv e 
+ / - 
+ / - 
+ / - 
Excl u d e s u bj ect if p ositiv e at scr e e ni n g
n e g ativ e 
p ositiv e 
+ / - 
n e g at iv e 
M ay e nr oll s u bj ect wit h p hysici a n c o ns ult a n d 
H B V D N A m o nit ori n g d uri n g st u dy
A d diti o n al f or J a p a n :
n e g ativ e 
n e g ativ e 
p ositiv e 
n e g ativ e 
M ay e nr oll s u bj ect wit h p hysici a n c o ns ult a n d 
H B V D N A m o nit ori n g d uri n g st u dy
+ / - = eit h er p ositiv e or n e g at iv e t est r es ult
A b br evi ati o ns: H Bc A b = h e p atitis B c or e a nti b o dy ; H Bs A b =h e p atitis B s urf ac e a nti b o dy ; H Bs A g =h e p atitis B s urf ac e 
a nti g e n ; H B V =h e p atitis B vir us .
If a s u bject bec o mes H B V D N A p ositi ve d uri n g t he c o urse of t he st u d y, n otif y  t he 
me dical m o nit or .  Disc o nti n ue f urt her treat me nt wit h i n vesti gati o nal pr o d uct a n d 
c o nti n ue t o f oll o w t he s u bject f or safet y as part of t he F oll o w - u p Peri o d .
E xtra visits o utsi de t h ose defi ne d i n t he pr ot oc ol ma y  be nee de d f or s u bjects w h o re q uire 
he patitis m o nit ori n g.
6. 3. 1 1. 
Ot h er S af et y  O ut c o m e s
6. 3. 1 1. 1. 
Vit al Si g n s
T he f oll o wi n g vital si g n assess me nts will be meas ure d b y t he i n vesti gat or or me dicall y 
q ualifie d desi g nee at t he visits descri be d i n Ta ble 6- 1 :
 
S itti n g s yst olic a n d diast olic bl o o d press ure after at least 5 mi n utes of rest. Use t he 
sa me ar m at eac h visit.
 
Heart rate i n t he sitti n g p ositi o n a n d at t he ti me of t he bl o o d press ure meas ure me nt.
 
T e m perat ure.  
6. 3. 1 1. 2. 
T w el v e -l e a d El e ctr o c ar di o gr am
( E C G)
T he i n vesti gat or or me dicall y - q ualifie d desi g nee will perf or m a sta n dar d 1 2 -lea d E C G as 
part of t he Scree ni n g assess me nts . The E C G s h o ul d be o btai ne d as per t he st u d y ce nter’s 
us ual practice. T he i n vesti gat or or me dicall y- q ualifie d desi g nee will e val u ate t he E C G 

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f or a ny a b n or malities t hat s h o ul d e xcl u de t he s u bject fr o m t he st u d y.   If t he Q Tc e xcee ds 
≥4 5 0 msec ( ≥4 8 0 msec f or s u bjects wit h a b u n dle bra nc h bl oc k), t he s u bject will be 
e xcl u de d fr o m partici pati o n i n t he st u d y .
Ofat u m u ma b, b y its mec ha nis m of acti o n (l ys is of C D 2 0 + B-l ym p h oc y tes), d oes n ot 
affect Q Tc; t heref ore, Q Tc is n ot r o uti nel y  m o nit ore d d uri n g t his st u d y. A re peat E C G 
will be o btai ne d at Wee k 6 0
or earl y wit h dra wal.
6. 3. 1 2. 
M e di c al D e vi c e
I n ci d e nt s
* I n J a p a n , me dic al devices t h at are a p pr ove d i n ot her c o u ntries b ut n ot a p pr ove d i n 
J a p a n will be pr ovi de d by N ov artis f or use i n t his st u dy.  Refer t o A p pe n dix 2 f or me dic al 
device i nci de nt defi niti o ns a n d det ails o n d oc u me nti n g, re p orti n g, a n d f oll o w -u p of 
device i nci de nts. *

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6. 5. 
P h ar m a c o ki n eti c s
T he f oll o wi n g p har mac o ki netic e n d p oi nts will be e val uate d , as data per mit:
 
Plas ma (tr o u g h) c o nce ntrati o ns of ofat u m u ma b
 
E x p os ure -res p o nse relati o ns hi p
F or s u bjects i n t he p h ar m ac oki netic -p h ar m ac o dy n a mic s u bst u dy : phar mac o ki netic 
en d p oi nts will i ncl u de m o del-base d esti mati o n of t he f oll o wi n g , as data per mit:
 
Ma xi m u m ofat u m u ma b c o nce ntrati o n ( C
ma x )
 
Ti me of ma xi m u m c o nce ntrati o n ( T ma x )
 
Area u n der t he ti me -c o nce ntrati o n c ur ve ( A U C)
Data per mitti n g, t here will a ls o be a n e xa mi nati o n of t he effect of de m o gra p hic fact ors, 
i ncl u di n g baseli ne c o variates, o n t he p har mac o ki netic e n d p oi nts.
Plas ma a nal y sis will be perf or me d u n der t he c o ntr ol of N o vartis . The details of sa m ple 
c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p pi n g are i ncl u de d i n t he  
 i n vesti gat or 
ma n ual .  C o nce ntrati o ns of ofat u m u ma b will be deter mi ne d i n plas ma sa m ples usi n g t he 
c urre ntl y a p pr o ve d bi oa nal ytical met h o d ol o g y.  Ra w data will be arc hi ve d at t he 
bi oa nal y tical site, as per N o vartis pr ot oc ol .
O nc e t he plas ma has bee n a nal yz e d f or ofat u m u ma b, a n y re mai ni n g plas ma ma y  be 
a nal yz e d f or ot her c o m p o u n d -relate d meta b olites a n d t he res ults re p orte d u n der a 
se parate N o vartis pr ot oc ol.
6. 6. 
P h ar m a c o d y n a mi c s
T he f oll o wi n g p har mac o d y na mic e n d p oi nts will be e val uat e d:
 
C ha n ge fr o m baseli ne i n B -l ym p h oc y te c o u nts i n peri p heral bl o o d.
 
Ti me t o re pleti o n of C D 1 9 + B- cells t o eit her ≥baseli ne le vel or ≥L L N, w hic he ver 
is l o wer.
 
B- cell de pleti o n a n d re -p o p ulati o n as meas ure d b y C D 1 9 peri p heral bl o o d 
B- l ym p h oc y te c o u nt via ro uti ne fl u oresce nt acti vate d cell s orti n g a nal ys is.
 
F or s u bjects i n t he p h ar m ac oki netic -p h ar m ac o dy n a mic s u bst u dy: C D 1 9 + peri p heral 
bl o o d B -l ym p h oc y te c o u nt via r o uti ne fl u oresce nt acti vate d cell s orti n g a nal y sis wit h 
s u bsets i ncl u di n g, b ut n ot restricte d to, naï ve a n d me m or y  p he n ot ypes .
6. 7. 
P h ar m a c o g e n eti c s ( P G x)
I nf or mati o n re gar di n g p har mac o ge netic ( P G x) researc h is i ncl u de d i n A p pe n di x 1 . 

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7. 
D A T A  MA N A G E M E N T
F or t his st u d y  s u bject data will be e ntere d i nt o GS K -defi ne d e C R Fs, tra ns mitte d 
electr o nicall y t o N o vartis or desi g nee a n d c o m bi ne d wit h data pr o vi de d fr o m ot her 
s o urces i n a vali date d data s yste m.
M a na ge me nt of cli nical data will be perf or me d i n acc or da nce wit h a p plica ble N o vartis
sta n dar ds a n d data cleani n g pr oce d ures t o e ns ure t he i nte grit y of t he data, e g, re m o vi n g 
err ors a n d i nc o nsiste ncies i n t he data. A d verse e ve nts a n d c o nc o mita nt me dicati o ns 
ter ms will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities (Me d D R A ), 
t he W orl d Healt h Or ganizati o n Dr u g Dicti o nar y , a n d a n i nter nal vali date d me dicati o n 
dicti o nar y .  A n a p pr o priate me dical dicti o nar y  t hat c o vers all a p pr o ve d dr u gs in st u dies 
w here Ja pa n is partici pati n g will be refere nce d.  Electr o nic C R Fs (i ncl u di n g q ueries a n d 
a u dit trails) w ill be retai ne d b y N o vartis , a n d c o pies will be se nt t o t he i n vesti gat or t o 
mai ntai n as t he i n vesti gat or c o p y. I n all cases, s u bject i nitials will n ot be c ollecte d or 
tra ns mitte d t o N o vartis acc or di n g t o N o vartis p olic y .
8. 
D A T A  AN A L Y SI S A N D S T A TI S TI C A L C O N S I D E R ATI O N S
8. 1. 
H y p ot h e s e s
T he o verall n ull h y p ot hes is is t hat t here is n o differe nce i n ti me t o S R o n mi ni mal ster oi d 
t hera py b y Wee k 6 0 , a n d t here is n o differe nce i n d urati o n of re missi o n o n mi ni mal 
ster oi d t hera py bet wee n s u bjects i n t he ofat u m u ma b S C gr o u p vers us s u bjects i n t he 
place b o gr o u p . T he alter nati ve h y p ot hesis is t hat ofat u m u ma b S C is s u peri or t o place b o 
i n at least o ne of t he c o-pri mar y  e n d p oi nts.
8. 2. 
St u d y D e si g n C o n s i d er ati o n s
8. 2. 1. 
S a m pl e Si z e A s s u m pti o n s
Ass u mi n g t hat t he pr o p orti o n of s u bjects ac hie v i n g S R o n mi ni mal ster oi d t hera p y stat us 
is 5 4 % a n d 8 0 % i n t he place b o a n d t he ofat u m u ma b S C gr o u ps , res pecti vel y
[Beissert , 2 0 1 0], wit h pr o p orti o nal hazar ds acr oss t he vario us strata, a sa m ple size of 
6 8 s u bjects p er gr o u p will gi ve ≥9 0 % p o wer f or a statisticall y  si g nifica nt differe nce 
bet wee n t he t w o gr o u ps i n ti me t o S R o n mi ni mal ster oi d t hera py, usi n g a t w o -si de d 0. 0 5 
le vel of si g nifica nce. N ote t hat f or t he p ur p ose of sa m ple size calc ulati o n of ti me t o S R , 
“s ur vi val” mea ns: “N o t i n S R”, a n d he nce ( 1 0 0-5 4 =) 4 6 %, a n d ( 1 0 0 -8 0 =) 2 0 % are t he 
s ur vi val rates f or t he place b o a n d ofat u m u ma b S C treat me nt gr o u ps res pecti vel y nee de d 
t o calc ulate sa m ple size f or t he l o g-ra n k test. T he st u d y  is desi g ne d to detect a hazar d 
rati o of 0. 4 82 4 8 ( me dia n ti me t o res p o nse o n ofat u m u ma b S C / me dia n ti me t o res p o nse 
o n place b o) . It is ass u me d t hat n o m ore t ha n 1 3 % of t he s u bjects i n b oth gr o u ps will be 
l ost t o f oll o w-u p bef ore t heir Wee k 6 0
visit. Wit h t he pr ojecte d 5 4 % a n d 8 0 % S R rates 
i n t he place b o an d acti ve gr o u ps res pecti ve l y, a t otal of a p pr o xi matel y 8 0 s u bjects wit h 
S R i n b ot h treat me nt gr o u ps c o m bi ne d are nee de d at t he e n d of t he st u dy. Beca use t his 
st u d y has 2 c o -pri mar y efficac y e n d p oi nts, a n e val uati o n of t he o verall p o wer t o detect at 
least o ne si g nifica nt e n d p oi nt was ma de usi n g si m ulati o ns. T he a nal ys is pr o p ose d f or t he 

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c o-pri mar y  e n d p oi nts is a se q ue ntial test base d o n t he met h o d of Al os h a n d H u q ue [ Al os h ,
2 0 1 0]. Res ults of t he si m ulati o ns are dis pl a ye d i n Ta ble 8- 2 .
8. 2. 2. 
S a m pl e Si z e S e n siti vit y
T he sa m ple size pr ojecte d f or t his st u d y  is base d o n t he ass u m pti o n of 5 4 % a n d 8 0 % S R
rates i n t he place b o a n d ofat u m u ma b S C treat me nt gr o u ps res pecti vel y. F or a l o g ra n k
test, t he pr ojecte d hazar d rati o is 0. 4 8 2 4 8 ( ofat u m u ma b S C / place b o) a n d t he pr ojecte d 
n u m ber of s u bjects wit h S R o n mi ni mal ster oi d t hera p y is 8 0. If t he hazar d rati o is 
i n dee d 0. 4 8 2 4 8 , b ut t he res p o nse rates i n b ot h gr o u ps are l o wer, t he n m ore s u bjects will 
nee d t o be e nr olle d i n or der t o ha ve at least 8 0 s u bjects wit h S R at t he e n d of t he st u d y. 
Ta ble 8- 1 s h o ws t he se nsiti vit y of t he sa m ple size t o t he res p o nse rates i n eac h treat me nt 
ar m, ass u mi n g a hazar d rat i o of 0. 4 8 2 4 8.
T a bl e 8- 1 
S a m pl e Si z e S e n siti vit y
Pl a c e b o 
R e s p o n s e R at e
Of at u m u m a b S C
R e s p o n s e R at e
T ot al S a m pl e Siz e N e e d e d f or At L e a st 
8 0 R e s p o n s e s
( A s s u mi n g a 1 3 % Dr o p o ut R at e)
0. 4 2
0. 6 8
1 6 6
0. 4 4
0. 7 0
1 6 0
0. 4 6
0. 7 2
1 5 4
0. 4 8
0. 7 4
1 4 8
0. 5 0
0. 7 6
1 4 4
0. 5 2
0. 7 8
1 4 0
0. 5 4 a
0. 8 0
1 3 6
a. 
Pr oj ect e d f or t h e st u dy .
T he pri mar y  a nalys is is base d o n a se q ue ntial test of t he 2 c o-pri mar y  e n d p oi nts: ti me t o 
S R o n mi ni mal ster oi d t hera p y, a n d d urat i o n of re missi o n, usi n g t he met h o d of Al os h a n d 
H u q ue [Al os h , 2 0 1 0], descri be d i n detail i n S ecti o n 8. 3. 6. 5 . I n t his met h o d, a se q ue ntial 
testi n g of t he c o- pri mar y e n d p oi nts is ma de usi n g critical p oi nts t hat pr o vi de c o nsiste nc y 
res ults f or t he 2 c o -pri mar y  e n d p oi nts. T w o para meters were c o nsi dere d i n t he 
si m ulati o n: ti me t o S R o n mi ni mal ster oi d t hera p y , a n d d urati o n of re missi o n o n mi ni mal 
ster oi d t hera py.  Si m ulati o ns were ma de usi n g a n e x p o ne ntial ti me t o e ve nt (ti me t o 
re missi o n, a n d ti me t o flare), a n d usi n g t he pr ot oc ol defi niti o ns of S R a n d d urati o n of 
re missi o n. T he ra n ges of val ues f or t hese para meters were selecte d t o pr o vi de 
a p pr o xi matel y 5 4 % a n d 8 0 % re missi o n rates i n t he placeb o a n d acti ve gr o u ps 
res pecti vely, ass u me d f or t his st u d y .

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T a bl e 8- 2 
O v er all P o w er f or t h e C o- pri m ar y  En d p oi nt s
P a r a m et er
Pl a c e b o 
Of at u m u m a b S C 
O v er all P o w er
Ti m e t o r e missi o n ( w e eks)
D ur ati o n of r e missio n ( w e eks)
2 8
8
1 6
1 7
95 %
Ti m e t o r e missi o n ( w e eks)
D ur ati o n of r e missi o n ( w e eks)
3 2
9
1 6
1 7
90 %
Ti m e t o r e missi o n ( w e eks)
D ur ati o n of r e missi o n ( w e eks)
4 4
1 0
2 0
1 9
93 %
A b br evi ati o n: S C =s u bc ut a n e o us.
N ot e: B as e d o n si m ul ati o n of 1 0 0 tri als wit h 5 9 s u bj ects p er gr o u p.
8. 2. 3. 
Bli n d e d S a m pl e Si z e R e -e sti m ati o n
T he p o wer of 9 0 % f or t his st u d y ass u mes t hat 8 0 s u bjects will ha ve S R o n mi ni mal 
ster oi d t hera py b y t he e n d of t he st u d y. T his n u m ber will be m o nit ore d i n a bli n de d wa y , 
a n d if necessar y, m ore t ha n 1 3 6 s u bjects will be ra n d o m ize d t o e ns ure t hat at least 
8 0 s u bjects will ha ve S R o n mi ni mal ster oi d t hera p y  at t he e n d of t he st u d y. Beca use t he 
sa m ple size re-esti mati o n is d o ne i n a bli n de d ma n ner, base d o n t he t otal n u m ber of S R s, 
n o pe nalt y  f or ty pe -1 err or i nfl ati o n is warra nte d . T he re p orti n g a n d anal ys is p la n ( R A P) 
will s pecif y  t he met h o d of m o nit ori n g a n d a dj ust me nt t o t he sa m ple size.
8. 3. 
D at a A n al y si s C o n si d er ati o n s
A d diti o nal details of data a nal ys es will be s pecifie d i n t he R A P.
8. 3. 1. 
A n al y si s P o p ul ati o n s
T he I nte nt -t o-Treat (I T T) p o p ulati o n will c o nsist of all s u bjects ra n d o mize d t o treat me nt .  
T his will be t he pri mar y  p o p ulati o n use d f or t he efficac y a nalys es. T he Per Pr ot oc ol ( P P) 
p o p ulati o n will c o nsist of t h ose me m bers of t he I T T p o p ulati o n w h o ha ve n o maj or 
pr ot oc ol vi olati o ns. If t he P P p o p ulati o n c o m prises m ore t ha n 9 5 % or less t ha n 5 0 % of 
t he I T T p o p ulati o n, it will n ot be a nalyz e d. T his p o p ulati o n will be use d f or a 
c o nfir mat or y a nalys is of t he pri mar y efficac y e n d p oi nt a n d a n y k e y sec o n dar y efficac y 
e n d p oi nts. T he pri mar y  p o p ulati o n f or safety a nal yses will be t he safety p o p ulati o n 
w hic h will c o nsist of all s u bjects w h o were ra n d o mize d a n d were a d mi nistere d least 
1 d ose of i n vesti gati o nal pr o d uct. T he P har mac o ki netic P o p ulati o n will i ncl u de all
s u bjects i n t he I T T p o p ulati o n pr o vi di n g a nal yze d p har mac o ki netic sa m ples.
T he P har mac o ge netic P o p ulati o n will i ncl u de all s u bjects i n t he I T T p o p ulati o n w h o 
c o nse nte d t o pr o vi di n g a ge netics sa m ple, pr o vi de d a sa m ple, a n d di d n ot wit h dra w t heir 
c o nse nt.
8. 3. 2. 
A n al y si s D at a S et s
T he O bser ve d Case dataset ma kes n o ass u m pti o ns a b o ut missi n g data a n d will lea d t o 
missi n g assess me nts bei n g e xcl u de d fr o m t he a nal y sis. T he pri mar y  a nalys is dataset f or 
t he a nalys is of ti me t o S R o n mi ni mal ster oi d t hera p y will be t he O bser ve d Case dataset.

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S u bjects w h o disc o nti n ue fr o m t he st u d y  bef ore t he y reac h S R , or fi nis h t he st u d y 
wit h o ut a n S R will be c o nsi dere d as ce ns ore d at t heir last visit. F or t he a nal y sis of 
d urati o n of re missi o n o n mi ni mal ster oi d t hera p y , s u bjects w h o disc o nti n ue d pri or t o t he 
e n d of t he st u d y will be c o nsi dere d as n ot i n re missi o n fr o m t heir last k n o w n visit till 
Wee k 6 0 . F or t he a nal ys is of pr o p orti o n of s u bjects w h o ac hie ve re missi o n at Wee k 6 0 , 
s u bjects w h o disc o nti n ue d bef ore Wee k 6 0
will be c o nsi dere d as n ot i n re missi o n. 
8. 3. 3. 
Tr e at m e nt C o m p ari s o n s
8. 3. 3. 1. 
Pri m ar y  C o m p ari s o n s of I nt er e st
T he pri mar y  c o m paris o n of i nterest of t his st u d y is bet wee n place b o a n d ofat u m u ma b S C
o n ti me t o S R o n mi ni mal ster oi d t hera p y, a n d d urati o n of re missi o n o n mi ni mal ster oi d 
thera p y. T h es e c o m paris o n s will be ma de usi n g t he se q ue ntial m et h o d of Al os h a n d 
H u q ue [Al os h , 2 0 1 0], descri be d i n S ecti o n 8. 3. 6. 5 .
8. 3. 3. 2. 
Ot h er C o m p ari s o n s of I nt er e st
Sec o n dar y  co m paris o ns of i nterest will be ma de bet wee n place b o a n d ofat u m u ma b S C o n 
t he sec o n dar y e n d p oi nts, se q ue ntial l y i n t he or der prese nte d i n Secti o n 6. 2. 2 , o nl y  if t he 
2 c o-pri mar y  e n d p oi nts ha ve bee n fo u n d si g nific a nt.
All tests will be d o ne at t w o-si de d 
0. 0 5 le vel of si g nifica nce. T o pr otect a gai nst a n i nflati o n of t y p e -1 err or, if a n y  of t he 
c o m paris o ns are f o u n d n ot statisticall y si g nifica nt, n o s u bse q ue nt tests of si g nifica nce 
will be perf or me d o n t he seco n dar y e n d p oi nts.
C o m paris o ns of i nterest will be ma de bet wee n place b o a n d ofat u m u ma b S C o n t he ot her 
e n d p oi nts.
8. 3. 4. 
I nt eri m An al y si s
A n i nteri m a nalys is f or f utilit y will be c o n d ucte d w he n 6 0 e ve nts of S R o n mi ni mal 
ster oi d t hera py ha ve bee n o bser ve d. T he a nal ys is will be c o n d ucte d b y a n u n bli n de d 
statisticia n n ot i n v ol ve d i n t he c o n d uct of t he st u d y a n d res ults will be prese nte d t o t he 
I D M C. A c o n diti o nal p o wer a nal y sis will be c o n d ucte d base d pri maril y o n pr ojecti n g t he 
o bser ve d tre n d of t he differe nce bet wee n ofat u m u ma b a n d place b o i n ti me t o re missi o n 
o n mi ni mal ster oi d t hera p y .  If t he a nal ysis i n dicates t hat the c o n diti o nal p o wer f or a 
p ositi ve o utc o me f or ti me t o re missi o n o n mi ni mal ster oi d t hera p y ( p < 0. 0 2 5 o ne -si de d) is 
less t ha n 3 0%, t he I D M C
will c o m m u nicate t o desi g nate d Sp o ns or’s re prese ntati ves t hat 
t he st u d y is u nli kel y t o meet its pri mar y o bjecti ves.  T he S p o ns or ma y  e val uate a d diti o nal 
i nf or mati o n s uc h as p har mac o ki netics a n d p har mac o d y na mics a n d ma ke a fi nal decisi o n 
re gar di n g c o nti n uati o n of t he st u d y.
If e nr oll me nt is s u bsta ntiall y  sl o wer t ha n a ntici pate d a n d/ or t he rate of S R s is m uc h 
s maller t ha n pr ojecte d, c o nsi derati o n will be gi ve n t o perf or mi n g t he i nteri m a nal y sis f or 
f utilit y at a n earlier ti me p oi nt .  If a decisi o n is ma de t o perf or m a n earl y i nteri m a nal ys is, 
t he I D M C will be n otifie d of t his decisi o n a n d pre parati o n will be ma de f or a n 
u nsc he d ule d I D M C meeti n g.  After re vie w of t he i nteri m data, t he I D M C ma y:
 
R ec o m men d c o nti n u i n g t he st u d y as pla n ne d.

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 
Deter mi ne t hat c o nti n uati o n of t he st u d y is u nli kel y t o reac h a s uccessf ul 
c o ncl usi o n o n t he basis of t he sl o w e nr oll me nt a n d/ or l o w rate of re missi o ns a n d 
t h us rec o m me n d st o p pi n g t he st u dy earl y f or f utilit y .
T he i nteri m a nal ys is will n ot be use d t o st o p t he st u d y earl y f or a p ositi ve o utco me; 
t heref ore, n o a dj ust me nt t o t he fi nal a nalys is t yp e - 1 err or is i n dicate d.  Details of t he 
i nteri m a nal ysis will be s pecifie d i n t he I D M C c harter, as well as i n t he R A P.
8. 3. 5. 
R e p orti n g Ti m e P oi nt s
Re p orti n g of t he st u d y will occ ur at 2 ti me p oi nts:
 
S p o ns or u n bli n di n g f or a nal y ses t o s u p p ort re g ulat or y s u b missi o ns will occ ur after 
all s u bjects ha ve c o m plete d t he Wee k 6 0 visit ( pri mar y a nal ys is ti me p oi nt) or bee n 
wit h dra w n fr o m t he Treat me nt Peri o d; all data will be clea ne d a n d t he data base u p t o 
t his ti me p oi nt will be fr oze n.  
 
T he fi nal a nal ysis will occ ur after t he last s u bject’s last visit i n t he I n di vi d ualize d 
F oll o w -u p Peri o d (ie, after all s u bjects ha ve c o m plete d t he f ull st u d y  or bee n 
wit h dra w n pre mat urel y); data fr o m t he I n di vi d ualize d F oll o w -u p Peri o d will be 
re p orte d i n a n a d de n d u m t o t he cli nical st u d y re p ort.
8. 3. 6. 
K e y  El e m e nt s of An al y si s Pl a n
8. 3. 6. 1. 
Mi s si n g D at a
T he c o-pri mar y  efficac y e n d p oi nt of ti me t o S R o n mi ni mal ster oi d t hera p y will be 
a nal yz e d usi n g t he I T T O bser ve d Case dataset. S u bjects w h o disc o nti n ue fr o m t he st u d y  
bef ore t he e n d of t he st u d y, or reac h t heir last pla n ne d visit wit h o ut ac hie vi n g S R o n 
mi ni mal ster oi d t hera p y , will be ce ns ore d i n t he a nal ysis at t heir last visit. If 
disc o nti n uati o n s fr o m t he st u d y are f or reas o ns t hat are i n de pe nde nt of t his e n d p oi nt, t he n 
t his a nal ysis is n ot biase d. If disc o nti n uati o ns are f or reas o ns t hat are c orrelate d wit h t he 
e n d p oi nt, t he statistical test ma y be biase d, partic ularl y, if 1 of t he treat me nt ar ms has a 
mar ke dl y lar ger n u m ber of disc o nti n uati o ns. A n earl y disc o nti n uati o n of a s u bject bef ore 
ac hie vi n g a n e n d p oi nt ma y ha ve a n u n d ul y fa v ora ble bias t o war ds t he treat me nt ar m t hat 
has m ore disc o nti n uati o ns, si nce t he ti me- t o-e ve nt a nal ys is uses t he s h orte ne d e x p os ure 
ti me d ue t o t he disc o nti n uati o n. O ne ca n ma ke a n ass u m pti o n t hat if t he disc o nti n uati o n 
is d ue t o lac k of efficac y, or f or safety reas o ns, t hat s u bject w o ul d n ot ha ve ac hie ve d t he 
e n d p oi nt ha d t he s u bject c o nti n ue d t o t he e n d of t he st u d y. T heref ore, as a se nsiti vit y  
a nal ys is, s u bjects w h o disc o nti n ue d bef ore t he e n d of t he st u d y will be c o nsi dere d as 
ce ns ore d at t he e n d of t he st u d y rat her t ha n at t heir last visit. F or t he ot her c o-pri mar y  
e n d p oi nt, d urati o n of re missi o n o n mi ni mal ster oi d t hera p y , s u bjects w h o disc o nti n ue d 
bef ore t h e e n d of t he st u d y will be c o nsi dere d as n ot i n re missi o n fr o m t he last k n o w n 
visit till Wee k 6 0 .
F or t he sec o n dar y  e n d p oi nt of t he pr o p orti o n of s u bjects i n re missi o n o n mi ni mal ster oi d 
t hera py at Wee k 6 0 , s u bjects w h o disc o nti n ue d pri or t o Wee k 6 0
will b e c o nsi dere d as 
n ot i n re missi o n at Wee k 6 0 .

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8. 3. 6. 2. 
D eri v e d a n d Tr a n sf or m e d D at a
F or varia bles t hat re q uire t he a nal ys is of c ha n ge fr o m baseli ne, t he p ost-baseli ne 
assess me nt val ue mi n us t he baseli ne assess me nt val ue will be use d t o deri ve c ha n ge fr o m 
baseli ne .  If eit her val ue is missi n g t he n t he c ha n ge fr o m baseli ne will als o be missi n g.
F ull details o n t he deri vati o n of e n d p oi nts a n d a n y data tra nsf or mati o ns t o be perf or me d 
will be descri be d i n t he R A P .
8. 3. 6. 3. 
A s s e s s m e nt Wi n d o w s
T he R A P will defi ne details of visit sl otti n g a n d visit wi n d o ws of rele va nce t o t he 
c o n d uct of t he a nal ys is. All data c ollecte d will be liste d e ve n if it is n ot use d i n s u m mar y  
ta bles/fi g ures or statistical a nal yses.
8. 3. 6. 4. 
R a n d o mi z ati o n a n d Str atifi c ati o n
A ce ntral ra n d o mizati o n pr oce d ure will be us e d t o all ocate s u bjects t o t he t w o treat me nt 
ar ms. Beca use t he p ossi bilit y  e xists f or a s mall n u m ber of s u bjects i n ma n y sites, t he 
ra n d o mizati o n will n ot be stratifie d by site. Rat her, stratificati o n will be ma de o n disease 
d urati o n ( 1 ye ar , > 1 ye ar ), a n d baseli ne pre d nis o ne d ose ( < 6 0 m g , 6 0 m g ). 
Ra n d o mizati o n will be set u p t o mi ni mize treat me nt i m bala nces wit hi n stratificati o n 
fact ors.
8. 3. 6. 5. 
Effi c a c y  An al y s e s
Gra p hical dis pla y s a n d ta bles will prese nt a n d s u m marize all efficac y meas ures o ver t he 
c o urse of t he st u d y. Mea ns, S D s, me dia ns, ma xi m u m, mi ni m u m, a n d n u m ber of s u bjects 
will s u m marize c o nti n u o us data. Cate g orical data will be s u m marize d b y c o u nts a n d 
perce nta ges. C o nfi de nce i nter vals ( Ci s) ( 9 5 %) a n d p-val ues will be dis pla y e d w here 
a p plica ble.
Pr i m ar y E n d p oi nt A n al y se s
Baseli ne pre d nis o ne/ pre d nis ol o ne d ose a n d disease d urati o n will be use d t o stratif y  all 
pri mar y  a n d sec o n dar y a nal yses. T he pri mar y  a nal ysis f or t he c o-pri mar y  e n d p oi nts will 
use t he I T T p o p ul ati o n.
T he c o-pri mar y  efficac y e n d p oi nt of ti me t o S R o n mi ni mal ster oi d t hera p y b y Wee k 6 0
will be a nal yz e d usi n g a l o g -ra n k test stratifie d by baseli ne pre d nis o ne/ pre d nis ol o ne d ose 
a n d disease d urati o n strata. S u bjects w h o disc o nti n ue pre mat urel y ( pri or t o Wee k 6 0 ) 
will be ce ns ore d at t he ti me t he y  disc o nti n ue d. S u bjects w h o reac h Wee k 6 0
wit h o ut 
re missi o n will be ce ns ore d at t heir last visit. Calc ulati o n of ti me t o SR will be ma de fr o m 
ra n d o mizati o n date t o t he first ti me t he s u bject was i n re missi o n f or 8 c o nsec uti ve wee ks
w hile o n mi ni ma l ster oi d t hera py a n d s ustai ne d t hat re missi o n u ntil Wee k 6 0 .
T he c o -pri mar y  e n d p oi nt of d urati o n of re missi o n o n mi ni mal ster oi d t hera p y  will be 
a nal yz e d usi n g a ra n k a nal ysis of c o varia nce ( A N C O V A) [St o kes , 2 0 0 0], wit h treat me nt 
as a mai n effect, a n d baseli ne pre d nis o ne/ pre d nis ol o ne d ose a n d disease d urati o n strata as 
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a gai n ( or p ossi bl y m ore t ha n 2 e pis o des of re missi o n), t he d urati o n of re missi o n will be 
t he t otal ti me (s u m) of all peri o ds of re missi o n w hile o n mi ni mal ster oi d t hera p y  u p t o 
Wee k 6 0 . If a s u bject disc o nti n ue d t he st u d y pri or t o Wee k 6 0 , t he s u bject will be 
c o nsi dere d as n o t i n re missi o n fr o m t he last k n o w n visi t till Wee k 6 0 .
T o pr otect t he o verall t y p e -1 err or at 0. 0 5 ( o ne -si de d 0. 0 2 5), t he a nal ysis of t he 
c o-pri mar y  e n d p oi nts will f oll o w t he pr oce d ure pr o p ose d b y Al os h a n d H u q ue 
[Al os h , 2 0 1 0].  I n t his pr oce d ure, a c o nsiste nc y criteri o n is a p plie d, s o t hat t he c o-pri mar y  
e n d p oi nts ca n be dee me d si g nific a nt o nl y if o ne of t he f oll o wi n g e ve nts occ ur:
1. 
T he ti me t o S R o n mi ni mal ster oi d t hera p y is si g nifica nt at o ne- si de d 0. 0 2 .  If 
si g nifica nt, t he n d urati o n of re missi o n o n mi ni mal ster oi d t hera p y is teste d at 
o ne- si de d 0. 0 2 5.
2. 
If ti me t o SR o n mi ni mal ster oi d t hera p y has a o ne- si de d p- val ue ( P) bet wee n 0. 0 2 
a n d 0. 0 2 5, t he n d urati o n of re missi o n) o n mi ni mal ster oi d t hera p y ca n be rejecte d at 
a o ne-si de d le vel:
0. 0 2 5- ((0. 0 2 5- γ 1 )/(0. 0 2 5- 0. 0 2 )) *(P- 0. 0 2). 
If d urati o n of re missi o n is rejecte d, s o is ti me t o SR o n mi ni mal ster oi d t hera p y.
3. 
If ti me to S R o n mi ni mal ster oi d t hera p y has a o ne- si de d p- val ue ( P) bet wee n 0. 0 2 5 
a n d 0. 1 , t he n d urati o n of re missi o n o n mi ni mal ster oi d t hera p y m ust be si g nifica nt 
at a o ne- si de d le vel: 
0. 0 1 8- ((γ 1-γ 2)/(0. 1- 0. 0 2 5 )) *(P- 0. 0 2 5). 
T i me t o SR o n mi ni mal ster oi d t hera p y ca n n ot be rejecte d i n t his case .
T he val ues γ 1 a n d γ 2 are selecte d t o c o ntr ol t he o verall t y p e -1 err or. Beca use t he 
c o-pri mar y  e nd p oi nts are e x pecte d t o be c orrelate d, we use Ta ble 2 of Al os h a n d H u q ue 
[Al os h , 2 0 1 0] t o deter mi ne γ 1 a n d γ 2. As dis pla ye d i n t hat ta ble, selecti n g γ 2 = 0. 0 0 1, a n d 
γ1 = 0. 0 1 8, lea d t o a c o nser vati ve ( < 0. 0 2 5 o ne-si de d) t ype- 1 err or f or all c orrelati o ns 0. 9. 
O ur si m ulati o ns s u g gest t hat t he c orrelati o n bet wee n t he c o -pri mar y  e n d p oi nts is 
e x pecte d t o be 0. 9, he nce t he val ues selecte d f or γ 1 a n d γ 2 will lea d t o a n o verall 
o ne- si de d ty pe -1 err or < 0. 0 2 5.
T o ill ustrate t he a b o ve pr oce d ure, we c o nsi der t he f oll o wi n g h y p ot hetical o utc o mes:
1. 
P 1 = ti me t o SR o n mi ni mal ster oi d t hera p y p- val ue = 0. 0 1. P 2 = d urati o n of re missi o n
o n mi ni mal ster oi d t hera p y p- val ue = 0. 0 2 4. Si nce P 1 ≤0. 0 2, ti me t o S R is si g nifica nt. 
Si nce P 2 ≤0. 0 2 5, d urati o n of re missi o n is si g nifica nt.
O verall, we c o ncl u de t hat o fat u m u ma b S C is s u peri or t o place b o ( o n b ot h e n d p oi nts).
2. 
P 1 = 0. 0 1, P 2 = 0. 0 3. Si nce P 1 ≤0. 0 2, ti me t o S R is si g nifica nt. Si nce P 2 > 0. 0 2 5, 
d urati o n of re missi o n is n ot si g nifica nt.
O verall, we c o ncl u de t h at o fat u m u ma b S C is s u peri or t o place b o ( o n ti me t o SR) .
3. 
P 1 = 0. 0 2 3, P 2 = 0. 0 1 5. Si nce 0. 0 2 ≤P 1 ≤0. 0 2 5, we test d urati o n of re missi o n at le vel:
0. 0 2 5- ((0. 0 2 5- γ 1 )/(0. 0 2 5- 0. 0 2 )) *(P- 0. 0 2 ) = 0. 0 2 0 8 (s u bstit uti n g 0. 0 1 8 f or γ1 a n d 

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0. 0 2 3 f or P) . Si nce P 2 ≤0 . 0 2 0 8, d uratio n of re missi o n is rejecte d, a n d he nce als o 
ti me t o SR.
O verall, we c o ncl u de t hat o fat u m u ma b S C is s u peri or t o place b o ( o n b ot h e n d poi nts).
4. 
P 1 = 0. 0 6, P 2 = 0. 0 0 6. S i nce 0. 0 2 5≤P 1 ≤0. 1, we test d urati o n of re missi o n at le vel:
0. 0 1 8- ((γ 1-γ 2)/(0. 1- 0. 0 2 5 )) *(P- 0. 0 2 5 ). = 0.0 1 0 0 6 7. Si nce P 2 < 0. 0 1 0 0 6 7 , d urati o n of 
re missi o n is rejecte d, b ut n ot ti me t o S R.
O verall, we c o ncl u de t hat o fat u m u ma b S C is s u peri or t o placeb o ( o n d urati o n of 
re missi o n).
S e c o n d ar y E n d p oi nt A n al y s e s
T he sec o n dar y  e n d p oi nt of t he pr o p orti o n of s u bje cts wit h re missi o n o n mi ni mal ster oi d 
t hera py at Wee k 6 0
will be a nal yz e d usi n g a C oc hra n – Ma ntel – Hae nszel (C M H ) test 
stratifie d b y baseli ne pre d nis o ne/ pre d nis ol o ne d ose a n d disease d urati o n strata. T his 
a nal ys is will be c o n d ucte d o n t he I T T p o p ulati o n. In t his a nal y sis, s u bjects w h o 
disc o nti n ue d pri or t o Wee k 6 0
will be c o nsi dere d as n ot ha vi n g re missi o n at Wee k 6 0 .
Ot her sec o n dar y  a nalys es base d o n ti me t o e ve nt e n d p oi nts will be a nal y ze d usi n g a 
stratifie d l o g-ra n k test si milarl y t o t he pri mar y e n d p oi nt a nal yses. Sec o n dar y  e n d p oi nts 
t hat are base d o n pr o p orti o ns will be a nal yze d usi n g a stratifie d C M H test. C o nti n u o us 
data will be a nal yz e d usi n g A N C O V A wit h Treat me nt as a mai n effect a n d t he strata as 
c o variates. If a c o nti n u o us e n d p oi nt is base d o n a c ha n ge fr o m baseli ne, t he n baseli ne 
will be i ncl u de d as a n a d diti o nal c o variate. S u m mar y  statistics will als o be pr o vi de d f or 
t he pri mar y a n d ke y sec o n dar y varia bles b y st u d y ce nter.
All statistical tests will be perf or me d wit h si g nifica nce i nter prete d at t he t w o-si de d 5 % 
si g nifica nce le vel.
8. 3. 6. 6.  
P h ar m a c o ki n eti c A n al y s e s
T he ofat u m u ma b plas ma c o nce ntrati o n data will be a nal yz e d usi n g n o nli near mi xe d 
effects m o deli n g . T he effect of de m o gra p hic fact ors will be e xa mi ne d if data per mit.
8. 3. 6. 7. 
P h ar m a c o d y n a mi c A n al y s e s
P eri p heral bl o o d B -l ym p h oc y te c o u nts will be use d as a p har mac o d y na mic mar ker. 
T hese data will be ta b ulate d b y  se x at eac h ti me p oi nt wit h t he ta bles s h o wi n g N, mea n, 
S D, me dia n , a n d ra n ge. Si milar s u m maries will be pr o vi de d f or ne utr o p hil c o u nts, w hic h 
are c o nsi dere d a ne gati ve c o ntr ol.
8. 3. 6. 8. 
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 n al y s e s
T he ofat u m u ma b plas ma c o nce ntrati o n a n d peri p heral l y m p h oc y te c o u nts will be 
a nal yz e d usi n g n o nli near mi xe d effects m o deli n g a n d relate d t o st u d y  pri mar y a n d 
sec o n dar y e n d p oi nts if data per mit. T he effect of de m o gra p hic fact ors a n d baseli ne 
c o variates will be e xa mi ne d if data per mit .

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8. 3. 6. 9. 
S af et y  An al y s e s
T he a nal ys is of safety data will use t he S afet y p o p ulati o n. T hese data will n ot u n der g o 
a n y f or mal statistical a nal ysis.
A d v er s e E v e n t s
A d verse e ve nts will be c o de d usi n g t he Me d D R A a n d s u m marize d b y  sys te m or ga n class 
a n d preferre d ter m. 
S u m maries b y  treat me nt gr o u ps, of t he n u m ber a n d perce nta ge of s u bjects wit h t he 
f oll o wi n g A E s will be pr o vi de d:
 
All A Es
 
A d verse e ve nt fre q ue nc y, se verit y, a n d relati o ns hi p t o i n vesti gati o nal pr o d uct
 
Fre q ue nc y  a n d se verit y of i nfecti o ns
 
Fre q ue nc y  of S A Es
 
Perce nta ge of s u bjects wit h dra wi n g d ue t o A Es assesse d b y t he i n vesti gat ors as at 
least p ossi bl y relate d t o treat me nt
 
A d verse e ve nts lea di n g t o per ma ne nt disc o nti n uati o n of i n vesti gati o nal pr o d uct
 
A d verse e ve nts of s pecial i nterest (see Secti o n 6. 3. 2. 3 )
 
P osti njecti o n s y ste mic reacti o ns
 
I njecti o n site reacti o ns
T he hierarc hical relati o ns hi p bet wee n Me d D R A, s yste m or ga n classes, a n d preferre d 
ter ms a n d ver bati m te xt will be dis pla y e d f or rele va nt A E s.
Cli ni c al L a b or at or y E v al u ati o n s
S u m mar y  statistics will be prese nte d f or eac h la b orat or y test, a n d c ha n ge fr o m baseli ne, 
at eac h assess me nt ti me p oi nt b y  treat me nt gr o u p. La b orat or y test val ues will be fla g ge d 
t o s h o w w het her t he y are a val ue wit hi n, bel o w, or a b o ve t he n or mal ra n ge a n d if t he y are 
a val ue of p ote ntial cli nical c o ncer n. T he n u m ber a n d perce nta ge of s u bjects wit h val ues 
i n eac h of t hese cate g ories at eac h assess me nt ti me p oi nt will be s u m marize d f or eac h 
la b orat or y test. 
Vit al Si g n s
Eac h varia ble a n d c ha n ge fr o m baseli ne i n eac h varia ble will be s u m marize d at eac h 
assess me nt ti me p oi nt b y treat me nt gr o u p. I n a d diti o n, t he n u m ber a n d perce nta ge of 
s u bjects wit h vital si g n val ues wit hi n, bel o w, a n d a b o ve val ues of p ote ntial cli nical 
c o ncer n will be s u m marize d f or eac h varia ble.
8. 3. 6. 1 0. 
Cli ni c al M e a s ur e s
S u m mar y  statistics will be pr o vi de d f or all ot her efficac y a n d safety e n d p oi nts .

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9. 
S T U D Y C O N D U C T C O N SI D E R A TI O N S
9. 1. 
P o sti n g of I nf or m ati o n o n P u bli cl y  Av ail a bl e Cli ni c al Tri al 
R e gi st er s
St u d y  i nf or mati o n fr o m t his pr ot oc ol will be p oste d o n p u blicl y a vaila ble cli nical trial 
re gisters bef ore e nr oll me nt of s u bjects be gi ns.
9. 2. 
R e g ul at or y  a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e 
I nf or m e d C o n s e nt Pr o c e s s
Pri or t o i nitiati o n of a st u d y  ce nter, N o vartis will o btai n fa v ora ble o pi ni o n/a p pr o val fr o m 
t he a p pr o priate re g ulat or y a ge nc y t o c o n d uct t he st u d y i n acc or da nce wit h I nter nati o nal 
C o u ncil f or Har m o nisati o n ( I CH) G o o d Cli nical Practice ( G C P) a n d a p plica ble c o u ntr y-
s pecific re g ulat or y re q uire me nts.
T he st u d y  will be c o n d ucte d i n acc or da nce wit h all a p plica ble re g ulat or y re q uire me nts.
T he st u d y  will be c o n d ucte d i n acc or da nce wit h I C H G C P, all a p plica ble s u bject pri vac y  
re q uire me nts, a n d t he et hical pri nci ples t hat are o utli ne d i n t he D eclarati o n of Helsi n ki
2 0 0 8 , i ncl u di n g, b ut n ot li mite d t o:
 
I RB/I E C re vie w a n d fa v ora ble o pi ni o n/ a p pr o val of st u d y pr ot oc ol a n d a n y 
s u bse q ue nt a me n d me nts.
 
S u bject i nf or me d c o nse nt.
 
I n vesti gat or re p orti n g re q uire me nts.
N o vartis will pr o vi de f ull details of t he a b o ve pr oce d ures, eit her ver ball y , i n writi n g, or 
b ot h.
Writte n i nf or me d c o nse nt m ust be o btai ne d fr o m eac h s u bject pri or t o partici pati o n i n t he 
st u d y.
I n a p pr o vi n g t he cli nical pr ot oc ol, t he I E C/IR B a n d, w here re q uire d, t he a p plica ble 
re g ulat or y a ge nc y m ust als o a p pr o ve t he P G x assess me nts (ie, a p pr o val of A p pe n di x 1 ), 
u nless ot her wise i n dicate d.  W here per mitte d b y re g ulat or y  a ut h orities, a p pr o val of t he 
P G x assess me nts ca n occ ur after a p pr o val is o btai ne d f or t he rest of t he st u d y .  If s o, t he n 
t he writte n a p pr o val will clearl y i n dicate a p pr o val of t he P G x assess me nts is bei n g 
deferre d a n d t he st u d y, e xce pt f or P G x assess me nts, ca n be i nitiate d.  W he n P G x 
assess me nts are n ot a p pr o ve d, t he n t he a p pr o val f or t he rest of t he st u d y will clearl y 
i n dicate t his a n d t heref ore, P G x assess me nts will n ot be c o n d ucte d.
* I n J a p a n , refer t o A p pe n dix 2 f or c o u ntry-s pecific re g ul at ory a n d et hic al 
c o nsi der ati o ns. *
9. 3. 
Q u alit y C o ntr ol ( St u d y  M o nit ori n g)
I n acc or da nce wit h a p plica ble re g ulati o ns, G C P, a n d N o v artis pr oce d ures, N o vartis
m o nit ors will c o ntact t he site pri or t o t he start of t he st u d y  t o re vie w wit h t he site staff t he 

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pr ot oc ol, st u d y  re q uire me nts, a n d t heir res p o nsi bilities t o satisf y re g ulat or y, et hical, a n d 
N o vartis re q uire me nts. W he n re vie wi n g data c ollecti o n pr oce d ures, t he disc ussi o n will 
i ncl u de i de ntificati o n, a gree me nt, a n d d oc u me ntati o n of data ite ms f or w hic h t he C R F
will ser ve as t he s o urce d oc u me nt.
N o vartis will m o nit or t he st u d y  t o e ns ure t hat t he:
 
Data are a ut he ntic, acc urate, a n d c o m plete.
 
Safet y  a n d ri g hts of s u bjects are bei n g pr otecte d.
 
St u d y  is c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her 
st u d y a gree me nts, G C P, a n d all a p plica ble re g ulat or y re q uire me nts.
T he i n vesti gat or a n d t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) a grees t o 
all o w t he m o nit or direct access t o all rele va nt d oc u me nts .
9. 4. 
Q u alit y A s s ur a n c e
T o e ns ure c o m plia nce wit h G C P a n d all a p plica ble re g ulat or y  re q uire me nts, N o vartis
ma y  c o n d uct a q ualit y ass ura nce assess me nt a n d/ or a u dit of t he site rec or ds, a n d t he 
re g ulat or y a ge ncies ma y c o n d uct a re g ulat or y i ns pecti o n at a n y ti me d uri n g or after 
c o m pleti o n of t he st u d y. I n t he e ve nt of a n assess me nt, a u dit or i ns pecti o n, t he 
i n vesti gat or (a n d i nstit uti o n) m ust a gree t o gra nt t he a d vis or(s), a u dit or(s) a n d 
i ns pect or(s) direct access t o all rele va nt d oc u me nts a n d t o all ocate t heir ti me a n d t he ti me 
of t heir staff t o disc uss t he c o n d uct of t he st u d y, a n y  fi n di n gs/rele va nt iss ues a n d t o 
i m ple me nt a n y c orrecti ve a n d/ or pre ve ntati ve acti o ns to a d dress a n y fi n di n gs/iss ues 
i de ntifie d.
9. 5. 
St u d y a n d Sit e Cl o s ur e
T he e n d of t he st u d y will occ ur w he n t he last re mai ni n g ra n d o mize d s u bject has 
c o m plete d t he fi nal visit ( ie, date of last s u bject last visit) a n d all q ueries relati n g t o 
s u bject data ha ve bee n a ns were d.
U p o n c o m pleti o n or ter mi nati o n of t he st u d y , t he N o vartis m o nit or will c o n d uct site 
cl os ure acti vities wit h t he i n vesti gat or or site staff (as a p pr o priate), i n acc or da nce wit h 
a p plica ble re g ulati o ns, G C P, a n d N o vartis Sta n dar d O perati n g Pr oce d ures.
N o vartis reser ves t he ri g ht t o te m p oraril y s us pe n d or ter mi nate t he st u d y at a n y ti me f or 
reas o ns i ncl u di n g ( b ut n ot li mite d t o) safet y iss ues, et hical iss ues, or se vere 
n o nc o m plia nce . If N o vartis deter mi nes t hat s uc h acti o n is re q uire d, N o vartis wi ll disc uss 
t he reas o ns f or ta ki n g s uc h acti o n wit h t he i n vesti gat or or hea d of t he me dical i nstit uti o n 
( w here a p plica ble). W he n feasi ble, N o vartis will pr o vi de a d va nce n otice t o t he 
i n vesti gat or or hea d of t he me dical i nstit uti o n of t he i m pe n di n g acti o n.
If a st u d y is s us pe n de d or ter mi nate d f or s afet y re as o ns, N o vartis will pr o m ptl y  i nf or m 
all i n vesti gat ors, hea ds of t he me dical i nstit uti o ns ( w here a p plica ble),a n d/ or i nstit uti o ns 
c o n d ucti n g t he st u d y. N o vartis will als o pr o m ptl y  i nf or m t he rele va nt re g ulat or y 
a ut h orities of t he s us pe nsi o n/ter mi nati o n al o n g wit h t he reas o ns f or s uc h acti o n . W here 

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re q uire d by a p plica ble re g ulati o ns, t he i n vesti gat or or hea d of t he me dical i nstit uti o n 
m ust i nf or m t he I R B/I E C pr o m ptl y  a n d pr o vi de t he reas o n(s) f or t he 
s us pe nsi o n/ter mi nati o n.
9. 6. 
R e c or d s R et e nti o n
F oll o wi n g cl os ure of t he st u d y , t he i n vesti gat or or hea d of t he me dical i nstit uti o n ( w here 
a p plica ble) m ust mai ntai n all site st u d y rec or ds (e xce pt f or t h ose re q uire d b y  l ocal 
re g ulati o ns t o be mai ntai ne d else w here) i n a safe a n d sec ure l ocati o n. T he rec or ds m ust 
be easil y accessi ble w he n nee de d ( e g, f or a N o vartis a u dit or re g ulat or y i ns pecti o n) a n d 
m ust be a vaila ble f or re vie w i n c o nj u ncti o n wit h assess me nt of t he facilit y , s u p p orti n g 
s yste ms, a n d rele va nt site staff.
W here per mitte d b y l ocal la ws/re g ulati o ns or i nstit uti o nal p olic y, s o me or all of t he 
rec or ds ma y be mai ntai ne d i n a f or mat ot her t ha n har d c o p y (e g, micr ofic he, sca n ne d, 
electr o nic); h o we ver, ca uti o n m ust be e xercise d bef ore s uc h acti o n is ta ke n . T he 
i n vesti gat or m ust e ns ure t hat all re pr o d ucti o ns are le gi ble a n d are a tr ue a n d acc urate 
c o p y of t he ori gi nal. I n a d diti o n, t he y m ust meet accessi bilit y a n d retrie val sta n dar ds, 
i ncl u di n g re ge nerati o n of a har d c o py, if re q uire d . T he i n vesti gat or m ust als o ens ure t hat 
a n acce pta ble bac k -u p of t he re pr o d ucti o ns e xists a n d t hat t here is a n acce pta ble q ualit y  
c o ntr ol pr oce d ure i n place f or creati n g t he re pr o d ucti o ns.
N o vartis will i nf or m t he i n vesti gat or of t he ti me peri o d f or retai ni n g t he site rec or ds i n 
or der t o c o m ply wit h all a p plica ble re g ulat or y  re q uire me nts.
T he mi ni m u m rete nti o n 
ti me will meet t he strictest sta n dar d a p plica ble t o a partic ular site, as dictate d b y l ocal 
la ws/re g ulati o ns, N o vartis sta n dar d o perati n g pr oce d ures, a n d/ or i nstit uti o nal 
re q uire me nts.
T he i n vesti gat or m ust n otif y  N o vartis of a n y c ha n ges i n t he arc hi val arra n ge me nts, 
i ncl u di n g, b ut n ot li mite d t o arc hi val of rec or ds at a n off-site facilit y or tra nsfer of 
o w ners hi p of t he rec or ds i n t he e ve nt t hat t he i n vesti gat or is n o l o n ger ass ociate d wit h t he 
site.
9. 7. 
Pr o vi si o n of St u d y  R e s ult s t o I n v e sti g at or s, P o sti n g of 
I nf or m ati o n o n P u bli cl y Av ail a bl e Cli ni c al Tri al s R e gi st er s 
a n d P u bli c ati o n
W here re q uire d b y a p plica ble re g ulat or y  re q uire me nts, a n i n vesti gat or si g nat or y will be 
i de ntifie d f or t he a p pr o val of t he cli nical st u d y re p ort. T he i n vesti gat or will be pr o vi de d 
reas o na ble access t o statistical ta bles, fi g ures, a n d rele va nt re p orts a n d will ha ve t he 
o p p ort u nit y  t o re vie w t he c o m plete st u d y res ults at a N o vartis site or ot her m ut uall y-
agreea ble l ocati o n.
N o vartis will als o pr o vi de t he i n vesti gat or wit h t he f ull s u m mar y  of t he st u d y res ults. 
T he i n vesti gat or is e nc o ura ge d t o s hare t he s u m mar y  res ults wit h t he st u d y s u bjects, as 
a p pr o priate.   N o vartis will pr o vi de t he i n vesti gat or wit h t h e ra n d o mizati o n c o des f or t heir 
site o nl y  after c o m pleti o n of t he f ull statistical a nal ysis.
T he res ults s u m mar y  will be p oste d t o t he Cli nical St u d y Re gister n o later t ha n 8 m o nt hs 
after t he fi nal pri mar y c o m pleti o n date, t he date t hat t he fi nal s u bject was e xa mi ne d or 

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recei ve d a n i nter ve nti o n f or t he p ur p oses of fi nal c ollecti o n of data f or t he pri mar y 
o utc o me.  I n a d diti o n, a ma n uscri pt will be s u b mitte d t o a peer re vie we d j o ur nal f or 
p u blicati o n n o later t ha n 1 8 m o nt hs after t he last s u bject’s last visi t.  W he n ma n uscri pt 
p u blicati o n i n a peer re vie we d j o ur nal is n ot feasi ble, a state me nt will be a d de d t o t he 
re gister t o e x plai n t he reas o n f or n ot p u blis hi n g.
9. 8. 
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e (I D M C)
A n I D M C will be utilize d i n t his st u d y  t o e ns ure e xter nal o bjecti ve me dical a n d/ or 
statistical re vie w of safet y a n d efficac y iss ues i n or der t o pr otect t he et hical a n d safety 
i nterests of s u bjects a n d t o pr otect t he scie ntific vali dit y of t he st u d y.  T he sc he d ule of 
a n y pla n ne d i nteri m a nal ys es a n d t he a nal ysis pla n f or I D M C re vie w is descri be d i n t he 
c harter, w hic h is a vaila ble u p o n re q uest.
9. 9. 
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) 
A d j u di c ati o n
A n y  case of s us pecte d or c o nfir me d P M L will g o t hr o u g h i n de pe n de nt P M L a dj u dicati o n 
a n d a n o pi ni o n will b e pr o vi de d t o t he S p o ns or.

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1 0. 
R E F E R E N C E S
A h me d A R, S pi gel ma n Z, Ca vaci ni L A, P os ner M R. Treat me nt of pe m p hi g us v ul garis 
wit h rit u xi ma b a n d i ntra ve n o us i m m u ne gl o b uli n. N E n gl J Me d. 2 0 0 6; 3 5 5: 1 7 7 2 - 1 7 7 9.
Al os h M, H u q ue M F.  A c o nsiste nc y -a dj uste d al p ha -a da pti ve strate g y f or se q ue ntial 
testi n g. Statist Me d. 2 0 1 0; 2 9: 1 5 5 9 - 1 5 7 1.
A ma gai M, Is hii K, Has hi m ot o T, Ga m o u S, S hi miz u N, Nis hi ka wa T.
C o nf or mati o nal 
e pit o pes of pe m p hi g us a nti ge ns ( Ds g 1 a n d Ds g 3) are calci u m de pe n de nt a n d 
gl yc os yl ati o n i n de pe n de nt.  J I nve st Der mat ol . 1 9 9 5; 1 0 5( 2): 2 4 3- 2 4 7.
Beissert S, Mi m o u ni D, Ka n war AJ, S ol o m o ns N, Kalia V, A n halt GJ. Treati n g 
pe m p hi g us v ul garis wit h pre d nis o ne a n d m yc o p he n olate m ofetil: a m ultice nter, 
ra n d o mize d, place b o-c o ntr olle d trial.  J In ves t Der mat ol. 2 0 1 0; 1 3 0( 8): 2 0 4 1- 2 0 4 8.
Cars o n PJ, Ha mee d A, A h me d A R. I nfl ue nce of treat me nt o n t he cli nical c o urse 
of pe m p hi g us v ul garis.  J A m Aca d Der mat ol 1 9 9 6; 3 4: 6 4 5 - 6 5 2.
Cia nc hi ni G, C or o na R, Frezz oli ni A, R uffelli M, Di d o na B, P u d d u P. Treat me nt of 
se vere pe m p hi g us wit h rit u xi ma b: re p ort of 1 2 cases a n d a re vie w of t he literat ure.  
Arc h Der mat ol. 2 0 0 7; 1 4 3( 8): 1 0 3 3- 1 0 3 8. 
C olli o u N, Picar d D, Caill ot F, Cal b o S, C orre SJ, Li m A, et al.  L o n g -ter m re missi o ns of 
se vere pe m p hi g us after rit u xi ma b t hera p y are ass ociate d wit h pr ol o n ge d fail ure of 
des m o glei n B cell res p o nse. Sci Tra nsl Me d.  2 0 1 3; 5 ( 1 7 5): 1 7 5ra 3 0.  
D oi: 1 0. 1 1 2 6/scitra nsl me d. 3 0 0 5 1 6 6.
Cra y t h or ne E E, M ufti G, D u Vi vier A W. Rit u xi ma b use d as a first-li ne si n gle a ge nt i n t he 
treat me nt of pe m p hi g us v ul garis.  J A m Aca d Der mat ol. 2 0 1 1; 6 5( 5): 1 0 6 4- 1 0 6 5.
Da niel B S, Hertl M, Wert h V P, E mi n g R, M urrell D F.  Se verit y  sc ore i n de xes f or 
blisteri n g diseases.  Cli n Der mat ol.  2 0 1 2; 3 0: 1 0 8 - 1 1 3.  
E mi n g R, Na gel A, W olff- Fra n ke S, P o dsta wa E, De b us D, Hertl M. Rit u xi ma b e xerts a 
d ual effect i n pe m p hi g us v ul garis. J In vest Der mat ol. 2 0 0 8; 1 2 8( 1): 2 8 5 0 - 2 8 5 8.
Gree n ber g B M, Gra ves D, Re mi n gt o n G, Har de ma n P, Ma n n M, Kara n di kar N, et al. 
Rit u xi ma b d osi n g a n d m o nit ori n g strate gies i n ne ur o m y eliti s o ptica patie nts: creati n g 
strate gies f or t hera pe utic s uccess.  M ult Scler. 2 0 1 2; 1 8( 7 ): 1 0 2 2- 1 0 26. E p u b 2 0 1 2 Ja n 1 9.
Har ma n K E, Al bert S, Blac k M M. Britis h Ass ociati o n of Der mat ol o gists. G ui deli nes f or 
t he ma na ge me nt of pe m p hi g us v ul garis.  Br J Der mat ol. 2 0 0 3; 1 4 9( 5): 9 2 6- 9 3 7.  A vaila ble 
at: htt p:// w w w . ba d. or g. u k/ P ortals/ _ Ba d/ G ui deli nes/ Cli nical % 2 0 Gui deli nes/ Pe m p hi g us %
2 0 V ul garis. p df.  Accesse d: Fe br uar y  2 0 1 3.

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Har ma n K E, See d P T, Gratia n MJ, B h o gal B S, C hallac o m be SJ, Blac k M M.  T he 
se verity of c uta ne o us a n d oral pe m p hi g us is relate d t o des m o glei n 1 a n d 3 a nti b o d y  le vels.  
Br J Der mat ol.  2 0 0 1; 1 1( 4): 7 7 5 -7 8 0.  Article first p u blis he d o nli ne: 2 0 0 2; 
D OI: 1 0. 1 0 4 6/j. 1 3 6 5 -2 1 3 3. 2 0 0 1. 0 4 1 3 2. x.
Ja mes LP, Letzi g L, Si m ps o n P M, Ca p parelli E, R o berts D W, Hi ns o n J A, Da ver n TJ, 
Lee W M. P har mac o ki netics of a ceta mi n o p he n -a d d uct i n a d ults wit h aceta mi n o p he n 
o ver d ose a n d ac ute li ver fail ure. Dr u g Meta b Dis p os. 2 0 0 9; 3 7: 1 7 7 9 - 1 7 8 4.
J ol y P, M o u q uet H, R o ujea u J C, D’I nca n M, Gil bert D, Jac q u ot S, et al. A si n gle c ycle of 
rit u xi ma b f or t he treat me nt of se vere pe m p hi g us. N E n gl J Me d. 2 0 0 7; 3 5 7( 6): 5 4 5- 5 5 2.
Kas per kie wics M, S hi ma n o vic h I , Meier M, et al.  Treat me nt of se vere pe m p hi g us wit h a 
c o m bi nati o n of i m m u n oa ds or pti o n, rit u xi ma b, p ulse d de xa met has o ne a n d 
azat hi o pri ne/ m yc o p he n olate m ofetil: a pil ot st u d y  of 2 3 patie nts.  Br J Der mat ol. 
2 0 1 2; 1 6 6: 1 5 4 - 1 6 0.
Ki m J H, Ki m Y H, Ki m M R, Ki m S C.  Cli nical efficac y  of differe nt d oses of rit u xi ma b i n 
t he treat me nt of pe m p hi g us: a retr os pecti ve st u d y of 2 7 patie nts.  Br J Der mat ol. 
2 0 1 1; 1 6 5( 3): 6 4 6 - 6 5 1. Doi: 1 0. 1 1 1 1/j. 1 3 6 5 - 2 1 3 3. 2 0 1 1.1 0 4 1 1. x.
La n ga n S M, S meet h L , H u b bar d R, Fle mi n g K M, S mit h CJ P, West J.  B ull o us 
pe m p hi g oi d a n d pe m p hi g us v ul garis — i nci de nce a n d m ortalit y i n t he U K: p o p ulati o n 
base d c o h ort st u d y.  Br Me d J.  2 0 0 8; 3 3 7:a 2 0 9.
Le Gal F, G or die n E, Aff ola bi D, Ha nsli k T, All o ui C, Dé n y  P, et al.  Q ua ntificati o n of 
he patitis delta vir u s R N A i n ser u m b y c o nse ns us real-ti me P C R i n dicates differe nt 
patter ns of vir ol o gical res p o nse t o i nterfer o n t hera p y  i n c hr o nically i nfecte d patie nts.  
Cli n Micr o bi ol. 2 0 0 5; 4 3( 5): 2 3 6 3 - 2 3 6 9.
Les he m Y A, H o da k E, Da vi d M, A n halt GJ, Mi m o u ni D.  S uccessf ul treat me nt of 
pe m p hi g us wit h bi wee kl y  1-g i nf usi o ns of rit u xi ma b: A retr os pecti ve st u d y of 4 7 patie nts.  
J A m Aca d Der mat ol. 2 0 1 3; 6 8: 4 0 4- 4 1 1.  
L u nar d o n L, Tsai KJ, Pr o pert KJ, Fett N, Sta nle y  J R, Wert h V P, et al.  A dj u va nt 
rit u xi ma b t hera py of pe m p hi g us: a si n gle -ce nter e x perie nce wit h 3 1 patie nts.  Arc h 
Der mat ol. 2 0 1 2; 1 4 8( 9): 1 0 3 1- 1 0 3 6.  D oi: 1 0. 1 0 0 1/arc h der mat ol. 2 0 1 2. 1 5 2 2.
Marti n L K, Wert h V P, Villa ne u va E V, M urrell D F.  A s ys te matic re vie w of ra n d o mize d 
c o ntr olle d trials f or pe m p hi g us v ul garis a n d pe m p hi g us f oliace us. J A m Aca d Der mat ol. 
2 0 1 1; 6 4( 5): 9 0 3 - 9 0 8.
M o u q uet H, M usette P, G o u ge o n M L, Jac q u ot S, L e mercier B, Li m A, et al. B-cell 
de pleti o n i m m u n ot hera p y i n pe m p hi g us: effects o n cell ular a n d h u m o ral i m m u ne 
res p o nses. J I nvest Der mat ol. 2 0 0 8; 1 2 8( 1 2): 2 8 5 9 - 2 8 6 9.
M urrell D F, Dic k S, A h me d A R, A ma gai M, Bar na das M A, B orra d ori L, et al. 
C o nse ns us state me nt o n defi niti o ns of disease, e n d p oi nts, a n d t hera pe utic res p o nse f or 
pe m p hi g us.  J A m Aca d Der mat ol . 2 0 0 8; 5 8( 6): 1 0 4 3- 1 0 4 6.

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Nati o nal Ca ncer I nstit ute.  C o m m o n ter mi n ol o g y  criteria f or a d verse e ve nts ( C T C A E) 
v 4. 0 3.  2 0 1 0.  A vaila ble at: htt p://e vs . nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0- 0 6-
1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df.  Accesse d: Ja n uar y  2 0 1 3.
Ofat u m u ma b/ O M B 1 5 7/ G S K 1 8 4 1 1 5 7 I n vesti gat or’s Br oc h ure (I B).  Versi o n 0 9.  
D oc u me nt n u m ber 0 9 0 0 9 5a 8 8 8 b 3f d 5 0.  1 2 A pril 2 0 1 6.
R ose n bac h M 1, M urrell D F, B y str yn J C, D ula y  S, Dic k S, Fa k harza de h S, et al. 
Relia bilit y  a n d c o n ver ge nt vali dit y of t w o o utc o me instr u me nts f or pe m p hi g us.  J I n vest 
Der mat ol. 2 0 0 9; 1 2 9( 1 0): 2 4 0 4- 2 4 1 0.
St o kes, M E, Da vis C S, K oc h G G. Cate g orical data a nal ys is usi n g t he S A S s yste m, 
Sec o n d E diti o n, Car y , N C: S A S Instit ute I nc., 2 0 0 0.

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1 1. 
A P P E N DI C E S
1 1. 1. 
A p p e n di x 1 – P h ar m a c o g e n eti c R e s e ar c h
P h ar m a c o g e n eti c s – B a c k gr o u n d
P har mac o ge netics ( P G x) is t he st u d y  of varia bilit y i n dr u g res p o nse d ue t o here ditar y 
fact ors i n p o p ulati o ns.  T here is i ncreasi n g e vi de nce t hat a n i n di vi d ual’s ge netic 
bac k gr o u n d ( i e, ge n oty pe) ma y i m pact t he p har mac o ki netics (a bs or pti o n, distri b uti o n, 
meta b olis m, a n d eli mi nati o n), p har mac o d y n a mics (re lati o ns hi p bet wee n c o nce ntrati o ns 
a n d p har mac ol o gic effects or t he ti me c o urse of p har mac ol o gic effects) a n d/ or cli nical 
o utc o me (i n ter ms of efficac y  a n d/ or safet y a n d t olera bilit y).  S o me re p orte d e xa m ples of 
P G x ass ociati o ns wit h safet y /a d verse e ve nts incl u de :
Dr u g 
Di s e a s e 
G e n e V ari a nt
O ut c o m e
A b ac avir 
HI V 
[H et h eri n gt o n ,
2 0 0 2; 
M all al , 2 0 0 2; 
M all al , 2 0 0 8]
H L A -B* 
5 7: 0 1 
( H u m a n 
L e uk ocyt e 
A nti g e n B)
C arri a g e of t h e H L A -B* 5 7 :0 1 v ari a nt h as b e e n 
s h o w n t o i ncr e as e a p ati e nt’s risk f or ex p eri e nci n g 
hy p ers e nsitivity t o a b ac avir. Pr os p ectiv e H L A -
B* 5 7 :0 1 scr e e ni n g a n d excl usi o n of H L A -B* 5 7 :0 1 
p ositiv e p ati e nts fr o m a b ac avir tr e at m e nt si g nific a ntly 
d ecr e as e d t h e i nci d e nc e of a b ac avir hy p ers e nsitivity.  
Tr e at m e nt g ui d eli n es a n d a b ac avir pr o d uct l a b eli n g 
i n t h e U nit e d St at es a n d E ur o pe n o w r ec o m m e n d 
( U S) or r e q uir e ( E U) pr os p ectiv e H L A-B* 5 7 :0 1 
scr e e ni n g pri or t o i niti ati o n of a b ac avir t o r e d uc e t h e 
i nci d e nc e of a b ac avir hy p ers e nsitivity.  H L A-B* 5 7 :0 1 
scr e e ni n g s h o ul d s u p pl e m e nt b ut m ust n ev er r e pl ac e 
cli nic al risk m a n a g e m e nt str at e gi es f or a b ac avir 
hy p ers e nsitivity.
C ar b a m az e pi n e 
S eiz ur e, Bi p ol ar 
dis or d e rs & 
A n al g esi a 
[C h u n g , 2 0 1 0; 
F err ell , 200 8]
H L A -B* 1 5 :0 2 
I n d e p e n d e nt st u di es i n dic at e d t h at p ati e nts of E ast 
Asi a n a nc estry w h o c arry H L A -B* 1 5 : 0 2 ar e at hi g h er 
risk of St ev e ns-J o h ns o n Sy n dr o m e a n d t oxic 
e pi d er m al n ecr olysis.  R e g ul at ors, i ncl u di n g t h e U S 
F D A a n d t h e T ai w a n es e T F D A, h av e u p d at e d t h e 
c ar b a m az e pi n e dr u g l a b el t o i n dic at e t h at p ati e nts 
wit h a nc estry i n g e n etic ally at risk p o p ul ati o ns s h o ul d 
b e scr e e n e d f or t h e pr es e nc e of H L A -B* 1 5 :0 2 pri or 
t o i niti ati n g tr e at m e nt wit h c ar b a m az e pi n e.
Iri n ot ec a n 
C a nc er 
[I n n oc e nti, 2 0 0 4; 
Li u , 2 0 0 8; 
Sc h ulz ,2 0 0 9]
U G T 1 A 1* 2 8 
V ari ati o ns i n t h e U G T 1 A 1 g e n e c a n i nfl u e nc e a 
p ati e nt’s a bility t o br e ak d o w n iri n ot ec a n, w hic h c a n 
l e a d t o i ncr e as e d bl o o d l ev els of t h e dr u g a n d a 
hi g h er risk of si d e eff ects. A d os e of iri n ot ec a n t h at 
is s af e f or o n e p ati e nt wit h a p artic ul ar U G T 1 A 1 g e n e 
v ari ati o n mi g ht b e t o o hi g h f or a n ot h er p ati e nt 
wit h o ut t his v ari ati o n, r aisi n g t h e risk of c ert ai n si d e -
eff ects, i ncl u d i n gn e utr o p e ni a f oll o wi n g i niti ati o n of 
iri n ot ec a n tr e at m e nt.  T h e iri n ot ec a n dr u g l a b el 
i n dic at es t h at i n divi d u als w h o h av e 2 c o pi es of t h e 
U G T 1 A 1* 2 8 v ari a nt ar e at i ncr e as e d risk of 
n e utr o p e ni a . A g e n etic bl o o d t est is av ail a bl e t h at 
c a n d et ect v ari ati o ns i n t h e g e n e.

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A ke y  c o m p o ne nt t o s uccessf ul P G x researc h is t he c ollecti o n of sa m ples d uri n g t he 
c o n d uct of cli nical st u dies.
C ollecti o n of w h ole bl o o d sa m ples, e ve n w he n n o a pri or i h y p ot hesis has bee n i de ntifie d, 
ma y  e na ble P G x a nalys is t o be c o n d ucte d if at a n y ti me it a p pears t hat t here is a p ote ntial 
u ne x pecte d or u ne x pl ai ne d variati o n i n res p o nse t o ofat u m u ma b . 
P h ar m a c o g e n eti c R e s e ar c h O bj e cti v e s
T he o bjecti ve of t he P G x researc h (if t here is a p ote ntial u ne x pecte d or u ne x plai ne d 
variati o n) is t o i n vesti gate a p ossi ble ge netic relati o ns hi p t o ha n dli n g or res p o nse t o 
ofa t u m u ma b.  If at a ny ti me it a p pears t here is p ote ntial varia bilit y i n res p o nse i n t his 
cli nical st u d y or i n a series of cli nical st u dies wit h ofat u m u ma b t hat ma y be attri b uta ble 
t o ge netic variati o ns of s u bjects, t he f oll o wi n g o bjecti ves ma y be i n vesti gated:
 
Relati o ns hi p bet wee n ge netic varia nts a n d t he p har mac o ki netics a n d/ or 
p har mac o d y n a mics of ofat u m u ma b
 
Relati o ns hi p bet wee n ge netic varia nts a n d safet y a n d/ or t olera bilit y of ofat u m u ma b 
 
Relati o ns hi p bet wee n ge netic vari a nts a n d efficac y of ofat u m u ma b
St u d y  P o p ul ati o n
A n y  s u bject w h o has gi ve n i nf or me d c o nse nt t o partici pate i n t he cli nical st u d y, has met 
all t he e ntr y criteria f or t he cli nical st u d y, a n d recei ves st u d y treat me nt ma y ta ke part i n 
t he P G x researc h. A n y s u bject w h o has recei ve d a n all o ge nei c b o ne marr o w tra ns pla nt 
m ust be e xcl u de d fr o m t he P G x researc h.
S u bject partici pati o n i n t he P G x researc h is v ol u ntar y  a n d ref usal t o partici pate will n ot 
i n dicate wit h dra wal fr o m t he cli nical st u d y.  Ref usal t o partici pate will i n v ol ve n o pe nalt y 
or l oss of be nefits t o w hic h t he s u bject w o ul d ot her wise be e ntitle d.
St u d y A s s e s s m e nt s a n d Pr o c e d ur e s
Bl o o d sa m ples ca n be ta ke n f or D N A e xtracti o n a n d use d i n P G x assess me nts.
I n a d diti o n t o a n y bl o o d sa m ples ta ke n f or t he cli nical st u d y, a w h ole bl o o d sa m ple 
( ~ 6 m L ) will be c ollecte d f or t he P G x researc h usi n g a t u be c o ntai ni n g E D T A.  It is 
rec o m me n de d t hat t he bl o o d sa m ple be ta ke n at t he first o p p ort u nit y after a s u bject has 
bee n ra n d o mize d a n d pr o vi de d i nf or me d c o nse nt f or P G x researc h, b ut ma y be ta ke n at 
an y  ti me w hile t he s u bject is partici pati n g i n t he cli nical st u d y.
T he P G x sa m ple is la bele d ( or “c o de d ”) wit h a st u d y s pecific n u m ber t hat ca n be trace d 
or li n ke d bac k t o t he s u bject b y t he i n vesti gat or or site staff. C o de d sa m ples d o n ot carr y  
pers o nal i de ntifiers (s uc h as na me or s ocial sec urit y  n u m ber). T he bl o o d sa m ple is ta ke n 
o n a si n gle occasi o n u nless a d u plicate sa m ple is re q uire d d ue t o i na bilit y  t o utilize t he 
ori gi nal sa m ple.

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T he D N A e xtracte d fr o m t he bl o o d sa m ple ma y  be s u bjecte d t o sa m ple qualit y  c o ntr ol 
a nal ys is. T his a nal ys is will i n v ol ve t he ge n oty pi n g of se veral ge netic mar kers t o c o nfir m 
t he i nte grity of i n di vi d ual sa m ples. If i nc o nsiste ncies are n ote d i n t he a nal ysis, t he n t h ose 
sa m ples ma y be destr o ye d.
T he nee d t o c o n d uct P G x a nal y sis ma y be i de ntifie d after a st u d y ( or a set of st u dies) of 
ofat u m u ma b has bee n c o m plete d a n d t he st u d y  data re vie we d.
I n s o me cases, t he sa m ples ma y n ot be st u die d (e g, if n o q uesti o ns are raise d a b o ut h o w 
pe o ple res p o n d t o ofat u m u ma b ).
N o vartis will sec urel y st ore sa m ples a n d ma y kee p t he m f or u p t o 1 5 ye ars after t he last 
s u bject c o m pletes t he st u d y; or N o vartis m a y  destr o y t he sa m ples s o o ner. N o vartis or 
t h ose w or ki n g wit h N o vartis (f or e xa m ple, ot her researc hers) will use sa m ples c ollecte d 
fr o m t he st u d y f or t he p ur p ose state d i n t his pr ot oc ol a n d i n t he i nf or me d c o nse nt f or m.
S u bjects ca n re q uest t heir sa m ple t o be destr o ye d at a n y  ti me.
S u bj e ct Wit h dr a w al fr o m St u d y
If a s u bject w h o has c o nse nte d t o partici pate i n P G x researc h a n d has ha d a sa m ple t a ke n 
f or P G x researc h wit h dra ws fr o m t he cli nical st u d y  f or a n y reas o n ot her t ha n bei n g l ost t o 
f oll o w- u p, t he n t he s u bject will be gi ve n a c h oice of 1 of t he f oll o wi n g o pti o ns 
c o ncer ni n g t he P G x sa m ple:
 
C o nti n ue t o partici pate i n t he P G x researc h wit h t he P G x sa m ple retai ne d f or 
a nal ys is 
 
Wit h dra w fr o m t he P G x researc h a n d destr o y t he P G x sa m ple
If a s u bject wit h dra ws c o nse nt fr o m t he P G x researc h or re q uests sa m ple destr ucti o n, t he 
i n vesti gat or m ust re q uest sa m ple destr ucti o n by c o m pleti n g t he a p pr o priat e 
d oc u me ntati o n wit hi n t he s pecifie d ti mefra me, a n d mai ntai n t he d oc u me ntati o n i n t he site 
st u d y rec or ds. T he i n vesti gat or s h o ul d f or war d t he P har mac o ge netic Sa m ple Destr ucti o n 
Re q uest F or m t o N o vartis as directe d o n t he f or m.  T his ca n be d o ne at a n y ti me w he n a 
s u bject wis hes t o wit h dra w fr o m t he P G x researc h or ha ve t heir sa m ple destr o ye d 
w het her d uri n g t he st u d y or d uri n g t he rete nti o n peri o d f oll o wi n g cl ose of t he mai n st u d y .
S cr e e n a n d B a s eli n e F ail ur e s
If a bl o o d sa m ple f or P G x researc h has bee n c ollecte d a n d it is deter mi ne d t hat t he 
s u bject d oes n ot meet t he e ntr y criteria f or partici pati o n i n t he cli nical st u d y, t he n t he 
i n vesti gat or s h o ul d i nstr uct t he partici pa nt t hat t heir P G x sa m ple will be destr o y e d . N o 
f or ms are re q uire d t o c o m plete t his process as it will be c o m plete d as part of t he c o nse nt 
a n d sa m ple rec o nciliati o n pr ocess.  I n t his i nsta nce a sa m ple destr ucti o n f or m will n ot be 
a vaila ble t o i ncl u de i n t he site files.

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P h ar m a c o g e n eti c s A n al y s e s
1. 
S pecific ge nes ma y  be st u die d t hat e nc o de t he dr u g tar gets, or dr u g mec ha nis m of 
acti o n pat h wa ys, dr u g meta b olizi n g e nz y mes, dr u g tra ns p orters or w hic h ma y 
u n der pi n a d verse e ve nts, disease ris k or dr u g res p o nse. T hese ca n di date ge nes ma y  
i ncl u de a c o m m o n set of A D M E (abs or pti o n, d istri b uti o n, m eta b olis m, a n d 
e xcreti o n) ge nes t hat are st u die d t o deter mi ne t he relati o ns hi p bet wee n ge ne varia nts 
or treat me nt res p o nse a n d/ or t olera nce. 
I n a d diti o n, c o nti n ui n g researc h ma y i de ntif y ot her e nz ymes, tra ns p orters, pr otei ns , or 
rece pt ors t hat ma y be i n v ol ve d in res p o nse t o ofat u m u ma b .  T he ge nes t hat ma y c o de f or 
t hese pr otei ns ma y als o be st u die d.
2. 
Ge n o me -wi de sca ns i n v ol vi n g a lar ge n u m ber of p ol y m or p hic mar kers ( e g, si n gle 
n ucle oti de p ol y m or p his ms) at defi ne d l ocati o ns i n t he ge n o me, ofte n c orrelate d wit h 
a ca n di date ge ne, ma y be st u die d t o deter mi ne t he relati o ns hi p bet wee n ge netic 
varia nts a n d treat me nt res p o nse or t olera nce. T his a p pr oac h is ofte n e m pl o y e d 
w he n a defi niti ve ca n di date ge ne(s) d oes n ot e xist a n d/ or t he p ote ntial ge netic 
effects are n ot well u n derst o o d . 
If a p plica ble a n d P G x researc h is c o n d ucte d, a p pr o priate statistical a nalys is met h o ds will 
be use d t o e val uate p har mac o ge netic data i n t he c o nte xt of t he ot her cli nical data. Res ults 
of P G x i n vesti gati o ns will be re p orte d eit her as part of t h e mai n cli nical st u d y re p ort or as 
a se parate re p ort. E n d p oi nts of i nterest fr o m all c o m paris o ns will be descri pti vel y  a n d/ or 
gra p hicall y s u m marize d as a p pr o priate t o t he data . A detaile d descri pti o n of t he a nal ys is 
t o be perf or me d will be d oc u me nte d i n t he st u d y R A P or i n a se parate p har mac o ge netics 
R A P, as a p pr o priate .  
I nf or m e d C o n s e nt
S u bjects w h o d o n ot wis h t o partici pate i n t he P G x researc h ma y  still partici pate i n t he 
cli nical st u d y.  P G x i nf or me d c o nse nt m ust be o btai ne d pri or t o a ny bl o o d bei n g ta ke n f or 
P G x researc h.
Pr o vi si o n of St u d y R e s ult s a n d C o nfi d e nti alit y  of S u bj e ct’ s P G x D at a
N o vartis m a y  s u m marize t he P G x researc h res ults i n t he cli nical st u d y re p ort, or
se paratel y, or ma y  p u blis h t he res ults i n scie ntific j o ur nals. 
N o vartis d oes n ot i nf or m t he i n vesti gat or, s u bject, or a n yo ne else ( e g, fa mil y me m bers, 
st u d y i n vesti gat ors, pri mar y care p hys icia ns, i ns urers, or e m pl oye rs) of i n di vi d ual 
ge n ot y pi n g res ults t hat are n ot k n o w n t o be rele va nt t o t he s u bject’s me dical care at t he 
ti me of t he st u d y, u nless re q uire d by la w. T his is d ue t o t he fact t hat t he i nf or mati o n 
ge nerate d fr o m P G x st u dies is ge nerall y preli mi nar y i n nat ure, a n d t heref ore t he 
si g nifica nce a n d scie ntific vali dit y of t he res ults are u n deter mi ne d.

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R ef er e n c e s
C h u n g W H, H u n g S L,  C he n Y T. Ge netic pre dis p ositi o n of life-t hreate ni n g a ntie pile ptic-
i n d uce d s ki n reacti o ns.  E x pert O pi n Dr u g Saf. 2 0 1 0; 9: 1 5- 2 1.
Ferrell P B, Mc Le o d H L.  Car ba maze pi ne, H L A -B * 1 5 0 2 a n d ris k of Ste ve ns -J o h ns o n 
s yn dr o me a n d t o xic e pi der mal necr ol ys is: U S F D A rec o m me n dati o ns.  
P har mac o ge n o mics. 2 0 0 8; 9: 1 5 4 3 - 1 5 4 6.
Het heri n gt o n S, H u g hes A R, M osteller M, S h orti n o D, Ba ker K L, S pree n W, et al. 
Ge netic variati o ns i n H L A -B re gi o n a n d h y p erse nsiti vit y reacti o ns t o a baca vir. La ncet. 
2 0 0 2; 3 5 9: 1 1 2 1 - 1 1 2 2.
I n n oce nti F, U n de via S D, I yer L, C he n P X, Das S, K oc her gi ns k y M, et al.  Ge netic 
varia nts i n t he U D P -gl uc ur o n os y ltra nsferase 1 A 1 ge ne pre dict t he ris k of se vere 
ne utr o pe nia of iri n oteca n. J Cli n O nc ol. 2 0 0 4; 2 2: 1 3 8 2 - 1 3 8 8.
Li u C Y, C he n P M, C hi o u TJ, L i u J H, Li n J K, Li n T C, et al.  U G T 1 A 1 * 2 8 p ol y m or p his m 
pre dicts iri n oteca n -i n d uce d se vere t o xicities wit h o ut affecti n g treat me nt o utc o me a n d 
s ur vi val i n patie nts wit h metastatic c ol orectal carci n o ma.  Ca ncer. 2 0 0 8; 1 1 2: 1 9 3 2 - 1 9 4 0.
Mallal S, N ola n D, Witt C, Masel G, Marti n A M, M o or e C, et al.  Ass ociati o n bet wee n 
prese nce of H L A - B * 5 7 0 1, H L A-D R 7, a n d H L A -D Q 3 a n d h y perse nsiti vit y t o HI V - 1 
re verse-tra nscri ptase i n hi bit or a baca vir.  La ncet. 2 0 0 2; 3 5 9: 7 2 7- 7 3 2.
Mallal S, P hilli ps E, Car osi G, M oli na J M, W or k ma n C, T o mazic J, et al.  H L A -B * 5 7 0 1 
scree ni n g f or hy perse nsiti vit y  t o a baca vir. N E n gl J Me d. 2 0 0 8; 3 5 8; 5 6 8-5 7 8.
Sc h ulz C, Hei ne ma n n V, Sc hal h or n A, M o os ma n n N, Z wi n gers T, B oec k S, et al. 
U G T 1 A 1 ge ne p ol y m or p his m: I m pact o n t o xicit y  a n d efficac y of iri n oteca n-base d 
re gi me ns i n metastatic c ol orectal ca ncer.  W orl d J. Gastr oe nter ol. 2 0 0 9; 1 5: 5 0 5 8- 5 0 6 6.

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1 1. 2. 
A p p e n di x 2 – C o u ntr y  S p e cifi c R e q uir e m e nt s
U nless ot her wise s pecifie d, no c o u ntr y -s pecific re q uire me nts are a p plica ble.

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1 1. 2. 1. 
A p p e n di x 2 – C o u ntr y -S p e cifi c R e q uir e m e nt s: J a p a n
T he f oll o wi n g c o u ntr y -s pecific i nf ormati o n a n d st u d y  c o n duct c o nsi derati o ns f or 
O P V 1 1 6 9 1 0 Pr ot oc ol A me n d me nt 8 are a p plica ble t o all s u bjects e nr olle d at st u d y  
ce nters i n Ja pa n.
T hese pr ot oc ol m o dificati o ns were re q ueste d d uri n g re vie w by t he Ja pa n P har mace uticals 
a n d Me dical De vices A ge nc y ( P M D A) ( n ote: a gree me nts wit h a ge nc y  were base d o n t he 
Ja pa nese la n g ua ge versi o n).  T his i nf or mati o n was pre vi o usl y  i ncl u de d i n a n ‘a d de n d u m’ 
t o Pr ot oc ol A me n d me nt 3.
Pr ot o c ol M o difi c ati o n s a n d S u p pl e m e nt ar y D et ail s
( N ot e: S e cti o n n u m b er s r ef er t o t h e c orr e s p o n di n g s e cti o n of t h e pr ot o c ol)
S e cti o n 4. 2 
I n cl u si o n Crit eri a – Crit eri o n 7 b
7. b. I n t he list of “acce pta ble met h o ds of c o ntrace pti o n, ” 
t he f oll o wi n g met h o ds are n ot a p plic a ble i n J a p a n : 
 
Oral c o ntrace pti ve s wit h pr o gest o ge n al o ne
 
I njecta ble pr o gester o ne 
 
Le v o n or gestrel i m pla nts 
 
Estr o ge nic va gi nal ri n g 
 
Perc uta ne o us c o ntrace pti ve patc hes 
 
Va gi nal s per mici dal f oa m, gel , fil m, a n d crea m
S e cti o n 4. 3  
E x cl u si o n Crit eri o n 6 ( a d d e d a d diti o n al s u b-crit eri a )
6. 
E vi de nce or hist or y  of cli nicall y si g nifica nt i nfecti o n or me dic al c o n diti o n
i ncl u di n g …
 
P ne u m oc y stis p ne u m o nia or i nterstitial p ne u m o nia ( base d o n res ults of scree ni n g
p osteri or -a nteri or c hest X-r a y, K L - 6, a n d β- D gl uc a n ).  O r der t hese tests fr o m a 
l ocal la b orat or y d uri n g scree ni n g a n d as part of a w or k -u p f or a s u bject wit h si g ns 
or s y m pt o ms of p ote ntial c o ncer n d uri n g t he st u d y .
 
Base d o n t he Ja pa nese G ui deli ne f or He patitis B, f or s u bjects w h o are H Bs A g 
ne gati ve, a nti -H Bc ( H Bc A b ) ne gati ve, b ut H Bs A b p ositi ve , a n H B V D N A test 
will be perf o r me d a n d t he s u bject will be e xcl u de d fr o m t he st u d y if res ults are 
p ositi ve.
 
If a n y of t he f oll o wi n g criteria f or T B scree ni n g are met:
 
Past me dical hist or y  f or late nt or acti ve T B bef ore scree ni n g .
 
Si g n(s) or s y m pt o m (s) s u g gesti ve of acti ve T B i n me dical hist or y  o n 
e xa mi nati o n.
 
Rece nt cl ose c o ntact wit h a patie nt wit h acti ve T B. 
 
P ositi ve i nterfer o n -ga m ma release a ssa y ( Q ua nti F E R O N-T B G ol d I n -T u be )
or t u berc uli n s ki n test wit hi n 1 m o nt h bef ore t he first d ose of st u d y  treat me nt.  

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 
C hest x -ra y, ta ke n wit hi n 3 m o nt hs bef ore first d ose of st u d y treat me nt ,
s h o ws e vi de nce i n dicati n g c urre ntl y acti ve or pre vi o us T B.
S e cti o n 4 . 4. 3 Wit h dr a w al fr o m t h e St u d y
I n Ja pa n, “ Sp o ns or re q uest (after disc ussi o n wit h t he i n vesti gat or)” will be ma de i n t he 
case of s u bjects l os t t o f oll o w-u p or w he n t he (s u b)i n vesti gat or c o nsi ders it necessar y t o 
wit h dra w t he s u bject fr o m t he st u d y .  
T he st u d y  ce nter s h o ul d ma ke 3 c o ntact atte m pts b y 2 ty pes of c orres p o n de nce 
pr oce d ures (e g, p h o ne calls, cell -p h o ne te xt messa gi n g, e -mail, certi fie d letter) bef ore 
c o nsi deri n g a s u bject l ost t o f oll o w -u p.  C orres p o n de nce m ust be d oc u me nte d.
S e cti o n 5. 3 
Pr o d u ct A c c o u nt a bilit y
I n Ja pa n, u n use d i n vesti gati o nal pr o d ucts will be c ollecte d at t he e n d of t he st u d y b y t he 
S p o ns or or S p o ns or’s c o nsi g n or .
S e cti o n 5. 6. 2 Pr o hi bit e d M e di c ati o n s a n d N o n -Dr u g T h er a pi e s
I n Ja pa n, ale mt uz u ma b ( Ca m pat h) a n d a nti-C D 4 treat me nts are n ot a p pr o ve d.  
I m m u n o gl o b uli n t hera py is pr o hi bite d as a n i m m u n os u p pressi ve a ge nt.
S e cti o n 6. 1. 
Criti c al B a s eli n e A s s e s s m e nt s
I n Ja pa n, increase d i nci de nces of p ne u m oc y stis p ne u m o nia a n d i nterstitial p ne u m o nia 
ha ve bee n n ote d i n Ja pa nese patie nts ta ki n g ot her bi ol o gic a ge nts. It is rec o m me n de d t o 
scree n f or T B b y c o n d uct i n g a me dical i nter vie w, perf or mi n g i nterfer o n- ga m ma release 
assa y or t u berc uli n s ki n test, a n d c hest x-ra y, pri or t o t he start of bi ol o gic treat me nt. 
T heref ore, t he f oll o wi n g assess me nts s h o ul d be c o n d ucte d f or s u bjects i n Ja pa n d uri n g 
t he Scree ni n g Peri o d a n d re peate d if cli nicall y- i n dicate d d uri n g st u d y partici pati o n:
 
C h est x -ra y
 
K L -6 assa y
 
β- D- gl uca n assa y
 
I nterfer o n-ga m ma release assa y  ( Q ua nti F E R O N-T B G ol d I n -T u be) or t u berc uli n 
s ki n test wit hi n 1 m o nt h bef ore t he first d ose of st u d y treat me nt .
S e cti o n 6. 3. 1 1 
M e di c al D e vi c e s I n ci d e nt s
Me dical de vices t hat are a p pr o ve d i n ot her c o u ntries b u t n ot a p pr o ve d i n Ja pa n 
( N o na p pr o ve d Me dical De vices i n Ja pa n) will be pr o vi de d by N o vartis f or use i n t his 
st u d y. 
N o na p pr o ve d Me dical De vice i n Ja pa n i nci de nts, i ncl u di n g t h ose res ulti n g fr o m 
malf u ncti o ns of t he de vice, m ust be detecte d, d oc u me nte d, a n d re p orte d by t he 
(s u b)i n vesti gat or t hr o u g h o ut t he st u d y.

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G e n er al N a m e 
M a n uf a ct ur er n a m e 
C at al o g N o./ Pr o d u ct N o.
V ac u u m b l o o d c oll ecti o n t u b e 
Str eck
Cyt o -C h ex B C T
Pr efill e d syri n g e wit h n e e dl e 
B ect o n Dicki ns o n a n d C o m p a ny 
Hy p ak -S C F
I nci de nt – A n y  malfu ncti o n or deteri orati o n i n t he c haracteristics a n d/ or perf or ma nce of 
a de vice, as well as a n y i na de q uac y i n t he la beli n g or t he i nstr ucti o ns f or use w hic h, 
directl y  or i n directly mi g ht lea d t o or mi g ht ha ve le d t o t he deat h of a patie nt, or user or 
of ot h er pers o ns or t o a seri o us deteri orati o n i n t heir state of healt h.
N ot all i nci de nts lea d t o deat h or seri o us deteri orati o n i n healt h .  The n o n -occ urre nce of 
s uc h a res ult mi g ht ha ve bee n d ue t o ot her f ort u nate circ u msta nces or t o t he i nter ve nti o n 
of healt h care pers o n nel.
I nci de nts i ncl u de t he f oll o wi n gs:
 
A n i nci de nt ass ociate d wit h a de vice ha p pe ne d a n d
 
T he i nci de nt was s uc h t hat, if it occ urre d a gai n, it mi g ht lea d t o deat h or seri o us 
deteri orati o n i n healt h
A seri o us deteri orati o n i n state of healt h ca n i ncl u de:
 
A life -t hreate ni n g ill ness (a)
 
Per ma ne nt i m pair me nt of b o d y  f u ncti o n or per ma ne nt da ma ge t o a b o dy str uct ure ( b)
 
A c o n diti o n necessitati n g me dical or s ur gical i nter ve nti o n t o pre ve nt (a) or ( b)
 
A n y  i n direct har m as a c o nse q ue nce of a n i nc orrect dia g n ostic or i n vitr o dia g n ostic
(I V D) test res ults w he n use d wit hi n t he ma n ufact urer’s i nstr ucti o ns f or use
 
Fetal distress, fetal deat h or a n y c o n ge nital a b n or malit y  or birt h defects
M alf u ncti o n
– A fail ure of a de vice t o perf or m i n acc or da nce wit h its i n te n de d p ur p ose 
w he n use d i n acc or da nce wit h t he ma n ufact urer’s i nstr ucti o ns.
Re me di al Acti o n – A n y acti o n ot her t ha n r o uti ne mai nte na nce or ser vici n g of a de vice 
w here s uc h acti o n is necessar y  t o pre ve nt rec urre nce of a re p orta ble i nci de nt (i ncl u di n g 
a n y ame n d me nt t o t he desi g n t o pre ve nt rec urre nce). 
D o c u m e nti n g M e di c al D e vi c e I n ci d e nt s
A n y  me dical de vice i nci de nt occ urri n g d uri n g t he st u d y will be d oc u me nte d i n t he 
s u bject’s me dical rec or ds, i n acc or da nce wit h t he (s u b)i n vesti gat or’s n or mal cli nical 
prac tice, a n d o n t he “ Me dical De vice I nci de nt Re p ort F or m”. I n a d diti o n, f or i nci de nts 
f ulfilli n g t he defi niti o n of a n A E or a n S A E, t he a p pr o priate A E/ S A E data c ollecti o n t o ol 
i n t he C R F will be c o m plete d as pre vi o usl y  descri be d.
T he f or m will be c o m plete d a s t h or o u g hly as p ossi ble a n d si g ne d b y t he (s u b)i n vesti gat or 
bef ore tra ns mittal t o N o vartis .  It is ver y i m p orta nt t hat t he (s u b)i n vesti gat or pr o vi des 
his/ her assess me nt of ca usalit y  t o t he me dical de vice pr o vi de d by N o vartis at t he ti me of 

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t he i nitial re port, a n d descri bes a n y c orrecti ve or re me dial acti o ns ta ke n t o pre ve nt 
rec urre nce of t he i nci de nt.
Tr a n s mi s si o n of M e di c al D e vi c e I n ci d e nt R e p ort s
I m me diate facsi mile tra ns missi o n of t he Me dical De vice I nci de nt Re p ort F or m is t he 
preferre d met h o d t o tra ns m it t his i nf or mati o n t o N o vartis .
I n t he a bse nce of facsi mile e q ui p me nt, n otificati o n b y tele p h o ne is acce pta ble f or 
i nci de nts, wit h a c o py of t he Me dical De vice I nci de nt Re p ort F or m se nt b y o ver ni g ht 
mail or deli ver y  ser vice.
I niti al R e p ort
F oll o w -u p I nf o r m ati o n o n a Pr e vi o u s R e p ort
T y p e of E v e nt 
Ti m e 
Fr a m e
D o c u m e nt s 
Ti m e 
Fr a m e
D o c u m e nt s
M e dic al d evic e 
inci d e nt
2 4 h o urs 
M e dic al D evic e 
I nci d e nt R e p ort F or m
2 4 h o urs 
U p d at e d M e dic al D evic e 
I nci d e nt R e p ort F or m
Ti m e P eri o d of D et e cti n g M e di c al D e vi c e I n ci d e nt
Me dical d e vice inci de nt s will be c ollecte d fr o m t he start of t he st u d y u ntil t he f oll o w - u p 
c o ntact. 
F oll o w -u p of M e di c al D e vi c e I n ci d e nt s
All me dical de vice i nci de nts i n v ol vi n g a n A E will be f oll o we d u ntil res ol uti o n of t he 
e ve nt, u ntil t he c o n diti o n sta bilizes, u ntil t he c o n diti o n is ot her wise e x plai ne d, or u ntil t he 
s u bject is l ost t o f oll o w- u p. T his a p plies t o all s u bjects, i ncl u di n g t h ose wit h dra w n 
pre mat urel y. T he (s u b)i n vesti gat or is res p o nsi ble f or e ns uri n g t hat f oll o w-u p i ncl u des 
a n y s u p ple mental i n vesti gati o ns as ma y  be i n dicate d t o el uci date as c o m pletel y as 
practical t he nat ure a n d/ or ca usalit y of t he i nci de nt.
Ne w or u p date d i nf or mati o n will be rec or de d o n t he ori gi nall y  c o m plete d f or m wit h all 
c ha n ges si g ne d a n d date d b y t he (s u b)i n vesti gat or.
P o st -St u d y M e di c al D e vi c e I n ci d e nt s
T he (s u b)i n vesti gat ors are n ot o bli gate d t o acti vel y see k re p orts of me dical de vice 
i nci de nts i n f or mer s u bjects.  H o we ver, if t he (s u b)i n vesti gat or lear ns of a n y i nci de nt at 
a n y ti me after a s u bject has bee n disc har ge d fr o m t he st u d y, a n d s uc h i nci de nt is 
reas o na bly relate d t o a N o vartis me dical de vice pr o vi de d f or t he st u d y, t he 
(s u b)i n vesti gat or will pr o m ptl y  n otif y N o vartis .
R e g ul at or y 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 s
T he (s u b)i n vesti gat or will pr o m ptl y re p ort all i nci de nts occ urri n g wit h a n y N o vartis
me dical de vice pr o vi de d f or use i n t he st u d y t o N o vartis . N o vartis n otifies a p pr o priate 
re g ulat or y b o dies a n d ot her e ntities a b o ut certai n safety i nf or mati o n relati n g t o me dical 
de vices bei n g use d i n cli n ical st u dies. Pr o m pt n otificati o n of i nci de nts b y t he 

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(s u b)i n vesti gat or t o N o vartis is esse ntial i n or der t o meet le gal o bli gati o ns a n d et hical 
res p o nsi bilit y t o war ds t he safety of s u bjects.
T he (s u b)i n vesti gat or or hea d of c orres p o n di n g cli nical i nstit ut e, will c o m pl y wit h t he 
a p plica ble l ocal re g ulat or y re q uire me nts relati n g t o t he re p orti n g of i nci de nts a n d near -
i nci de nts t o t he IR B/I E C.
S e cti o n 9. 2
R e g ul at or y  a n d Et hi c al C o n si d er ati o n s, I n cl u di n g t h e I nf or m e d 
C o n s e nt Pr o c e s s
R e g ul at or y a n d Et hi c al C o n s i d er ati o n s
T he st u d y  will be c o n d ucte d i n acc or da nce wit h “t he Mi nisterial Or di na nce o n t he 
Sta n dar ds f or t he C o n d uct of Cli nical Trials of Me dici nal Pr o d ucts ( M H W N otificati o n 
N o. 2 8 date d 2 7 Marc h
1 9 9 7)” a n d Article 1 4 -3 a n d 8 0 - 2 of t he P har mace utical Affairs 
La w.
T he state me nt “I ac k n o wle d ge t hat I a m res p o nsi ble f or o verall st u d y c o n d uct.” O n t he 
I n vesti gat or Pr ot oc ol A gree me nt Pa ge mea ns t he i n vesti gat or’s res p o nsi bilit y as defi ne d 
b y  Ja pa nese G C P.
N o vartis will s u b mit t he C T N t o t he re g ulat or y  a ut h orities i n acc or da nce wit h Article 
8 0- 2 of t he P har mace utical Affairs La w bef ore c o ncl usi o n of a n y c o ntract wit h st u d y  
ce nters f or t he c o n d uct of t he st u d y.
I nf or m e d C o n s e nt
Pri or t o partici pati o n i n t he st u d y , t he (s u b)i n vesti gat or s h o ul d f ull y i nf or m t he p ote ntial 
s u bject a n d/ or t he s u bject’s le gall y acce pta ble re prese ntati ve ( N ote: i n Ja pa n, t he 
descri pti o n of le gall y acce pta ble re prese ntati ve is a p plica ble w he n t he s u bject is y o u n ger 
t ha n 2 0 years ol d) a b o ut t he st u d y i ncl u di n g pr o vi di n g writte n i nf or mati on. T he 
(s u b)i n vesti gat or s h o ul d pr o vi de t he s u bject a n d/ or t he s u bject’s le gall y acce pta ble 
re prese ntati ve a m ple ti me a n d o p p ort u nit y t o i n q uire a b o ut details of t he st u d y. T he 
s u bject a n d/ or t he s u bject’s le gall y acce pta ble re prese ntati ve s h o ul d si g n a n d pers o nall y 
date t he c o nse nt f or m .  If t he s u bject wis hes t o c o nsi der t he c o nte nt of t he writte n 
i nf or mati o n at h o me, he/s he ma y si g n t he c o nse nt f or m at h o me.  The pers o n w h o 
c o n d ucte d t he i nf or me d c o nse nt disc ussi o n a n d t he st u d y  c olla b orat or gi vi n g 
s u pple me ntar y  e x pla nati o n, w here a p plica ble, s h o ul d si g n a n d pers o nall y date t he c o nse nt 
f or m.  If a n i m partial wit ness is re q uire d, t he wit ness s h o ul d si g n a n d pers o nall y date t he 
c o nse nt f or m .  The (s u b)i n vesti gat or s h o ul d retai n t his si g ne d a n d date d f or m (a n d ot her 
writte n i nf or mati o n) t o get her wit h t he s o urce me dical rec or ds, s uc h as cli nical c harts (i n 
acc or da nce wit h t he r ules f or rec or ds rete nti o n, if a n y, at eac h me dical i nstit uti o n) a n d 
gi ve a c o p y of t he f or m t o t he s u bject a n d/ or t he s u bject’s le ga ll y acce pta ble 
re prese ntati ve.

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1 1. 3. 
A p p e n di x 3 – Li v er C h e mi str y  St o p pi n g a n d F oll o w-u p 
Crit eri a
Li v er C h e mi str y St o p pi n g Crit eri a – Li v er St o p pi n g E v e nt
A L T – A b s ol ut e
A L T 8x U L N
A L T – I n cr e a s e
A L T 5x U L N b ut < 8x U L N  p ersists f or 2 w e eks
A L T 3x U L N b ut < 5x U L N  p ersists f or 4 w e eks
Bilir u bi n 1,2
A L T 3x U L N a n d bilir u bi n 2x U L N ( > 3 5 % dir ect bilir u bi n) 
I N R 2
A L T 3x U L N a n d I N R > 1. 5, if I N R m e as ur e d
C a n n ot M o nit or
A L T 5x U L N b ut < 8x U L N a n d c a n n ot b e m o nit or e d w e ekly f or 2 w e eks
A L T 3x U L N b ut < 5x U L N a n d c a n n ot b e m o nit or e d w e ekly f or 4 w e eks
S y m pt o m ati c 3
A L T 3x U L N ass oci at e d wit h sy m pt o ms ( n e w or w ors e ni n g) b eli ev e d t o b e 
r el at e d t o  liv er i nj ury or hy p ers e nsitivity
R e q uir e d A cti o n s a n d F oll o w -u p A s s e s s m e nt s f oll o wi n g A N Y Li v er St o p pi n g E v e nt
A cti o n s
F oll o w -U p A s s e s s m e nt s
 
I m m e di at ely disc o nti n u e  st u dy tr e at m e nt 
 
R e p ort t h e ev e nt t o N ov artis wit hi n 2 4 h o ur s
 
C o m pl et e t h e l iv er ev e nt C R F a n d S A E d at a 
c oll ecti o n t o ol if t h e ev e nt als o m e ets t h e crit eri a 
f or a n S A E2
 
P erf or m liv er ev e nt f oll o w -u p ass ess m e nts 
 
M o nit or t h e s u bj ect u ntil liv er c h e mistri es 
r es olv e, st a biliz e, or r et ur n t o wit hi n b as eli n e 
(s e e M o nit ori n g b el o w)
 
D o n ot r e st art s u bj ect wit h st u dy tr e at m e nt 
u nl ess all o w e d p er pr ot oc ol a n d N ov artis
M e dic al G ov er n a nc e a p pr ov al is gr a nt e d
 
If r est art isn ot  all o w e d or n ot gr a nt e d, 
p er m a n e ntly disc o nti n u e st u dy tr e at m e nt a n d 
m ay c o nti n u e s u bj ect i n t h e st u dy f or a ny 
pr ot oc ol -s p ecifi e d f oll o w-u p
 
Vir al h e p atitis s er ol o gy 4
 
O nly i n t h os e wit h u n d erlyi n g c hr o nic h e p atitis B 
at st u dy e ntry (i d e ntifi e d by p o sitiv e h e p atitis B 
s urf ac e a nti g e n) q u a ntit ativ e h e p atitis B D N A 
a n d h e p atitis d elt a a nti b o dy 5
 
Bl o o d s a m pl e f or p h ar m ac oki n etic ( P K) 
a n alysis, o bt ai n e d wit hi n 6 w e eks aft er l ast 
d os e 6
 
S er u m cr e ati n e p h os p h oki n as e ( C P K) a n d 
l act at e d e hy dr o g e n as e ( L DH)
 
Fr act i o n at e bilir u bi n, if t ot al bilir u bi n2x U L N
 
O bt ai n c o m pl et e bl o o d c o u nt wit h diff er e nti al t o 
ass ess e osi n o p hili a
 
R ec or d t h e a p p e ar a nc e or w ors e ni n g of cli nic al 
sy m pt o ms of liv er i nj ury or hy p ers e nsitivity o n 
t h e A E r e p ort f or m
 
R ec or d us e of c o nc o mit a nt m e di c ati o ns o n t h e 
c o nc o mit a nt m e dic ati o ns r e p ort f or m i ncl u di n g 
ac et a mi n o p h e n, h er b al r e m e di es, ot h er ov er t h e 
c o u nt er m e dic ati o ns
 
R ec or d alc o h ol us e o n t h e liv er ev e nt alc o h ol 
i nt ak e C R F

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M O NI T O RI N G:
F or bilir u bi n or I N R crit eri a:
 
R e p e at liv er c h e mistri es (i ncl u d e A L T, A S T, 
alk ali n e p h os p h at as e, bilir u bi n) a n d p erf or m 
liv er ev e nt f oll o w-u p ass ess m e nts wit hi n  
2 4 h o ur s
 
A s p eci alist or h e p at ol o gy c o ns ult ati o n is 
r ec o m m e n d e d 
 
M o nit or s u bj ects t wic e w e ekly u ntil liv er 
c h e mistri es r es olv e, st a biliz e, or r et ur n t o wit hi n 
b as eli n e
F or all ot h er crit eri a: 
 
R e p e at liv er c h e mistri es (i ncl u d e A L T, A S T, 
alk ali n e p h os p h at as e, bilir u bi n) a n d p erf or m 
liv er ev e nt f oll o w-u p ass ess m e nts wit hi n  
2 4 t o 7 2 h o ur s
 
M o nit or s u bj ects w e ekly u ntil liv er c h e mistri es 
r es olv e, st a bilize, or r et ur n t o wit hi n b as eli n e
F or bilir u bi n or I N R crit eri a:
 
A nti -n ucl e ar a nti b o dy, a nti -s m o ot h m uscl e 
a nti b o dy, Ty p e 1 a nti -liv er ki d n ey micr os o m al 
a nti b o di es, a n d q u a ntit ativ e t ot al 
i m m u n o gl o b uli n G (I g G or g a m m a gl o b uli ns).
 
S er u m ac et a mi n o p h e n a d d uct 
hi g h -p erf or m a nc e li q ui d c hr o m at o gr a p hy ass ay 
( q u a ntifi es p ot e nti al ac et a mi n o p h e n c o ntri b uti o n 
t o liv er i nj ury i n s u bj ects wit h d efi nit e or lik ely 
ac et a mi n o p h e n us e i n t h e pr ec e di n g w e ek 
[J a m es, 2 0 0 9]). 
N ot e: n ot r e q ui r e d i n C hi n a
 
Liv er i m a gi n g ( ultr as o u n d, m a g n etic r es o n a nc e, 
or c o m p ut eriz e d t o m o gr a p hy) a n d/ or liv er 
bi o psy t o ev al u at e liv er dis e as e; c o m pl et e Liv er 
I m a gi n g a n d/ or Liv er Bi o psy C R F f or ms.
a. 
S er u m bilir u bi n fr acti o n ati o n s h o ul d b e p erf or m e d if t esti n g is a v ail a bl e.  If s er u m bilir u bi n fr acti o n ati o n is n ot 
i m m e di at ely av ail a bl e, disc o nti n u e st u dy tr e at m e nt f or t h at s u bj ect if A L T 3x U L N a n d bilir u bi n 2x U L N .  
A d diti o n ally, if s er u m bilir u bi n fr acti o n ati o n t esti n g is u n av ail a bl e, r e c or d pr e s e n c e of d et e ct a bl e uri n ar y 
bilir u bi n o n di p sti c k , i n dic ati n g dir ect bilir u bi n el ev ati o ns a n d s u g g esti n g liv er i nj ury. 
b. 
All ev e nts of A L T 3x U L N a n d bilir u bi n 2x U L N ( > 3 5 % dir ect bilir u bi n) or A L T 3x U L N a n d I N R > 1. 5, if I N R 
m e as ur e d w hic h m ay i n dic at e s ev er e liv er i nj ury ( p ossi bl e ‘ Hy’s L a w’), m u st b e r e p ort e d a s a n S A E ; I N R 
m e as ur e m e nt is n ot r e q uir e d a n d t h e t hr es h ol d v al u e st at e d will n ot a p pl y t o s u bj ects r ec eivi n g a ntic o a g ul a nts.
c. 
N e w or w ors e ni n g sy m pt o ms b eli ev e d t o b e r el at e d t o liv er i nj ury (s uc h as f ati g u e, n a us 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 ess, or j a u n dic e) or b eli ev e d t o b e r el at e d t o hy p ers e nsitivity (s uc h as f ev er, r as h, or 
e osi n o p hili a).
d. 
I ncl u d es: H e p atitis A I g M a nti b o dy; H e p atitis B s urf ac e a nti g e n a n d H e p atitis B C or e A nti b o dy (I g M); H e p at itisC 
R N A; Cyt o m e g al ovir us I g M a nti b o dy; E pst ei n -B arr vir al c a psi d a nti g e n I g M a nti b o dy ( or if u n av ail a bl e, o bt ai n 
h et er o p hil e a nti b o dy or m o n os p ot t esti n g); H e p atitis E I g M a nti b o dy.
e. 
If h e p atitis d elt a a nti b o dy ass ay c a n n ot b e p erf or m e d, it c a n b e r e pl ace d wit h a P C R of h e p atitis D R N A vir us 
( w h er e n e e d e d) [L e G al , 2 0 0 5].
f. 
P K s a m pl e m ay n ot b e r e q uir e d f or s u bj ects k n o w n t o b e r ec eivi n g pl ac e b o.  R ec or d t h e d at e/ti m e of t h e P K bl o o d 
s a m pl e dr a w a n d t h e d at e/ti m e of t h e l ast d os e of st u dy tr e at m e nt pri or t o bl o o d s a m pl e dr a w o n t h e C R F.  If t h e 
d at e or ti m e of t h e l ast d os e is u ncl e ar, pr ovi d e t h e s u bj ect’s b est a p pr oxi m ati o n .  If t h e d at e/ti m e of t h e l ast d os e 
c a n n ot b e a p pr oxi m at e d O R a P K s a m pl e c a n n ot b e c oll ect e d i n t h e ti m e p eri o d i n dic at e d a b ov e, d o n ot o bt ai n a 
P K s a m pl e .  Instr ucti o ns f or s a m pl e h a n dli n g a n d s hi p pi n g ar e i n t h e S P M.  

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Li v er C h e mi str y I n cr e a s e d M o nit ori n g Crit eri a wit h C o nti n u e d T h er a p y – Li v er M o nit ori n g E v e nt
Crit eri a
A cti o n s
A L T 5x U L N a n d < 8x U L N a n d bilir u bi n 
< 2x U L N wit h o ut sy m pt o ms b eli ev e d t o b e 
r el at e d t o liv er i nj ury or hy p ers e nsitivity, 
a n d w h o c a n b e m o nit or e d w e ekly f or 
2 w e eks.
O R
A L T 3x U L N a n d < 5x U L N a n d bilir u bi n 
< 2x U L N wit h o ut sy m pt o ms b eli ev e d t o b e 
r el at e d t o liv er i nj ury or hy p ers e nsitivity, 
a n d w h o c a n b e m o nit or e d w e ekly f or 
4 w e eks.
 
N otify t h e N ov artis m e dic al m o nit or wit hi n 2 4 h o urs of 
l e ar ni n g of t h e a b n or m ality t o disc uss s u bj ect s af ety. 
 
S u bj ect c a n c o nti n u e st u dy tr e at m e n t.
 
S u bj ect m ust r et ur n w e ekly f or r e p e at liv er c h e mistri es 
( A L T, A S T, alk ali n e p h os p h at as e, bilir u bi n) u ntil t h ey 
r es olv e, st a biliz e, or r et ur n t o wit hi n b as eli n e.
 
If at a ny ti m e s u bj ect m e ets t h e liv er c h e mistry 
st o p pi n g crit eri a, pr oc e e d as d escri b e d a b ov e.
 
If A L T d ecr e as es fr o m A L T 5x U L N a n d < 8x U L N t o 
≥3x U L N b ut < 5x U L N, c o nti n u e t o m o nit or liv er 
c h e mistri es w e ekly. 
 
If, aft er 4 w e eks of m o nit ori n g, A L T < 3x U L N a n d 
bilir u bi n < 2x U L N, m o nit or s u bj ects t wic e m o nt hly u ntil 
liv er c h e mistri es n or m aliz e or r et ur n t o wit hi n b as eli n e.

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1 1. 4. 
A p p e n di x 4 – Al g orit h m f or P M L M o nit ori n g
M o nit ori n g f or pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y ( P M L) will be a n i m p orta nt 
part of t he safet y m o nit ori n g f or t his st u d y.  
P M L  is a viral-i n d uce d de m yeli nati n g disease of t he ce ntral ner v o us s ys te m us uall y 
occ urri n g i n t he i m m u n oc o m pr o mise d i n di vi d ual a n d has bee n re p orte d wit h ofat u m u ma b.  
J C vir us (J C V) i nfecti o n res ulti n g i n P M L a n d deat h has bee n re p orte d i n rit u xi ma b-
treate d s u bjects wit h he mat ol o gic mali g na ncies or wit h s yste mic l u p us er yt he mat os us, a n 
i n dicati o n f or w hic h rit u xi ma b has n ot bee n a p pr o ve d.  I n vesti gat ors a n d n urses s h o ul d 
pa y  caref ul atte nti o n f or si g ns a n d sy m pt o ms c o nsiste nt wi t h a dia g n osis of P M L.  Si g ns 
a n d s ym pt o ms of P M L i ncl u de vis ual dist ur ba nces, oc ular m o ve me nts, ata xia, a n d 
c ha n ges i n me ntal stat us s uc h as dis orie ntati o n or c o nf usi o n.
T hese s y m pt o ms are n ot a n e x ha usti ve list, a n d t he i n vesti gat or s h o ul d e xercise j u d g me nt 
i n deci di n g to re p ort si g ns a n d s y m pt o ms t o S p o ns or pr o m ptl y .  If a s u bject de vel o ps 
ne ur ol o gical si g ns or s y m pt o ms c o nsiste nt wit h P M L , treat me nt s h o ul d be halte d a n d t he 
s u bject referre d t o a ne ur ol o gist f or e val uati o n.  Bl o o d J C V (P C R a n d/ or J C V a nti b o d y 
testi n g) s h o ul d be perf or me d.  If i n dicate d, cere br os pi nal fl ui d ( C S F) J C V testi n g s h o ul d 
als o be perf or me d.  Ma g netic res o na nce i ma gi n g ( M RI) is str o n gl y rec o m me n de d.  If test 
res ults are ne gati ve, t he i n vesti gat or s h o ul d c o ntact t he S p o ns or f or a p pr o priate acti o n t o 
be ta ke n.  If P M L  is c o nfir me d, t he s u bject s h o ul d be wit h dra w n fr o m treat me nt, pr ocee d 
t o t he F oll o w-U p Peri o d, a n d be f oll o we d u ntil res ol uti o n.  S er u m ba n ke d fr o m t he 
Baseli ne visit ma y  als o be teste d f or J C V as part of t he P M L w or k- u p.  
T here are n o k n o w n tests t hat ca n relia bl y deter mi ne w h o is at i ncrease d ris k f or 
de vel o pi n g P M L.  T here are n o k n o w n i nter ve n ti o ns t hat ca n relia bly pre ve nt P M L  or 
a de q uatel y treat P M L  if it occ urs.
T he basic c o m p o ne nts of t his m o nit ori n g i ncl u de:
1. 
Pri or t o st u d y  start, the S p o ns or will pr o vi de i nf or mati o n re gar di n g P M L a n d its 
prese ntati o n .
2. 
Q ualifie d site staff will a d mi nister t he Ne ur ol o gical S y m pt o ms Q uesti o n naire at 
e ver y visit.
3. 
I n t he e ve nt of p ositi ve s y m pt o ms o n t he Ne ur ol o gical S ym pt o ms Q uesti o n naire, 
t he i n vesti gat or will c o ntact t he me dical m o nit or a n d t he s u bject will be referre d t o a 
ne ur ol o gist.
4. 
A n y  case of s us pecte d or c o nfir me d P M L will g o t hr o u g h i n de pe n de nt P M L 
adj u dicati o n a n d a n o pi ni o n will be pr o vi de d t o t he Sp o ns or.   T he i n de pe n de nt P M L  
a dj u dicat or ca n re q uest a d diti o nal testi n g a n d f urt her data c ollecti o n.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
9 9
Fi g ur e 1 1 - 1 
Al g orit h m f or P M L M o nit ori n g
N e ur ol o gist/ P M L s p e ci ali st w or k -u p :
 
Bl o o d J C V ( P C R a n d/ or J C V a nti b o dy t esti n g).  
 
C er e br os pi n al fl ui d ( C S F) J C V t esti n g if 
i n dic at e d.  
 
M RI str o n gly r ec o m m e n d e d.
 
P er m a n e ntly disc o nti n u e st u dy tr e at m e nt. 
 
Pr oc e e d t o t h e F oll o w -U p P eri o d.
 
F oll o w u ntil r es ol uti o n.
S u bj ect pr es e nts wit h n e w p o siti v e s y m pt o m s o n 
t h e N e ur ol o gic al Sy m pt o ms Q u esti o n n air e
 
H ol d d osi n g of st u dy tr e at m e nt
 
C o nt act m e dic al m o nit or .
 
R ef er t o n e ur ol o gi st .
N e g ati v e
C o nt act s p o ns or f or 
a p pr o pri at e acti o n t o t ak e.
I n d e p e n d e nt P M L 
a dj u di c ati o n
P M L C o nfir m e d

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0 0
1 1. 5. 
A p p e n di x 5 – N e ur ol o gi c al S y m pt o m s Q u e sti o n n air e
Y E S 
N O
1. 
D o es t h e s u bj ect r e p ort a ny n e w f oc al w e ak n ess ?
2. 
D o es t h e s u bj ect r e p ort a ny n e w diffic ulty wit h c o or di n ati o n or w alki n g ?
3. 
D o es t h e s u bj ect r e p ort a ny n e w si g ns of c o nf usi o n, i m p air e d m e m ory, or att e nti o n ?
4. 
D o es t h e s u bj ect a p p e ar a p at h etic c o m p ar e d t o pr evi o us c o nt acts ?
5. 
D o es t h e s u bj ect r e p ort a ny n e w vis u al dist ur b a nc es ?
6. 
H as t h e s u bj ect h a d a ny n e w tr o u bl e s p e aki n g, eit h er sl urri n g s p e ec h, diffic ulty 
g etti n g o ut w or ds, diffic ulty u n d erst a n di n g w or ds, or diffic ulty c o m pr e h e n di n g 
s p ok e n l a n g u a g e ?
7. 
D o es t h e s u bj ect h av e a ny ot h er n e w n e ur ol o gi c al sy m pt o ms, i ncl u di n g b ut 
n ot li mit e d t o:
 
N e w o ns et s eiz ur e
 
N e w s e ns ory l oss
 
N e w e m oti o n al l a bility
If a ny of t he a b o ve are a ns were d “ Yes” at a n y visit, t he i n vesti gat or will c o ntact t he 
me dical m o nit or.
A n y  ne ur ol o gical sy m pt o m t hat ca n n ot be directl y  attri b ute d t o a c o nc urre nt me dical 
c o n diti o n or c o nc o mita nt me dicati o n m ust be referre d t o a ne ur ol o gist .

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0 1

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0 2

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0 3

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0 4

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0 5

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0 6

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0 8

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 0 9

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 0

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 1

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 2

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 3

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 4

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 5

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 6
1 1. 1 3. 
A p p e n di x 1 3 – C e ntr al L a b or at or y R ef er e n c e R a n g e s
* N ote: refer t o t he  
 I n vesti g at or M a n u al f or t he c urre nt refere nce r a n ges. *
 R E F E R E N C E R AN G E S
T h e r ef er e nc e r a n g es r e p ort e d ar e g e n d er a n d a g e s p ecific a n d r e pr es e nt a h et er o g e n e o us cli nic al tri als 
p o p ul ati o n. A ny v al u e t h at is o utsi d e of t h e est a blis h e d r ef er e nc e r a n g e will b e i n dic at e d o n t h e l a b or at ory 
r e p ort.  Pr ot oc ol s p ecific a n d Sp o ns or -d efi n e d al erts will b e i n dic at e d o n t h e l a b or at ory r e p ort.
C H E MI S T R Y P A N E L – C O N V E N TI O N A L U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
**P H O N E A L E R T R A N G E
P R O T EI N, T O T A L 
G/ D L 
6. 0 -8. 5 ( 1 3 -6 4y)
5. 8 -8. 1 ( 6 5 +y)
A L B U MI N
G/ D L 
3. 2 -5. 0 ( 3 +y)
A L T ( S G P T)
U/ L 
0 -4 8 ( 1 3 +y)
A S T ( S G O T)
U/ L 
0 -4 2 ( 3 -6 4y)
0- 5 5 ( 6 5 +y)
A L K A LI N E P H O S.
U/ L 
M 
: 3 0-2 2 5 ( 1 6 -1 9y) ■
F 
: 3 0-1 6 5 ( 1 6 -1 9y) ■
2 0 -1 2 5 ( 2 0 +y)
G G T
U/ L 
M 
: 0-6 5 ( 1 3 -6 4y)
F 
: 0- 4 5 ( 1 3-6 4y)
0- 7 5 ( 6 5 +y)
BI LI R U BI N, T O T A L 
M G/ D L 
0. 0 -1. 3 ( 1 +y)
BI LI R U BI N, DI R E C T 
M G/ D L 
0. 0 -0. 4 ( 0 +y)
U R E A NI T R O G E N 
M G/ D L 
7 -2 5 ( 1 3 -6 4y)
7- 3 0 ( 6 5 +y)
C R E A TI NI N E, E N Z 
M G/ D L 
M : 0. 6 7-1. 2 6 ( 1 8 -1 9y)
F : 0. 4 8-1. 0 1 ( 1 8 -1 9y)
M : 0. 8 0-1. 3 0 ( 2 0 -2 9y)
F : 0. 5 7-1. 0 3 ( 2 0 -2 9y)
M : 0. 7 9-1. 3 3 ( 3 0 -3 9y)
F : 0. 5 8-1. 0 6 ( 3 0 -3 9y)
M : 0. 7 8-1. 3 4 ( 4 0 -4 9y)
F : 0. 59- 1. 0 7 ( 4 0 -4 9y)
M : 0. 7 6-1. 4 6 ( 5 0 -5 9y)
F : 0. 6 0-1. 1 0 ( 5 0 -5 9y)
M : 0. 7 6-1. 4 6 ( 6 0 -6 9y)
F : 0. 6 0-1. 1 8 ( 6 0 -6 9y)
M : 0. 6 7-1. 5 4 ( > 6 9y)
F : 0. 6 3-1. 2 2 ( > 6 9y)
S O DI U M
M E Q/ L 
1 3 5 -1 4 6 ( 0 +y)
< 1 2 0 or > 1 6 0
P O T A S SI U M
M E Q/ L 
3. 5 -5. 3 ( 1 3 +y)
< 2. 8 or > 6. 5
C H L O RI D E
M E Q/ L 
9 5 -1 0 8 ( 0 +y)
y = y e ars
■In individuals bet ween 12-18 years of age, alkaline phosphatase levels vary according to period of maxi mu m 
bone gro wth.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 7
C H E MI S T R Y P A N E L – C O N V E N TI O N A L U NI T S (c o nt’ d)
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
** P H O N E A L E R T R A N G E
C A L CI U M
M G/ D L 
8. 5 -1 0. 3 ( 3 +y)
< 6. 0 or > 1 3. 0
C O 2 C O N T E N T
M E Q/ L 
2 0 -3 2 ( 1 3 +y)
G L U C O S E
M G/ D L 
7 0 -1 1 5 ( 1 3 -4 9y)
7 0 -1 2 5 ( 5 0 +y)
< 4 0 or > 5 0 0
y = y e ars
L E, L1, L2, L3, L Q, L R, L P
E V E N T O C C U R R E N C E
R E P O R T
F L A G
G UI D A N C E C O M M E N T S
O N R E P O R T A N D I N W E B R E S U L T\ VI E W
A L T 3 X U L N a n d Bilir u bi n 
2 X U L N ( > 3 5 % Dir ect Bilir u bi n)  
All P h a s e s
L E
Call s u bject; st o p st u dy dr u g i m me diately .  R e q uest 
s pecialist or he pat ol o gist c o ns ult .  F oll o w u p cli nic a n d 
la b eval uati o n wit hi n 24 h o urs
A L T 3 X U L N  P h a s e I 
L 1
St o p dr u g i m me diately; call s u bject f or pr o m pt cli nic 
eval uati o n re q uire d, as per pr ot oc ol
A L T 5 X U L N  P h a s e II
L 2
St o p dr u g i m me diately; call s u bject f or pr o m pt cli nic 
eval uati o n re q uire d, as per pr ot oc ol
A L T 8 X U L N  P h a s e III/I V
L 3
St o p dr u g i m me diately; cal l s u bject f or pr o m pt cli nic 
eval uati o n re q uire d, as per pr ot oc ol
A L T 3 X U L N a n d < 5 X U L N a n d 
Bilir u bi n < 2 X U L N  P h a s e II 
L Q
Call s u bject; pr o m pt cli nic eval uati o n re q uire d, as per 
pr ot oc ol ( Revie w A L T a n d Bilir u bi n i n Q uick Tre n d)
A L T 5 X U L N a n d < 8 X U L N 
Bilir u bi n < 2 X U L N P h a s e III -I V
L R
Call s u bject; pr o m pt cli nic eval uati o n re q uire d, as per 
pr ot oc ol ( Revie w A L T a n d Bilir u bi n i n Q uick Tre n d)
A L T 3 X U L N  P h a s e s II -I V
L P
Call s u bject; pr o m pt cli nic eval uati o n re q uire d, as per 
pr ot oc ol ( Revie w A L T i n Q uick Tre n d)

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 8
C H E MI S T R Y P A N E L – SI U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
**P H O N E A L E R T R A N G E
P R O T EI N, T O T A L 
G/ L 
6 0 -8 5 ( 1 3 -6 4y)
5 8 -8 1 ( 6 5 +y)
A L B U MI N
G/ L 
3 2 -5 0 ( 3 +y)
A L T ( S G P T)
U/ L 
0 -4 8 ( 1 3 +y)
A S T ( S G O T)
U/ L 
0 -4 2 ( 3 -6 4y)
0- 5 5 ( 6 5 +y)
A L K A LI N E P H O S.
U/ L 
M 
: 3 0-2 2 5 ( 1 6 -1 9y) ■
F 
: 3 0-1 6 5 ( 1 6 -1 9y) ■
2 0 -1 2 5 ( 2 0 +y)
G G T
U/ L 
M 
: 0-6 5 ( 1 3 -6 4y)
F 
: 0- 4 5 ( 1 3-6 4y)
0- 7 5 ( 6 5 +y)
BI LI R U BI N, T O T A L 
U M O L/ L 
0 -2 2 ( 1 +y)
BI LI R U BI N, DI R E C T 
U M O L/ L 
0 -6 ( 0 +y)
U R E A NI T R O G E N 
M M O L/ L 
2. 5 -9. 0 ( 1 3 -6 4y)
2. 5 -1 0. 5 ( 6 5 +y)
C R E A TI NI N E, E N Z 
U M O L/ L 
M : 5 9. 2-1 1 1. 4 ( 1 8 -1 9y)
F : 4 2. 4-8 9. 3 ( 1 8 -1 9y)
M : 7 0. 7-1 1 4. 9 ( 2 0 -2 9y)
F : 5 0. 4-9 1. 1 ( 2 0 -2 9y)
M : 6 9. 8-1 1 7. 6 ( 3 0 -3 9y)
F : 5 1. 3-9 3. 7 ( 3 0 -3 9y)
M : 6 9. 0-1 1 8. 5 ( 4 0 -4 9y)
F : 5 2. 2-9 4. 6 ( 4 0 -4 9y)
M : 6 7. 2-1 2 9. 1 ( 5 0 -5 9y)
F : 5 3. 0-9 7. 2 ( 5 0 -5 9y)
M : 6 7. 2-1 2 9. 1 ( 6 0 -6 9y)
F : 5 3. 0-1 0 4. 3 ( 6 0 -6 9y)
M : 5 9. 2-1 3 6. 1 ( > 6 9y)
F : 5 5. 7-1 0 7. 8 ( > 6 9y)
S O DI U M
M M O L/ L 
1 3 5 -1 4 6 ( 0 +y)
< 1 2 0 or > 1 6 0
P O T A S SI U M
M M O L/ L 
3. 5 -5. 3 ( 1 3 +y)
< 2. 8 or > 6. 5
C H L O RI D E
M M O L/ L 
9 5 -1 0 8 ( 0 +y)
C A L CI U M
M M O L/ L 
2. 1 2 -2. 5 6 ( 3 +y)
< 1. 5 0 or > 3. 2 4
C O 2 C O N T E N T
M M O L/ L 
2 0 -3 2 ( 1 3 +y)
G L U C O S E
M M O L/ L 
3. 9 -6. 4 ( 1 3 -4 9y)
3. 9 -6. 9 ( 5 0 +y)
< 2. 2 or > 2 7. 8
y = y e ars
■In individuals bet ween 12-18 years of age, alkaline phosphatase levels vary according to period of maxi mu m 
bone gro wth.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 1 9
L E, L1, L2, L3, L Q, L R, L P
E V E N T O C C U R R E N C E
R E P O R T
F L A G
G UI D A N C E C O M M E N T S
O N R E P O R T A N D I N W E B R E S U L T \VI E W
A L T 3 X U L N a n d Bilir u bi n 
2 X U L N ( > 3 5 % Dir ect Bilir u bi n)  
All P h a s e s
L E
Call s u bject; st o p st u dy dr u g i m me diately .  R e q uest 
s pecialist or he pat ol o gist c o ns ult .  F oll o w u p cli nic a n d 
la b eval uati o n wit hi n 24 h o urs
A L T 3 X U L N  P h a s e I 
L 1
St o p dr u g i m me diately; call s u bject f or pr o m pt cli nic 
eval uati o n re q uire d, as per pr ot oc ol
A L T 5 X U L N  P h a s e II
L 2
St o p dr u g i m me diately; call s u bject f or pr o m pt cli nic
eval uati o n re q uire d, as per pr ot oc ol
A L T 8 X U L N  P h a s e III/I V
L 3
St o p dr u g i m me diately; call s u bject f or pr o m pt cli nic 
eval uati o n re q uire d, as per pr ot oc ol
A L T 3 X U L N a n d < 5 X U L N a n d 
Bilir u bi n < 2 X U L N  P h a s e II 
L Q
Call s u bject; pr o m pt cli nic eval uat i o n re q uire d, as per 
pr ot oc ol ( Revie w A L T a n d Bilir u bi n i n Q uick Tre n d)
A L T 5 X U L N a n d < 8 X U L N 
Bilir u bi n < 2 X U L N P h a s e III -I V
L R
Call s u bject; pr o m pt cli nic eval uati o n re q uire d, as per 
pr ot oc ol ( Revie w A L T a n d Bi lir u bi n i n Q uick Tre n d)
A L T 3 X U L N  P h a s e s II -I V
L P
Call s u bject; pr o m pt cli nic eval uati o n re q uire d, as per 
pr ot oc ol ( Revie w A L T i n Q uick Tre n d)

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 0
H E M A T O L O G Y – C O N V E N TI O N A L U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
**P H O N E A L E R T R A N G E
P L A T E L E T C O U N T
P E R C U M M 
1 3 0, 0 0 0 -4 0 0, 0 0 0 ( 1 +y) 
< 3 1, 0 0 0 or > 1, 4 9 9, 0 0 0
R E D C E L L C O U N T
MI L L/ M C L 
M 
: 4. 4-5. 8 ( 1 8 -6 4y)
M 
: 3. 7-5. 5 ( 6 5 +y)
F 
: 3. 9-5. 2 ( 1 8 -6 4y)
F 
: 3. 6-5. 1 ( 6 5 +y)
H E M O G L O BI N
G/ D L 
M 
: 1 3. 8-1 7. 2 ( 1 8 -6 4y)
M 
: 1 1. 8-1 6. 8 ( 6 5 +y)
F 
: 1 2. 0-1 5. 6 ( 1 8 -6 4y)
F 
: 1 1. 1-1 5. 5 ( 6 5 +y)
< 7. 1 or > 1 9. 9 
H E M A T O C RI T
%
M 
: 4 1. 0-5 0. 0 ( 1 8 -6 4y)
M 
: 3 6. 0-4 9. 0 ( 6 5 +y)
F 
: 3 5. 0-4 6. 0 ( 1 8 -6 4y)
F 
: 3 3. 0-4 6. 0 ( 6 5 +y)
< 2 0. 1 or > 5 9. 9 
W HI T E C E L L C O U N T
T H O U/ M C L 
3. 8 -1 0. 8 ( 1 8 +y)
< 1. 1
T O T A L N E U T R O P HI L S, A B S. 
T H O U/ M C L 
1. 8 0 -8. 0 0 ( 1 +y)
T O T A L N E U T R O P HI L S 
%
4 0. 0 -7 5. 0 ( 1 8 +y)
N E U T R O P HI L S , S E G S.  A B S. 
T H O U/ M C L 
1. 8 0 -8. 0 0 ( 1 +y)
N E U T R O P HI L S, S E G S. 
%
4 0. 0 -7 5. 0 ( 1 8 +y)
N E U T R O P HI L S, B A N D S, A B S. ■
T H O U/ M C L 
0. 0 0 -0. 8 6 ( 1 8 +y)
N E U T R O P HI L S, B A N D S ■
%
0. 0 -8. 0 ( 1 8 +y)
L Y M P H O C Y T E S, A B S. 
T H O U/ M C L 
0. 8 5 -4. 1 0 ( 1 +y)
L Y M P H O C Y T E S
%
1 6. 0 -4 6. 0 ( 1 8 +y)
M O N O C Y T E S, A B S.
T H O U/ M C L 
0. 2 0 -1. 1 0 ( 1 +y)
M O N O C Y T E S
%
0. 0 -1 2. 0 ( 1 8 +y)
E O SI N O P HI L S, A B S.
T H O U/ M C L 
0. 0 5 -0. 5 5 ( 0 +y)
E O SI N O P HI L S
%
0. 0 -7. 0 ( 1 8 +y)
B A S O P HI L S, A B S.
T H O U/ M C L 
0. 0 0 -0. 2 0 ( 1 +y)
B A S O P HI L S
%
0. 0 -2. 0 ( 0 +y)
y = y e ars
■ N e utr o p hil, B a n ds ar e r e p ort e d o nly if s e e n o n a m a n u al diff er e nti al.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 1
H E M A T O L O G Y – SI U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
**P H O N E A L E R T R A N G E
P L A T E L E T C O U N T
GI/ L 
1 3 0 -4 0 0 ( 1 +y)
< 3 1 or > 1, 4 9 9
R E D C E L L C O U N T
TI/ L 
M 
: 4. 4-5. 8 ( 1 8 -6 4y)
M 
: 3. 7-5. 5 ( 6 5 +y)
F 
: 3. 9-5. 2 ( 1 8 -6 4y)
F 
: 3. 6-5. 1 ( 6 5 +y)
H E M O G L O BI N
G/ L 
M 
: 1 3 8-1 7 2 ( 1 8 -6 4y)
M 
: 1 1 8-1 6 8 ( 6 5 +y)
F 
: 1 2 0-1 5 6 ( 1 8 -6 4y)
F 
:  1 1 1 -1 5 5 ( 6 5 +y)
< 7 1 or > 1 9 9
H E M A T O C RI T
1 
M 
: 0. 4 1 0-0. 5 0 0 ( 1 8 -6 4y)
M 
: 0. 3 6 0-0. 4 9 0 ( 6 5 +y)
F 
: 0. 3 5 0-0. 4 6 0 ( 1 8 -6 4y)
F 
: 0. 3 3 0-0. 4 6 0 ( 6 5 +y)
< 0. 2 0 1 or > 0. 5 9 9 
W HI T E C E L L C O U N T
GI/ L 
3. 8 -1 0. 8 ( 1 8 +y)
< 1. 1
T O T A L N E U T R O P HI L S, A B S. 
GI/ L 
1. 8 0 -8. 0 0 ( 1 +y)
T O T A L N E U T R O P HI L S 
% 
4 0. 0 -7 5. 0 ( 1 8 +y)
N E U T R O P HI L S, S E G S .  A B S. 
GI/ L 
1. 8 0 -8. 0 0 ( 1 +y)
N E U T R O P HI L S, S E G S. 
% 
4 0. 0 -7 5. 0 ( 1 8 +y)
N E U T R O P HI L S, B A N D S, A B S. ■
GI/ L 
0. 0 0 -0. 8 6 ( 1 8 +y)
N E U T R O P HI L S, B A N D S ■
% 
0. 0 -8. 0 ( 1 8 +y)
L Y M P H O C Y T E S, A B S. 
GI/ L 
0. 8 5 -4. 1 0 ( 1 +y)
L Y M P H O C Y T E S
% 
1 6. 0 -4 6. 0 ( 1 8 +y)
M O N O C Y T E S, A B S.
GI/ L 
0. 2 0 -1. 1 0 ( 1 +y)
M O N O C Y T E S
% 
0. 0 -1 2. 0 ( 1 8 +y)
E O SI N O P HI L S, A B S.
GI/ L 
0. 0 5 -0. 5 5 ( 0 +y)
E O SI N O P HI L S
% 
0. 0 -7. 0 ( 1 8 +y)
B A S O P HI L S, A B S.
GI/ L 
0. 0 0 -0. 2 0 ( 1 +y)
B A S O P HI L S
% 
0. 0 -2. 0 ( 0 +y)
y = y e ars
■ N e utr o p hil, B a n ds ar e r e p ort e d o nly if s e e n o n a m a n u al diff er e nti al.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 2
U RI N A L Y SI S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
**P H O N E A L E R T R A N G E
A P P E A R A N C E
C L E A R
S P E CI FI C G R A VI T Y
1.001-1.035
U RI N E R E A C TI O N p H
4.6-8.0
P R O T EI N Q U A L.
N E G A TI V E
G L U C O S E
N E G A TI V E
K E T O N E
N E G A TI V E
L E U K O C Y T E S
N E G A TI V E
O C C U L T B L O O D
N E G A TI V E
MI C R O S C O PI C:
R B C
W B C
P E R H P F
P E R H P F
M: 0 -3
F: 0 -3
M: 0 -5
F: 0 -10
O T H E R FI N DI N G S WILL B E R E P O R T E D O NL Y I F O B S E R V E D U N D E R MI C R O S C O PI C E X A MI N A TI O N
O T H E R T E S T S – C O N V E N TI O N A L U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
**P H O N E A L E R T R A N G E
C R E A TI NI N E CL E A R A N C E, 
E S TI M A T E D (using seru m 
creatinine only)
ML/ MI N 
R E F E R E N C E R A N G E 
N O T E S T A BLI S H E D
MI C R O AL B U MI N/
C R E A TI NI N E R A TI O
M G/ G 
C R E A T.
< 30
H E P A TI TI S Bs Ag
N O N R E A C TI V E O R N E G A TI V E
H E P A TI TI S Bs Ab
N O N -R E A C TI V E
H E P A TI TI S B C O R E Ab T O T AL
N O N R E A C TI V E O R N E G A TI V E
H E P A TI TI S B D N A P C R 
Q U A N TI T A TI V E:
H B V D N A P C R
I U/ M L 
< 2 0
H B V D N A L O G
L O G I U/ M L 
< 1. 3 0
H B V D N A P C R C O PI E S 
C O PI E S/ M L 
< 1 1 6
H E P A TI TI S C A N TI B O D Y
N O N R E A C TI V E
P R E G N A N C Y T E S T S E R U M
Males and Non -Pregnant 
Fe males = N E G A TI V E
Pregnant = P O SI TI V E
F S H
MI U/ ML 
F : F ollic ul ar P h as e: 2. 5-1 0. 2
F : Mi dcycl e P e ak: 3. 1-1 7. 7
F : L ut e al P h as e: 1. 5-9. 1
F : P ost m e n o p a us al: 2 3. 0-1 1 6. 3
E S T R A DI OL, L C/ M S/ M S 
P G/ ML 
A D UL T F E M AL E (18 + y):
Follicular Stage: 39 -375
Mid Cycle Stage: 94 -762
Luteal Stage: 48-440
Post menopausal: ≤ 10
y = y e ars

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 3
O T H E R T E S T S – C O N V E N TI O N A L U NI T S (c o nt’ d)
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
**P H O N E A L E R T R A N G E
C -R E A C TI V E P R O T EI N ( C R P) 
HI G HL Y S E N SI TI V E
M G/L 
< 3.1 (18 +y)
S E R U M B A N KI N G F O R J C V
N O T D E T E C T E D
I M M U N O-GL O B ULI N G (Ig G) 
M G/ DL 
694-1,618 (16 +y)
I M M U N O-GL O B ULI N M (Ig M) 
M G/ DL 
48-271 (16 +y)
I M M U N O-GL O B ULI N A (Ig A) 
M G/ DL 
81-463 (16 +y)
B -L Y M P H S TI M UL A T O R 
P G/ ML 
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
B -L Y M P H C H E M O KI N E 
P G/ ML 
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
D E S M O GL EI N A N TI B O DI E S (1 
A N D 3)
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
T E T A N U S A N TI T O X A B 
I U/ ML 
> O R = 0.50
P N E U M O C O C C AL A B A S S A Y
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
T B N K ( C D4/ C D8/ C D19 -B C ELL 
C O U N T)
P E R C M M 
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
B C ELL P A N EL
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
y = y e ars

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 4
F L O W C Y T O M E T R Y – C O N V E N TI O N A L U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S
FL O W C Y T O M E T R Y –
T & B C ELL S:
% C D 3 ( M at ur e T C ells)
% 
6 1 -8 2 ( 1 3 -1 8y)
5 7 -8 5 ( 1 9 +y)
A bs ol ut e C D 3 +
P E R C M M 
8 6 0 -2 4 2 0( 1 3 -1 8y)
8 4 0 -3 0 6 0( 1 9 +y)
% C D 8 ( S u p pr ess or T C ells)
% 
1 7 -3 6( 1 3 -1 8y)
1 2 -4 2 ( 1 9 +y)
A bs ol ut e C D 8
P E R C M M 
2 4 0 -8 9 0( 1 3 -1 8y)
1 8 0 -1 1 7 0( 1 9 +y)
% C D 4 ( H el p er C ells)
% 
3 3 -5 3( 1 3 -1 8y)
3 0 -6 1( 1 9 +y)
A bs ol ut e C D 4 +
P E R C M M 
5 1 0 -1 4 5( 1 3 -1 8y)
4 9 0 -1 7 4 0( 1 9 +y)
% C D 1 9 ( B C ells)
% 
9 -3 0( 1 3 -1 8y), 6 -6 -2 9( 1 9 +y)
A bs ol ut e C D 1 9 + 
P E R C M M 
1 3 0 -8 0 0( 1 3 -1 8y)
1 1 0 -6 6 0( 1 9 +y)
A bs ol ut e Ly m p h ocyt e ( C D 4 5 +)
P E R C M M 
8 5 0 -4 1 0 0
% C D 4 ( H el p er C ells) / % C D 8 ( S u p pr ess or 
T C ells)
N O N E 
1. 0 -2. 9( 1 3 -1 8y)
0. 8 6 -5. 0( 1 9 +y)
FL O W C Y T O M E T R Y –
B- C ELL P A N EL:
C D 1 9 + C D 2 7 + %  
% C D 1 9 
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 + A bs ol ut es 
P E R 
C U M M
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + C D 1 0 + % 
% C D 1 9 
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + C D 1 0 + 
A bs ol ut es 
P E R 
C U M M
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + C D 1 0- %  
% C D 1 9 
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + C D 1 0-
A bs ol ut es
P E R 
C U M M
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + bri g ht C D 1 0 + %  
% C D 1 9 
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + bri g ht C D 1 0 +
A bs ol ut es 
P E R 
C U M M
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 +I g D + % 
% C D 1 9 
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 +I g D + A bs ol ut es
P E R 
C U M M
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D- %
% C D 1 9 c 
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D- A bs ol ut es
P E R 
C U M M
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 +I g D - %
% C D 1 9 
R E F E R E N C E R A N G E N O T 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 5
F L O W C Y T O M E T R Y – C O N V E N TI O N A L U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S
E S T A B LI S H E D
C D 1 9 + C D 2 7 +I g D - A bs ol ut es 
P E R 
C U M M
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 + bri g ht C D 3 8 + bri g ht %  
% C D 1 9 
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 2 7 + bri g ht C D 3 8 + bri g ht 
A bs ol ut es
P E R 
C U M M
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 6 9 + %
% C D 1 9 
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
C D 1 9 + C D 6 9 + A bs ol ut es 
P E R 
C U M M
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
y = y e ars

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 6
O T H E R T E S T S – SI U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
** P H O N E A L E R T R A N G E
C R E A TI NI N E CL E A R A N C E, 
E S TI M A T E D
(using seru m creatinine only)
ML/ MI N 
R E F E R E N C E R A N G E 
N O T E S T A BLI S H E D
MI C R O AL B U MI N/
C R E A TI NI N E R A TI O
M G/ M M OL 
C R E A T.
< 3.4
H E P A TI TI S Bs Ag
N O N R E A C TI V E O R 
N E G A TI V E
H E P A TI TI S Bs Ab
N O N -R E A C TI V E
H E P A TI TI S B C O R E Ab 
T O T AL
N O N R E A C TI V E O R 
N E G A TI V E
H E P A TI TI S B D N A P C R 
Q U A N TI T A TI V E:
H B V D N A P C R
I U/ M L 
< 2 0
H B V D N A L O G
L O G I U/ M L 
< 1. 3 0
H B V D N A P C R C O PI E S 
C O PI E S/ M L 
< 1 1 6
H E P A TI TI S C A N TI B O D Y
N O N R E A C TI V E
P R E G N A N C Y T E S T S E R U M
Males and Non -Pregnant 
Fe males = N E G A TI V E
Pregnant = P O SI TI V E
F S H
I U/L 
F : F ollic ul ar P h as e: 2. 5-1 0. 2
F : Mi dcycl e P e ak: 3. 1-1 7. 1
F : L ut e al P h as e: 1. 5-9. 1
F : P ost m e n o p a us al: 2 3. 0-1 1 6. 3
E S T R A DI OL, L C/ M S/ M S 
P M OL/L 
A D UL T F E M AL E (18 + y):
Follicular Stage: 143 -1377
Mid Cycle Stage: 345 -2797
Luteal Stage: 176 -1615
Post menopausal: ≤ 37
y = y e ars

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 7
O T H E R T E S T S – SI U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
** P H O N E A L E R T R A N G E
S E R U M B A N KI N G F O R J C V
N O T D E T E C T E D
I M M U N O-GL O B ULI N G (Ig G) 
G/L 
6.94-16.18 (16 +y)
I M M U N O-GL O B ULI N M (Ig M) 
G/L 
0.48-2.71 (16 +y)
I M MU N O -GL O B ULI N A (Ig A) 
G/L 
0.81-4.63 (16 +y)
B -L Y M P H S TI M UL A T O R 
N G/L 
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
B -L Y M P H C H E M O KI N E 
N G/L 
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
D E S M O GL EI N A N TI B O DI E S 
(1 A N D 3)
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
T E T A N U S A N TI T O X A B 
I U/ ML 
> O R = 0.50
P N E U M O C O C C AL A B A S S A Y
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
C -R E A C TI V E P R O T EI N ( C R P) 
HI G HL Y S E N SI TI V E
M G/L 
< 3.1 (18 +y)
T B N K ( C D4/ C D8/ C D19 -B 
C ELL C O U N T)
P E R C M M 
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
B C ELL P A N EL
R E F E R E N C E R A N G E
N O T E S T A BLI S H E D 
y = y e ars

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 8
F L O W C Y T O M E T R Y – SI U NI T S
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S
F L O W C Y T O M E T R Y –
T & B C E L L S:
% C D 3 ( M at ur e T C ells)
% 
6 1 -8 2 ( 1 3 -1 8y)
5 7 -8 5 ( 1 9 +y)
A bs ol ut e C D 3 +
GI/ L 
0. 8 6 0 -2. 4 2( 1 3 -1 8y)
0. 8 4 0 -3. 0 6 0( 1 9 +y)
% C D 8 ( S u p pr ess or T C ells)
% 
1 7 -3 6 ( 1 3-1 8y)
1 2 -4 2 ( 1 9 +y)
A bs ol ut e C D 8
GI/ L 
0. 2 4 0 -0. 8 9 0( 1 3 -1 8y)
0. 1 8 0 -1. 1 7 0( 1 9 +y)
% C D 4 ( H el p er C ells)
% 
3 3 -5 3( 1 3 -1 8y)
3 0 -6 1( 1 9 +y)
A bs ol ut e C D 4 +
GI/ L 
0. 5 1 0 -1. 4 5 0( 1 3 -1 8y)
0. 4 9 0 -1. 7 4 0( 1 9 +y)
% C D 1 9 ( B C ells)
% 
9 -3 0( 1 3 -1 8y)
6- 2 9( 1 9 +y)
A bs ol ut e C D 1 9 + 
GI/ L 
0. 1 3 0 -0. 8 0 0( 1 3 -1 8y)
0. 1 1 0 -0. 6 6 0( 1 9 +y)
A bs ol ut e Ly m p h ocyt e ( C D 4 5 +)
GI/ L 
0. 8 5 0 -4. 1 0 0
% C D 4 ( H el p er C ells) / % C D 8 ( S u p pr ess or T 
C ells)
N O N E 
1. 0 -2. 9( 1 3 -1 8y)
0. 8 6 -5. 0( 1 9 +y)
FL O W C Y T O M E T R Y –
B- C ELL P A N EL:
C D 1 9 + C D 2 7 + %  
% C D 1 9 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 + A bs ol ut es 
GI/ L 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + C D 1 0 + % 
% C D 1 9 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + C D 1 0 + A bs ol ut es  
GI/ L 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + C D 1 0- % 
% C D 1 9 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + C D 1 0- A bs ol ut es 
GI/ L 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + bri g ht C D 1 0 + %  
% C D 1 9 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D + C D 3 8 + bri g ht C D 1 0 +
A bs ol ut es 
GI/ L 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 +I g D + % 
% C D 1 9 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 +I g D + A bs ol ut es
GI/ L 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D- %
% C D 1 9 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 -I g D- A bs ol ut es
GI/ L 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 +I g D - %
% C D 1 9 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 +I g D - A bs ol ut es 
GI/ L 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 + bri g ht C D 3 8 + bri g ht % 
% C D 1 9 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 2 7 + bri g ht C D 3 8 + bri g ht A bs ol ut es 
GI/ L 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 6 9 + %
% C D 1 9 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
C D 1 9 + C D 6 9 + A bs ol ut es 
GI/ L 
R E F E R E N C E R A N G E N O T E S T A B LI S H E D
y = y e ars

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 2 9
C H E MI S T R Y P A N E L – LI V E R E V E N T A S S E S S M E N T – C O N V E N TI O N A L
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
** P H O N E A L E R T R A N G E
A L T ( S G P T)
U/ L
0 -4 8 ( 1 3 +y)
A S T ( S G O T)
U/ L
0 -4 2 ( 3 -6 4y)
0- 5 5 ( 6 5 +y)
A L K A LI N E P H O S.
U/ L
M: 3 0 -2 2 5 ( 1 6 -1 9y) 
F: 3 0- 1 6 5 ( 1 6 -1 9y) 
2 0 -1 2 5 ( 2 0 +y)
BI LI R U BI N, T O T A L
M G/ D L 
0. 0 -1. 3 ( 1 +y)
BI LI R U BI N, DI R E C T ♦
M G/ D L 
0. 0 -0. 4 ( 0 +y)
C P K, T O T A L
U/ L
M 
: 0-2 3 5 ( 0 +y)
F 
: 0-1 9 0 ( 0 +y)
L A C T A T E 
D E H Y D R O G E N A S E
U/ L
0 -2 5 0 ( 3 -6 4y)
0- 2 7 0 ( 6 5 +y)
y = y e ars
♦If T ot al Bilir u bi n is > 2. 5 m g/ dl, Dir ect Bilir u bi n will b e r e p ort e d.
C H E MI S T R Y P A N E L – LI V E R E V E N T A S S E S S M E N T – SI
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
** P H O N E A L E R T R A N G E
A L T ( S G P T)
U/ L
0 -4 8 ( 1 3 +y)
A S T ( S G O T)
U/ L
0 -4 2 ( 3 -6 4y)
0- 5 5 ( 6 5 +y)
A L K A LI N E P H O S.
U/ L
M: 3 0 -2 2 5 ( 1 6 -1 9y) 
F: 3 0- 1 6 5 ( 1 6 -1 9y) 
2 0 -1 2 5 ( 2 0 +y)
BI LI R U BI N, T O T A L
U M O L/ L 
0 -2 2 ( 1 +y)
BI LI R U BI N, DI R E C T ♦
U M O L/ L 
0 -6 ( 0 +y)
C P K, T O T A L
U/ L
M 
: 0-2 3 5 ( 0 +y)
F 
: 0-1 9 0 ( 0 +y)
L A C T A T E 
D E H Y D R O G E N A S E
U/ L
0 -2 5 0 ( 3 -6 4y)
0- 2 7 0 ( 6 5 +y)
y = y e ars
♦If Total Bilirubin is > 43 u mol/l, Direct Bilirubin will be reported.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 0
H E M A T O L O G Y – LI V E R E V E N T A S S E S S M E N T – C O N V E N TI O N A L
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
** P HO N E A L E R T R A N G E
P L A T E L E T C O U N T
P E R C U M M 
1 3 0, 0 0 0 -4 0 0, 0 0 0 ( 1 +y) 
< 3 1, 0 0 0 or > 1, 4 9 9, 0 0 0
R E D C E L L C O U N T
MI L L/ M C L 
M 
: 4. 4-5. 8 ( 1 8 -6 4y)
M 
: 3. 7-5. 5 ( 6 5 +y)
F 
: 3. 9-5. 2 ( 1 8 -6 4y)
F 
: 3. 6-5. 1 ( 6 5 +y)
H E M O G L O BI N
G/ D L 
M 
: 1 3. 8-1 7. 2 ( 1 8 -6 4y)
M 
: 1 1. 8-1 6. 8 ( 6 5 +y)
F 
: 1 2. 0-1 5. 6 ( 1 8 -6 4y)
F 
: 1 1. 1-1 5. 5 ( 6 5 +y)
< 7. 1 or > 1 9. 9 
H E M A T O C RI T
%
M 
: 4 1. 0-5 0. 0 ( 1 8 -6 4y)
M 
: 3 6. 0-4 9. 0 ( 6 5 +y)
F 
: 3 5. 0-4 6. 0 ( 1 8 -6 4y)
F 
: 3 3. 0-4 6. 0 ( 6 5 +y)
< 2 0. 1 or > 5 9. 9 
W HI T E C E L L C O U N T
T H O U/ M C L 
3. 8 -1 0. 8 ( 1 8 +y)
< 1. 1
T O T A L N E U T R O P HI L S, A B S. 
T H O U/ M C L 
1. 8 0 -8. 0 0 ( 1 +y)
T O T A L N E U T R O P HI L S 
%
4 0. 0 -7 5. 0 ( 1 8 +y)
N E U T R O P HI L S, S E G S .  A B S. 
T H O U/ M C L 
1. 8 0 -8. 0 0 ( 1 +y)
N E U T R O P HI L S, S E G S. 
%
4 0. 0 -7 5. 0 ( 1 8 +y)
N E U T R O P HI L S, B A N D S, A B S. ■
T H O U/ M C L 
0. 0 0 -0. 8 6 ( 1 8 +y)
N E U T R O P HI L S, B A N D S ■
%
0. 0 -8. 0 ( 1 8 +y)
L Y M P H O C Y T E S, A B S. 
T H O U/ M C L 
0. 8 5 -4. 1 0 ( 1 +y)
L Y M P H O C Y T E S
%
1 6. 0 -4 6. 0 ( 1 8 +y)
M O N O C Y T E S, A B S.
T H O U/ M C L 
0. 2 0 -1. 1 0 ( 1 +y)
M O N O C Y T E S
%
0. 0 -1 2. 0 ( 1 8 +y)
E O SI N O P HI L S, A B S.
T H O U/ M C L 
0. 0 5 -0. 5 5 ( 0 +y)
E O SI N O P HI L S
%
0. 0 -7. 0 ( 1 8 +y)
B A S O P HI L S, A B S.
T H O U/ M C L 
0. 0 0 -0. 2 0 ( 1 +y)
B A S O P HI L S
%
0. 0 -2. 0 ( 0 +y)
y = y e ars
■ N e utr o p hil, B a n ds ar e r e p ort e d o nly if s e e n o n a m a n u al diff er e nti al.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 1
H E M A T O L O G Y – LI V E R E V E N T A S S E S S M E N T – SI
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
** P H O N E A L E R T R A N G E
P L A T E L E T C O U N T
GI/ L 
1 3 0 -4 0 0 ( 1 +y)
< 3 1 or > 1, 4 9 9
R E D C E L L C O U N T
TI/ L 
M 
: 4. 4-5. 8 (18-6 4y)
M 
: 3. 7-5. 5 ( 6 5 +y)
F 
: 3. 9-5. 2 ( 1 8 -6 4y)
F 
: 3. 6-5. 1 ( 6 5 +y)
H E M O G L O BI N
G/ L 
M 
: 1 3 8-1 7 2 ( 1 8 -6 4y)
M 
: 1 1 8-1 6 8 ( 6 5 +y)
F 
: 1 2 0-1 5 6 ( 1 8 -6 4y)
F 
:  1 1 1-1 5 5 ( 6 5 +y)
< 7 1 or > 1 9 9
H E M A T O C RI T
1 
M 
: 0. 4 1 0-0. 5 0 0 ( 1 8 -6 4y)
M 
: 0. 3 6 0-0. 4 9 0 ( 6 5 +y)
F 
: 0. 3 5 0-0. 4 6 0 ( 1 8-6 4y)
F 
: 0. 3 3 0-0. 4 6 0 ( 6 5 +y)
< 0. 2 0 1 or > 0. 5 9 9 
W HI T E C E L L C O U N T
GI/ L 
3. 8 -1 0. 8 ( 1 8 +y)
< 1. 1
T O T A L N E U T R O P HI L S, A B S. 
GI/ L 
1. 8 0 -8. 0 0 ( 1 +y)
T O T A L N E U T R O P HI L S
% 
4 0. 0 -7 5. 0 ( 1 8 +y)
N E U T R O P HI L S, S E G S .  A B S. 
GI/ L 
1. 8 0 -8. 0 0 ( 1 +y)
N E U T R O P HI L S, S E G S.
% 
4 0. 0 -7 5. 0 ( 1 8 +y)
N E U T R O P HI L S, B A N D S, A B S. ■
GI/ L 
0. 0 0 -0. 8 6 ( 1 8 +y)
N E U T R O P HI L S, B A N D S ■
% 
0. 0 -8. 0 ( 1 8 +y)
L Y M P H O C Y T E S, A B S.
GI/ L 
0. 8 5 -4. 1 0 ( 1 +y)
L Y M P H O C Y T E S
% 
1 6. 0 -4 6. 0 ( 1 8 +y)
M O N O C Y T E S, A B S.
GI/ L 
0. 2 0 -1. 1 0 ( 1 +y)
M O N O C Y T E S
% 
0. 0 -1 2. 0 ( 1 8 +y)
E O SI N O P HI L S, A B S.
GI/ L 
0. 0 5 -0. 5 5 ( 0 +y)
E O SI N O P HI L S
% 
0. 0 -7. 0 ( 1 8 +y)
B A S O P HI L S, A B S.
GI/ L 
0. 0 0 -0. 2 0 ( 1 +y)
B A S O P HI L S
% 
0. 0 -2. 0 ( 0 +y)
y = y e ars
■ N e utr o p hil, B a n ds ar e r e p ort e d o nly if s e e n o n a m a n u al diff er e nti al.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 2
LI V E R E V E N T A S S E S S M E N T
A N A L Y T E
U NI T S 
R E F E R E N C E R A N G E S 
** P H O N E A L E R T R A N G E
H E P A TI TI S Bs Ag
N O N R E A C TI V E
H E P A TI TI S B C O R E A b I g M
N O N R E A C TI V E
H E P A TI TI S A I g M
N O N R E A C TI V E
C M V I g M A b
I N D E X 
< 0. 9
E B V I g M A b
I S R
N E G A TI V E
≤ 0. 9 0 ( Str e n gt h of Si g n al)
H E P A TI TI S C VI R U S R N A 
I U/ ML
L O G I U/ M L
< 4 3
< 1. 6 3
H E P A TI TI S E I g M
N O T D E T E C T E D
A N A S C R E E N W/ R E F L E X T O 
TI T E R A N D P A T T E R N
TI T E R 
N E G A TI V E ( Scr e e n)
< 4 0 (I F A Tit er)
A C TI N
U NI T S 
< 2 0
T Y P E 1 A N TI -LI V E R KI D N E Y 
MI C R O S O M A L A b
U NI T S
2 0
T O T A L I g G:
M G/ D L
( C o nv. U nit)
6 9 4 -1 6 1 8 ( 1 6 -9 9y)
G/ L
( SI U nit)
6. 9 4 -1 6. 1 8 ( 1 6 -9 9y)
A C E T A MI N O P H E N A D D U C T 
A S S A Y
N M O L/ M L 
R E F E R E N C E R A N G E N O T 
E S T A B LI S H E D
H E P A TI TI S B D N A P C R 
Q U A N TI T A TI V E:
H B V D N A P C R
I U/ M L 
< 2 0
H B V D N A L O G
L O G I U/ M L 
< 1. 3 0
H B V D N A P C R C O PI E S 
C O PI E S/ M L 
< 1 1 6
H E P A TI TI S D A b
N E G A TI V E
y = y e ars 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 3
1 1. 1 4. 
A p p e n di x 1 4 – P h o n e Vi sit Q u e sti o n n air e
P h o ne visits will be c o n d ucte d at Wee k 1 0, Wee k 1 4, Wee k 1 8, a n d Wee k 2 2.  D uri n g 
eac h of t hese p h o ne visits, t he f oll o wi n g q uesti o ns s h o ul d be disc usse d: 
As k o pe n -e n de d a n d n o nlea di n g q uesti o ns t o i n q uire a b o ut t he occ urre nce of A Es.  
A p pr o priate q uesti o ns i ncl u de t he f oll o wi n g:
 
“ H o w are y o u feeli n g?”
 
“ Ha ve y o u ha d a n y ( ot her) me dical pr o ble ms si nce yo ur last visit/c o ntact?”
 
“ Ha ve y o u ta ke n a n y ne w me dici nes, ot her t ha n t h ose pr o vi de d i n t his st u d y, si nce 
y o ur last visit/c o ntact?” 
As k a b o ut c ha n ges t o c o nc o mita nt me dicati o ns a n d t he s u bject’s c urre nt ster oi d d ose a n d 
pr o gress wit h t he ster oi d ta per.  
 
Ha ve y o u c ha n ge d t he d osa ge of a n y of y o ur ot her me dici nes?
 
W hat d ose of pre d nis o ne/ pre d nis ol o ne are y o u c urre ntl y ta ki n g?
 
W he n di d y o u last c ha n ge y o ur d ose of pre d nis o ne/ pre d nis ol o ne?
 
W hat was t he reas o n f or y o ur last c ha n ge i n d ose of pre d nis o ne/ pre d nis ol o ne 
(e g, decrease d acc or di n g t o sc he d ule d ta per or i ncrease d beca use of disease fl are)?
As k q uesti o ns fr o m t he ne ur ol o gical s y m pt o ms q uesti o n naire (see A p pe n di x 5 ).
Gi ve s u bjects t he o p p ort u nit y  t o as k a ny a d diti o nal q uesti o ns a n d t o disc uss a n y p ote ntial 
c o ncer ns.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 4
1 1. 1 5. 
A p p e n di x 1 5 – Pr ot o c ol C h a n g e s
Pr o t o c ol A m e n d m e nt 1: 2 1 J u n e 2 0 1 3
A p plic a bl e t o all c o u ntri es a n d st u dy c e nt ers .
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Titl e p a g e 
N A
P r ot oc ol a m e n d m e nt n u m b er a n d 
r evisi o n c hr o n ol o gy
N A
S p o ns or 
i nf or m ati o n
Gl ax o Gr o u p Li mit e d d/ b/ a 
Gl ax o S mit h Kli n e
Gl a xo W ellc o m e H o us e 
B erk el ey Av e n u e,
Gr e e nf or d , Mi d dl es ex, 
U B 6 0 N N , U K
Gl ax o Gr o u p Li mit e d, E n gl a n d d/ b/ a 
Gl ax o S mit h Kli n e
9 8 0 Gr e at W e st R o a d
Br e ntf or d , Mi d dl es ex, T W 8 9 G S , 
U K
C h a n g e of S p o ns or ’sl e g al 
r e gist er e d a d dr ess
Pr ot oc ol -
s p ecific 
d efi niti o ns
A bs e n c e of n e w or n o n h e ali n g 
( est a blis h e d) l esi o ns f or 
8 w e eks 
A bs e nc e of n e w or n o n h e ali n g 
( est a blis h e d) l esi o ns f or 8 w e eks 
( N ot e: S u bj e ct s wit h e xi sti n g, 
h e ali n g l e si o n s m a y b e 
c o n si d er e d i n r e mi s si o n if ot h er 
crit eri a ar e m et.)
Cl arific ati o n
Pr ot oc ol 
s um m ary; 
S ecti o n 3. 1
S u bj ects will visit t h e cli nic 
d uri n g Scr e e ni n g, at B as eli n e 
( W e ek 0), at W e eks 2 a n d 4, 
a n d ev ery 4 w e eks fr o m W e ek 
4 t hr o u g h W e ek 6 0 .  S u bj ects 
will als o h av e str uct ur e d p h o n e 
visits b et w e e n e ac h of t h e cli nic 
visits fr o m W e ek 6 t hr o u gh 
W e ek 2 2.
S u bj ects will visit t h e cli nic d uri n g 
Scr e e ni n g; at B as eli n e ( W e ek 0); at 
W e eks 2, 4, 6 , a n d 8; a n d t h e n 
ev ery 4 w e eks fr o m W e e k 8 t hr o u g h 
W e ek 6 0 .  S u bj ects will als o h av e 
str uct ur e d p h o n e visits b et w e e n 
e ac h of t h e cli nic visits fr o m W e e k 
1 0 thr o u g h W e ek 2 2.
U p d at e d t o r efl ect c h a n g e 
fr o m a p h o n e visit t o a cli nic 
visit at W e ek 6.
Fi g ur e 3- 1 ; 
T a bl e 6- 1
W e ek 6 = P h o n e visit
W e ek 6 = Cli ni c visit
A d diti o n al cli nic visit t o 
m o nit or pr o gr ess wit h 
st er oi d t a p er.
Pr ot oc ol 
s u m m ary; 
S ecti o n 3. 1
… eli gi bl e s u bj ects will b e 
c e ntr ally r a n d o miz e d …
… eli gi bl e s u bj ects will b e c e ntr ally 
r a n d o miz e d 1: 1 a cr o s s 2 str at a 
( di s e a s e d ur ati o n [1 y e ar, > 1 
y e ar] a n d b a s eli n e pr e d ni s o n e 
d o s e [ < 6 0 m g, 6 0 m g]) …
A d diti o n al d escri pti o n of 
r a n d o miz ati o n i n st u dy 
d esi g n s e cti o n f or cl arity
Pr ot oc ol 
s u m m ary; 
S ecti o n 3. 1
& S ecti o n 
3. 1. 3 ; 
T a bl e 6- 1
N A
S u bj ects w h o wit h dr a w fr o m 
tr e at m e nt will als o e nt er t h e 
I n divi d u aliz e d F oll o w-u p P eri o d.
Cl arific ati o n t h at all 
s u bj ects, i ncl u di n g e arly 
wit h dr a w als fr o m tr e at m e nt, 
s h o ul d b e tr a nsiti o n e d t o t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 5
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T a bl e 3- 2 
N A
a. …   F or s u bj ects at a st arti n g d os e 
> 1 6 0 m g, t a p er d os e by 2 0 m g 
ev ery 2 w e eks u ntil t h e d os e is 
1 6 0 m g, at w hic h p oi nt t h e 
d ecr e m e nts s h o w n o n t h e t a bl e 
a b ov e s h o ul d b e us e d.
A d d e d g ui d a nc e f or 
i niti ati o n of st er oi d t a p er f or 
s u bj ects at st arti n g d os es 
> 1 6 0 m g
S ecti o n 4. 2 
2. Hist ory of bi o psy c o nsist e nt 
wit h P V …
2. Hist ory of bi o psy c o nsist e nt wit h 
P V... If n o hi st or y, a bi o p s y m a y 
b e p erf or m e d d uri n g t h e 
S cr e e ni n g P eri o d.
T h er e is a c h a nc e t h at n ot 
all p ot e nti al s u bj ects will 
h av e h a d a bi o psy pri or t o 
scr e e ni n g.
S ecti o n 4. 3 
4. Pri or tr e at m e nt wit h …  
Syst e mic a nti bi otic p e m p hi g us 
tr e at m e nts ( e g, mi n ocycli n e or 
d oxycycli n e)
4. Pri or tr e at m e nt wit h …  
m et h otr e x at e
T h e eff ect of a nti bi otics f or 
tr e ati n g p e m p hi g us l esi o ns 
is mi ni m al, b ut s u bj ects m ay 
r e q uir e tr e at m e nt f or 
i nf ecti o n d uri n g t h e st u dy.  
A d d e d excl usi o n f or
m et h otr ex at e as itis us e d 
by s o m e p hysici a ns f or t h e 
tr e at m e nt of p e m p hi g us.
S ecti o n 5. 6.
2
A ny ot h er syst e mic tr e at m e nt 
f or P V (i ncl u di n g rit uxi m a b, 
myc o p h e n ol at e, az at hi o pri n e, 
d a ps o n e, syst e mic a nti bi otic 
tr e at m e nts s uc h as 
mi n ocycli n e, d oxycycli n e) ev e n 
if n ot s p ecific ally b ei n g 
pr escri b e d f or P V.
A ny ot h er syst e mic tr e at m e nt f or P V 
(i ncl u di n g rit uxi m a b, myc o p h e n ol at e, 
az at hi o pri n e, d a ps o n e, a n d 
m et h otr e x at e ) ev e n if n ot 
pr escri b e d s p ecifi c ally f or P V.
S ecti o n 4. 3 
6. Evi d e nc e or hist ory of 
cli nic ally si g nific a nt i nf ecti o n 
i ncl u di n g: Pri or tr e at m e nt wit h 
a ny ly m p h ocyt e -d e pl eti n g 
t h er a pi es, i ncl u di n g, b ut n ot 
li mit e d t o cl a dri bi n e, a nti-C D 4, 
t ot al b o dy irr a di ati o n, or b o n e 
m arr o w tr a ns pl a nt ati o n.
4. Pri or tr e at m e nt wit h … 
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, 
cl a dri bi n e
M or e acc ur at ely 
r e pr es e nt e d u n d er h e a di n g 
of tr e at m e nt r estricti o ns 
t h a n cli nic ally si g nific a nt 
i nf ecti o ns.
S ecti o n 4. 3 
6. F o r H Bs A g n e g ativ e, b u t
H B sA b p osi tiv e (r e g ar dl ess of
H Bs A b st at us) …
6. F o r H Bs A g n e g ativ e, b u t H B c A b 
p ositiv e (r e g ar dl ess o f H Bs A b 
st at us) …
C orr ecti o n 
S ecti o n 4. 3 
9. Pl at el ets < 1. 3 x 1 0 5 GI/ L 
9. Pl at el ets < 1 3 0 GI/ L 
( < 1 3 0, 0 0 0/ m m3)
C orr ecti o n
S ecti o n 4. 3 ; 
T a bl e 6- 1
1 1. Pl a ns t o c h a n g e s m oki n g 
st at us d uri n g t h e c o urs e of t h e 
st u dy.
C oll ect s m oki n g st at us at Scr e e ni n g, 
B as eli n e, W e ek 2 4, W e ek 6 0 , a n d 
e arly wit h dr a w al
C o nsi d er e d m or e r el ev a nt 
t o c oll ect i nf or m ati o n o n 
s m oki n g st at us r at h er t h a n 
excl u d e s u bj ects w h o m ay 
b e pl a n ni n g a c h a n g e 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 6
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 4. 3 
N A
1 1. El ectr oc ar di o gr a m ( E C G) 
s h o wi n g a cli nic ally si g nific a nt 
a b n or m ality or s h o wi n g a Q Tc 
i nt erv al ≥4 5 0 ms ec ( ≥4 8 0 ms ec f or 
s u bj ects wit h a b u n dl e br a nc h bl ock) 
( E C G t o b e o bt ai n e d d uri n g 
Scr e e ni n g/ pri or t o r ec eiv i n g t h e first 
d os e of st u dy dr u g).
Excl usi o n of s u bj ects wit h a 
p ot e nti al risk f act or f or 
a dv ers e c ar di ac o utc o m es.
T a bl e 6- 1; 
S ecti o n 
6. 3. 1 0. 2
E C G at B as eli n e
E C G at S cr e e ni n g
T o all o w ti m e t o o bt ai n t h e 
E C G a n d r es ults b ef or e t h e 
first d os e of i nv esti g ati o n al 
pr o d uct.
S ecti o n 
4. 4. 1
N e utr o p e ni a Gr a d e 3 ( < 1 0 0 0 -
5 0 0 / m m3; < 1. 0-0. 5 x 1 0 9/ L) or 
Gr a d e 4 ( < 5 0 0/ m m 3; < 0. 5 x 
1 0 9/ L)
N e utr o p e ni a wit h a n a b s ol ut e 
n e utr o p hil c o u nt < 1 GI/ L 
( < 1 0 0 0/ m m3; < 1. 0 x 1 09/ L) 
(i e, C T C A E Gr a d e 3 a n d hi g h er)
Cl arific ati o n of d os e -h ol di n g 
t hr es h ol d v al u e 
S ecti o n 
4. 4. 2
A ny s u bj ect w h o disc o nti n u es 
tr e at m e nt s h o ul d e nt er t h e 
F oll o w -u p P eri o d …
A ny s u bj ect w h o disc o nti n u es 
tr e at m e nt pri or t o st u d y 
c o m pl eti o n s h o ul d e nt er t h e 
I n di vi d u aliz e d F oll o w -u p P eri o d …
Cl arific ati o n
S ecti o n 
5. 1. 1
T r ai n e d sit e p ers o n n el will 
a d mi nist er i nv esti g ati o n al 
pr o d uct at W e eks 0, 1 2, 2 4, 3 6, 
a n d 4 8 …
Tr ai n e d sit e p ers o n n el will 
a d mi nist er 0. 6 m L of i nv esti g ati o n al 
pr o d uct at W e eks 0, 1 2, 2 4, 3 6, 
a n d 4 8 …
Cl arific ati o n t h at e ac h d os e 
will b e 0. 6 m L (i ncl usiv e of
d os es fr o m vi als a n d fr o m 
pr efill e d syri n g es)
S ecti o n 
5. 1. 2
… pr e m e dic ati o n wit h 
ac et a mi n o p h e n/ p ar ac et a m ol 
a n d a n a nti hist a mi n e, as 
d escri b e d i n T a bl e 5 -1.
… pr e m e dic ati o n wit h 
ac et a mi n o p h e n/ p ar ac et a m ol a n d a n 
a nti hist a mi n e (s e e T a bl e 5 -1), 
w hi c h will b e a d mi ni st er e d at t h e 
cli ni c.
Cl arific ati o n t h at all 
pr e m e dic ati o n will b e 
a d mi nist er e d at t h e st u dy 
c e nt er.
S ecti o n
5. 3
Aft er t h e W e ek 6 0 visit a n d all
I n divi d u aliz e d F oll o w- u p visits …
Aft er t h e W e ek 6 0 visit a n d e a c h
I n divi d u aliz e d F oll o w-u p visit …
Cl ar ific ati o n t h at n otific ati o n 
will b e aft er e ac h visit n ot 
aft er all f oll o w -u p visits h av e 
b e e n c o m pl et e d.
T a bl e 6- 1 
N A
A d d e d I g G, I g M, I g A at Scr e e ni n g 
I m m u n o gl o b uli n lev els ar e 
p art of t h e excl usi o n crit eri a, 
b ut w er e n ot s p ecifi e d as 
p art of scr e e ni n g l a b or at ory 
t ests.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 7
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T a bl e 6- 1 
N ot e: Visits s h o ul d b e 
sc h e d ul e d wit hi n 3 d ays of t h e 
s p ecifi e d ti m e p oi nt.
N ot e: Visits fr o m W e e k 0 t hr o u g h 
W e e k 6 0 s h o ul d b e sc h e d ul e d 
wit hi n 3 d ays of t h e s p ecifi e d ti m e 
p oi nt.
Vi sit s d uri n g t h e I n di vi d u aliz e d 
F oll o w -u p P eri o d s h o ul d b e 
s c h e d ul e d wit hi n 7 d a y s of t h e 
s p e cifi e d ti m e p oi nt.
A wi d er visit wi n d o w is m or e 
pr actic al d uri n g t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d a n d v ari ati o ns i n 
ti mi n g of t h e ass ess m e nts 
will n ot i m p act t h e a n alys es.
T a bl e 6- 2 
D ay 0 bl o o d dr a ws will occ ur 
pr e d os e a n d 1 2 h o urs
p ost d os e.
D ay 0 bl o o d dr a ws will occ ur 
pr e d os e a n d 4 h o ur s p ost d os e.
F e asi bility a t t h e st u dy 
c e nt ers.
S ecti o n 
6. 3. 2. 3
S u bj ects s h o ul d b e wit h dr a w n 
fr o m i nv esti g ati o n al pr o d uct 
( a n d G S K m e dic al m o nit or 
n otifi e d as s o o n as p ossi bl e) f or 
t h e f oll o wi n g r e as o ns: 
T h e m e dic al m o nit or s h o ul d b e 
n otifi e d of t h e f oll o wi n g A Es of 
s p eci al i nt er est.  R ef er t o 
S ecti o n 4. 4. 2 a n d S ecti o n 4. 4. 3 f or 
disc o nti n u ati o n crit eri a.
C orr ecti o n/cl arific ati o n
S ecti o n 
6. 3. 1 0. 1
Or al t e m p er at ur e
T e m p er at ur e
S u bj ects wit h or al l esi o ns 
m ay r e q uir e ot h er m e a ns of 
o bt ai ni n g a t e m p er at ur e.
S ecti o n 
8. 3. 4
A n i nt eri m a n alysis f or f utility … 
will b e c o n d uct e d b y t h e I D M C.
A n i nt eri m a n alysis f or f utility … will 
b e c o n d uct e d by a n u n bli n d e d 
st ati sti ci a n n ot i n v ol v e d i n t h e 
c o n d u ct of t h e st u d y a n d 
pr e s e nt e d t o t h e I D M C.
Cl arific ati o n
S ecti o n 
8. 3. 5. 5
… l e a d t o a c o ns erv ativ e ( < 0. 0 2 5 
o n e -si d e d) ty p e-1 err or f or all
c orr el ati o ns < 0. 9.
… l e a d t o a c o ns erv ativ e ( < 0. 0 2 5 
o n e -si d e d) ty p e-1 err or f or all 
c orr el ati o ns 0. 9.
C orr ecti o n
(c h a n g e d fr o m < t o )
A p p e n dix 4 
At a mi ni m u m, bl o o d J C V P C R 
a n d/ or M RI s h o ul d b e 
p erf or m e d; if eit h er t est is 
p ositiv e, c er e br os pi n al fl ui d 
( C S F) J C V P C R s h o ul d b e 
p erf or m e d.  If bl o o d J C V P C R
a n d M RI ar e n e g ativ e, t h e 
i nv esti g at or s h o ul d c o nt act t h e 
S p o ns or f or a p pr o pri at e acti o n 
t o b e t ak e n.  If bl o o d J C V P C R
a n d/ or M RI ar e p ositiv e …
At a mi ni m u m, bl o o d J C V ( P C R 
a n d/ or J C V a nti b o d y t e sti n g ) wit h 
or wit h o ut a n M RI s h o ul d b e 
p erf or m e d; if a n y t est is p ositiv e, 
c er e br os pi n al fl ui d ( C S F) J C V 
t e sti n g s h o ul d b e p erf or m e d.  If 
bl o o d J C V t e sti n g a n d M RI ar e 
n e g ativ e, t h e i nv esti g at or s h o ul d 
c o nt act t h e S p o ns or f or a p pr o pri at e 
acti o n t o b e t ak e n.  I f bl o o d J C V 
t e sti n g a n d/ or M RI ar e p ositiv e …
J C V a nti b o dy t esti n g m ay 
b e us e d i nst e a d of P C R 
A p p e n dix 1 3 
N A
C e ntr al l a b or at ory r ef er e nc e r a n g es 
F or r ef er e nc e

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 8
Pr ot o c ol A m e n d m e nt 2:  2 6 S e pt e m b er 2 0 1 3
A p plic a bl e t o all c o u ntri es a n d st u dy c e nt ers.  
** This a m e n d m e nt w as s u p ers e d e d by Pr ot oc ol A m e n d m e nt 3 b ef or e i m pl e m e nt ati o n at a ny st u dy c e nt er **
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Titl e p a g e 
N A
Pr ot oc ol a m e n d m e nt n u m b er a n d 
r evisi o n c hr o n ol o gy
S p o ns or 
i nf or m ati o n
N A
M e dic al m o nit or n a m e a n d c o nt act 
i nf or m ati o n f or Asi a P acific r e gi o n.
Pr ot oc ol 
s u m m ary; 
S ecti o n 1. 2, 
S ecti o n 1 0
… r e d uci n g m ort ality t o 
a p pr oxi m at ely 5 % t o 1 0 %
[ R o bi ns o n, 1 9 9 7].  
… r es p o ns e t o rit uxi m a b h as 
c orr el at e d wit h B-c ell d e pl eti o n 
[ M o u q u et, 2 0 0 8; E mi n g, 2 0 0 8].
… r e d uci n g m ort ality t o a p pr oxi m at ely 
5 % t o 1 5 % [ R o bi ns o n, 1 9 9 7; 
L a n g a n 2 0 0 8 ].  
… r es p o ns e t o rit uxi m a b h as 
c orr el at e d wit h B-c ell d e pl eti o n 
[ M o u q u et, 2 0 0 8; E mi n g, 2 0 0 8; 
C olli o u, 2 0 1 3 ].
M or e r ec e nt r ef er e nc e s
r e g ar di n g P V m ort ality a n d 
cli nic al r es p o ns e t o 
rit uxi ma b .
Pr ot oc ol 
s u m m ary; 
S ecti o n 3. 1
… of at u m u m a b S C i n s u bj ects 
wit h activ e P V …
… of at u m u m a b S C i n s u bj ects wit h 
P V …
Cl arity.  
Pr ot oc ol 
s u m m ary; 
T a bl e 3 - 1; 
S ecti o n 2. 3
Ot h er O bj ectiv es: 
 
T o ass ess t h e 
p h ar m ac o dy n a mics of 
of at u m u m a b ...
Ot h er O bj ectiv es: 
 
T o ass ess t h e p o p ul ati o n
p h ar m ac o dy n a mics of 
of at u m u m a b ….
Cl arific ati o n.
Pr ot oc ol 
s u m m ary; 
T a bl e 3 -1; 
S ecti o n 6. 5
N A
P h ar m ac oki n etic e n d p oi nts:
 
Pl a s m a (tr o u g h) 
c o n c e ntr ati o n s of of at u m u m a b
 
E x p o s ur e -r e s p o n s e 
r el ati o n s hi p
N e w e n d p oi nts t o d et er mi n e 
of at u m u m a b pl as m a 
c o nc e ntr ati o ns acr oss t h e 
w h ol e st u dy p o p ul ati o n.
S ecti o n 
3. 1. 1
A Scr e e ni n g P eri o d of u p t o 
1 2 w e eks will all o w s u bj ects 
w h o h av e activ e l esi o ns at t h e 
i niti al Scr e e ni n g Visitt o ac hi ev e 
dis e as e c o ntr ol usi n g a st a bl e 
d os e of 2 0 m g/ d ay u p t o 
1 2 0 m g/ d ay …  
A Scr e e ni n g P eri o d of u p t o 
1 2 w e eks will all o w s u bj ects t o 
ac hi ev e dis e as e c o ntr ol (i e, n o n e w 
l e si o n s f or 2 w e e k s) usi n g a 
st a bl e d os e of 2 0 m g/ d ay u p t o 
1 2 0 m g/ d ay... 
R ef er t o t h e st u d y pr o c e d ur e s 
m a n u al ( S P M) f or r et e sti n g a n d/ or 
r e s cr e e ni ng pr o c e d ur e s .
Cl arific ati o n.
T a bl e 3 - 2 
F o ot n ot e c. … a n att e m pt at 
r e d uci n g t h e st er oi d t a p er
f urt h er n e e d o nly b e att e m pt e d...
F o ot n ot e c. … a n att e m pt at 
r e d uci n g t h e st er oi d d o s e f urt h er 
n e e d o nly b e att e m pt e d …
Cl arific ati o n.
S ecti o n 
3. 1. 4
T h e s u bst u d y … will e nr oll 
a p pr oxi m at ely 1 5 s u bj ects.  
T h e s u bst u dy … will e nr oll 
a p pr oxi m at ely 2 5 s u bj ects.  
I ncr e as e lik eli h o o d of 
o bt ai ni n g d at a fr o m at l e ast 
1 0 ev al u a bl e s u bj ects.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 3 9
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T a bl e 3 - 3 
Pl ac e b o gr o u p: M axi m u m -4 2. 1 5
F o ot n ot e b: T h e l o w 
mi ni m u m % c h a n g e i n C D 1 9 + 
B- c ells …
Pl ac e b o gr o u p: M axi m u m + 4 2. 1 5  
Err or c orr ecti o n.
F o ot n ot e w as n ot a p plic a bl e 
t o D ay 8 5 ti m e p oi nt.
S ecti o n 4. 3 
6. P ositiv e t est f o r H Bs A g.  F o r
H Bs A g n e g ativ e, b u t H Bc A b
p ositiv e (r e g ar dl ess o f H Bs A b 
st at us), a n H B V D N A t est will 
b e p erf or m e d a n d t h e s u bj ect 
will b e excl u d e d if r es ults ar e 
p ositiv e.  
6. P ositiv e t est f o r H Bs A g.  F o r
H Bs A g n e g ativ e, b ut a nti -H B c
p ositiv e (r e g ar dl ess o f H Bs A b 
st at us), a n H B V D N A t est will b e 
p erf or m e d a n d t h e s u bj ect will b e 
excl u d e d if r es ults ar e p ositiv e. 
C o n s ult wit h a p h y si ci a n 
e x p eri e n c e d i n t h e c ar e a n d 
m a n a g e m e nt of s u bj e ct s wit h 
h e p atiti s B t o m a n a g e/tr e at 
s u bj e ct s w h o ar e a nti -H B c 
p o siti v e.
C o nsist e ncy wit h r ec e nt 
pr o p os e d c h a n g e t o U S 
pr escri bi n g i nf or m ati o n f or 
A R Z E R R A.
S ecti o n 4. 3 
9. A ny of t h e f oll o wi n g 
scr e e ni n g l a b or at ory v al u es:
• Bilir u bi n > 1. 5 x U L N.
• C D 4 c o u nt < 5 0 0 c ells/ m m3.
9. A ny of t h e f oll o wi n g scr e e ni n g 
l a b or at ory v al u es:
• Bilir u bi n > 1. 5 x U L N (e x c e pt i n 
c a s e s of i s ol at e d pr e d o mi n a ntl y 
i n dir e ct h y p er bilir u bi n e mi a d u e t o 
Gil b ert’ s s y n dr o m e).
Gil b ert’s sy n dr o m e is a 
b e ni g n, b ut f airly pr ev al e nt, 
c o n diti o n. 
C D 4 c o u nt is n ot ty pic ally 
ass ess e d pri or t o i niti ati o n 
of a nti -C D 2 0 tr e at m e nt 
( pri m arily rit uxi m a b) i n P V, 
a n d C D 4 c o u nt h as n ot 
b e e n a r e q uir e d excl usi o n 
crit eri o n acr oss t h e 
of a t u m u m a b pr o gr a m.  
R e m ovi n g t h e excl usi o n of 
s u bj ects wit h C D 4 c o u nt 
< 5 0 0 c ells/ m m 3 is n ot 
ex p ect e d t o a dv ers ely 
i m p act s u bj ect s af ety d uri n g 
t h e st u dy.
Excl u di n g s u bj ects o n t h e 
b asis of u n d erlyi n g Gil b ert’s 
sy n dr o m e or b as eli n e C D 4 
c o u nt m ay u n n ec ess arily
li mit t h e st u dy p o p ul ati o n a n d 
m ay n ot b e r e pr es e nt ativ e of 
t h e ov er all P V p o p ul ati o n.
S ecti o n 
5. 1. 1
D os e pr e p ar ati o n i nstr ucti o ns 
will b e pr ovi d e d i n t h e S P M. 
S e e t h e S P M f or d et ail e d 
i nstr ucti o ns r el at e d t o t h e 
d estr ucti o n of u n us e d m at eri als. 
D os e p r e p ar ati o n i nstr ucti o ns ar e 
pr ovi d e d i n t h e u n bli n d e d 
p h ar m a ci st m a n u al .  
D et ail e d i nstr ucti o ns r el at e d t o t h e 
d estr ucti o n of u n us e d m at eri als ar e 
pr o vi d e d i n t h e u n bli n d e d 
p h ar m a ci st m a n u al.
Cl arific ati o n of sit e 
r ef er e nc e d oc u m e nt.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 0
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 5. 3 
F ull d et ails f or c o nt acti n g t h e 
c e ntr al I V R syst e m t o u n bli n d a 
s u bj ect ar e c o nt ai n e d wit hi n t h e 
S P M.
E m er g e ncy u n bli n di n g will b e 
av ail a bl e vi a t h e c e ntr al I V R syst e m 
(r ef er t o t h e S P M a n d I V R S 
g ui d eli n e s f or a p pr o pri at e 
pr o c e d ur e s t o f oll o w) .
Cl arity – t h e st u dy c e nt er 
s h o ul d n ot u n bli n d vi a I V R 
wit h o ut first att e m pti n g t o 
c o nt act t h e m e dic al m o nit or.
T a bl e 6 -1 
Ti m e a n d 
ev e nts t a bl e
N A
Pl as m a s a m pl es will b e c oll ect e d 
fr o m all s u bj ects pr e d os e at 
B as eli n e a n d at W e eks 1 2, 2 4, 3 6, 
4 8, a n d 6 0 ( or e arly wit h dr a w al) t o 
d et er mi n e of at u m u m a b tr o u g h 
c o nc e ntr ati o ns.
T o d et er mi n e of at u m u m a b 
pl as m a c o nc e ntr ati o ns 
acr oss t h e w h ol e st u dy 
p o p ul ati o n.
T a bl e 6 -2 
S u bst u dy
N A
Pr e d os e p h ar m ac oki n etic s a m pl es 
a d d e d t o W e ek 2 4 a n d W e ek 3 6.
S a m pl es will b e c oll ect e d 
fr o m all s u bj ects at t h es e 
ti m e p oi nts.
S ecti o n 
6. 3. 1
I nstr ucti o ns f or s a m pl e h a n dli n g 
a n d s hi p pi n g ar e i n t h e S P M .
I nstr ucti o ns f or s a m pl e h a n dli n g a n d 
s hi p pi n g ar e pr ovi d e d i n t h e  
 
i n v e sti g at or m a n u al.
Cl arific ati o n of sit e 
r ef er e nc e d oc u m e nt.
S ecti o n 
6. 3. 2. 1
T h e si g ns a n d sy m pt o ms 
a n d/ or cli nic al s e q u el a e 
r es ulti n g fr o m l ack of effic acy 
will b e r e p ort e d if t h ey f ulfill t h e 
d efi niti o n of a n A E or S A E.  
Als o, “l ack of effic acy” or 
“f ail ur e of ex p ect e d 
p h ar m ac ol o gic al acti o n” als o 
c o nstit ut es a n A E or S A E.
N A
Err o n e o us t ext.
S ecti o n 
6. 3. 9
T h e S P M pr ovi d es t h e m et h o d 
of r ec or di n g, ev al u ati n g, a n d 
f oll o w-u p of A Es a n d S A Es, 
pr oc e d ur es f or c o m pl eti n g a n d 
tr a ns mitti n g S A E r e p orts t o 
G S K, a n d pr oc e d ur es f or p ost -
st u dy A Es/ S A Es.
T h e S P M pr ovi d es dir e cti o n 
r e g ar di n g t h e r ec or di n g, r e p orti n g/ 
tr a n s mitti n g, a n d f oll o w -u p of 
S A Es.
Cl arific ati o n/c orr ecti o n of 
s u p pl e m e nt al i nf or m ati o n 
pr ovi d e d i n t h e S P M.
S ecti o n 
6. 3. 9. 2
R ef er t o t h e S P M f or 
a p pr o pri at e pr oc essi n g a n d 
h a n dli n g of s a m pl es...
R ef er t o t h e  
 i n v e sti g at or 
m a n u a l f or a p pr o pri at e pr oc essi n g 
a n d h a n dli n g of s a m pl es... 
Cl arific ati o n of sit e 
r ef er e nc e d oc u m e nt.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 1
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 
6. 3. 9. 2
F or s u bj ects w h o ar e H Bc A b 
p ositiv e a n d H B V D N A 
n e g ativ e, p erf or m H B V D N A
P C R t esti n g at a mi ni m u m of 
ev ery 2 m o nt hs d uri n g t h e 
Tr e at m e nt a n d F oll o w -u p
P eri o ds .  If a s u bj ect b ec o m es 
H B V D N A + d uri n g t h e c o urs e 
of t h e st u dy, disc o nti n u e f urt h er 
tr e at m e nt … S u bj ects m ay 
r ec eiv e f urt h er tr e at m e nt p er 
l oc al g ui d eli n es at discr eti o n of 
i nv esti g at or.  S u bj ects w h o are
H Bc A b p ositiv e m ay r ec eiv e 
pr o p hyl axis at t h e i nv esti g a tor's 
discr eti o n .
S u bj e ct s w h o ar e H B s A g 
n e g ati v e, a nti -H B c p o siti v e, a n d 
H B V D N A n e g ati v e m a y b e 
i n cl u d e d i n t h e st u d y, b ut m u st 
u n d er g o H B V D N A m o nit ori n g. 
C o n s ult wit h a p h y si ci a n 
e x p eri e n c e d i n t h e c ar e a n d 
m a n a g e m e nt of s u bj e c t s wit h 
h e p atiti s B t o m a n a g e/tr e at 
s u bj e ct s w h o ar e a nti -H B c 
p o siti v e.  A nti vir al t h er a p y t o b e 
i niti at e d if r e q uir e d.
C o nsist e ncy wit h r ec e nt 
pr o p os e d c h a n g e t o U S 
pr escri bi n g i nf or m ati o n f or 
A R Z E R R A.
S ecti o n 6. 5 
Pl as m a a n alysis will b e 
p erf or m e d u n d er t h e c o ntr ol of 
G S K P T S -D M P K/ Sci n ov o, t h e 
d et ails of w hic h will b e i ncl u d e d 
i n t h e S P M.  …  R a w d at a will 
b e arc hiv e d at t h e bi o a n alytic al 
sit e ( d et ail e d i n t h e S P M).
Pl as m a a n alysis will b e p erf or m e d 
u n d er t h e c o ntr ol of G S K P T S -
D M P K/ Sci n ov o .  T h e d et ail s of 
s a m pl e c oll e cti o n, pr o c e s si n g, 
st or a g e, a n d s hi p pi n g ar e i ncl u d e d 
i n t h e 
 i n v e sti g at or m a n u al.  
…   R a w d at a will b e arc hiv e d at t h e 
bi o a n alytic al sit e , a s p er G S K 
P T S -D M P K pr ot o c ol.
Cl arific ati o n of sit e 
r ef er e nc e d oc u m e nt.
A p p e n dix 4 
At a mi ni m u m , bl o o d J C V ( P C R 
a n d/ or J C V a nti b o dy t esti n g) wit h 
or wit h o ut a n M RI s h o ul d b e 
p erf or m e d ; if a ny t est is p ositiv e, 
c er e br os pi n al fl ui d ( C S F) J C V 
t esti n g s h o ul d b e p erf or m e d.  If 
bl o o d J C V t esti n g a n d M RI ar e 
n e g ativ e, t h e i nv esti g at or s h o ul d 
c o nt act t h e S po ns or f or 
a p pr o pri at e acti o n t o b e t ak e n.  
If bl o o d J C V t esti n g a n d/ or M RI 
ar e p ositiv e …
Bl o o d J C V ( P C R a n d/ or J C V 
a nti b o dy t esti n g) s h o ul d b e 
p erf or m e d.  If i n di c at e d,
c er e br os pi n al fl ui d ( C S F) J C V t esti n g 
s h o ul d als o b e p erf or m e d.  M a g n eti c 
r e s o n a n c e i ma gi n g ( M RI) i s 
str o n gl y r e c o m m e n d e d. If bl o o d 
J C V t esti n g a n d M RI ar e n e g ativ e, 
t h e i nv esti g at or s h o ul d c o nt act t h e 
S p o ns or f or a p pr o pri at e acti o n t o b e 
t ak e n.  If P M L i s c o nfir m e d …  
4. T h e i n d e p e n d e nt P M L a dj u dic at or 
c a n r e q u est a d diti o n al t esti n g a n d 
furt h er d at a c oll ecti o n.
C h a n g es r e q u est e d by 
i n d e p e n d e nt P M L 
a dj u dic at or.
A p p e n dix 1 4 
N A
S p ecific ati o n of s u g g est e d q u esti o ns 
t o ask s u bj ects d uri n g t h e sc h e d ul e d 
p h o n e visits.
A d diti o n al i nf or m ati o n 
r e g ar di n g str uct ur e of p h o n e 
visits p er F D A r e q u est .
A p p e n dix 1 5 
A p p e n dix 1 4
A p p e n dix 1 5.  Li st of all c h a n g e s 
i n Pr ot o c ol A m e n d m e nt 2.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 2
Pr ot o c ol A m e n d m e nt 3:  1 3 M arc h 2 0 1 4
A p plic a bl e t o all c o u ntri es a n d st u dy c e nt ers.  
At t h e ti m e of t his a m e n d m e nt, n o s u bj ects h a d b e e n r a n d o miz e d i n t h e st u dy.
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Titl e p a g e 
N A
P r ot oc ol a m e n d m e nt n u m b er, d at e,
r evisi o n c hr o n ol o gy, a n d a ut h ors .
T hr o u g h o ut 
N A
Mi n or c h a n g es i n t ext a n d 
f or m atti n g.
T o i m pr ov e cl arity.
List of 
d efi niti o ns
S u m of all p eri o ds of r e missi o n 
o n mi ni m al st er oi d t h er a py u p 
t o W e ek 6 0
… a n d m ai nt ai n e d d os e at 
≤1 0 m g/ d ay …
T ot al ti m e ( s u m) of all p eri o ds of 
r e missi o n w hil e o n mi ni m al st er oi d 
t h er a py ( or al pr e d ni s o n e/ 
pr e d ni s ol o n e d o s e ≤1 0 m g/ d a y) 
u p t o W e ek 6 0
… a n d m ai nt ai n e d ≤1 0 m g/ d ay of 
or al pr e d ni s o n e/ pr e d ni s ol o n e …
C o nsist e ncy of w or di n g 
b et w e e n d efi niti o ns a n d
e n d p oi nts.
Titl e p a g e; 
Pr ot oc ol 
s u m m ary; 
S ecti o n 1. 4 ;
S ecti o n 2 . 1;
S ecti o n 3. 1 ; 
Fi g ur e 3- 1; 
T a bl e 3- 1
… 6 0 m g a d mi nist er e d ev ery 
1 2 w e eks …
… 6 0 m g a d mi nist er e d ev ery 
1 2 w e ek s f or 4 8 w e eks …
… ev ery 1 2 w e eks f or a t ot al of 
4 8 w e eks ( 5 d os es , wit h t h e
first d os e occ urri n g o n D ay 0 
s u bs e q u e nt t o e nr oll m e nt a n d 
r a n d o miz ati o n).
… 2 0 m g a d mi nist er e d ev ery
4 w e eks ( wit h a n a d diti o n al 2 0-m g 
‘l o a di n g’ d o s e [i e, 4 0 m g t ot al] at 
b ot h W e e k 0 a n d W e e k 4) …
… 2 0 m g a d mi nist er e d ev ery 
4 w e eks f or 5 6 w e eks …
… ev ery 4 w e eks ( wit h a n a d diti o n al 
2 0 -m g ‘l o a di n g’ d o s e at b ot h W e e k 
0 a n d W e e k 4) f or a t ot al of 5 6 w e eks 
(t ot al of 1 7 i nj e cti o n s a cr o s s 
1 5 m o nt hl y d o si n g vi sit s ).
C h a n g e i n d os e a n d d osi n g 
i nt erv al.
Pr ot oc ol 
s u m m ary; 
S ecti o n 3. 1; 
T a bl e 3 -1; 
Fi g ur e 3 - 1
… 4 8 -w e e k Tr e at m e nt P eri o d …
… a 4 8 -w e ek Tr e at m e nt P eri o d, 
a n d a 1 2 -w e ek F oll o w- u p 
P eri o d …
Aft er t h e l ast d os e … at 
W e ek 4 8 … f oll o w e d -u p f or a 
mi ni m u m of 1 2 w e eks, wit h 
visits sc h e d ul e d at W e eks 5 2 , 
5 6 , a n d 6 0.  
… 5 6 -w e ek Tr e at m e nt P eri o d …
… a 5 6 -w e ek Tr e at m e nt P er i o d a n d 
a 4- w e ek F oll o w -u p vi sit …
Aft er t h e l ast d os e … at W e ek 5 6 … 
f oll o w e d-u p f or a mi ni m u m of 
4 w e eks, wit h a visit sc h e d ul e d at 
W e ek 6 0.  
C h a n g e ti mi n g of l ast d os e 
wit h s u bs e q u e nt c h a n g e i n 
i niti al F oll o w-u p t o ali g n wit h 
c h a n g e i n d osi n g i nt erv al 
(n o c h a n g e t o I n divi d u aliz e d 
F oll o w -u p) .
Pr ot oc ol 
s u m m ary; 
S ecti o n 2. 2 ; 
T a bl e 3- 1
S ec o n d ary O bj ectiv es: 
• …t ol er a bility of of at u m u m a b 
S C at a d os e of 6 0 m g 
a d mi nist er e d ev ery 1 2 w e eks .
• … a n d r e pl eti o n f oll o wi n g 
of at u m u m a b S C at a d os e of 
6 0 m g a d mi nist er e d ev ery 
1 2 w e eks .
S ec o n d ary O bj ectiv es: 
• …t ol er a bility of of at u m u m a b.
• … a n d r e pl eti o n f oll o wi n g 
of at u m u m a b S C.
Si m p lific ati o n.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 3
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Pr o t oc ol 
s u m m ary; 
S ecti o n 6. 2. 2; 
S ecti o n 6. 3; 
T a bl e 3- 1
S af ety :
• C u m ul ativ e d os e of 
c ortic ost er oi ds
S af ety:
• P erc e nt a g e of s u bj ects
wit h dr a wi n g d u e t o A Es 
ass ess e d by t h e i nv esti g at ors 
as at l e ast p ossi bly r el at e d t o 
tr e at m e nt
S e c o n d ar y E n d p oi nt s :
• C u m ul ativ e d os e of c ortic ost er oi ds
S af ety: 
• Fr e q u e n c y of wit h dr a w als d u e t o 
tr e at m e nt-r el at e d A Es.
• Fr e q u e n c y of A E s of s p e c i al 
i nt er e st, p o sti nj e cti o n s y st e mi c 
r e a cti o n s, a n d i nj e cti o n sit e 
r e a cti o n s.
C o nsist e ncy acr oss 
s ecti o ns.
S ecti o n 2. 3 
• T o ev al u at e t h e p o p ul ati o n 
p h ar m ac o dy n a mics of 
of at u m u m a b S C a d mi nist er e d 
at a d os e of 6 0 …
• T o a s s e s s t h e p o p ul ati o n 
p h ar m ac o dy n a mic s of of at u m u m a b 
S C …
C o nsist e ncy acr oss 
s ecti o ns.
S ecti o n 3. 1. 3 
… W e ek 6 0 st u dy ass ess m e nts 
will b e c o m pl et e d pri or t o 
i niti ati n g t h e b as eli n e visit oft h e 
O L E st u dy.
N A
… W e ek 6 0 st u dy ass ess m e nts will 
b e c o m pl et e d b ef or e t h e fir st d o s e 
of of at u m u m a b S C i n t h e O L E 
st u dy.
N ot e: S u bj e ct s w h o ar e H B s A g 
n e g ati v e, a nti -H B c p o siti v e, a n d 
H B V D N A n e g ati v e m u st c o nti n u e 
H B V D N A P C R m o nit ori n g at a 
mi ni m u m of e v er y 2 m o nt h s f or 
6 m o nt h s aft er t h e l a st d o s e of 
st u d y tr e at m e nt.
Cl arific ati o n.
S ecti o n 3. 2 
N A
Wit hi n t h e pr ot o c ol, r ef er e n c e t o 
Gl a x o S mit h Kli n e ( G S K) a n d/ or 
, a G S K c o m p a n y (  
) 
i s i n cl u si v e of t a s k s a n d 
r e s p o n si biliti e s t h at will b e 
p erf or m e d b y a c o ntr a ct r e s e ar c h 
or g a niz ati o n ( e g,   
).
Cl arific ati o n.
S ecti o n 3. 3 
** D at a fr o m s m all si n gl e-d os e 
st u dy of of at u m u m a b S C i n 
s u bj ects wit h r h e u m at oi d 
art hritis us e d t o s u p p ort d osi n g 
r e gi m e n of 6 0 m g ev ery 
1 2 w e eks.
** E ntir e d os e r ati o n al e s ecti o n 
r evis e d t o i ncl u d e d at a fr o m r e p e at-
d os e st u dy of of at u m u m a b S C i n 
s u bj ects wit h R R M S, w hic h i n dic at e 
a d osi n g r e gi m e n of 2 0 m g ev ery 
4 w e eks will b e m or e lik ely t o 
m ai nt ai n d esir e d B -c ell d e pl eti o n. 
N e wly -av ail a bl e d at a a n d 
p h ar m ac o m etric m o d eli n g 
s u p p ort c h a n gi n g t h e d os e 
a n d d osi n g r e gi m e n.
S ecti o n 4. 2 
… di a g n osis of P V f or 
> 2 m o nt hs a n d < 5 y e ars.
… di a g n osis of P V f or > 2 m o nt hs 
a n d < 1 0 y e ars.
I nv esti g at or f e e d b ack h as 
i n dic at e d t h at p er mitti n g a 
l o n g er p eri o d si nc e di a g n osis 
m ay i ncr e as e f e asi bility 
wit h o ut a dv ers ely i m p acti n g 
s u bj ects.  U p t o 1 0 y e ars is 
still n ot c o nsi d er e d 
r ec alcitr a nt dis e as e.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 4
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 4. 4. 1 
I nv esti g ati o n al pr o d uct d osi n g 
will b e h el d f or u p t o 2 w e eks i n 
t h e f oll o wi n g sit u ati o ns:
I nv esti g ati o n al pr o d uct d osi n g will 
b e h el d i n t h e f oll o wi n g sit u ati o ns:
If t h e c o n diti o n r e s ol v e s wit hi n 
1 w e e k, a d mi ni st er t h e h el d d o s e 
a n d t h e n r et ur n t o t h e r e g ul ar 
d o si n g s c h e d ul e.  If t h e c o n diti o n 
d o e s n ot r e s ol v e wit hi n 1 w e e k ….
Wi n d o w f or d os e h ol di n g 
s h ort e n e d t o acc o m m o d at e 
t h e c h a n g e i n d osi n g 
i nt erv al.  A d d e d g ui d a nc e 
f or w h e n t o a d mi nist er a 
h el d d os e.
S ecti o n 5. 1. 1 
… pr ovi d e d i n 3 m L gl ass vi al s 
c o nt ai ni n g 1 m L of 
c o nc e ntr ati o n 1 0 0 m g/ m L dr u g 
pr o d uct …
… will a d mi nist er 0. 6 m L of 
i nv esti g ati o n al pr o d uct at 
W e eks 0, 1 2, 2 4, 3 6, a n d 4 8 …
… d osi n g o n t h e s p ecific visit 
sc h e d ul e ( e g, ev ery 1 2 w e eks).
I niti all y, s yri n g e s c o nt ai ni n g 
0. 6 m L ( 6 0 m g) of c o n c e ntr ati o n 
1 0 0 m g/ m L dr u g pr o d uct will b e 
pr o vi d e d. 
F or st u d y c e nt er s i niti at e d u si n g 
t h e dil uti o n m et h o d f or st u d y 
tr e at m e nt pr e p ar ati o n a n 
u n bli n d e d p h ar m a ci st ( or 
a p pr o pri at el y -q u alifi e d d e si g n e e) 
at t h e st u d y c e nt er will pr e p ar e 
e a c h d o s e vi a a dil uti o n 
pr o c e s s …
W h e n a v ail a bl e, G S K will s u p pl y 
of at u m u m a b S C i n pr efill e d gl a s s 
s yri n g e s c o nt ai ni n g 0. 4 m L 
( 2 0 m g) of c o n c e ntr ati o n 
5 0 m g/ m L dr u g pr o d u ct a n d 
m at c hi n g pl a c e b o pr efill e d gl a s s 
s yri n g e s c o nt ai ni n g 0. 4 m L of 
n or m al s ali n e.
… will a d mi nist er 0. 4 m L of 
i nv esti g ati o n al pr o d uct …
… d osi n g o n t h e s p ecific visit 
sc h e d ul e a s s h o w n i n T a bl e 6- 1 .
C h a n g e i n h o w 
i nv esti g ati o n al pr o d uct will 
b e s u p pli e d, d os e, a n d 
d osi n g i nt erv al.
S ecti o n 5. 3 
E ac h sit e m ust d esi g n at e a n 
u n bli n d e d p h ar m acist ( or 
d esi g n e e) f or d r u g pr e p ar ati o n; 
a n u n bli n d e d cli nic al r es e arc h 
assist a nt will m o nit or sit es t o 
e ns ur e dr u g acc o u nt a bility.
E ac h sit e t h at pr e p ar e s st u d y 
i nj e cti o n s u si n g t h e dil uti o n 
m et h o d m ust d esi g n at e a n 
u n bli n d e d p h ar m acist ( or 
a p pr o pri at el y -q u alifi e d d esi g n e e) 
f or dr u g pr e p ar ati o n.
Cl arific ati o n t h at u n bli n d e d 
p h ar m acist is o nly n e e d e d if 
st u dy tr e at m e nt will b e 
mix e d at t h e sit e.  L a b els 
will b e bli n d e d; t h er ef or e, a n 
u n bli n d e d cli nic al r es e arc h 
assist a nt is n ot r e q uir e d.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 5
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T a bl e 6 - 1 
Tr e at m e nt P eri o d ( 4 8 W e eks)
I nvesti g ati o n al pr o d uct 
a d mi nistr ati o n, vit al si g ns, a n d 
pr e g n a ncy t esti n g ev ery 
1 2 w e eks.
Cli nic al ass ess m e nts,   
, 
B L C
 P D 
m ark
   
 
 
 
.
Tr e at m e n t P eri o d (5 6 W e eks)
I nv esti g ati o n al pr o d uct 
a d mi nistr ati o n, vit al si g ns, a n d 
pr e g n a ncy t esti n g ev ery 4 w e eks.
Cli nic al ass ess m e nts,  
, B L C, 
, P D m ark ers, 
a n d P K s a m pl es 
 
 
Ass ess m e nt ti m e p oi nts 
u p d at e d t o r efl ect c h a n g e i n 
d osi n g i nt erv al.
T a bl e 6 - 1 
N A
N e ur ol o gi c al s y m pt o m s 
q u e sti o n n air e at s cr e e ni n g.
T o b e c o nsist e nt wit h 
excl usi o n crit eri o n 5.
T a bl e 6 - 2   
… D ay 0 t hr o u g h D ay 7, 
p h ar m ac oki n etic s a m pl es … 
(2 h o urs) …
… D ay 1 t hr o u g h D ay 7, 
p h ar m ac oki n etic s a m pl es … 
(2 h o urs) …
P K a n d P D s a m pl es a d d e d at 
W e ek 1 6 a n d 2 0. P D s a m pl es 
a d d e d at W e eks 4 a n d 8.
F o ot n ot e t h at s a m pl es s h o ul d b e 
c oll ect e d pr e d os e o n d osi n g d ays.
C oll ecti o n wi n d o w of 
2 h o urs d o es n ot a p ply t o 
D ay 0 s a m pl es.
U p d at e d t o r efl ect c h a n g e i n 
d osi n g i nt erv al.
S ecti o n 6. 1 
…f act ors will b e ass ess e d at 
B as eli n e.
…f act ors will b e ass ess e d at 
S cr e e ni n g / B as eli n e.
I nf or m ati o n m ay b e 
c oll ect e d at eit h er visit.
S ecti o n 6. 2. 1 
…t ot al ti m e of all p eri o ds d uri n g 
6 0 w e eks, fr o m w h e n t h e 
s u bj ect i niti ally t a p er e d his/ h er 
or al pr e d nis o n e/ pr e d nis ol o n e 
d os e t o ≤1 0 m g/ d ay a n d h a d 
r e missi o n, u ntil i niti al 
fl ar e/r el a ps e or W e ek 6 0, 
w hic h ev er c o m es first.
…t ot al ti m e [ s u m] of all p eri o ds of 
r e mi s si o n w hil e o n mi ni m al 
st er oi d t h er a p y [ or al pr e d nis o n e/ 
pr e d nis ol o n e d os e of ≤1 0 m g/ d ay] 
u p t o W e ek 6 0.
C o nsist e ncy of d efi niti o n 
w or di n g wit h e n d p oi nts.
S ecti o n 6. 3. 1, 
A p p e n dix 3
** Liv er c h e mistry st o p pi n g a n d 
f oll o w-u p crit eri a: d et ail e d 
i nf or m ati o n i n t ext a n d fi g ur e i n 
a p p e n dix.
** Liv er c h e mistry st o p pi n g a n d 
f oll o w-u p crit eri a: d et ail e d 
i nf or m ati o n i n a p p e n dix a n d fi g ur es 
i n t ext.
U p d at e d f or m atti n g a n d 
pr es e nt ati o n of fl o w 
di a gr a ms a n d i nstr ucti o n al 
t ext t o i m pr ov e cl arity.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 6
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 
6. 3. 9. 2; 
T a bl e 6 - 4
T a bl e F o ot n ot e c.  F or s u bj ects 
w h o ar e a nti -H Bc p ositiv e a n d 
H B V D N A n e g ativ e, p erf or m 
H B V D N A P C R t esti n g at a 
mi ni m u m of ev ery 2 m o nt hs 
d uri n g t h e Tr e at m e nt a n d 
F oll o w -u p P eri o ds.
H e p atitis B Scr e e ni n g a n d M o nit ori n g
… m ust u n d er g o H B V D N A P C R 
m o nit ori n g at a mi ni m u m of e v er y 
2 m o nt h s d uri n g t h e Tr e at m e nt 
P eri o d a n d f or 6 m o nt h s aft er t h e 
l a st d o s e.
M ov e d fr o m t a bl e f o ot n ot e t o 
S ecti o n 6. 3. 9. 2 t o k e e p all 
r el ev a nt i nf or m ati o n t o g et h er.  
A d d e d ti m e p eri o d f or 
p ost d os e m o nit ori n g t o 
acc o u nt f or v ari ati o ns i n t h e 
F oll o w -u p P eri o d d ur ati o n.
S ecti o n 8. 3 ;
S ecti o n 
8. 3. 5. 9
T h e R A P will pr ovi d e c o m pl et e 
d et ails of t h e s af ety a n alys es.
A d diti o n al d et ails of d at a a n alys es 
will b e s p ecifi e d i n t h e R A P.
T ext a d d e d t o S ecti o n 8. 3.
S ecti o n 8. 3. 4 
A n i nt eri m a n alysis f or f utility 
will b e c o n d uct e d w h e n 
6 0 ev e nts of r e missi o n …
N A
A n i nt eri m a n alysis f or f utility will b e 
c o n d uct e d w h e n 6 0 ev e nts of 
s u st ai n e d r e missi o n …
If e nr oll m e nt i s s u b st a nti all y 
sl o w er t h a n a nti ci p at e d a n d/ or t h e 
r at e of s u st ai n e d r e mi s si o n s i s 
m u c h s m all er t h a n pr oj e ct e d, 
c o n si d er ati o n will b e gi v e n t o 
p erf or mi n g t h e i nt eri m a n al y si s f or 
f utilit y at a n e arli er ti m e p oi nt …
Cl arific ati o n t h at f utility 
a n alysis s h o ul d b e b as e d 
o n s ust ai n e d r e missi o ns.
It is diffic ult t o pr e dict 
e nr oll m e nt r at es f or t his r ar e 
dis e as e; t h er ef or e, a n 
e arli er f utility a n alysis m ay 
b e c o nsi d er e d a p pr o pri at e.
S ecti o n 
8. 3. 5. 6
… pl as m a c o nc e ntr ati o n d at a 
o bt ai n e d fr o m t h e 
p h ar m ac oki n etic s u bst u dy will 
b e a n alyz e d …
… pl as m a c o nc e n tr ati o n d at a will b e 
a n alyz e d …
Pl as m a c o nc e ntr ati o n d at a 
will b e ev al u at e d i n all 
s u bj ects.
A p p e n dix 5 
1. D o es t h e s u bj ect r e p ort a ny 
n e w w e ak n ess ?
1. D o es t h e s u bj ect r e p ort a ny n e w 
f o c al w e ak n ess ?
Cl arific ati o n.
A p p e n dix 1 5 
N A
Li st of all c h a n g e s i n 
Pr ot o c ol A m e n d m e nt 3.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 7
Pr ot o c ol A m e n d m e nt 4:  1 8 S e pt e m b er 2 0 1 4
A p plic a bl e t o all r el ev a nt c o u ntri es wit h c o u ntry -s p ecific r e q uir e m e nts.  
At t h e ti m e of t his a m e n d m e nt, n o s u bj ects h a d b e e n r a n d o miz e d i n t h e st u dy.
** T his a m e n d m e nt w as s u p ers e d e d by Pr otoc ol A m e n d m e nt 5 b ef or e i m pl e m e nt ati o n at a ny st u dy c e nt er **
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 3 
N A
A d d e d: ** R ef er t o A p p e n di x 2 ( or 
pr ot o c ol a d d e n d u m) f or a n y 
a p pli c a bl e c o u ntr y -s p e cifi c 
r e q uir e m e nt s. **
R e g ul at ory a ut h oriti es fr o m 
t h e U K a n d Fr a nc e 
r e q u est e d pr ot oc ol 
c h a n g e(s) t h at h av e b e e n 
a d d e d t o A p p e n dix 2, 
C o u ntry -S p ecific 
R e q uir e m e nts ; t h er ef or e, 
cr oss-r ef er e nc es t o t his 
a p p e n dix h av e b e e n a d d e d 
wit hi n t h e pr ot oc ol.
S ecti o n 4 
N A
A d d e d: ** R ef er t o A p p e n di x 2 ( or 
pr ot o c ol a d d e n d u m) f or a n y 
a p pli c a bl e c o u ntr y -s p e cifi c 
r e q uir e m e nt s f or s u bj e ct i n cl u si o n 
i n t hi s st u d y. **
A p p e n dix 2 
– Fr a nc e 
a n d 
A p p e n dix 2 
– U K 
C h a n g e r e g ar di n g S ecti o n 4. 2, 
I ncl usi o n crit eri o n 7 b. … 
us e of acc e pt a bl e m et h o ds of 
c o ntr ac e pti o n … i nf or m e d 
c o ns e nt a n d l asti n g u ntil 
6 m o nt hs aft er l ast d os e,,,
… us e of acc e pt a bl e m et h o ds of 
c o ntr ac e pti o n …  i nf or m e d c o ns e nt 
a n d l asti n g u ntil 1 2 m o nt h s aft er l ast 
d os e,,,
R e q u est by Fr a nc e a n d U K 
n ati o n al c o m p et e nt 
a ut h oriti es f or ali g n m e nt 
wit h A R Z E R R A 
( of at u m u m a b f or I V
i nf usi o n) E U S P C.
A p p e n dix 2 
– U K
C h a n g e r e g ar di n g S ecti o n 4. 2, 
I ncl usi o n crit eri o n 7 b. … 
C o m pl et e a bsti n e nc e fr o m 
h et er os ex u al i nt erc o urs e
C o m pl et e a bsti n e nc e fr o m 
h et er os ex u al i nt erc o urs e, w h e n t hi s 
i s i n li n e wit h t h e pr ef err e d a n d 
u s u al lif e st yl e of t h e s u bj e ct
R e q u est by U K n ati o n al 
c o m p et e nt a ut h ority.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 8
Pr ot o c ol A m e n d m e nt 5:  0 2 A pril 2 0 1 5
A p plic a bl e t o al l c o u ntri es a n d st u dy c e nt ers, unl ess ot h er wis e s p ecifi e d as a c o u ntry -s p ecific r e q uir e m e nt.
At t h e ti m e of t his a m e n d m e nt, 5 s u bj ects h a d b e e n ra n d o miz e d i n t h e st u dy.
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Titl e p a g e 
N A
Pr ot oc ol a m e n d m e nt n u m b er, d at e, 
a n d r evisi o n c hr o n ol o gy.
A m e n d m e nt 5.
T hr o u g h o ut 
N A
C orr ecti o ns a n d cl arific ati o ns f or 
c o nsist e ncy t hr o u g h o ut pr ot oc ol,
Cr oss -r ef er e nc es t o co u ntry -s p ecific 
crit eri a, as a p plic a bl e.
T o a d dr ess i nc o nsist e nci es 
a n d q u esti o ns i d e ntifi e d 
w hil e i niti ati n g st u dy c e nt ers 
a n d s u bj ect e nr oll m e nt.
D efi niti o ns 
N A
A d d e d d efi niti o ns f or st u dy p eri o ds 
A d d e d st u dy p eri o d 
d efi niti o ns t o list of cli nic al  
d efi niti o ns f or e as e of 
l oc ati n g.
S u m m ary; 
S ecti o n 1 . 2
… m ort ality r at e of < 1 0 % .  
… m ort ality t o a p pr oxi m at ely 
5 % t o 1 5 % [ R o bi ns o n, 1 9 9 7 ; 
L a n g a n, 2 0 0 8].
… m ort ality r at e of < 2 0 %.
… m ort ality fr o m 7 0 % t o l e s s 
t h a n 2 0 % [ C ar s o n, 1 9 9 6 ; 
L a n g a n, 2 0 0 8].
U p d at e d wit h p u blic ati o n of 
a r etr os p ectiv e a n alysis of 
m ort ality r at es.
S u m m ary; 
T a bl e 3 - 1
T o d et er mi n e t h e ext e nt of 
B- c ell d e pl eti o n a n d r e pl eti o n 
f oll o wi n g of at u m u m a b S C.
T o ass ess t h e p o p ul ati o n 
p h ar m ac o dy n a mics of 
of at u m u m a b S C i n s u bj ects 
wit h P V.
T o ass ess p o p u l ati o n 
p h ar m ac o dy n a mics a n d t h e ext e nt 
of B -c ell d e pl eti o n a n d r e pl eti o n 
f oll o wi n g of at u m u m a b S C.
C o m bi n e si mil ar o bj ectiv es 
f or cl arity.
S u m m ary
C o ns ist e ncy wit h T a bl e3- 1, 
O bj ectiv es a n d E n d p oi nts 
a n d S ecti o n 6. 2. 3.
S u m m ary; 
S ecti o n 6. 3
N A
Fr e q u e n c y of A E s l e a di n g t o 
p er m a n e nt di s c o nti n u ati o n of 
i n v e sti g ati o n al pr o d u ct.
C o nsist e ncy wit h T a bl e 3 -1, 
O bj ectiv es a n d E n d p oi nts
Fi g ur e 3 - 2 
N A
N e w fi g ur e t o s h o w fl o w of s u bj ects 
fr o m C or e St u dy P eri o d t o t h e 
ext e nsi o n st u dy, I F U P eri o d, a n d 
st u dy exit.
I m pr ov e cl arity.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 4 9
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 3. 1 
T h e st u dy i ncl u d es a Scr e e ni n g 
P eri o d, a 5 6 -w e ek Tr e at m e nt 
P eri o d, a n d a 4 -w e ek F oll o w -u p 
visit.
… e nt er t h e I n divi d u aliz e d 
F ol l o w-u p P eri o d.
T h e st u dy i ncl u d es a Scr e e ni n g 
P eri o d, a C or e St u d y P eri o d 
( c o n si sti n g of t h e 5 6-w e ek 
Tr e at m e nt P eri o d a n d 4 -w e ek 
F oll o w - u p visit), a n d a n 
I n di vi d u aliz e d F oll o w-u p P eri o d 
( a s a p pli c a bl e).
… e nt er t h e I n divi d u aliz e d F oll o w -u p 
P eri o d ( a s a p plic a bl e; g ui d a n c e 
will b e pr o vi d e d wit hi n t h e   
 
vi sit r e p ort, l a bor at or y v al u e s will 
r e m ai n bli n d e d).
I m pr ov e cl arity.
T a bl e 3 - 2 
Or al Pr e d nis o n e/ Pr e d nis ol o n e 
D os e- t a p er Sc h e d ul e – by 
st u dy w e ek a n d st arti n g d os e
Or al Pr e d nis o n e/ Pr e d nis ol o n e 
D os e- t a p er Sc h e d ul e – by c urr e nt 
d o s e a n d di s e a s e st at u s (t a p eri n g 
or d os e i ncr e as e f or fl ar e/r el a ps e)
T o i m pr ov e cl arity a n d 
i ncl u d e d os e i ncr e as e 
g ui d eli n es f or fl ar es a n d 
r ei niti ati n g d os e t a p er.
S ecti o n 
3. 1. 2
… pri or t o e ac h a d mi nistr ati o n of 
i nv esti g ati o n al pr o d uct.
… pri or t o e ac h a d mi nistr ati o n of 
i nv esti g ati o n al pr o d uct t o l e s s e n 
t h e li k eli h o o d of l o c aliz e d 
r e a cti o n s.
I ncl u d e r ati o n al e f or 
pr e m e dic ati o n.
S ecti o n 
3. 1. 3
N A
U ntil …
Ot h er crit eri a f or st u d y 
wit h dr a w al/ e xit ar e m et ( s e e 
S e cti o n 4. 4. 3).
S u bj ects wit h d r a wi n g fr o m 
t h e st u dy will n ot c o nti n u e i n 
t h e I n divi d u aliz e d F oll o w-u p 
P eri o d.
S ecti o n 
3. 1. 3
F or s u bj ects w h o p artici p at e i n 
t h e O L E st u dy, W e ek 6 0 st u dy 
ass ess m e nts will b e c o m pl et e d 
b ef or e t h e first d os e of 
of at u m u m a b S C i n t h e O L E
st u dy..
F or s u bj ects w h o p artici p at e i n t h e 
e xt e n si o n st u dy, O P V 1 1 6 9 1 0
W e ek 6 0 st u dy ass ess m e nts will b e 
c o m pl et e d b ef or e a n y st u d y -
r el at e d a s s e s s m e nt s ar e 
p erf or m e d f or t h e e xt e n si o n st u dy.
Cl arific ati o n b ec a us e n ot all 
s u bj ects will r ec eiv e 
of at u m u m a b at t h e b as eli n e 
visit of ext e nsi o n st u dy.
S ecti o n 
3. 1. 3; 
S ecti o n 
6. 3. 1 0. 2
… H B V D N A P C R m o nit ori n g at 
a mi ni m u m of ev ery 2 m o nt hs …
… H B V D N A P C R m o nit ori n g at a 
mi ni m u m of ev ery 1 2 w e e k s …
R evis e d m o nit ori n g i nt erv al 
c o nsi d er e d acc e pt a bl e t o 
m o nit or f or h e p atitis B 
r e activ ati o n.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 0
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 4. 2 
3.  At l e ast 1 pr evi o us e pis o d e 
of a f ail e d st er oi d t a p er 
(i e, dis e as e fl ar e/r el a ps e at a 
pr e d nis o n e/ pr e d nis ol o n e d os e 
> 1 0 m g/ d ay).
3.  At l e ast 1 pr evi o us e pis o d e of 
a f ail e d st er oi d t a p er (i e, dis e as e 
fl ar e/r el a ps e) at a pr e d nis o n e/ 
pr e d nis o l o n e d os e > 1 0m g/ d ay , 
wit h a P e m p hi g u s S e v erit y of 
Cli ni c al Di s e a s e s c or e of 
m o d er at e ( 2) or s e v er e ( 3) ( m a y b e 
hi st ori c al/r etr o s p e cti v e 
a s s e s s m e nt [ s e e A p p e n di x 6 a n d 
S P M f or g ui d a n c e]), w h er e 
s e v erit y of di s e a s e at 
fl ar e/r el a p s e n e c e s sit at e d a n 
i n cr e a s e of > 2 0 m g/ d a y.  
N ot e: pr e d ni s o n e/ pr e d ni s ol o n e 
d o s e s h o ul d n ot b e i n cr e a s e d f or 
t h e s ol e p ur p o s e of e ntr y i nt o t hi s 
st u d y .
R e q u est by Fr a nc e f or m or e 
s p ecific cli nic al dis e as e 
s ev erity crit eri a r el at e d t o 
st at us at t h e ti m e of t h e 
f ail e d st er oi d t a p er (c h a n g e
i nc or p or at e d as a gl o b al 
r e q uir e m e nt).
Cl arific ati o n t h at st er oi d 
d osi n g s h o ul d b e 
i n d e p e n d e nt of st u dy.
S ecti o n 4. 2 
7 b. … us e of acc e pt a bl e 
m et h o ds of c o ntr ac e pti o n … 
i nf or m e d c o ns e nt a n d l asti n g 
u ntil 6 m o nt hs aft er l ast d os e …
C o m pl et e a bsti n e nc e fr o m 
h et er os ex u al i nt erc o urs e.
7 b. … us e of acc e pt a bl e m et h o ds of 
c o ntr ac e pti o n …  i nf or m e d c o ns e nt 
a n d l asti n g u ntil 1 2 m o nt h s aft er 
l ast d os e …
C o m pl et e a bsti n e nc e fr o m 
h et er os ex u al i nt erc o urs e, w h e n t hi s 
i s i n li n e wit h t h e pr ef err e d a n d 
u s u al lif e st yl e of t h e s u bj e ct.
C h a n g e fr o m c o u ntry -
s p ecific r e q uir e m e nt i n 
A m e n d m e nt 4 t o gl o b al 
r e q uir e m e nt i n 
A m e n d m e nt 5.
S ecti o n 4. 3 
N A
4. A d d e d excl usi o ns f or t acr oli m us, 
al e mt uz u m a b, mit ox a ntr o n e, a n d 
C D -2 0 tr e at m e nts. 
C o nsist e ncy wit h pr o hi bit e d 
m e dic ati o ns s ecti o ns.
S ecti o n 
4. 4. 1
N A
P o siti v e s y m pt o m s o n 
n e ur ol o gi c al s y m pt o m s 
q u e sti o n n air e ( s e e A p p e n di x 4 
a n d A p p e n di x 5).
D os e- h ol di n g f or p ositiv e 
sy m pt o ms w as i ncl u d e d i n 
t h e P M L al g orit h m b ut n ot i n 
t h e d os e-h ol di n g s ecti o n.
S ecti o n 
4. 4. 2
A ny s u bj ect w h o disc o nti n u es
tr e at m e nt pri or t o c o m pl eti o n
s h o ul d e nt er t h e I n divi d u aliz e d 
F oll o w -u p P eri o d u nl ess h e/s h e 
m e ets a crit eri o n f or m a n d at ory 
wit h dr a w al fr o m t h e st u dy.
A ny s u bj ect w h o disc o nti n u es fr o m 
t h e Tr e at m e nt P eri o d s h o ul d 
c o m pl et e a n E arl y Wit h dr a w al 
Vi sit a n d tr a n siti o n i nt o t h e 
I n divi d u aliz e d F oll o w-u p P eri o d f or 
i m p ort a nt s af ety m o nit ori n g ( as 
a p plic a bl e; s e e S ecti o n 3. 1. 3), 
u nl ess h e/s h e m e ets a crit eri o n f or 
m a n d at ory wit h dr a w al fr o m t h e 
st u dy.
I m pr ov e cl arity.
S ecti o n 
4. 4. 3
N A
S u bj e ct i niti at e s tr e at m e nt wi t h a 
pr o hi bit e d P V di s e a s e m o dif yi n g 
dr u g t h at d e pl et e s B c ell s 
( e g, rit u xi m a b).
If s u bj ect i niti at es n e w B-c ell 
d e pl eti n g t h er a py, 
m o nit ori n g h as li mit e d utility 
f or ass essi n g r e pl eti o n aft er 
of at u m u m a b tr e at m e nt.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 1
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 
5. 1. 1, 
S ecti o n 5. 3
N A
I n c o u ntrie s (i n cl u di n g J a p a n) 
a n d/ or st u d y c e nt er s n ot u si n g 
t h e dil uti o n m et h o d t o pr e p ar e 
st u d y i nj e cti o n s, K e n d all 5 mi cr o n 
filt er n e e dl e s will n ot b e u s e d a n d 
t h er e i s n o n e e d t o d e si g n at e a n 
u n bli n d e d p h ar m a ci st ( or 
a p pr o pri at el y -q u alifi e d d e si g n e e) 
f or dr u g pr e p ar ati o n.
Cl arific ati o n
S ecti o n 5. 2 
G S K will n ot c oll ect el ectr o nic 
c as e r e p ort f or m ( e C R F) 
i nf or m ati o n f or scr e e n f ail ur es 
u nl ess t h e s u bj ect ex p eri e nc es 
a n S A E d uri n g t h e Scr e e ni n g 
P eri o d.
I n or d er t o e n s ur e tr a n s p ar e nt 
r e p orti n g of s cr e e n f ail ur e 
s u b j e ct s, m e et t h e C o n s oli d at e d 
St a n d ar d s of R e p orti n g Tri al s 
p u bli s hi n g r e q uir e m e nt s, a n d 
r e s p o n d t o q u eri e s fr o m r e g ul at or y 
a ut h oriti e s, a mi ni m al s et of s cr e e n 
f ail ur e i nf or m ati o n will b e c oll e ct e d 
i n cl u di n g d e m o gr a p h y, s cr e e n 
f ail ur e d et ail s, eli gi bilit y crit eri a, 
a n d a n y S A E s.
G S K p olicy h as b e e n 
u p d at e d t o c oll ect mi ni m al 
i nf or m ati o n o n s u bj ects w h o 
ar e scr e e n f ail ur es. 
S ecti o n 5. 3 
N A
S p o n s or u n bli n di n g f or a n al y s e s 
will o c c ur aft er all s u bj e ct s h a v e 
c o m pl et e d t h e W e e k 6 0 vi sit or 
b e e n wit h dr a w n fr o m t h e tr e at m e nt 
p eri o d ( s e e S e cti o n 8. 3. 4).
Cl arific ati o n 
S ecti o n 
5. 6. 2
B ull et e d list of pr o hi bit e d 
m e dic ati o ns
T a b ul ar f or m at f or pr o hi bit e d 
m e di c ati o n s wit h w a s h o ut p eri o d s.
List w as h o ut p eri o ds i n 
s a m e s ecti o n as 
m e dic ati o ns.
Fi g ur e 6 - 1 
N A
N e w fi g ur e t o s h o w r el ati v e ti mi n g 
of at u m u m a b S C d o si n g.
T a bl e 6 - 1 
N A
D o c u m e nt st er oi d d o s e ( all vi sit s) 
S p ecifi e d t o i m pr ov e cl arity.
T a bl e 6 -1 
F o ot n ot es
Visits fr o m W e ek 0 t hr o u g h 
W e ek 6 0 t o b e sc h e d ul e d wit hi n 
3 d ays …
d. A Es will b e c oll ect e d fr o m t h e 
st art of st u dy tr e at m e nt t hr o u g h 
t h e pr ot oc ol -s p ecifi e d F oll o w-u p 
P eri o d.
Visits fr o m W e e k 2 t hr o u g h W e ek 
6 0 t o b e sc h e d ul e d wit hi n 3 d ays …
b. S u bj e ct s r e q uiri n g a d diti o n al 
H B V t e sti n g will r et ur n f or I F U 
vi sit s e v er y 1 2 w e e k s f or 
6 m o nt h s aft er t h e l a st d o s e.
d . A Es will b e c oll ect e d fr o m t h e 
st art of st u dy tr e at m e nt t hr o u g h t h e 
C or e St u d y P eri o d . 
D ay 0 d o es n ot h av e a visit 
wi n d o w.
C o nsist e ncy wit h H B V 
t esti n g r e q uir e m e nts i n 
S ecti o n 6. 3. 9. 2 a n d 
c o nv e ni e nc e of s u bj ect i n 
ov er all visit sc h e d uli n g.
O nly S A Es a n d A Es of 
s p eci al i nt er est will b e 
c oll ect e d d uri n g 
I n divi d u aliz e d F oll o w-u p 
P eri o d.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 2
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T a bl e 6 - 2 
N A
A d d e d s e p ar at e t a bl e f or 
I n divi d u aliz e d F oll o w-u p P eri o d. 
A d d e d d oc u m e nt st er oi d d os e, 
n e ur ol o gic al sy m pt o ms 
q u esti o n n air e, h e m at ol o gy, a n d 
pr e g n a ncy t esti n g t o t h e I F U visits.
S e p ar at e d d u e t o c o nf usi o n 
r e g ar di n g visit sc h e d ul e.
T o c o nti n u e m o nit ori n g f or 
s af ety.  T h e o ns et of P M L 
m ay occ ur aft er 
disc o nti n u ati o n of st u dy 
tr e at m e nt.
S ecti o n 
6. 3. 2. 3
N A
• H e p atiti s B vir u s r e a cti v ati o n 
( s e e S e ctio n 6. 3. 1 0. 2).
• S e v er e m u c o c ut a n e o u s 
r e a cti o n s ( e g, t o xi c e pi d er m al 
n e cr ol y si s a n d St e v e n s J o h n s o n 
s y n dr o m e).
• C yt o p e ni a s.
• C ar di o v a s c ul ar e v e nt s ( s e e 
S e cti o n 6. 3. 4).
U p d at e d list of A Es of 
s p eci al i nt er est f or 
c o nsist e ncy wit h t h e I B.  
T h es e p ot e nti al A Es ar e n ot 
n e w c o nc er ns, b ut w er e n ot 
s p ecifi e d i n t h e pr evi o us 
v ersi o n of t h e pr ot oc ol.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 3
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 
6. 3. 1 0. 2
… H B V D N A P C R m o nit ori n g at 
a mi ni m u m of ev ery 2 m o nt hs …
… H B V D N A P C R m o nit ori n g at a 
mi ni m u m of ev ery 1 2 w e e k s …
Ali g n m e nt wit h t h e 
A m eric a n Ass oci at i o n f or 
t h e St u dy of Liv er Dis e as e 
g ui d a nc e a n d ot h er 
of at u m u m a b cli nic al 
pr o gr a ms.
T a bl e 6 - 6 
N A
A d d e d t a bl e of h e p atiti s B t e st 
r e s ult s s c e n ari o s f or eli gi bilit y.
T o i m pr ov e cl arity ov er t ext -
o nly d escri pti o ns. 
S ecti o n 
8. 3. 5
N A
N e w h e a di n g i n s ert e d: 
R e p orti n g Ti m e P oi nt s 
T o s e p ar at e d at a r e p orti n g  
ti m e p oi nts fr o m d escri pti o n 
of i nt eri m a n alys es.
A p p e n dix 2   
A p p e n dix 2 – Fr a nc e 
A p p e n dix 2 – U K 
N A
C h a n g e d fr o m c o u ntry -
s p ecific t o gl o b al 
r e q uir e m e nts.
A p p e n dix 2 –
J a p a n
( wit h cr oss-
r ef er e nc es 
fr o m 
a p plic a bl e 
s ecti o ns 
wit hi n b o dy of 
pr ot oc ol)
N A
A d diti o n of c o u nty -s p ecific 
r e q uir e m e nts f or J a p a n: m et h o ds of 
c o ntr ac e pti o n; a d diti o n al scr e e ni n g 
pr oc e d ur es; excl usi o n crit eri a 
s p ecific ati o ns; cl arific ati o n of 
wit h dr a w al fr o m st u dy d u e t o 
S p o ns or r e q u est; o nly of at u m u m a b 
2 0 m g pr efill e d syri n g es will b e 
utiliz e d; u n bli n d e d p h ar m acists n ot 
r e q uir e d; pr o hi bit e d m e dic ati o ns; 
m e dic al d evic es; a n d r e g ul at ory a n d 
et hics c o nsi d er ati o ns.
Pr ot oc ol m o dific ati o ns a n d 
s u p pl e m e nt ary d et ails  
r e q u est e d d uri n g r evi e w by 
t h e P M D A w er e i niti ally 
pr es e nt e d i n a J a p a n -
s p ecific ‘ a d d e n d u m’ t o 
Pr ot oc ol A m e n d m e nt 3.  
T h es e d et ails ar e n o w 
s p ecifi e d wit h t h e c urr e nt 
gl o b al pr ot oc ol.
A p p e n dix 4, 
Fi g ur e 1 1 - 3
N A
A d d e d P M L m o nit ori n g al g orit h m 
fl o w c h art.
Vis u al r e pr es e nt ati o n of 
P M L ev al u ati o n fl o w.
A p p e n dix 5 
If a ny of t h e a b ov e ar e 
a ns w er e d “ Y es” at a ny visit, t h e 
i nv esti g at or will c o nt act t h e 
m e dic al m o nit or a n d t h e s u bj ect 
will b e r ef err e d t o a n e ur ol o gist .
If a ny of t h e a b ov e ar e a ns w er e d 
“ Y es” at a ny visit, t h e i nv esti g at or 
wil l c o nt act t h e m e dic al m o nit or.
A n y n e ur ol o gi c al s y m pt o m t h at 
c a n n ot b e dir e ctl y attri b ut e d t o a 
c o n c urr e nt m e di c al c o n diti o n or 
c o n c o mit a nt m e di c ati o n m u st b e 
r ef err e d t o a n e ur ol o gi st.
If sy m pt o ms h av e a n 
i d e ntifi a bl e c a us e, t h e n 
r ef err al t o a n e ur ol o gist m ay 
n ot b e a p pr o pri at e.
A p p e n dix 6 
… (i e, hist oric al ass ess m e nt).   
… (i e, m a y b e a hist oric al/ 
r etr o s p e cti v e ass ess m e nt).  R ef er 
t o t h e S P M f or a d diti o n al 
g ui d a n c e.
Cl arific ati o n

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 4
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
A p p e n dix 1 5 
N A
Li st of all c h a n g e s i n 
Pr ot o c ol A m e n d m e nt 5.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 5
Pr ot o c ol A m e n d m e nt 6:  2 8 S e pt e m b er 2 0 1 5
A p plic a bl e t o all c o u ntri es a n d st u dy c e nt ers, u nl ess ot h er wis e s p ecifi e d as a c o u ntry -s p ecific r e q uire m e nt.
At t h e ti m e of t his a m e n d m e nt, 2 1 s u bj ects h a d b e e n r a n d o miz e d i n t h e st u dy.
** G S K ask e d t h at t h e sit es r ev ert b ack t o A m e n d m e nt 5 a n d t h e Et hics C o m mitt e es i n t h e U S A w er e 
n otifi e d; t h er ef or e, n o n e of t h e c h a n g es i n t his a m e n d m e nt w er e i m pl e m e nt e d at a ny st u dy c e nt er. T his 
a m e n d m e nt w as t h e n s u p ers e d e d by Pr ot oc ol A m e n d m e nt 7**
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Titl e p a g e 
N A
Pr ot oc ol a m e n d m e nt n u m b er, 
d at e, a n d r evisi o n c hr o n ol o gy.
A m e n d m e nt 6
T hr o u g h o ut 
N A
C orr ecti o ns a n d cl arific ati o ns f or 
c o nsist e ncy t hr o u g h o ut pr ot oc ol
T o a d dr ess i nc o nsist e nci es 
a n d q u esti o ns i d e ntifi e d 
w hil e i niti ati n g st u dy c e nt ers 
a n d s u bj ect e nr oll m e nt.
A b br evi ati o ns 
N A
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
Cl arific ati o n
Pr ot oc ol -
s p ecific 
d efi niti o ns, 
St u dy P eri o ds
C or e St u dy P eri o d
C or e St u dy P eri o d ( al s o r ef err e d 
t o a s c o m pl et e tr e at m e nt 
c o ur s e)
Cl arific ati o n
Pr ot oc ol -
s p ecific 
d efi niti o ns , 
St u dy 
p eri o ds, 
I n divi d u aliz e d 
F oll o w -u p
If B c ell c o u nts h av e n ot 
r ec ov er e d by t h e W e ek 6 0 visit, 
s u bj ects n ot e nt eri ng t h e 
ext e nsi o n st u dy will r e m ai n i n
I n divi d u aliz e d F oll o w-u p P eri o d 
u ntil eit h er t h e C D 1 9 + B-c ell 
c o u nts or circ ul ati n g I g G l ev els 
ar e ≥L L N or u ntil 2 y e ars aft er 
t h e l ast d os e of i nv esti g ati o n al 
pr o d uct ( w hic h ev er c o m es first). 
S u bj ects w h o wit h dr a w fr o m
tr e at m e nt will als o e nt er t h e 
I n divi d u aliz e d F oll o w-u p P eri o d.
Aft er c o m pl eti n g t h e C or e St u d y 
P eri o d ( or e arl y di s c o nti n u ati o n 
of tr e at m e nt), s u bj e ct s w h o d o 
n ot e nr oll i n t h e e xt e n si o n st u d y 
will e nt er t h e I n di vi d u aliz e d 
F oll o w -u p P eri o d f or a mi ni m u m 
o f 1 y e ar. Aft er t h e fir st y e ar, 
s u bj e ct s will r e m ai n i n t h e
I n divi d u aliz e d F oll o w-u p P eri o d 
u ntil t h e C D 1 9 + B -c ell c o u nts or 
circ ul ati n g I g G l ev els ar e ≥L L N or 
b as eli n e l ev els (if < L L N), st u d y 
wit h dr a w al crit eri a ar e m et, or 
f or a m a xi m u m of 2 y e ars aft er 
t h e l ast d os e of i nv esti g ati o n al 
pr o d uct ( w hic h ev er c o m es first).
A mi ni m u m 1 -y e ar 
I n divi d u aliz e d F oll o w-u p 
P eri o d f or s u bj ects w h o d o 
n ot e nr oll i n t h e ext e nsi o n 
st u dy will all o w t h e 
c oll ecti o n of a d diti o n al 
s af ety d at a f oll o wi n g t h e 
c o m pl eti o n of tr e at m e nt. 
T h e 1 st y e ar of 
I n divi d u aliz e d F oll o w-u p is 
ex p ect e d t o pr ovi d e 
a d e q u at e ti m e f or B -c ell 
r e pl eti o n i n t h e m aj ority of 
s u bj ects. T h e 2 n d y e ar will 
c o nti n u e t o m o nit or f or 
B- c ell r e pl eti o n i n t h e 
r e m ai ni n g s u bj ects.
Pr ot oc ol -
s p ecific 
d efi niti o ns, 
Cli nic al 
d efi niti o ns
N A
B- c ell r e c o v er y/r e pl eti o n: C D 1 9 + 
B- c ell c o u nt s gr e at er t h a n or 
e q u al t o t h e l o w er li mit of 
n or m al or b a s eli n e l e v el s (if l e s s 
t h a n t h e l o w er li mit of n or m al). 
N ot e: B -c ell c o u nt s a n d I g G 
r e s ult s will b e bli n d e d aft er t h e 
S cr e e ni n g vi sit a n d t hr o u g h o ut 
t h e st u d y.
D efi niti o n a d d e d f or 
c o m pl et e n ess a n d cl arity.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 6
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Pr ot oc ol -
s p ecific 
d efi niti o ns, 
Cli nic al 
d efi niti o ns, 
R e missi o n
A bs e nc e of n e w or n o n h e ali n g 
( est a blis h e d) l esi o ns f or ≥8 
w e eks ( N ot e: S u bj ects wit h
existi n g, h e ali n g l esi o ns m ay b e 
c o nsi d er e d i n r e missi o n if ot h er 
crit eri a ar e m et.)
A bs e nc e of n e w or n o n h e ali n g 
( est a blis h e d) l esi o ns f or ≥8 w e eks 
( N ot e: S u bj ects w h o o nl y h a v e
existi n g, h e ali n g l esi o ns m ay b e 
c o nsi d er e d i n r e missi o n.)
Cl arific ati o n
Tr a d e m ark 
I nf or m ati o n
Tr a d e m ar k s of t h e 
Gl a x o S mit h Kli n e gr o u p of 
c o m p a ni e s
A R Z E R R A
Tr a d e m ar k s n ot o w n e d b y t h e 
Gl a x o S mit h Kli n e gr o u p of 
c o m p a ni e s
C a m p at h
E Q -5 D
Q u a nti F E R O N
Tr a d e m ar k s of t h e 
Gl a x o S mit h Kli n e gr o u p of 
c o m p a ni e s
N o n e
Tr a d e m ar k s n ot o w n e d b y t h e 
Gl a x o S mit h Kli n e gr o u p of 
c o m p a ni e s
A R Z E R R A
C a m p at h
E Q -5 D
M a b C a m p at h
Q u a nti F E R O N
U p d at e d i nf or m ati o n
Pr ot oc ol 
s u m m ary, 
Ot h er 
o bj ectiv es; 
Pr ot oc ol 
s u m m ary 
Ot h er 
e n d p oi nts; 
S ecti o n 2. 3; 
T a bl e 3 -1; 
S ecti o n 6. 2. 3
N A
Ot h er O bj ectiv e :
T o e v al u at e di s e a s e r e mi s si o n 
a n d di s e a s e fl ar e/r el a p s e aft er 
t h e c o m pl eti o n of tr e at m e nt wit h 
of at u m u m a b S C
Ot h er E n d p oi nts:
 
D ur ati o n of r e mi s si o n o n 
mi ni m al st er oi d t h er a p y b y 
t h e e n d of t h e 
I n di vi d u aliz e d F oll o w-u p 
P eri o d
 
D ur ati o n of r e mi s si o n off 
st e r oi d t h er a p y b y t h e en d 
of I n di vi d u aliz e d F oll o w -u p 
P eri o d.
 
Ti m e t o fl ar e/r el a p s e 
b et w e e n W e e k 6 0 a n d t h e 
e n d of t h e I n di vi d u aliz e d 
F oll o w -u p P eri o d.
O bj ectiv e a n d 
c orr es p o n di n g e n d p oi nts 
a d d e d t o ass ess d ur ati o n of 
r e missi o n o n mi ni m al 
st er oi d t h er a py a n d ti m e t o 
fl ar e/r el a ps e i n t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d aft er c o m pl eti o n of a 
tr e at m e nt c o urs e.  T h es e 
r es ults, i n c o nj u ncti o n wit h 
t h os e o bt ai n e d i n ext e nsi o n 
st u dy O P V 1 1 7 0 5 9, will b e 
us e d t o ass ess if c o nti n u o us 
tr e at m e nt wit h of at u m u m a b 
S C is n ec e ss ary or if 
i nt er mitt e nt tr e at m e nt 
c o urs es ar e eff ectiv e.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 7
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Pr ot oc ol 
su m m ary, 
S ecti o n 2. 2 
a n d 
S ecti o n 2. 3
Pr ot o c ol S u m m ar y, S e c o n d ar y 
O bj e cti v e s:
T o ass ess p o p ul ati o n 
p h ar m ac o dy n a mics a n d t h e 
ext e nt of B -c ell d e pl eti o n a n d 
r e pl eti o n f oll o wi n g of at u m u m a b 
S C
2. 2 S e c o n d ar y O bj e cti v e s:
T o d et er mi n e t h e ext e nt of B-c ell 
d e pl eti o n a n d r e pl eti o n f oll o wi n g 
of at u m u m a b S C.
2. 3 Ot h er O bj e cti v e s
T o ass ess t h e p o p ul ati o n 
p h ar m ac o dy n a mics of 
of at u m u m a b S C i n s u bj ects wit h 
P V
Pr ot o c ol S u m m ar y, S e c o n d ar y 
O bj e cti v e s:
T o ass e ss p o p ul ati o n 
p h ar m ac o dy n a mics i n cl u di n g t h e 
ext e nt of B -c ell d e pl eti o n a n d 
r e pl eti o n f oll o wi n g of at u m u m a b S C
2. 2 S e c o n d ar y O bj e cti v e s:
T o a s s e s s p o p ul ati o n 
p h ar m a c o d y n a mi c s i n cl u di n g 
t h e ext e nt of B-c ell d e pl eti o n a n d 
r e pl eti o n f oll o wi n g of at u m u m a b 
S C.
2. 3 Ot h er O bj e cti v e s
N A
Cl arific ati o n a n d c orr ecti o ns 
f or c o nsist e ncy b et w e e n 
s ecti o ns.
T a bl e 3 - 1 
S ec o n d ary Effic acy E n d p oi nts -
s u p p orti n g pri m ary o bj ectiv e:
 
Ti m e t o r e missi o n w hil e o n 
mi ni m al st er oi d t h er a py
S ec o n d ary O bj ectiv es - Effic acy 
a n d P h ar m ac o dy n a mi c:
T o d et er mi n e p o p ul ati o n 
p h ar m ac o dy n a mics a n d t h e 
ext e nt of B -c ell d e pl eti o n a n d 
r e pl eti o n f oll o wi n g of at u m u m a b 
S C
S ec o n d ary Effic acy E n d p oi nts -
s u p p orti n g pri m ary o bj ectiv e:
 
Ti m e t o r e missi o n w hil e o n 
mi ni m al st er oi d t h er a py b y 
W e e k 6 0
S ec o n d ary O bj ectiv es - Effic acy 
a n d P h ar m ac o dy n a mic:
T o a s s e s s p o p ul ati o n 
p h ar m ac o dy n a mics i n cl u di n g t h e 
ext e nt of B -c ell d e pl eti o n a n d 
r e pl eti o n f oll o wi n g of at u m u m a b S C

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 8
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Pr ot oc ol 
s u m m ary, 
St u dy d esi g n
T h e st u dy i ncl u d es a Scr e e ni n g 
P eri o d, a 5 6 -w e ek Tr e at m e nt 
P eri o d, a n d a 4- w e ek F oll o w -u p 
visit. S u bj ects will visit t h e cli nic 
d uri n g Scr e e ni n g ; at B as eli n e 
( W e ek 0); at W e eks 2, 4, 6, a n d 
8; a n d t h e n ev ery 4 w e eks fr o m 
W e ek 8 t hr o u g h W e ek 6 0.
S u bj ects will als o h av e str uct ur e d 
p h o n e visits b et w e e n e ac h of t h e 
cli nic visits fr o m W e ek 1 0 t hr o u g h 
W e ek 2 2. It is a ntici p at e d t h at
t ot al d ur ati o n of p artici p ati o n i n 
t his st u dy will b e a p pr oxi m at ely 
7 2 w e eks .
T h e st u dy i ncl u d es a Scr e e ni n g
P eri o d, a C or e St u d y P eri o d 
( c o n si sti n g of a 5 6 -w e ek 
Tr e at m e nt P eri o d, a n d a 4 -w e ek 
F oll o w -u p v isit) a n d a n 
I n di vi d u aliz e d F oll o w-u p P eri o d. 
F or s u bj e ct s n ot e nr olli n g i n 
e xt e n si o n st u d y O P V 1 1 7 0 5 9, t h e 
d ur ati o n of t h e I n di vi d u aliz e d 
F oll o w -u p P eri o d will b e a 
mi ni m u m of 1 y e ar wit h a 
m a xi m u m f oll o w -u p of 2 y e ar s 
d e p e n di n g o n ti mi n g of B -c ell or 
I g G r e pl eti o n.
T h e t ot al d ur ati o n of p artici p ati o n 
i nt h e st u dy will b e a p pr oxi m at ely 
2 y e ar s, wit h a m a xi m u m of 
3 y e ar s i n cl u di n g t h e f ull 2 -y e ar 
d ur ati o n of t h e I n di vi d u aliz e d 
F oll o w -u p P eri o d.
C or e St u d y P eri o d
S u bj ects will visit t h e cli nic at 
B as eli n e ( W e ek 0); at W e eks 2, 4, 
6, a n d 8; a n d t h e n ev ery 4 w e eks 
fr o m W e ek 8 t hr o u g h W e ek 6 0. 
S u bj ects will als o h av e str uct ur e d 
p h o n e visits b et w e e n e ac h of t h e 
cli nic visits fr o m W e ek 1 0 t hr o u g h 
W e ek 2 2.
A mi ni m u m 1 -y e ar 
I n divi d u aliz e d F oll o w-u p
P eri o d f or s u bj ect s n ot 
e nr olli n g i nt o ext e nsi o n 
st u dy O P V 1 1 7 0 5 9 will all o w 
t h e c oll ecti o n of a d diti o n al 
s af ety d at a f oll o wi n g t h e 
c o m pl eti o n of tr e at m e nt.
T h e 1st y e ar of 
I n divi d u aliz e d F oll o w-u p is 
ex p ect e d t o pr ovi d e 
a d e q u at e ti m e f or B -c ell 
r e pl eti o n i n t h e m aj ority of 
s u bj ects. T h e 2 n d y e ar will 
c o nti n u e t o m o nit or f or B-
c ell r e pl eti o n i n t h e 
r e m ai ni n g s u bj ects.
T ot al d ur ati o n of st u dy 
p artici p ati o n r evis e d f or 
c o nsist e ncy.
S u b h e a di n gs ( Scr e e ni n g 
P eri o d, C or e St u dy P eri o d, 
I n divi d u aliz e d F oll o w-u p 
P eri o d) h av e b e e n a d d e d t o 
t his s ecti o n f or cl arity.
T h e d escri pti o n of t h e visit 
sc h e d ul e is n o w i ncl u d e d 
u n d er e ac h a p pr o pri at e 
s u b h e a di n g.
Pr ot oc ol 
s u m m ary, 
St u dy d esi g n
Aft er t h e l ast d os e of 
of at u m u m a b S C or pl ac e b o at 
W e ek 5 6, s u bj ects will b e 
f oll o w e d u p f or a mi ni m u m of 4 
w e eks, wit h a visit sc h e d ul e d at 
W e ek 6 0. S u bj ects c o m pl eti n g 
t h e st u dy a n d m e eti n g all e ntry 
crit eri a will b e off er e d t h e o pti o n 
t o p artici p at e i n a n ext e nsi o n 
st u dy ( O P V 1 1 7 0 5 9), w hic h will 
st art aft er c o m pl eti o n of t h e W e ek 
6 0 visit.
If B c ell c o u nts h av e n ot 
r ec ov er e d by t h e W e ek 6 0 visit, 
s u bj ects n ot e nt eri n g t h e 
ext e nsi o n st u dy will r e m ai n i n a n 
I n divi d u aliz e d F oll o w-u p P eri o d 
u ntil eit h er t h e C D 1 9 + B -c ell 
c o u nts or circ ul ati n g I g G l ev els 
ar e ≥L L N or b as eli n e l ev els (if 
< L L N) or u ntil 2 y e ars aft e r t h e 
l ast d os e of i nv esti g ati o n al 
S u bj e ct s w h o wit h dr a w e arl y 
fr o m t h e Tr e at m e nt P eri o d will 
c o m pl et e a n e arl y wit h dr a w al 
vi sit a n d tr a n siti o n dir e ctl y i nt o 
t h e O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d.
S u bj e ct s w h o c o m pl et e t h e 
Tr e at m e nt P eri o d will b e 
f oll o w e d f or a mi ni m u m of 4 
w e e k s, wit h a F oll o w -u p Vi sit 
s c h e d ul e d at W e e k 6 0. At t h e 
W e e k 6 0 vi sit, t h e s u bj e ct’ s 
r e mi s si o n st at u s will b e 
c o nfir m e d t o d et er mi n e if t h e 
s u bj e ct i s p ot e nti all y eli gi bl e f or 
t h e e xt e n si o n st u d y 
( O P V 1 1 7 0 5 9) or if t h e s u bj e ct 
will tr a n siti o n dir e ctl y i nt o t h e 
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w - up P eri o d. Eli gi bl e a n d 
c o n s e nti n g s u bj e ct s will e nt er 
t h e e xt e n si o n st u d y wit hi n 4 
S u bj ects w h o ar e i n
s ust ai n e d r e missi o n o n 
mi ni m al st er oi d t h er a py will 
e nt er t h e I n divi d u aliz e d 
F oll o w -u p P eri o d t o all o w 
ass ess m e nt of d ur ati o n of 
r e missi o n a n d ti m e t o i niti al 
fl ar e/r el a ps e off tr e at m e nt.
T h es e s u bj ects will b e 
eli gi bl e f or t h e ext e nsi o n 
st u dy if a dis e as e 
fl ar e/r el a ps e is ex p eri e nc e d 
d uri n g t h e 1st y e ar of t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d. S u bj ects i n 
s ust ai n e d r e missi o n o n 
mi ni m al st er oi d t h er a py w h o 
b ec o m e eli gi bl e f or a n d 
e nr oll i nt o t h e ext e nsi o n 
st u dy m ay b e i n t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d f or l ess t h a n 1 y e ar.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 5 9
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
pr o d uct ( w hic h ev er c o m es first). 
I n divi d u aliz e d F oll o w-u p visits will 
b e sc h e d ul e d ev ery 1 2 w e eks. 
S u bj ects w h o wit h dr a w fr o m 
tr e at m e nt will als o e nt er t h e 
I n divi d u aliz e d F oll o w u p P eri o d
w e e k s of c o m pl eti n g t h e 
O P V 1 1 6 9 1 0 W e e k 6 0 vi sit.
S u bj e ct s w h o c o m pl et e St u d y 
O P V 1 1 6 9 1 0 t hr o u g h W e e k 6 0 
wit h o n e of t h e f oll o wi n g 
o ut c o m e s m a y b e eli gi bl e f or 
t h e O P V 1 1 7 0 5 9 ext e n si o n st u d y 
if all e ntr y crit eri a ar e m et:
 
Di d n ot a c hi e v e s u st ai n e d 
r e mi s si o n ( n o n e w or 
n o n -h e ali n g l e si o n s f or 
≥8 w e e k s t h at i s s u st ai n e d 
u ntil W e e k 6 0) o n mi ni m al 
st er oi d t h er a p y ( ≤1 0 
m g/ d a y)
 
A c hi e v e d s u st ai n e d 
r e mi s si o n ( n o n e w or n o n-
h e ali n g l e si o n s f or ≥8 
w e e k s t h at i s s u st ai n e d 
u ntil W e e k 6 0) o n mi ni m al 
st er oi d t h er a p y 
(≤1 0 m g/ d a y) b ut i s 
e x p eri e n ci n g a di s e a s e 
fl ar e/r el a p s e i n t h e fir st 
y e ar of t h e I n di vi d u aliz e d 
F oll o w -u p P eri o d.
I n di vi d u aliz e d F oll o w-u p P eri o d
S u bj e ct s w h o d o n ot e nr oll i nt o 
t he e xt e n si o n st u d y will e nt er
t h e O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w - u p P eri o d f or a mi ni m u m 
of 1 y e ar. T h e f oll o wi n g t y p e s of
s u bj e ct s will tr a n siti o n dir e ct l y 
i nt o t h e O P V 1 1 6 9 1 0
I n di vi d u aliz e d F oll o w-u p P eri o d 
aft er t h e W e e k 6 0 Vi sit:
 
S u bj e ct s w h o ar e i n 
s u s t ai n e d r e mi s si o n ( n o 
n e w or n o n -h e ali n g l e si o n s 
f or ≥8 w e e k s t h at i s 
s u st ai n e d u ntil W e e k 6 0) o n 
mi ni m al st er oi d t h er a p y 
(≥1 0 m g/ d a y) at t h e ti m e of 
t h e W e e k 6 0 vi sit. If t hi s 
t y p e of s u bj e ct e x p eri e n c e s 
a di s e a s e fl ar e/r el a p s e 
d uri n g t h e fir st y e ar of t h e 
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d, t h e n 
c o n s e nti n g s u bj e ct s m a y 
b e s cr e e n e d a n d e nr oll e d 
i nt o t h e e xt e n si o n st u d y at 
Cl arific ati o n of t h e p eri o d of 
ti m e all o w e d b et w e e n t h e 
W e ek 6 0 visit a n d t h e st art 
of t h e ext e nsi o n st u dy.
C o nsist e ncy wit h t h e n e w 
r e q uir e m e nt f or a mi ni m u m 
1- y e ar I n divid u aliz e d 
F oll o w -u p P eri o d f or 
s u bj ects w h o d o n ot e nr oll 
i nt o t h e ext e nsi o n st u dy.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 0
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
t h e ti m e of t h e i niti al 
fl ar e/r el a p s e. ( S e e 
Pr ot o c ol -S p e cifi c 
D efi niti o n s f or t h e
d efi niti o n of di s e a s e 
fl ar e/r el a p s e.) S u bj e ct s w h o 
e nr oll i nt o t h e e xt e n si o n 
st u d y m a y b e i n t h e 
I ndi vi d u aliz e d F oll o w -u p 
P eri o d f or l e s s t h a n 
o n e y e ar.
 
S u bj e ct s w h o wit h dr a w 
fr o m t h e O P V 1 1 6 9 1 0 C or e 
St u d y P eri o d.
 
S u bj e ct s w h o d o n ot 
c o n s e nt t o p arti ci p ati o n i n 
t h e e xt e n si o n st u d y.
 
E xt e n si o n st u d y s cr e e n 
f ail ur e s.
Aft er t h e fir st y e ar i n t h e 
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d, s u bj e ct s will 
r e m ai n i n t h e I n di vi d u aliz e d 
F oll o w -u p P eri o d f or u p t o 
1 m or e y e ar u ntil o n e of t h e 
f oll o wi n g e v e nt s o c c ur s 
( w hi c h e v er c o m e s fir st):
 
C D 1 9 + B -c ell c o u nt s or 
cir c ul ati n g I g G l e v el s ar e 
≥L L N or b a s eli n e l e v el s (if
< L L N) ( g ui d a n c e will b e 
pr o vi d e d wit hi n t h e   
 
vi sit r e p ort, l a b v al u e s will 
r e m ai n bli n d e d)
 
Crit eri a f or wit h dr a w al fr o m 
t h e st u d y ar e m et
 
T w o y e ar s aft er t h e l a st 
d o s e of i n v e sti g ati o n al 
pr o d u ct
Vi sit s d uri n g t h e I n di vi d u aliz e d 
F oll o w -u p P eri o d will b e 
s c h e d ul e d a p pr o xi m at el y e v er y 
1 2 w e e k s.
Pr ot oc ol 
s u m m ary, 
St u dy 
e n d p oi nts/ 
a ss ess m e nts
* N ot e: d efi niti o ns ar e pr ovi d e d 
wit h t h e list of a b br evi ati o ns a n d 
i n S ecti o n 6. 2.
* N ot e: d efi niti o ns ar e pr ovi d e d wit h 
t h e list of a b br evi ati o ns.
T h e cr oss -r ef er e nc e t o t h e 
b o dy of t h e pr ot oc ol h as 
b e e n r e m ov e d as t h e 
Pr ot oc ol S u m m ary is 
s o m eti m es us e d as a 
st a n d al o n e d oc u m e nt.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 1
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 1. 3; 
S ecti o n 4. 2
…is pr ovi d e d i n t h e I nv esti g at or’s 
Br oc h ur e.
…is pr ovi d e d i n t h e I nv esti g at or’s 
Br oc h ur e [ Gl a x o S mit h Kli n e 
D o c u m e nt N u m b er 
G M 2 0 0 8/ 0 0 1 4 7/ 1 0, 2 0 1 5].
Cl arific ati o n
S ecti o n 3 
… Ti m e a n d Ev e nts T a bl e 
( T a bl e 6- 1) …
… Ti m e a n d Ev e nts T a bl e 
( T a bl e 6- 1 a n d T a bl e 6- 2 ) …
Cl arific ati o n
S ecti o n 3. 1 
T h e st u dy i ncl u d es a Scr e e ni n g 
P eri o d, a C or e S t u dy P eri o d 
(c o nsisti n g of t h e 5 6-w e ek 
Tr e at m e nt P eri o d a n d 4 -w e ek 
F oll o w -u p visit), a n d a n 
I n divi d u aliz e d F oll o w-u p P eri o d 
( as a p plic a bl e).
T h e st u dy i ncl u d es a Scr e e ni n g 
P eri o d, a C or e St u dy P eri o d 
(c o nsisti n g of t h e 5 6-w e ek 
Tr e at m e nt P eri o d a n d 4 -w e ek 
F oll o w - u p visit), a n d a n 
I n divi d u aliz e d F oll o w-u p P eri o d 
( w hi c h i n cl u d e s a 1 y e ar 
mi ni m u m f oll o w -u p f or s u bj e ct s 
n ot e nr olli n g i n e xt e n si o n St u d y 
O P V 1 1 7 0 5 9 wit h a m a xi m u m 
f oll o w-u p of 2 y e ar s d e p e n di n g 
o n ti mi n g of B -c ell or I g G 
r e pl eti o n). T h e t ot al d ur atio n of 
p arti ci p ati o n i n t h e st u d y will b e 
a p pr o xi m at el y 2 y e ar s, wit h a 
m a xi m u m of 3 y e ar s i n cl u di n g 
t h e f ull 2-y e ar d ur ati o n of t h e 
I n di vi d u aliz e d F oll o w-u p P eri o d.
C o nsist e ncy wit h t h e n e w 
r e q uir e m e nt f or a mi ni m u m 
1- y e ar I n divi d u aliz e d 
F oll o w -u p P eri o d f or
s u bj ects w ho d o n ot e nr oll 
i nt o t h e ext e nsi o n st u dy.
S ecti o n 3. 1 
S u bj ects will visit t h e cli nic d uri n g 
Scr e e ni n g; at B as eli n e ( W e ek 0); 
at W e eks 2, 4, 6, a n d 8; a n d t h e n 
ev ery 4 w e eks fr o m W e ek 8 
t hr o u g h W e ek 6 0. S u bj ects will 
als o h av e str uct ur e d p h o n e visits 
b et w e e n e ac h of t h e cli nic visits 
fr o m W e ek 1 0 t hr o u g h W e ek 2 2 
(s e e A p p e n dix 1 4).
… usi n g a st a bl e or al d os e of 
pr e d nis o n e/ pr e d nis ol o n e 
( 2 0 m g/ d ay u p t o 1 2 0 m g/ d ay or 
1. 5 m g/k g/ d ay [ w hic h ev er is 
hi g h er] f or ≥2 w e eks). M ulti pl e 
visits t o t h e cli nic ar e p er mitt e d 
d uri n g t his Scr e e ni n g P eri o d t o 
ass ess dis e as e st at us a n d t o 
a dj ust t h e or al 
pr e d nis o n e/ pr e d nis ol o n e d os e . 
O nc e dis e as e c o ntr ol is ac hi ev e d, 
s u bj ects w h o c o nti n u e t o s atisfy 
t h e eli gi bility crit eri a m ay b e 
r a n d o miz e d. All scr e e ni n g 
pr oc e d ur es s h o ul d b e c o m pl et e d 
wit hi n 1 2 w e eks of i nf or m e d 
c o ns e nt b ei n g giv e n.
… usi n g a st a bl e or al d os e of 
pr e d nis o n e/ pr e d nis ol o n e 
( 2 0 m g/ d ay u p t o 1 2 0 m g/ d ay or 
1. 5 m g/k g/ d ay [ w hic h ev er is 
hi g h er] f or ≥2 w e eks) ( s e e 
S e cti o n 3. 1. 1) .  O nc e dis e as e 
c o ntr ol is ac hi ev e d, s u bj ects w h o 
c o nti n u e t o s atisfy t h e eli gi bility 
crit eri a m ay b e r a n d o miz e d.
D el et e d st at e m e nts h av e 
b e e n m ov e d t o 
S ecti o n 3. 1. 1. Scr e e ni n g 
P eri o d a n d S ecti o n 3. 1. 2 
C or e St u dy P eri o d as 
a p pr o pri at e.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 2
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 3. 1 
It is a ntici p at e d t h at t ot al d ur ati o n 
of p artici p ati o n i n t h e C or e St u dy 
P eri o d will b e a p pr oxi m at ely 
7 2 w e eks.
N A
I nc orr ect st at e m e nt 
r e m ov e d. ( D ur ati o n of t h e 
C or e St u dy P eri o d is 
6 0 w e eks; h o w ev er, t his 
st at e m e nt is n o l o n g er 
n e e d e d i n t his s ecti o n as 
t h e mi ni m u m a n d m axi m u m 
d ur ati o n of t h e s u bj ect’s 
p artici p ati o n i n t h e st u dy is 
n o w st at e d.)
S ecti o n 3. 1 
Aft er t h e l ast d os e of
of at u m u m a b S C or pl ac e b o at 
W e ek 5 6, s u bj ects will b e 
f oll o w e d u p f or a mi ni m u m of 
4 w e eks, wit h a visit s c h e d ul e d at 
W e ek 6 0. S u bj ects c o m pl eti n g 
t h e st u dy a n d m e eti n g all e ntry 
crit eri a will b e off er e d t h e o pti o n 
t o p artici p at e i n a n ext e nsi o n 
st u dy ( O P V 1 1 7 0 5 9), w hic h will 
st art aft er c o m pl eti o n of t h e W e ek 
6 0 visit.
If B c ell c o u nts h av e n ot 
r ec ov er e d by t h e W e ek 6 0 visit, 
s u bjects n ot e nt eri n g t h e 
ext e nsi o n st u dy will r e m ai n i n a n 
I n divi d u aliz e d F oll o w-u p P eri o d 
u ntil eit h er t h e C D 1 9 + B -c ell 
c o u nts or circ ul ati n g I g G l ev els 
ar e ≥L L N or b as eli n e l ev els (if 
< L L N) or u ntil 2 y e ars aft er t h e 
l ast d os e of i nv esti g ati o n al 
pr o d uct ( w h ic h ev er c o m es first) 
(s e e Fi g ur e 3 2). I n divi d u aliz e d 
F oll o w -u p visits will b e sc h e d ul e d 
ev ery 1 2 w e eks. S u bj ects w h o 
wit h dr a w fr o m tr e at m e nt will als o 
e nt er t h e I n divi d u aliz e d F oll o w u p 
P eri o d ( as a p plic a bl e; g ui d a nc e 
will b e pr ovi d e d wit hi n t h e   
 
visitr e p ort, l a b v al u es will r e m ai n 
bli n d e d).
S u bj e ct s w h o c o m pl et e t h e 
Tr e at m e nt P eri o d will b e 
f oll o w e d f or a mi ni m u m of 4 
w e e k s, wit h a F oll o w -u p vi sit 
s c h e d ul e d at W e e k 6 0. At t h e 
W e e k 6 0 vi sit, t h e s u bj e ct’ s 
r e mi s si o n st at u s will b e 
c o nfir m e d t o d et er mi n e if t h e 
s u bj e ct i s p ot e nti all y eli gi bl e f or 
t h e e xt e n si o n st u d y 
( O P V 1 1 7 0 5 9) or if t h e s u bj e ct 
will tr a n siti o n dir e ctl y i nt o t h e 
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d. F or s u bj e ct s 
n ot e nr olli n g i n e xt e n si o n st u d y 
O P V 1 1 7 0 5 9, t h e d ur ati o n of t h e 
I n di vid u aliz e d F oll o w -u p P eri o d 
will b e a mi ni m u m of 1 y e ar wit h 
a m a xi m u m f oll o w -u p of 2 y e ar s 
d e p e n di n g o n ti mi n g of B -c ell or 
I g G r e pl eti o n ( s e e Fi g ur e 3-2, 
S e cti o n 3. 1. 2. 1, a n d 
S e cti o n 3. 1. 3).
R evisi o ns m a d e f or 
c o nsist e ncy wit h t h e n e w 
r e q uir e m e nt f or a mi ni m u m 
1- y e ar I n divi d u aliz e d 
F oll o w -u p P eri o d f or 
s u bj ects n ot e nr olli n g i nt o 
t h e ext e nsi o n st u dy a n d f or 
c o nsist e ncy wit h eli gi bility 
crit eri a f or t h e ext e nsi o n 
st u dy. D et ails r e g ar di n g t h e 
W e ek 6 0 visit a n d t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d ar e n o w d escr i b e d i n 
S ecti o n 3. 1. 2. 1 a n d 
S ecti o n 3. 1. 3, r es p ectiv ely.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 3
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 3. 1; 
S ecti o n 9. 8
S ecti o n 3. 1:
A n i n d e p e n d e nt d at a m o nit ori n g 
c o m mitt e e (I D M C) will ev al u at e 
risks r el ativ e t o b e n efits t hr o u g h 
r evi e w of s af ety a n d effic acy
d at a …
S ecti o n 9. 8:
A n I D M C will b e utiliz e d i n t his 
st u dy t o e ns ur e ext er n al o bj ectiv e 
m e dic al a n d/ or st atistic al r evi e w 
of s af ety a n d effic acy iss u es …
S ecti o n 3. 1:
A n i n d e p e n d e nt d at a m o n it ori n g 
c o m mitt e e (I D M C) will ev al u at e 
s af ety d at a … T h e I D M C will 
r e vi e w effi c a c y d at a f or a n 
i nt eri m a n al y si s f or f utilit y 
( S e cti o n 8. 3. 4) a n d a s n e e d e d.
S ecti o n 9. 8:
A n I D M C will b e utiliz e d i n t his 
st u dy t o e ns ur e ext er n al o bj ectiv e 
m e dic al a n d/ or st ati stic al r evi e w of 
s af ety a n d/ or effic acy iss u es …
C orr ecti o n a n d cl arific ati o n
Fi g ur e 3 - 2 
Pr evi o us St u dy Fl o wc h art d el et e d 
N e w St u dy Fl o wc h art a d d e d 
R evis e d f or cl arific ati o n a n d 
c o nsist e ncy wit h t h e 
c h a n g es c o nt ai n e d i n t his 
a m e n d m e nt.
S ecti o n 3. 1. 1 
N A
Pr e d ni s o n e/ pr e d ni s ol o n e f or t h e 
tr e at m e nt of p e m p hi g u s v ul g ari s 
ar e t h e o nl y s y st e mi c st er oi d s 
all o w e d d uri n g t h e st u d y. 
S u bj e ct s w h o ar e r e c ei vi n g a 
diff er e nt st er oi d f or t h e 
tr e at m e nt of p e m p hi g u s v ul g ari s 
will b e s wit c h e d t o 
pr e d ni s o n e/ pr e d ni s ol o n e d uri n g 
t h e S cr e e ni n g P eri o d. H o w e v er, 
if t h e s u bj e ct r e q uir e s t h e 
c o nti n u e d u s e of a n ot h er 
s y st e mi c st er oi d f or t h e 
tr e at m e nt of p e m p hi g u s v ul g ari s 
or t h e u s e of a n y s y st e mi c 
st er oi d f or a c o n c urr e nt m e di c al 
c o n diti o n, t h e n t h e s u bj e ct will 
n ot b e eli gi bl e f or t h e st u d y.
M ulti pl e vi sit s t o t h e cli ni c ar e 
p er mitt e d d uri n g t hi s S cr e e ni n g 
P eri o d t o a s s e s s di s e a s e st at u s 
a n d t o a dj u st t h e or al 
pr e d ni s o n e/ pr e d ni s ol o n e d o s e. 
All s cr e e ni n g pr o c e d ur e s 
s h o ul d b e c o m pl et e d wit hi n 1 2 
w e e k s of i nf or m e d c o n s e nt 
b ei n g gi v e n.
T h e us e of syst e mic 
st er oi ds ot h er t h a n 
pr e d nis o n e/ pr e d nis ol o n e 
will p ot e nti ally c o nf o u n d t h e 
ev al u ati o n of t h e st u dy 
e n d p oi nts. T h e tr e at m e nt of 
a n ot h er m e dic al c o n diti o n 
wit h pr e d nis o n e/ 
pr e d nis ol o n e is n ot all o w e d 
d uri n g t h e st u dy as st er oi d 
d os e t a p eri n g is a r e q uir e d 
p art of t h e st u dy. A 
cl arific ati o n h as b e e n a d d e d 
t h at s u bj ects r ec eivi n g 
a n ot h er sys t e mic st er oi d f or 
t h e tr e at m e nt of p e m p hi g us 
v ul g aris c a n s witc h t o 
pr e d nis o n e/ pr e d nis ol o n e 
d uri n g t h e Scr e e ni n g 
P eri o d.
D et ails c o nc er ni n g t h e 
Scr e e ni n g P eri o d h av e 
b e e n m ov e d fr o m 
S ecti o n 3. 1 a n d 
c o ns oli d at e d.
S ecti o n 3. 1. 2; 
S ecti o n 3. 1. 3
S ecti o n 3. 1. 2 Tr e at m e nt P eri o d
N A
S ecti o n 3. 1. 2 C or e St u d y P eri o d
T h e C or e St u d y P eri o d i n cl u d e s 
t h e 5 6-w e e k d o u bl e -bli n d 
Tr e at m e nt P eri o d a n d t h e 
4- w e e k F oll o w -u p Vi sit at 
W e e k
6 0. S u bj e ct s will vi sit t h e 
S ecti o ns r e or g a niz e d f or 
cl arity. T h e 4- W e ek 
F oll o w -u p visit at W e ek 6 0 
( n o w S ecti o n 3. 1. 2. 1) is p art 
of t h e C or e St u dy P eri o d. 
T h e I n divi d u aliz e d 
F ol l o w-u p P eri o d ( n o w 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 4
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 3. 1. 3 F oll o w -u p P eri o d
S u bj ects will b e f oll o w e d -u p …
T h e f oll o w -u p visit will i ncl u d e …
If B-c ell c o u nts h av e n ot 
r ec ov er e d by t h e W e ek 6 0 visit, 
s u bj ects n ot e nt eri n g t h e 
ext e nsi o n st u dy ( O P V 1 1 7 0 5 9)
will r e m ai n i n I n divi d u aliz e d 
F oll o w -u p u ntil:
 
C D 1 9 + B -c ell c o u nts or 
circ ul ati n g I g G l ev els ar e 
≥L L N or b as eli n e l ev els (if 
< L L N)
 
Ot h er crit eri a f or st u dy 
wit h dr a w al / exit ar e m et (s e e 
S ecti o n 4. 4. 3) .
 
T w o y e ars aft er t h e l ast 
d os e of i nv esti g ati o n al 
pr o d uct ( w hic h ev er c o m es 
first).
T h e I n divi d u aliz e d F oll o w -u p 
ass ess m e nts s h o ul d b e 
sc h e d ul e d a p pr oxi m at ely ev ery 
1 2 w e eks.  S u bj ects w h o 
wit h dr a w fr o m tr e at m e nt will als o 
e nt er t h e I n divi d u aliz e d F oll o w -u p 
P eri o d.
F or s u bj ects w h o p artici p at e i n 
t h e ext e nsi o n st u dy, O P V 1 1 6 9 1 0 
W e ek 6 0 st u dy ass ess m e nts will 
b e c o m pl et e d b ef or e a ny 
st u dy-r el at e d ass ess m e nts ar e 
p erf or m e d f or t h e ext e nsi o n 
st u dy.
cli ni c at B a s eli n e ( W e e k 0); at 
W e e k s 2, 4, 6 , a n d 8; a n d t h e n 
e v er y 4 w e e k s fr o m W e e k
8 
t hr o u g h W e e k 6 0. S u bj e ct s will 
al s o h a v e str u ct ur e d p h o n e 
vi sit s fr o m W e e k 1 0 t hr o u g h 
W e e k
2 2 ( s e e A p p e n di x 1 4). 
S u bj e ct s s h o ul d b e i n str u ct e d t o 
c o nt a ct t h e st u d y sit e if a 
di s e a s e fl ar e/r el a p s e o c c ur s 
b et w e e n st u d y vi sit s.
S ecti o n 3. 1. 2. 1 F oll o w -u p Visit -
W e e k
6 0
S u bj ects will b e f oll o w e d …
T h e W e e k 6 0 f oll o w-u p visit will 
i ncl u d e …
At t h e W e e k 6 0 vi sit, t h e 
s u bj e ct’ s r e mi s si o n st at u s will 
b e c o nfir m e d t o d et er mi n e if t h e 
s u bj e ct i s p ot e nti all y eli gi bl e f or 
t h e e xt e n si o n st u d y 
( O P V 1 1 7 0 5 9) or if t h e s u bj e ct 
will e nt er t h e O P V 1 1 6 9 1 0 
I n di vi d u aliz e d F oll o w-u p P eri o d 
( s e e Fi g ur e 3-2 a n d S e cti o n 
3. 1. 3):
 
S u bj e ct s w h o ar e i n 
s u st ai n e d r e mi s si o n o n 
mi ni m al st er oi d t h er a p y will 
tr a n siti o n fr o m t h e 
O P V 1 1 6 9 1 0 C or e St u d y 
P eri o d i nt o t h e O P V 1 1 6 9 1 0 
I n di vi d u aliz e d F oll o w-u p 
P eri o d ( S e cti o n 3. 1. 3).
 
S u bj e ct s w h o ar e n ot i n
r e mi s si o n or w h o ar e i n
r e mi s si o n o n > 1 0 m g/ d a y
pr e d ni s o n e/ pr e d ni s ol o n e 
m a y b e eli gi bl e t o tr a n siti o n
dir e ctl y fr o m t h e 
O P V 1 1 6 9 1 0 W e e k 6 0 vi sit 
i nt o t h e O P V 1 1 7 0 5 9 
e xt e n si o n st u d y.
F or s u bj e ct s tr a n siti o ni n g i nt o 
t h e O P V 1 1 7 0 5 9 e xt e n si o n st u d y,
t h er e will b e a 4-w e e k wi n d o w
b e t w e e n t h e W e e k 6 0 vi sit a n d 
t h e e xt e n si o n st u d y B a s eli n e 
vi sit ( W e e k 0/ fir st d o s e i n 
e xt e n si o n st u d y). Wit hi n t hi s 
4- w e e k wi n d o w a n d pri or t o t h e 
s u bj e ct’ s fir st d o s e i n t h e 
S ecti o n 3. 1. 3) is d escri b e d 
i n a s e p ar at e s ecti o n.
D et ails c o nc er ni n g visits 
d uri n g t h e C or e St u dy 
P eri o d h av e b e e n m ov e d 
fr o m S ecti o n 3. 1 a n d 
c o ns oli d at e d.
R evisi o ns h av e b e e n m a d e 
t o e ns ur e c o nsist e ncy wit h 
t h e f oll o wi n g n e w 
r e q uir e m e nts: 1) t h e 1 y e ar 
mi ni m u m f or t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d f or s u bj ects n ot 
e nr olli n g i nt o t h e ext e nsi o n 
st u dy, a n d 2) s u bj ects i n 
s ust ai n e d r e missi o n o n 
mi ni m al st er oi d t h er a py at 
t h e W e ek 6 0 Visit will e nt er 
t h e I n divi d u aliz e d F oll o w-u p 
P eri o d. T h es e s u bj ects ar e 
eli gi bl e f or t h e ext e nsi o n 
st u dy if a dis e as e 
fl ar e/r el a ps e is ex p eri e nc e d 
d uri n g t h e first y e ar of t h e 
O P V 1 1 6 9 1 0 I n divi d u aliz e d 
F oll o w -u p P eri o d.
S u bj ects i n s ust ai n e d 
r e missi o n o n mi ni m al 
st er oi d t h er a py w h o b ec o m e 
eli gi bl e f or a n d e nr ol l i nt o 
t h e ext e nsi o n st u dy m ay b e 
i n t h e I n divi d u aliz e d 
F oll o w -u p P eri o d f or l ess 
t h a n 1 y e ar. It is 
r ec o m m e n d e d t h at t h e 
tr a nsiti o n t o t h e ext e nsi o n 
st u dy occ urs pri or t o 
i ncr e asi n g t h e st er oi d d os e 
t o all o w f or t h e ass ess m e nt 
of dis e as e r es p o ns e t o 
of at u m u m a b S C i n t h e 
ext e nsi o n st u dy.
Gr e at er d et ail h as b e e n 
pr ovi d e d t o assist i n t h e 
d et er mi n ati o n of w hic h 
s u bj ects ar e p ot e nti ally 
eli gi bl e f or t h e ext e nsi o n 
st u dy a n d w hic h s u bj ects 
will tr a nsiti o n i nt o t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d a n d h o w t h e 
tr a nsiti o n will occ ur.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 5
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
O P V 1 1 7 0 5 9 e xt e n si o n st u d y, 
i nf or m e d c o ns e nt m u st b e 
c oll e ct e d, 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, a n d t h e s u bj e ct’ s 
eli gi bilit y c o nfir m e d. It i s 
r e c o m m e n d e d t h at a p pr o pri at e 
sit e st aff r e vi e w t h e e xt e n si o n 
st u d y i nf or m e d c o n s e nt wit h 
e a c h s u bj e ct b ef or e t h e 
O P V 1 1 6 9 1 0 W e e k 6 0 vi sit.
O P V 1 1 6 9 1 0 W e ek 6 0 st u dy 
ass ess m e nts will b e c o m pl et e d 
a n d O P V 1 1 7 0 5 9 e xt e n si o n st u d y 
i nf or m e d c o n s e nt will b e 
o bt ai n e d b ef or e a ny st u dy -r el at e d 
ass ess m e nts ar e p erf or m e d f or t h e 
ext e nsi o n s t u dy. S o m e of t h e 
a s s e s s m e nt s p erf or m e d f or t h e
W e e k 6 0 vi sit will al s o b e u s e d 
f or e xt e n si o n st u d y s cr e e ni n g. 
All r e m ai ni n g O P V 1 1 7 0 5 9
S cr e e ni n g/ B a s eli n e 
a s s e s s m e nt s will b e p erf or m e d 
at t h e O P V 1 1 6 9 1 0 W e e k 6 0 vi sit 
or wit hi n t h e 4 -w e e k wi n d o w
b et w e e n t h e O P V 1 1 6 9 1 0 
W e e k
6 0 vi sit a n d t h e 
O P V 1 1 7 0 5 9 B a s eli n e ( W e e k 0) 
vi sit (fir st d o s e i n t h e e xt e n si o n 
st u d y).
S u bj e ct s s cr e e n e d f or t h e
O P V 1 1 7 0 5 9 e xt e n si o n st u d y ar e 
c o n si d er e d t o b e i n t h e
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F ol l o w-u p P eri o d u ntil eli gi bilit y 
f or t h e e xt e n si o n st u d y i s
c o nfir m e d a n d t h e s u bj e ct
r e c ei v e s t h e fir st d o s e of
of at u m u m a b S C at t h e B a s eli n e 
( W e e k 0) vi sit i n O P V 1 1 7 0 5 9
( m a xi m u m of 4 w e e k s i s 
p er mitt e d b et w e e n s cr e e ni n g 
a s s e s s m e nt s a n d t h e fir st d o s e 
at B a s eli n e). E xt e n si o n st u d y
s cr e e n f ail ur e s will r e m ai n i n t h e 
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d
S e cti o n 3. 1. 3 I n di vi d u aliz e d
F oll o w -u p P eri o d
S u bj e ct s w h o d o n ot e nr oll i nt o 
t h e e xt e n si o n st u d y will e nt er 
t h e O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
I n t h e ev e nt of a dis e as e 
fl ar e/r el a ps e b et w e e n st u dy 
visits, t h e s u bj ect m ay n e e d 
t o r et ur n t o t h e cli nic f or a n 
u nsc h e d ul e d visit s o t h at 
t h e dis e as e fl ar e/r el a ps e 
a n d st er oi d d os e c a n b e 
ev al u at e d. T h er ef or e, 
s u bj ects s h o ul d b e 
i nstr uct e d t o c o nt act t h e 
st u dy sit e if a dis e as e 
fl ar e/r el a ps e occ urs 
b et w e e n st u dy visits.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 6
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
F oll o w -u p P eri o d f or a mi ni m u m 
of 1 y e ar. T h e f oll o wi n g t y p e s of
s u bj e ct s will e nt er t h e 
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d:
a. 
S u bj e ct s w h o ar e i n 
s u st ai n e d r e mi s si o n ( n o 
n e w or n o n -h e ali n g l e si o n s 
f or ≥8 w e e k s t h at i s 
s u st ai n e d u ntil W e e k 6 0) 
o n mi ni m al st er oi d t h er a p y
(≤1 0 m g/ d a y) at t h e ti m e of 
t h e W e e k 6 0 vi sit.
- If t hi s t y p e of s u bj e ct 
e x p eri e n c e s a di s e a s e 
fl ar e/r el a p s e d uri n g t h e fir st 
y e ar of t h e O P V 1 1 6 9 1 0 
I n di vi d u aliz e d F oll o w-u p
P eri o d, t h e n c o n s e nti n g 
s u bj e ct s m a y b e s cr e e n e d 
a n d e nr oll e d i nt o t h e 
O P V 1 1 7 0 5 9 e xt e n si o n 
st u d y at t h e ti m e of t h e 
i niti al fl ar e/r el a p s e. ( S e e 
Pr ot o c ol -S p e cifi c
D efi niti o n s f or t h e d efi niti o n 
o f di s e a s e fl ar e/r el a p s e.) 
S u bj e ct s w h o e nr oll i nt o 
t h e e xt e n si o n st u d y m a y b e 
i n t h e I n di vi d u aliz e d
F oll o w -u p P eri o d f or l e s s 
t h a n o n e y e ar.
N ot e:
i. 
It i s r e c o m m e n d e d t h at t h e 
s u bj e ct e nt er s t h e 
e xt e n si o n st u d y b ef or e t h e 
st er oi d d o s e i s i n cr e a s e d.
ii. 
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d E arl y 
Wit h dr a w al vi sit 
a s s e s s m e nt s will b e 
c o m pl et e d a n d O P V 1 1 7 0 5 9 
e xt e n si o n st u d y i nf or m e d 
c o n s e nt will b e o bt ai n e d 
b ef or e a n y st u d y -r el at e d 
a s s e s s m e nt s ar e p erf or m e d 
f or t h e e xt e n si o n st u d y. 
S o m e of t h e a s s e s s m e nt s 
p erf or m e d f or t h e 
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d E arl y 
Wit h dr a w al vi sit will b e 
u s e d f or t h e e xt e n si o n 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 7
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
st u d y s cr e e ni n g 
a s s e s s m e nt s. All ot h er 
e xt e n si o n st u d y 
S cr e e ni n g/ B a s eli n e 
a s s e s s m e nt s will b e 
p erf or m e d at t h e ti m e of 
di s e a s e fl ar e/r el a p s e i n 
O P V 1 1 6 9 1 0 d uri n g t h e 
I n di vi d u aliz e d F oll o w-u p 
E arl y Wit h dr a w al vi sit. 
( R ef er t o t h e S P M f or 
a d diti o n al g ui d a n c e.)
iii.
S u bj e ct s ar e c o n si d er e d t o 
b e i n t h e O P V 1 1 6 9 1 0 
I n di vi d u aliz e d F oll o w-u p 
P eri o d u ntil eli gi bilit y f or 
t h e e xt e n si o n st u d y i s 
c o nfir m e d a n d t h e s u bj e ct 
r e c ei v e s t h e fir st d o s e of 
of at u m u m a b S C at t h e 
B a s eli n e ( W e e k 0) vi sit i n 
O P V 1 1 7 0 5 9.
b. 
S u bj e ct s w h o wit h dr a w 
fr o m t h e O P V 1 1 6 9 1 0 C or e 
St u d y P eri o d.
c. 
S u bj e ct s w h o d o n ot 
c o n s e nt t o p arti ci p ati o n i n 
t h e e xt e n si o n st u d y.
d. 
E xt e n si o n st u d y s cr e e n 
f ail ur e s.
Aft er t h e fir st y e ar of t h e 
O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d, s u bj e ct s will 
r e m ai n i n I n di vi d u aliz e d 
F oll o w -u p f or u p t o 1 m or e y e ar 
u ntil o n e of t h e f oll o wi n g e v e nt s 
o c c ur s ( w hi c h e v er c o m e s fir st):
 
C D 1 9 + B -c ell c o u nts or 
circ ul ati n g I g G l ev els ar e 
≥L L N or b as eli n e l ev els (if 
< L L N) ( g ui d a n c e will b e 
pr o vi d e d wit hi n t h e 
vi sit r e p ort, l a b v al u e s will 
r e m ai n bli n d e d)
 
Crit eri a f or wit h dr a w al fr o m
t h e st u dy ar e m et
 
T w o y e ars aft er t h e l ast d os e 
of i nv esti g ati o n al pr o d uct.
Vi sit s d uri n g t h e I n di vi d u aliz e d 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 8
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
F oll o w -u p P eri o d will b e 
s c h e d ul e d a p pr o xi m at el y e v er y 
1 2 w e e k s. S u bj e c t s s h o ul d b e 
i n str u ct e d t o c o nt a ct t h e st u d y 
sit e if a di s e a s e fl ar e/r el a p s e 
o c c ur s b et w e e n st u d y vi sit s.
S ecti o n 3, 1, 2; 
T a bl e 3- 2
S u bj ects’ d aily or al st er oi d d os e 
will b e r e d uc e d by 1 d os e l ev el 
e v ery 2 w e eks ( as ill ustr at e d i n 
T a bl e 3 -2) u ntil t h e o ns et of 
dis e as e fl ar e/ r el a ps e. F or a 
s u bj ect w h o ex p eri e nc es dis e as e 
fl ar e/r el a ps e, t h e 
pr e d nis o n e/ pr e d nis ol o n e d os e 
will b e i ncr e as e d by 1 t o 4 l ev els 
p er w e ek u ntil dis e as e c o ntr ol is 
ac hi ev e d (i e, n o n e w l esi o ns f or 
 2 w e eks); t h e
pr e d nis o n e/ pr e d nis ol o n e t a p er 
will t h e n b e r ei niti at e d aft er a 
2- w e ek p eri o d of dis e as e c o ntr ol.
T a bl e 3 - 2
D os e f or P ost-Fl ar e T a p er
F o ot n ot e:
a. 
Pr e d nis o n e/ pr e d nis ol o n e is 
r e d uc e d by 1 d os e l ev el 
ev ery 2 w e eks, wit h t h e g o al 
b ei n g eli mi n ati o n of 
pr e d nis o n e/ pr e d nis ol o n e.
c. 
O nc e t h e d os e is r e d uc e d t o 
1 0 m g, a n att e m pt at 
r e d uci n g t h e st er oi d d os e 
f urt h er n e e d o nly b e 
S u bj ects’ d ai ly or al st er oi d d os e 
will b e r e d uc e d by 1 d os e l ev el 
ev ery 2 w e eks ( as ill ustr at e d i n 
T a bl e 3 -2) u ntil eit h er t h e o ns et of 
dis e as e fl ar e/r el a ps e or a st er oi d 
d o s e of ≤1 0 m g/ d a y h a s b e e n 
a c hi e v e d. W h e n a st er oi d d o s e 
of ≤1 0 m g/ d a y h a s b e e n 
a c hi e v e d, t h e 
pr e d ni s o n e/ pr e d ni s ol o n e d o s e 
m a y c o nti n u e t o b e t a p er e d 
( T a bl e 3- 2) or m a y b e 
m ai nt ai n e d at ≤1 0 m g/ d a y 
a c c or di n g t o t h e i n v e sti g at or’ s 
j u d g m e nt.
F or a s u bj ect w h o ex p eri e nc es
dis e as e fl ar e/r el a ps e, t h e
pr e d nis o n e/ pr e d nis ol o n e d os e will 
b e i ncr e as e d by 1 t o 4 l ev els p er 
w e ek u ntil dis e as e c o ntr ol is 
ac hi ev e d (i e, n o n e w l esi o ns f or 
≥2 w e eks); t h e 
pr e d nis o n e/ pr e d nis ol o n e t a p er will 
t h e n b e r ei niti at e d aft er a 2-w e ek 
p eri o d of dis e as e c o ntr ol. If t h e 
d o s e of 
pr e d ni s o n e/ pr e d ni s ol o n e i s 
≤1 0 m g/ d a y at t h e ti m e di s e a se 
c o ntr ol i s a c hi e v e d, f urt h er 
st er oi d t a p eri n g att e m pt s will b e 
at t h e i n v e sti g at or’ s di s cr eti o n.
T a bl e 3 - 2
T a p er D os e aft er Fl ar e/ R el a p s e
F o ot n ot e:
a. 
Pr e d nis o n e/ pr e d nis ol o n e is 
r e d uc e d by 1 d os e l ev el ev ery 
2 w e eks, wit h t h e g o al b ei n g 
eli mi n ati o n of
pr e d nis o n e/ pr e d nis ol o n e or 
r e d u cti o n of t h e d o s e t o 
≤1 0 m g/ d a y.
c. 
I n t h e ev e nt of a fl ar e/r el a ps e 
at a pr e d nis o n e/ pr e d nis ol o n e 
d os e of ≤1 0 m g/ d ay, t h e 
st er oi d d os e will b e 
Cl arific ati o n a n d 
c o nsist e ncy wit h t h e g o al t o 
eli mi n at e or r e d uc e t h e 
s u bj ect’s st er oi d d os e t o 
≤1 0 m g/ d ay.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 6 9
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
att e m pt e d u ntil t h e first 
fl ar e/r el a ps e occ urs.  I n t h e 
ev e nt of a fl ar e/r el a ps e at a 
pr e d nis o n e/ pr e d nis ol o n e 
d os e of ≤1 0 m g/ d ay, t h e 
d os e will b e t e m p or arily 
i ncr e as e d i n or d er t o 
r e-est a blis h dis e as e c o ntr ol 
( n o n e w l esi o ns f or 
> 2 w e eks); aft er dis e as e 
c o ntr ol is m ai nt ai n e d, f urt h er 
st er oi d t a p eri n g att e m pts t o 
< 1 0 m g will b e t h e 
i nv esti g at or’s discr eti o n.
i ncr e as e d i n or d er t o 
r e-est a blis h dis e as e c o ntr ol 
( n o n e w l esi o ns f or 
≥2 w e eks). Aft er dis e as e 
c o ntr ol is m ai nt ai n e d, t h e 
st er oi d t a p er will b e 
r ei niti at e d if t h e d o s e of 
pr e d ni s o n e i s > 1 0 m g/ d a y.  
If t h e d o s e of 
pr e d ni s o n e/ pr e d ni s ol o n e i s 
≤1 0 m g/ d a y at t h e ti m e 
di s e a s e c o ntr ol i s a c hi e v e d, 
f urt h er st er oi d t a p eri n g 
att e m pts will b e at t h e 
i nv esti g at or’s discr eti o n.
S ecti o n 3. 1. 3; 
S ecti o n 
6. 3. 1 0. 2; 
T a bl e 6- 6
S ecti o n 3. 1. 3:
N ot e: S u bj ects w h o ar e H Bs A g 
n e g ativ e, a nti -H Bc p ositiv e, a n d 
H B V D N A n e g ativ e ( or if i n J a p a n 
a n d H Bs A g n e g ati v e, a nti-H Bc 
( H Bc A b) n e g ativ e, b ut H Bs A b 
p ositiv e) m ust c o nti n u e H B V D N A 
P C R m o nit ori n g at a mi ni m u m of 
ev ery 1 2 w e eks f or 6 m o nt hs 
aft er t h e l ast d os e of st u dy 
tr e at m e nt
S ecti o n 6. 3. 1 0. 2:
* I n J a p a n , if a s u bj ect is H Bs A g 
n e g ativ e, a nti -H Bc ( H Bc A b) 
n e g a tiv e, b ut H Bs A b p ositiv e, …
S u bj ects w h o ar e H bs A g
n e g ativ e, a nti -H Bc p ositiv e, a n d
H B V D N A n e g ativ e m ay b e
i ncl u d e d i n t h e st u dy, b ut m ust
u n d er g o H B V D N A P C R 
m o nit ori n g at a mi ni m u m of ev ery 
1 2 w e eks d uri n g t h e Tr e at m e nt 
P eri o d a n d f or 6 m o nt hs aft er t h e
l ast d os e.
T a bl e 6 -6:
A d diti o n al f or J a p a n :
S ecti o n 3. 1. 3:
S u bj ects w h o w er e H Bs A g 
n e g ativ e, a nti -H Bc p ositiv e, a n d 
H B V D N A n e g ativ e at s cr e e ni n g
( or, if i n J a p a n a n d S o ut h K or e a,
a n d H Bs A g n e g ativ e, a nti -H Bc 
( H Bc A b) n e g ativ e, b ut H Bs A b 
p ositiv e) m u st c o nti n u e H B V D N A 
P C R m o nit ori n g i n t h e 
I n di vi d u aliz e d F oll o w-u p P eri o d
at a mi ni m u m of ev ery 1 2 w e eks 
f or 6 m o nt hs aft er t h e l ast d os e of 
st u dy tr e at m e nt.
S ecti o n 6. 3. 1 0. 2:
* I n J a p a n a n d K or e a , if a s u bj ect 
isH Bs A g n e g ativ e, a nti -H Bc 
( H Bc A b) n e g ativ e, b ut H Bs A b 
p ositiv e, … …
S u bj ects w h o ar e H bs A g n e g ativ e,
a nti -H Bc p ositiv e ( or, if i n J a p a n 
a n d S o ut h K or e a, a n d H B s A g 
n e g ati v e, a nti -H B c ( H B c A b) 
n e g ati v e, b ut H B s A b p o siti v e) , 
a n d H B V D N A n e g ativ e m ay b e
i ncl u d e d i n t h e st u dy, b ut m ust
u n d er g o H B V D N A P C R
m o nit ori n g at a mi ni m u m of ev ery 
1 2 w e eks d uri n g t h e Tr e at m e nt 
P eri o d a n d e v er y 1 2 w e e k s 
d uri n g t h e I n di vi d u aliz e d 
F oll o w -u p P eri o d f or 6 m o nt hs 
aft er t h e l ast d os e of st u d y 
tr e at m e nt.
T a bl e 6 -6:
A d diti o n al f or J a p a n a n d S o ut h 
K or e a:
Cl arific ati o n a n d 
c o nsist e ncy wit h t h e 1-y e ar 
mi ni m u m r e q uir e m e nt f or 
t h e I n divi d u aliz e d F oll o w-u p
P eri o d f or s u bj ects n ot 
e nr olli n g i nt o t h e ext e nsi o n
st u dy.
Ali g n m e nt wit h 
c o u ntry-s p ecific excl usi o n 
crit eri a f or S o ut h K or e a as 
d escri b e d i n A p p e n dix 2.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 0
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 3. 2 
N A
T h e fir st y e ar of t h e 
I n di vi d u aliz e d F oll o w-u p P eri o d 
i s e x p e ct e d t o pr o vi d e a d e q u at e 
ti m e f or B-c ell r e pl eti o n i n t h e 
m aj orit y of s u bj e ct s. T h e 
s e c o n d y e ar will c o nti n u e t o 
m o nit or f or B -c ell r e pl eti o n i n 
t h e r e m ai ni n g s u bj e ct s. T h e 
d ur ati o n of r e mi s si o n a n d ti m e 
t o fl ar e/r el a p s e aft er c o m pl eti n g 
tr e at m e nt will al s o b e a s s e s s e d.
R ati o n al e f or c h a n g es t o 
I n divi d u aliz e d F oll o w-u p 
P eri o d.
S ecti o n 4. 2, 
I ncl usi o n 
crit eri o n # 3
3. At l e ast 1 pr evi o us e pis o d e of 
a f ail e d st er oi d t a p er (i e, dis e as e 
fl ar e/r el a ps e) at a 
pr e d nis o n e/ pr e d nis ol o n e d os e 
> 1 0 m g/ d ay, wit h a P e m p hi g us 
S ev erity of Cli nic al Dis e as e sc or e 
of m o d er at e ( 2) or s ev er e ( 3) 
( m ay b e hist oric al/r etr os p ectiv e 
ass ess m e nt [s e e A p p e n dix 6 a n d 
S P M f or g ui d a nc e ]), w h er e 
s ev erity of dis e as e at 
fl ar e/r el a ps e n ec essitat e d a n 
i ncr e as e of >2 0 m g/ d ay. N ot e: 
pr e d nis o n e/ pr e d nis ol o n e d os e 
s h o ul d n ot b e i ncr e as e d f or t h e 
s ol e p ur p os e of e ntry i nt o t his 
st u dy.
3. At l e ast 1 pr evi o us e pis o d e of a 
f ail e d st er oi d t a p er (i e, dis e as e 
fl ar e/r el a ps e) at a 
pr e d nis o n e/ pr e d nis ol o n e d os e
> 1 0 m g/ d ay. T h e f oll o wi n g 
crit eri a m u st h a v e b e e n m et a s 
e vi d e n c e of di s e a s e s e v erit y at 
t h e ti m e of t h e f ail e d st er oi d 
t a p er:
a.
A P e m p hi g us S ev erity of 
Cli nic al Dis e as e sc or e of 
m o d er at e ( 2) or s ev er e ( 3) 
( m ay b e
hist oric al/r etr os p ectiv e 
ass ess m e nt [s e e 
Ap p e n dix 6]).
b.
R e q uir e d a tr e at m e nt 
c h a n g e at t h e ti m e of t h e 
f ail e d st er oi d t a p er of at 
l e a st o n e of t h e f oll o wi n g:
i. 
A st er oi d i ncr e as e t o 
≥2 0 m g/ d ay O R 
ii. 
T h e a d diti o n of 
i m m u n o s u p pr e s si v e/ 
i m m u n o m o d ul at or y 
a g e nt/tr e at m e nt O R
iii.
A d o s e i n cr e a s e of 
i m m u n o s u p pr e s siv e/ 
i m m u n o m o d ul at or y 
a g e nt/tr e at m e nt 
N ot e: F or s u bj e ct s o n 
i m m u n o s u p pr e s si v e/ 
i m m u n o m o d ul at or y a g e nt s, 
pl e a s e r e vi e w r e stri cti o n s u n d er 
E x cl u si o n Crit eri o n 4, 
M e di c ati o n a n d Ot h er Tr e at m e nt 
R e stri cti o n s Pri or t o 
R a n d o miz ati o n ( S e cti o n 4. 3).
“ … A st er oi d i ncr e as e t o 
≥2 0 m g/ d ay …” T h es e 
c h a n g es ar e c orr ecti o ns. 
I nv esti g at ors h av e r e p ort e d 
t h at, i n t h eir cli nic al pr actic e, 
f ail e d st er oi d t a p ers m ay b e 
tr e at e d by t h e a d diti o n of a n 
i m m u n os u p pr essiv e/ 
i m m u n o m o d ul at ory 
a g e nt/tr e at m e nt or 
i ncr e asi n g t h e d os e of a n 
existi n g 
i m m u n os u p pr essiv e/ 
i m m u n o m o d ul at ory 
a g e nt/tr e at m e nt. T h es e 
tr e at m e nt c h a n g es m ay b e 
m a d e i nst e a d of, or i n 
a d diti o n t o, a n i ncr e as e d 
st er oi d d os e t o ≥2 0 m g/ d ay. 
T his c h a n g e will i m pr ov e 
t h e f e asi bility of t h e st u dy.
F urt h er g ui d a nc e will b e 
pr ovi d e d i n t h e S P M.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 1
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 4. 2, 
I ncl usi o n 
crit eri o n # 5; 
S ecti o n 4. 3, 
Excl usi o n 
crit eri o n # 4;
S ecti o n 4. 3, 
Excl usi o n 
crit eri o n # 8;
T a bl e 5 - 2
S ecti o n 4. 2, I ncl usi o n Crit eri o n 
#5:
( N ot e: s u bj ects w h o ar e o n 
ev ery -ot h er -d ay d osi n g r e gi m e ns 
n e e d t o c h a n g e t o a d aily d osi n g 
r e gi m e n f or ≥2 w e eks d uri n g t h e 
Scr e e ni n g P eri o d i n or d er t o 
q u alify.)
S ecti o n 4. 3, Excl usi o n Crit eri o n 
# 4:  N A
S ecti o n 4. 3, Excl usi o n Crit eri o n 
#8:
8. Si g nific a nt c o nc urr e nt, 
u nc o ntr oll e d m e dic al c o n diti o n …
T a bl e 5 -2:
N A
S ecti o n 4. 2, I ncl usi o n Crit eri o n # 5:
( N ot e: s u bj ects w h o ar e o n 
ev ery -ot h er -d ay d osi n g r e gi m e ns 
n e e d t o c h a n g e t o a d aily d osi n g 
r e gi m e n f or ≥2 w e eks d uri n g t h e 
Scr e e ni n g P eri o d i n or d er t o 
q u alify. S u bj e ct s w h o ar e 
r e c ei vi n g a diff er e nt s y st e mi c 
st er oi d f or t h e tr e at m e nt of 
p e m p hi g u s v ul g ari s n e e d t o 
s wit c h t o 
pr e d ni s o n e/ pr e d ni s ol o n e d uri n g 
t h e S cr e e ni n g P eri o d.)
S ecti o n 4. 3, Excl usi o n Crit eri o n # 4
(c ol u m n a d d e d t o t a bl e of 
M e dic ati o n a n d ot h er Tr e at m e nt 
R estricti o ns Pri or t o 
R a n d o miz ati o n):
2 w e e k s
S y st e mi c st er oi d s ( e x c e pt f or 
pr e d ni s o n e/ pr e d ni s ol o n e)
S ecti o n 4. 3, Excl usi o ns Crit eri o n 
#8:
8. Si g nific a nt c o nc urr e nt, 
u nc o ntr oll e d m e dic al c o n diti o n … 
T hi s i n cl u d e s s u bj e ct s w h o 
r e q uir e a n y s y st e mi c st er oi d 
tr e at m e nt f or a c o n c urr e nt 
m e di c al c o n diti o n ( ot h er t h a n 
p e m p hi g u s v ul g ari s ).
N ot e: S u bj e ct s w h o r e q uir e 
tr e at m e nt wit h 
pr e d ni s o n e/ pr e d ni s ol o n e f or 
c o n diti o n s ot h er t h a n
p e m p hi g u s v ul g ari s ar e n ot 
eli gi bl e f or t h e st u d y d u e t o t h e 
pr e d ni s o n e/ pr e d ni s ol o n e t a p er 
s c h e d ul e d uri n g t h e C or e St u d y 
P eri o d.
T a bl e 5 -2 ( r o w a d d e d):
M e dic ati o n or T h er a py:
S y st e mi c st er oi d s a ( s e e 
S e cti o n 3. 1. 1, S e cti o n 4. 2, a n d 
S e cti o n 4. 3.)
N ot e:
 
Pr e d ni s o n e/ pr e d ni s ol o n e 
f or t h e tr e at m e nt of 
p e m p hi g u s v ul g ari s i s 
all o w e d.
T h e us e of syst e mic 
st er oi ds ot h er t h a n 
pr e d nis o n e/ p re d nis ol o n e 
wit hi n 2 w e eks pri or t o 
r a n d o miz ati o n a n d d uri n g 
t h e st u dy will p ot e nti ally 
c o nf o u n d t h e ev al u ati o n of
t h e st u dy e n d p oi nts.
S u bj ects r ec eivi n g a n ot h er
syst e mic st er oi d f or t h e 
tr e at m e nt of p e m p hi g us
v ul g aris will n e e d t o s witc h 
t o pr e d nis o n e/ pr ed nis ol o n e
d uri n g t h e Scr e e ni n g 
P eri o d. T h e tr e at m e nt of 
a n ot h er m e dic al c o n diti o n
wit h 
pr e d nis o n e/ pr e d nis ol o n e is 
n ot all o w e d d uri n g t h e st u dy 
as st er oi d d os e t a p eri n g is a 
r e q uir e d p art of t h e st u dy.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 2
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
W as h o ut B ef or e R a n d o miz ati o n:
2 w e e k s
F o ot n ot e:
a. S u bj e ct s w h o r e q uir e
tr e at m e nt wit h 
pr e d ni s o n e/ pr e d ni s ol o n e or 
a n ot h er s y st e mi c st er oi d f or 
c o n diti o n s ot h er t h a n 
p e m p hi g u s v ul g ari s ar e n ot 
eli gi bl e f or t h e st u d y. S u bj e ct s 
will b e s wit c h e d fr o m ot h er 
s y st e mi c st er oi d s u s e d f or t h e 
tr e at m e nt of p e m p hi g u s v ul g ari s 
t o pr e d ni s o n e/ pr e d ni s ol o n e 
d u ri n g t h e S cr e e ni n g P eri o d. 
H o w e v er, s u bj e ct s w h o r e q uir e 
t h e c o nti n u e d u s e of s y st e mi c
st er oi d s ot h er t h a n
pr e d ni s o n e/ pr e d ni s ol o n e f or t h e
tr e at m e nt of p e m p hi gu s v ul g ari s 
ar e n ot eli gi bl e f or t h e st u d y.
S ecti o n 4. 3, 
T a bl e f or 
crit eri o n # 4
8 w e e k s a
1 8 m o nt h s
Rit uxi m a b or ot h er a nti - C D 2 0 
tr e at m e nts
8 w e e k s
1 8 m o nt h s
Rit uxi m a b or ot h er dr u g s 
aff e cti n g t h e n u m b er a n d 
f u n cti o n of B-c ell s
Err o n e o us hy p erscri pt e d “ a” 
d el et e d.
Cl arific ati o n.
S ecti o n 4. 3, 
crit eri o n # 6
N A
 
* I n S o ut h K or e a, r ef er t o 
A p p e n di x 2 f or a d diti o n al 
c o u ntr y -s p e cifi c s cr e e ni n g 
pr o c e d ur e s a n d e x cl u si o n 
crit eri a f or T B a n d 
h e p atiti s.*
A d d e d r ef er e nc e t o 
A p p e n dix 2 f or a d diti o n al 
c o u ntry-s p ecific pr oc e d ur es 
a n d excl usi o n crit eri a f or 
S o ut h K or e a.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 3
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 4. 4. 3 
N A
If a s u bj e ct e x p eri e n c e s
fl ar e s/r el a p s e s a n d t h e
i n v e sti g at 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 s u bj e ct 
t o i niti at e alt er n ati v e di s e a s e
m o dif yi n g tr e at m e nt t h at m a y
aff e ct B -c ell s, tr e at m e nt wit h
i n v e sti g ati o n al pr o d u ct will b e
di s c o nti n u e d (if t h e s u bj e ct i s i n 
t h e tr e at m e nt p h a s e) a n d t h e
s u bj e ct will b e wit h dr a w n fr o m 
t h e st u d y (i e, will n ot tr a n siti o n 
i nt o I n di vi d u aliz e d F oll o w-u p
P eri o d).
A s u bj e ct m a y wit h dr a w fr o m 
t h e st u d y at a n y ti m e at hi s/ h er 
o w n r e q u e st, or m a y b e 
wit h dr a w n at a n y ti m e at t h e 
di s cr eti o n of t h e i n v e sti g at or f or 
s af et y, b e h a vi or al, or 
a d mi ni str ati v e r e a s o n s. T h e 
r e a s o n( s) f or a s u bj e ct n ot 
c o m pl eti n g t h e st u d y will b e 
r e c or d e d i n t h e c a s e r e p ort f or m 
( C R F). If a p pli c a bl e, t h e
i n v e sti g at or m u st d o c u m e nt t h e
re a s o n f or wit h dr a w al of 
c o n s e nt (if s p e cifi e d b y t h e 
s u bj e ct).
If a s u bj e ct wit h dr a w s fr o m t h e 
st u d y, t h e s u bj e ct s h o ul d
c o m pl et e a n e arl y wit h dr a w al
vi sit.
Cl arific ati o n t h at t h e s u bj ect 
m ay wit h dr a w fr o m t h e 
st u dy at a ny ti m e at his/ h er
o w n r e q u est or at t h e
discr eti o n of t h e
i nv esti g at or.
S ecti o n 5. 1. 1  
Of at u m u m a b S C ( G S K 1 8 4 1 1 5 7; 
h u m a n m A b of at u m u m a b 
i nj ecti o n f or s u bc ut a n e o us us e) 
will b e s u p pli e d by G S K as a 
li q ui d c o nc e ntr at e i n a pr efill e d 
gl ass syri n g e wit h st ak e d n e e dl e, 
st o p p er, a n d pl u n g er, wit h a 
n e e dl e s af ety d evic e. I niti ally, 
syri n g es co nt ai ni n g 0. 6 m L 
( 6 0 m g) of c o nc e ntr ati o n 
1 0 0 m g/ m L dr u g pr o d uct will b e 
pr ovi d e d.
Pl ac e b o i n pr efill e d gl ass 
syri n g es t o m atc h t h e 
of at u m u m a b syri n g es, will b e 
m a d e a n d s u p pli e d by G S K, 
usi n g n or m al s ali n e (st eril e, 
pyr o g e n -fr e e 0. 9 % N a Cl) a n d 
fill e d t o 0. 6 m L i n a pr efill e d gl ass 
G S K will s u p ply of at u m u m a b S C 
(G S K 1 8 4 1 1 5 7; h u m a n m A b 
of at u m u m a b i nj e cti o n f or 
s u b c ut a n e o u s u s e ) i n pr efill e d 
gl ass syri n g es c o nt ai ni n g 0. 4 m L 
( 2 0 m g) of c o nc e ntr ati o n 
5 0 m g/ m L dr u g pr o d uct a n d
m atc hi n g pl ac e b o pr efill e d gl ass 
syri n g es c o nt ai ni n g 0. 4 m L of 
n or m al s ali n e.
C o nt e nts of t h e l a b el will b e i n 
acc or d a nc e wit h all a p plic a bl e 
r e g ul at ory r e q uir e m e nts.
T h e dil uti o n m et h o d is n o 
l o n g er b ei n g us e d. 
T h er ef or e, t ext p ert ai ni n g t o 
t h e dil uti o n m et h o d h as 
b e e n d el et e d.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 4
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
syri n g e wit h st ak e d n e e dl e, 
st o p p er, a n d pl u n g er, wit h a 
n e e dl e s af ety d evic e.
C o nt e nts of t h e l a b el will b e i n 
acc or d a nc e wit h all a p plic a bl e 
r e g ul at ory r e q uir e m e nts …
F or st u dy c e nt ers i niti at e d usi n g 
t h e dil uti o n m et h o d f or st udy 
tr e at m e nt pr e p ar ati o n, a n 
u n bli n d e d p h ar m acist ( or 
a p pr o pri at ely -q u alifi e d d esi g n e e) 
at t h e st u dy c e nt er will pr e p ar e 
e ac h d os e vi a a dil uti o n pr oc ess 
acc or di n g t o t h e d et ail e d 
i nstr ucti o ns i n t h e p h ar m acy 
m a n u al. Bri efly, t h e c o nt e nts of 
2 pr efill e d ( 0 . 6 m L) syri n g es 
( eit h er 1 of at u m u m a b 6 0 m g 
syri n g e pl us 1 pl ac e b o syri n g e or 
2 pl ac e b o syri n g es) will b e 
i nj ect e d i nt o a st eril e vi al a n d 
0. 4 m L of t h e r es ulti n g s ol uti o n 
will b e dr a w n i nt o a n e w syri n g e 
t o ac hi ev e t h e 2 0 m g 
of at u m u m a b (c o nc e ntr ati o n 
5 0 m g / m L) or pl ac e b o d os e. 
S ol uti o ns o bt ai n e d fr o m t h e 
dil uti o n m et h o d will b e filt er e d 
t hr o u g h K e n d all 5 micr o n filt er 
n e e dl es pri or t o i nj ecti o n. T h e 
i n-us e ti m e aft er t h e dr u g pr o d uct 
is dr a w n i nt o t h e syri n g e f or 
a d mi nistr ati o n s h o ul d n ot exc e e d 
2 h o urs; h o w ev er, it is 
r ec o m m e n d e d t h at t h e dr u g 
pr o d uct b e a d mi nist er e d 
i m m e di at ely.
I n c o u ntri es (i ncl u di n g J a p a n) 
a n d/ or st u dy c e nt ers n ot usi n g 
t h e dil uti o n m et h o d t o pr e p ar e 
st u dy i nj ecti o ns, K e n d all 5 micr o n 
filt er n e e dl es will n ot b e us e d a n d 
t h er e is n o n e e d t o d esi g n at e a n 
u n bl e n d e d p h ar m acist ( or 
a p pr o pri at ely -q u alifi e d d esi g n e e) 
f or dr u g pr e p ar ati o n.
W h e n av ail a bl e, G S K will s u p ply 
of at u m u m a b S C i n pr efill e d gl ass 
syri n g es c o nt ai ni n g 0. 4 m L 
( 2 0 m g) of c o nc e ntr ati o n 5 0 
m g/ m L dr u g pr o d uct a n d 
m atc hi n g pl ac e b o pr efill e d gl ass 
syri n g es c o nt ai ni n g 0. 4 m L of 

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 5
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
n or m al s ali n e.
S ecti o n 5. 1. 1 
T h e i nj ecti o n sit e m ay b e 
a dj ust e d at i nv esti g at or’s 
discr eti o n if t h er e ar e ext e nsiv e 
a b d o mi n al l esi o ns pr es e nt .
T h e i nj ecti o n sit e m ay b e a dj ust e d 
at t h e i nv esti g at or’s discr eti o n 
b a s e d o n m e di c al j u d g m e nt .
T h er e m a y b e m e dic al 
r e as o ns ot h er t h a n 
ext e nsiv e a b d o mi n al l esi o ns 
t h at w o ul d n ec essit at e a n 
alt er n at e i nj ecti o n sit e.
S ecti o n 5. 1. 1; 
S ecti o n 5. 4
S ecti o n 5. 1. 1:
D et ail e d i nstr ucti o ns r el at e d t o 
t h e d estr ucti o n of u n us e d 
m at eri als ar e pr ovi d e d i n t h e 
p h ar m acy m a n u al.
A M at eri al S af ety D at a S h e et 
d escri bi n g t h e occ u p ati o n al
h az ar ds a n d r ec o m m e n d e d
h a n dli n g pr ec a uti o ns will b e
pr ovi d e d t o sit e st aff i n t h e
p h ar m acy m a n u al .
S ecti o n 5. 4:
I n acc or d a nc e wit h l oc al 
r e g ul at ory r e q uir e m e nts, t h e 
i nv esti g at or, d esi g n at e d sit e st aff, 
or h e a d of t h e m e dic al i nstit uti o n 
( w h er e a p plic a bl e) m ust 
d oc u m e nt t h e a m o u nt of 
i nv esti g ati o n al pr o d uct 
a d mi nist er e d t o st u dy s u bj ects, 
a n d t h e a m o u nt r ec eiv e d fr o m 
a n d r et ur n e d t o G S K, w h e n 
a p plic a bl e. Pr o d uct acc o u nt a bility 
r ec or ds m ust b e m ai nt ai n e d 
t hr o u g h o ut t h e c o urs e of t h e 
st u dy.
T h e d esi g n at e d p h ar m acist m ust 
k e e p dr u g i nv e nt ory a n d 
acc o u nt a bility l o gs. T h e i nv e nt ory 
will i ncl u d e d et ails of of at u m u m a b 
S C a n d pl ac e b o r ec eiv e d a n d 
dis p e ns e d ( a d mi nist er e d) t o 
s u bj ects, b atc h, a n d I D n u m b ers. 
All u n us e d pr efill e d syri n g es 
(s u p pli e d by G S K) m ust b e k e pt 
u ntil r ec o ncili ati o n of d eliv ery 
r ec or ds wit h acc o u nt a bility l o gs 
by t h e m o nit or. Aft er t h e m o nit or 
h as p erf or m e d acc o u nt a bility, t h e 
sit e m ay d estr oy t h e syri n g es, 
u nl ess ot h er wis e i nstr uct e d . A n 
acc o u nti n g m ust b e m a d e of a ny 
dr u g d eli b er at ely or acci d e nt ally 
d estr oy e d. Discr e p a nci es 
b et w e e n t h e a m o u nt of 
of at u m u m a b S C a n d pl ac e b o 
S ecti o n 5. 1. 1:
N A
A M at eri al S af ety D at a S h e et
d escri bi n g t h e occ u p ati o n al 
h az ar ds a n d r ec o m m e n d e d 
h a n dli n g pr ec a uti o ns will b e 
pr ovi d e d t o sit e st aff i n t h e S P M .
S ecti o n 5. 4:
T h e i n v e sti g at or, i n stit uti o n, or 
t h e h e a d of t h e m e di c al 
i n stit uti o n ( w h er e a p pli c a bl e) i s 
r e s p o nsi bl e f or st u d y tr e at m e nt
a c c o u nt a bilit y, r e c o n c ili ati o n, 
a n d rec or d m ai nt e n a n c e (i. e. 
r e c ei pt, r e c o n cili ati o n a n d fi n al
di s p o siti o n r e c or d s). F urt h er
g ui d a n c e a n d i nf or m ati o n f or 
fi n al di s p o siti o n of u n u s e d 
st u d y tr e at m e nt ar e pr o vi d e d i n 
t h e S P M.
D et ails r e g ar di n g pr o d uct 
acc o u nt a bility a n d fi n al 
dis p ositi o n of u n us e d st u dy 
tr e at m e nt ar e n o w l oc at e d 
i n t h e S P M. A d diti o n ally, t h e 
M at eri al S af ety D at a S h e et 
will b e l oc at e d i n t h e S P M.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 6
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
r ec eiv e d a n d dis p e ns e d m ust b e 
r ec o ncil e d.
S ecti o n 5. 2 
T h e s u bj ects a n d t h e 
i nv esti g ativ e st aff, exc e pt t h e 
u n bli n d e d p h ar m acist, will b e 
bli n d e d t o t h e tr e at m e nt
assi g n m e nt.
All st u dy st aff (i ncl u di n g t h e 
i nv esti g at or, s u bi nv esti g at ors, 
ot h er sit e st aff, t h e s u bj ect, a n d 
S p o ns or) will b e bli n d e d t o t h e 
tr e at m e nt all oc at e d t o i n divi d u al 
s u bj ects.
T h e dil uti o n m et h o d is n o 
l o n g er b ei n g us e d s o t h er e 
is n o l o n g er a ne e d f or a n 
u n bli n d e d p h ar m acist.
S ecti o n 5. 3 
E ac h sit e t h at pr e p ar es st u dy 
i nj ecti o ns usi n g t h e dil uti o n 
m et h o d m ust d esi g n at e a n 
u n bli n d e d p h ar m acist ( or 
a p pr o pri at ely -q u alifi e d d esi g n e e) 
f or dr u g pr e p ar ati o n.  All ot h er 
st u dy st aff (i ncl u di n g t h e 
i nv estig at or, s u bi nv esti g at ors, 
ot h er sit e st aff, t h e s u bj ect, a n d 
S p o ns or) will b e bli n d e d t o t h e 
tr e at m e nt all oc at e d t o i n divi d u al 
s u bj ects.
I n c o u ntri es (i ncl u di n g J a p a n) 
a n d/ or st u dy c e nt ers n ot usi n g 
t h e dil uti o n m et h o d t o pr e p ar e 
st u dy i nj ecti o ns, t h er e is n o n e e d 
t o d esi g n at e a n u n bli n d e d 
p h ar m acist ( or 
a p pr o pri at ely -q u alifi e d d esi g n e e) 
f or dr u g pr e p ar ati o n.
Aft er t h e W e ek 6 0 visit a n d e ac h 
I n divi d u aliz e d F oll o w-u p visit, t h e 
c e ntr al l a b or at ory ( or d esi g n e e) 
will n otify t h e i nv esti g at or w h et h er 
or n ot a s u bj ect n e e ds t o r e m ai n 
i nf oll o w-u p ….
All st u dy st aff (i ncl u di n g t h e 
i nv esti g at or, s u bi nv esti g at ors, 
ot h er sit e st aff, t h e s u bj ect, a n d 
S p o ns or) will b e bli n d e d t o t h e 
tr e at m e nt all oc at e d t o i n divi d u al 
s u bj ects.
At t h e e n d of t h e fir st y e ar of 
O P V 1 1 6 9 1 0 I n divi d u aliz e d 
F oll o w -u p a n d aft er e a c h 
s u b s e q u e nt visit d uri n g t h e 
s e c o n d y e ar of I n di vi d u aliz e d 
F oll o w -u p, t h e c e ntr al l a b or at ory 
( or d esi g n e e) will n otify t h e 
i nv esti g at or w h et h er or n ota 
s u bj ect n e e ds t o r e m ai n i n
f oll o w-u p …
T h e dil uti o n m et h o d is n o 
l o n g er b ei n g us e d s o t h er e 
is n o l o n g er a n e e d f or a n 
u n bli n d e d p h ar m acist.
F or c o nsist e ncy wit h t h e 
c h a n g es t o t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d. S u bj ects w h o d o n ot 
e nt er t h e ext e nsi o n st u dy 
will e nt er t h e I n divi d u aliz e d 
F o ll ow- u p P eri o d f or a 
mi ni m u m of 1 y e ar. Aft er t h e 
first y e ar, t h e c e ntr al l a b will 
n otify t h e i nv esti g at or 
w h et h er or n ot t h e s u bj ect 
n e e ds t o r e m ai n i n t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d (l a b v al u es will 
r e m ai n bli n d e d).
T a bl e 5 - 2
 
al e mt uz u m a b ( C a m p at h) 
 
al e nt uz u m a b ( C a m p at h; 
M a b C a m p at h )
U p d at e d i nf or m ati o n

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 7
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 5. 6. 2; 
S ect i o n 
1 1. 2. 1 
( A p p e n dix 2 
C o u ntry -
s p ecific 
re q uir e m e nts: 
J a p a n)
S ecti o n 5. 6. 2:
* I n J a p a n , al e mt uz u m a b 
( C a m p at h) a n d a nti -C D 4 
tr e at m e nts ar e n ot a p pr ov e d.
S ecti o n 1 1. 2. 1 ( A p p e n dix 2):
S e ct i o n 5. 6. 2 Pr o hi bit e d 
M e di c ati o n s a n d N o n -Dr u g 
T h er a pi e s
I n J a p a n, al e mt uz u m a b 
( C a m p at h) a n d a nti C D 4 
tr e at m e nts ar e n ot a p pr ov e d. 
I m m u n o gl o b uli n t h er a py is 
pr o hi bit e d as a n 
i m m u n os u p pr essiv e a g e nt.
* I n J a p a n, m ar k et a ut h oriz ati o n 
h a s n ot b e e n gr a nt e d f or a nti -
C D 4 tr e at m e nts f or t h e tr e at m e nt 
of p e m p hi g u s v ul g ari s.
Al e mt uz u m a b is n o w 
a p pr ov e d i n J a p a n. 
St at e m e nt r e g ar di n g a nti -
C D 4 tr e at m e nts h as b e e n 
cl arifi e d. A s e p ar at e 
st at e m e nt r e g ar di n g 
i m m u n o gl o b uli n t h er a py 
w as n ot r e q uir e d as it is a 
pr o hi bit e d m e d ic ati o n i n 
T a bl e 5 -2.
S ecti o n 5. 7 
S u bj ects c o m pl eti n g t h e st u dy 
a n d m e eti n g e ntry crit eri a will b e 
off er e d t h e o pti o n t o p artici p at e i n 
a n ext e nsi o n st u dy 
( O P V 1 1 7 0 5 9), w hic h will st art 
aft er c o m pl eti o n of t h e W e ek 6 0 
visit.
S u bj ects c o m pl eti n g t h e st u d y an d 
m e eti n g e ntry crit eri a will b e 
off er e d t h e o pti o n t o p artici p at e i n 
a n ext e nsi o n st u dy ( O P V 1 1 7 0 5 9), 
w hic h will st art wit hi n 4 w e e k s of 
c o m pl eti n g t h e W e ek 6 0 visit ( s e e 
S e cti o n 3. 1. 2. 1) . S u bj e ct s w h o 
ar e i n s u st ai n e d r e mi s si o n o n 
mi ni m al st er oi d t h er a p y at t h e 
W e e k 6 0 vi sit ar e eli gi bl e f or t h e 
e xt e n si o n st u d y o nl y if a 
di s e a s e fl ar e/r el a p s e i s 
e x p eri e n c e d d uri n g t h e fir st y e ar
of t h e O P V 1 1 6 9 1 0 I n di vi d u aliz e d 
F oll o w -u p P eri o d, a n d t h e y 
c o n s e nt t o p arti ci p ati o n i n t h e 
e xt e n si o n st u d y ( s e e 
S e cti o n 3. 1. 3).
Cl arific ati o n of t h e p eri o d of 
ti m e all o w e d b et w e e n t h e 
W e ek 6 0 visit a n d t h e st art 
of t h e ext e nsi o n st u dy. 
T o ac hi ev e c o nsist e ncy wit h 
t h e pr ot oc ol c h a n g e t h at 
s u bj ects i n s ust ai n e d 
r e missi o n o n mi ni m al 
st er oi d t h er a py at t h e 
W e ek 6 0 Vis it will e nt er t h e
I n divi d u aliz e d F oll o w-u p 
P eri o d.
S ecti o n 6 
T a bl e 6 -1 pr es e nt s …
T a bl e 6 -1 a n d T a bl e 6 - 2 pr es e nt …
Cl arific ati o n
S ecti o n 6 
If a visit c a n n ot b e sc h e d ul e d o n 
t h e a p pr o pri at e d at e, t h e visit 
s h o ul d b e r e-sc h e d ul e d as cl os e 
as p ossi bl e t o t h e pl a n n e d d at e, 
i de ally wit hi n ± 3 d ays.
If a visit c a n n ot b e sc h e d ul e d o n 
t h e a p pr o pri at e d at e, t h e visit 
s h o ul d b e r e-sc h e d ul e d as cl os e 
as p ossi bl e t o t h e pl a n n e d d at e, 
i d e ally wit hi n ± 3 d ays d uri n g t h e 
C or e St u d y P eri o d (f or vi sit s 
fr o m W e e k 2 t hr o u g h W e e k 6 0) 
a n d wit hi n ± 7 d a y s d uri n g t h e 
I n di vi d u aliz e d F oll o w-u p P eri o d.
Cl arific ati o n

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 8
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T a bl e 6 - 1 
b. If s u bj ect is n ot e nt eri n g t h e 
ext e nsi o n st u dy a n d C D 1 9 + 
B- c ell c o u nts a n d circ ul ati n g I g G 
l ev els ar e < L L N at W e ek 6 0 ( or 
e arly wit h dr a w al visit) , t h e s u bj ect
will tr a nsiti o n i nt oI n divi d u aliz e d 
F oll o w -u p (s e e T a bl e 6 2). 
S u bj ects r e q uiri n g a d diti o n al H B V 
t esti n g will als o r et ur n f or f oll o w 
u p visits f or 6 m o nt hs aft er t h e 
l ast d os e.
b. If t h e s u bj ect is n ot e nt eri n g t h e
ex t e nsi o n st u dy, t h e s u bj ect will 
tr a nsiti o n i nt o I n divi du aliz e d 
F oll o w -u p f or a mi ni m u m of 1 
y e ar (s e e T a bl e 6 -2).
F o ot n ot e ( s e nt e nc e a d d e d):
f. H B V D N A— at S cr e e ni n g a n d
e v er y 1 2 w e e k s d uri n g t h e 
Tr e at m e nt P eri o d f or a p pli c a bl e 
s u bj e ct s ( s e e S e cti o n 6. 3. 1 0. 2).
C o nsist e ncy wit h t h e n e w
r e q uir e m e nt f or a mi nim u m
1- y e ar In divi d u aliz e d 
F oll o w -u p P eri o d f or 
s u bj ects n ot e nr olli n g i nt o
t h e ext e nsi o n st u dy.
R e mi n d er a d d e d t o f o ot n ot e
“f” f or H B V D N A t esti n g f or 
a p plic a bl e s u bj ects. H B V 
D N A t esti n g f or 6 m o nt hs 
aft er t h e l ast d os e of st u dy 
tr e at m e nt, if a p plic a bl e, will
b e p erf or m e d d uri n g t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d.
T a bl e 6 - 1 
N A
P h ot o gr a p h y j (Ti m e a n d Ev e nts 
T a bl e s h o ws t h at t his is p erf or m e d 
at t h e B as eli n e, W e ek 4, 8, a n d 1 2 
cli nic visits.)
F o ot n ot e:
j. O nl y sit e s pr ei d e ntifi e d t o 
p erf or m cli ni c al p h ot o gr a p h y. 
S u bj e ct p arti ci p ati o n i s 
v ol u nt ar y. I nf or m e d c o n s e nt 
m u st b e o bt ai n e d b ef or e t a ki n g 
p h ot o gr a p h s f or t h e st u d y. T h e 
s a m e ar e a s h o ul d b e 
p h ot o gr a p h e d at e a c h vi sit.
Cli nic al p h ot o gr a p hy will b e 
p erf or m e d at s el ect e d st u dy 
sit es f or us e in f ut ur e 
p u blic at i o ns a n d/ or 
pr es e nt ati o ns.
T a bl e 6 - 1 
N ot e: Visits fr o m W e ek 2 t hr o u g h 
W e ek 6 0 t o b e sc h e d ul e d wit hi n 
± 3 d ays of t h e s p ecifi e d ti m e 
p oi nt. Visits d uri n g I n divi d u aliz e d 
F oll o w u p t o b e sc h e d ul e d wit hi n 
± 7 d ays.
S ec o n d r o w:
Tr e at m e nt P eri o d ( 5 6 W e eks) 
( Vi sits ± 3 d a y s)
T h e i nf or m ati o n h as b e e n 
r e arr a n g e d. T h e visit 
wi n d o w f or t h e Tr e at m e nt
P eri o d is n o w at t h e t o p of
t h e t a bl e. T h e visit wi n d o w
f or t h e I n divi d u aliz e d
F oll o w -u p P eri o d is i n 
T a bl e 6- 2.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 7 9
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T a bl e 6 - 2 
Cli nic visits ev ery 1 2 w e eks a ( e g, 
u p t o 8 visits t ot al at 
a p pr oxi m at ely W e eks 7 2, 8 4, 9 6, 
1 0 8, 1 2 0, 1 3 2, 1 4 4, & 1 5 6) 
F o ot n ot e:
a. S u bj ects e nt eri n g t h e 
i n divi d u aliz e d f oll o w-u p p eri o d
will c o nti n u e t o b e m o nit or e d
ev ery 1 2 w e eks, u ntil C D 1 9 + 
B- ly m p h ocyt ec o u nts or I g G 
r ec ov er t o L L N or t o t h e s u bj ect’s 
B as eli n e v al u e (if < L L N) or if 
crit eri a f or st u dy wit h dr a w al ar e 
m et or f or a m axi m u m of 2 y e ars 
aft er t h e l ast d os e of of at u m u m a b 
S C .
T a bl e u p d at e d t o s h o w 
ass ess m e nts f or e ac h visit d uri n g 
t h e 2-y e ar I n divi d u aliz e d F oll o w-u p 
P eri o d.
F o ot n ot e:
a. S u bj e cts e nt eri n g t h e 
I n divi d u aliz e d F oll o w-u p P eri o d will 
c o nti n u e t o b e m o nit or e d ev ery 
1 2 w e eks f or a mi ni m u m of 1 
y e ar. ( T h e f oll o wi n g gr o u p of 
s u bj e ct s m a y b e i n t h e 
I n di vi d u aliz e d F oll o w-u p P eri o d 
f or < 1 y e ar: s u bj e ct s w h o w er e 
i n s u st ai n e d r e mi s si o n o n 
m i ni m al st er oi d t h er a p y at t h e 
W e e k 6 0 vi sit w h o e nt er t h e 
e xt e n si o n st u d y aft er 
e x p eri e n ci n g a di s e a s e/fl ar e 
r el a p s e d uri n g t h e 1 st y e ar of 
t h e I n di vi d u aliz e d F oll o w-u p 
P eri o d.) Aft er t h e 1 st y e ar, 
s u bj e ct s will r e m ai n i n t h e 
I n di vi d u aliz e d F oll o w-u p f or u p 
t o 1 m or e y e ar u ntil C D 1 9 + B -c ell 
c o u nts or circ ul ati n g I g G r ec ov er t o 
≥L L N or t o t h e b as eli n e v al u es (if 
< L L N) or if crit eri a f or st u dy 
wit h dr a w al ar e m et or f or 2 y e ars 
aft er t h e l ast d os e of 
i n v e sti g ati o n al pr o d u ct 
( w hi c h e v er c o m e s fir st).
F or cl arity a n d c o nsist e ncy 
wit h t h e r e q uir e d 1 -y e ar 
mi ni m u m I n divi d u aliz e d 
F oll o w - up P eri o d f or 
s u bj ects n ot e nr olli n g i nt o 
t h e ext e nsi o n st u dy.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 0
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T a bl e 6 - 2 
S eri o us a dv ers e ev e nts a n d 
a dv ers e ev e nts of s p eci al i nt er est
A d v er s e E v e nt s (i n cl u di n g S A E s 
a n d A E s of s p e ci al i nt er e st) b
( X f or w e eks 7 2, 8 4, 9 6, 1 0 8, E arly 
W D) 
S A E s a n d A E s of S p e ci al 
I nt er e stb
( X f or w e eks 1 2 0, 1 3 2, 1 4 4, 1 5 6, 
E arly W D)
F o ot n ot e:
b. A E s (i n cl u di n g A E s of s p e ci al 
i nt er e st) a n d S A E s will b e 
c oll e ct e d d uri n g t h e fir st y e ar of 
t h e I n di vi d u aliz e d F oll o w-u p 
P eri o d. O nl y S A E s a n d A E s of 
s p e ci al i nt er e st will b e c oll e ct e d
d uri n g t h e s e c o n d y e ar of t h e 
I n di vi d u aliz e d F oll o w-u p P eri o d. 
S A E s a s s e s s e d a s r el at e d t o 
st u d y p arti ci p ati o n will b e 
c oll e ct e d fr o m t h e ti m e a 
s u bj e ct c o n s e nt s t o p arti ci p at e 
i n t h e st u d y u p t o a n d i n cl u di n g 
a n y f oll o w -u p c o nt a ct.
All A Es will b e c oll ec t e d 
d uri n g t h e 1st y e ar of t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d i n or d er t o c oll ect 
a d diti o n al s af ety i nf or m ati o n 
i n s u bj ects w h o h av e 
disc o nti n u e d or c o m pl et e d 
tr e at m e nt wit h 
i nv esti g ati o n al pr o d uct. 
D uri n g t h e 2 n d y e ar of 
I n divi d u aliz e d F oll o w-u p, 
S A Es a n d A Es of s p eci al 
i nt er est will b e c oll ect e d.
T a bl e 6 - 2 
N A
P V l e si o n m a p pi n g
( Ti m e a n d Ev e nts T a bl e s h o ws 
t h at t his is r e q uir e d at e ac h visit.)
P V l esi o n m a p pi n g will b e 
p erf or m e d at ev ery visit 
d uri n g t h e I n divi d u aliz e d 
F oll o w -u p P eri o d t o ass ess 
T a bl e 6 - 2 
Cli nic al c h e mistry – o nly r e q uir e d 
f or s u bj ects m e eti n g liv er 
c h e mistry st o p pi n g/ m o nit ori n g 
crit eri a
Cli nic al c h e mistry
( Ti m e a n d Ev e nts Ta bl e s h o ws 
t h at t his is r e q uir e d at e ac h visit.)
A d d e d t o c oll ect a d diti o n al 
s af ety d at a d uri n g t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d.
T a bl e 6 - 2 
N A
H u m a n a nti h u m a n a nti b o d y 
( H A H A)
( Ti m e a n d Ev e nts T a bl e s h o ws 
t h at t his is r e q uir e d at W e ek 7 2 
a n d E arly Wit h dr a w al.)
A d d e d t o ev al u at e 
i m m u n o g enicity aft er 
disc o nti n u ati o n or 
c o m pl eti o n of i nv esti g ati o n al 
pr o d uct.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 1
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T a bl e 6 - 2 
N A
F o ot n ot es:
A b br evi ati o ns: A E = A d v er s e 
E v e nt; P V = p e m p hi g u s v ul g ari s; 
S A E = S eri o u s A d v er s e E v e nt; 
W D = wit h dr a w al
N ot e: Vi sit s d uri n g 
I n di vi d u aliz e d F oll o w u p t o b e 
s c h e d ul e d wi t hi n ± 7 d a y s.
A b br evi ati o ns a d d e d d u e t o 
t a bl e visit a n d ass ess m e nt 
c h a n g es.
Cl arific ati o n r e g ar di n g t h e 
visit wi n d o w.
S ecti o n 6. 1 
N A
* I n S o ut h K or e a, r ef er t o 
A p p e n di x 2 f or a d diti o n al 
s cr e e ni n g a s s e s s m e nt s f or T B.*
A d d e d r ef er e nc e t o 
A p p e n dix 2 f or a d diti o n al 
c o u ntry-s p ecific 
ass ess m e nts f or S o ut h 
K or e a.
S ecti o n 6. 2. 2 
A fl ar e/r el a ps e is d efi n e d as n e w 
l esi o ns t h at d o n ot h e al 
s p o nt a n e o usly wit hi n 1 w e ek, or 
w h e n t h er e is a n ext e nsi o n of 
l esi o ns t h at w er e pr es e nt at t h e 
r a n d o miz ati o n visit.
A fl ar e/r e l a ps e is d efi n e d as t h e 
a p p e ar a n c e of ≥3 n e w l esi o ns 
wit hi n 1 m o nt h t h at d o n ot h e al 
s p o nt a n e o usly wit hi n 1 w e ek, or
w h e n t h er e is a n ext e nsi o n of
l esi o ns t h at w er e pr es e nt at t h e
r a n d o miz ati o n visit.
C orr ecti o n f or c o nsist e ncy 
b et w e e n s ecti o ns.
S ecti o n 
6. 3. 2. 3
 
H e p atitis B vir us r e activ ati o n 
(s e e S ecti o n 6. 3. 1 0.2).
 
H e p atitis B vir us i nf e cti o n or 
r e activ ati o n (s e e 
S ecti o n 6. 3. 1 0. 2).
Cl arific ati o n
S ecti o n 6. 3. 5 
… will r e q uir e a s p ecific d e at h 
d at a c oll ecti o n t o ol t o b e 
c o m pl et e d.
… will r e q uir e a s p ecific d e at h d at a 
c oll ecti o n t o ol t o b e c o m pl et e d 
( e C R F p a g e).
Cl ari fic ati o n
S ecti o n 6. 3. 6 
Pr e g n a ncy i nf or m ati o n will b e 
c oll ect e d fr o m t h e st art of st u dy 
tr e at m e nt t hr o u g h t h e f oll o w-u p 
c o nt act.
Pr e g n a ncy i nf or m ati o n will b e 
c oll ecte d fr o m t h e st art of st u dy 
tr e at m e nt a n d u ntil t h e e n d of t h e 
st u d y.
Cl arific ati o n a n d 
c o nsist e ncy wit h t h e ti m e 
p eri o d f or c oll ecti n g A Es,
A Es of s p eci al i nt er est, a n d 
S A Es.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 2
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 6. 3. 7 
S A Es a n d A Es of s p eci al
i nt er est will c o nti n u e t o b e
c oll ect e d d uri n g t h e
I n divi d u aliz e d F oll o w-u p P eri o d.
F or s u bj e ct s w h o e nt er t h e 
I n di vi d u aliz e d F oll o w-u p P eri o d, 
all A E s will c o nti n u e t o b e 
c oll e ct e d d uri n g t h e fir st y e ar of 
t h e I n di vi d u aliz e d F oll o w-u p 
P eri o d. D uri n g t h e s e c o n d y e ar 
of t h e I n di vi d u aliz e d F oll o w -u p 
P eri o d, o nl y S A Es a n d A Es of 
s p eci al i nt er est will b e c oll ect e d. 
F or s u bj e ct s tr a n siti o ni n g i nt o 
e xt e n si o n st u d y O P V 1 1 7 0 5 9, 
A E s a n d S A E s t h at o c c ur pri or 
t o t h e fir st d o s e of of at u m u m a b 
S C i n O P V 1 1 7 0 5 9 will b e 
c oll e ct e d i n t h e O P V 1 1 6 9 1 0 
e C R F.
All A Es will b e c oll ect e d 
d uri n g t h e 1st y e ar of t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d i n or d er t o c oll ec t 
a d diti o n al s af ety i nf or m ati o n 
i n s u bj ects w h o h av e 
disc o nti n u e d or c o m pl et e d 
tr e at m e nt wit h 
i nv esti g ati o n al pr o d uct. 
Cl arific ati o n r e g ar di n g t h e 
c oll ecti o n of A Es f or 
s u bj ects wh o will b e 
tr a nsiti o ni n g i nt o t h e 
ext e nsi o n st u dy.
S ecti o n 
6. 3. 9. 1
N A
S e cti o n 6. 3. 9. 1 R e g ul at or y 
R e p orti n g R e q uir e m e nt s f or 
S A Es
S u b h e a di n g h as b e e n 
a d d e d f or cl arity a n d e as e i n 
l oc ati n g i nf or m ati o n.
S ecti o n 
6. 3. 1 0. 1
…i n acc or d a nc e wit h t h e   
 
i nv esti g at or m a n u al a n d Pr ot oc ol 
Ti m e a n d Ev e nts Sc h e d ul e 
( T a bl e 6- 1).
…i n acc or d a nc e wit h t h e   
 
i nv esti g at or m a n u al a n d Pr ot oc ol 
Ti m e a n d Ev e nts Sc h e d ul e 
( T a bl e 6- 1 a n d T a bl e 6- 2 ).
Cl arific ati o n
T a bl e 6 - 5 
N A
S er u m h C G pr e g n a n c y t e sti n g 
( w o m e n of r e pr o d u cti v e 
p ot e nti al) b
A b br evi ati o n:
h C G = h u m a n c h ori o ni c 
g o n a d otr o pi n
C orr ecti o n
T a bl e 6 - 5 
N ot e: R ef er t o t h e Ti m e a n d 
Ev e nts Sc h e d ul e ( T a bl e 6 -1) …
N ot e: R ef er t o t h e Ti m e a n d 
Ev e nts Sc h e d ul e ( T a bl e 6 -1 a n d 
T a bl e 6- 2 ) …
Cl arific ati o n
T a bl e 6 - 5 
a. .. Aft er t h e W e ek 6 0 visit a n d all 
I n divi d u aliz e d F oll o w-u p visits, 
t h e c e ntr al l a b or at ory ( or
d esi g n e e) will n otify t h e
i nv esti g at or w h et h er or n ot a
s u bj ect n e e ds t o r e m ai n i n 
F oll o w -u p, …
a. … At t h e e n d of t h e fir st y e ar 
of I n di vi d u aliz e d F oll o w -u p a n d 
aft er e a c h s u b s e q u e nt vi sit 
d uri n g t h e s e c o n d y e ar of
I n divi d u aliz e d F oll o w-u p, t h e 
c e ntr al l ab or at ory ( or d esi g n e e) 
will n otify t h e i nv esti g at or w h et h er 
or n ot a s u bj ect n e e ds t o r e m ai n i n 
F oll o w -u p …
F or c o nsist e ncy wit h t h e 
c h a n g es t o t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d. S u bj ects w h o d o n ot 
e nt er t h e ext e nsi o n st u dy 
will e nt er t h e I n divi d u aliz e d 
F oll o w -u p P eri o d f or a 
mi ni m u m of 1 y e ar. Aft er t h e 
first y e ar, t h e c e ntr al 
l a bor at ory will n otify t h e 
i nv esti g at or w h et h er or n ot 
t h e s u bj ect n e e ds t o r e m ai n 
i n t h e I n divi d u aliz e d 
F oll o w -u p P eri o d (l a b or at ory
v al u es will r e m ai n bli n d e d).

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 3
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 6. 8 
N A
6 . 8 A d diti o n al A s s e s s m e nt s-
P h ot o gr a p h y
Cli ni c al p h ot o gr a p h y will b e 
p erf or m e d at s el e ct e d st u d y 
sit e s f or p u bli c ati o n a n d/ or 
pr e s e nt ati o n p ur p o s e s. 
P h ot o gr a p h s will n ot b e u s e d i n 
t h e e v al u ati o n of effi c a c y 
e n d p oi nt s f or t h e st u d y. S u bj e ct 
p arti ci p ati o n i n t h e p h ot o gr a p h y 
p orti o n of t h e st u d y i s 
v ol u nt ar y. S e p ar at e s u bj e ct 
i nf or m e d c o n s e nt a n d 
p h ot o gr a p hi c r el e a s e will b e 
r e q uir e d. P h ot o gr a p h s of a 
r e pr e s e nt ati v e ar e a c o nt ai ni n g 
p e m p hi g u s v ul g ari s l e si o n s will 
b e s el e ct e d b y t h e i n v e sti g at or 
or d e si g n e e. T h e s a m e ar e a will 
b e p h ot o gr a p h e d at t h e cli ni c 
vi sit s s p e cifi e d i n T a bl e 6 -1. 
A d diti o n al d et ail s r e g ar di n g 
cli ni c al p h ot o gr a p h y will b e 
d e s cri b e d i n t h e S P M.
Cli nic al p h ot o gr a p hy will b e 
p erf or m e d at s el ect e d st u dy 
sit es f or us e i n f ut ur e 
p u blic ati o ns a n d/ o r 
pr es e nt ati o n s.
S ecti o n 
8. 3. 6. 9
T h e a n alysis of s af ety d at a will 
us e t h e S af ety p o p ul ati o n. T h es e 
d at a will n ot u n d er g o a ny f or m al 
st atistic al a n alysis.
T h e a n alysis of s af ety d at a will us e 
t h e S af ety p o p ul ati o n. T h es e d at a 
will n ot u n d er g o a ny f or m al 
statistic al a n alysis. All s af et y 
e n d p oi nt s will b e pr e s e nt e d b y 
tr e at m e nt p h a s e a n d d ur ati o n of 
f oll o w-u p, i n cl u di n g t h e 
I n di vi d u aliz e d F oll o w-u p P eri o d.  
S af et y s u m m ari e s will b e 
pr e s e nt e d s e p ar at el y f or t h e 
C or e St u d y P eri o d a n d 
I n di vi d u aliz e d F oll o w-u p 
Pe ri o d s. C or e St u d y P eri o d 
s af et y will b e e v al u at e d u p t o 4 
w e e k s aft er t h e W e e k 6 0 vi sit or 
t h e fir st d o s e of of at u m u m a b i n 
t h e O P V 1 1 7 0 5 9 e xt e n si o n st u d y 
(f or s u bj e ct s w h o g o i nt o t h e 
e xt e n si o n st u d y) w hi c h e v er 
c o m e s fir st, a n d A E s pri or t o 
t h at ti m e will be i n cl u d e d i n t h e 
C or e St u d y P eri o d r e p ort s.
Cl arific ati o n of t h e 
pr es e nt ati o n of s af ety d at a 
by st u dy p h as e. S af ety d at a 
f or t h e C or e St u dy P eri o d 
will b e ev al u at e d u p t o 
4 w e eks aft er t h e W e ek 6 0 
b ec a us e s u bj ects ar e 
all o w e d a 4 -w e ek wi n d o w 
b et w e e n t h e W e ek 6 0 visit 
a n d t h e B as eli n e visit 
( W e ek 0/first d os e) i n t h e 
ext e nsi o n st u dy.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 4
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 1 0 
N A
Gl a x o S mit h Kli n e D o c u m e nt 
N u m b er G M 2 0 0 8/ 0 0 1 4 7/ 1 0. 
G S K 1 8 4 1 1 5 7 I n v e sti g at or’ s 
Br o c h ur e (I B). V er si o n 0 8. 
0 5 M ar c h
2 0 1 5.
Ot h er sli g ht r evis io ns m a d e t o 
r ef er e nc es as eit h er c orr ecti o ns or 
cl arific ati o ns.
Cl arific ati o n
S ecti o n 
1 1. 2. 1 
( A p p e n dix 2-
C o u ntry -
s p ecific 
re q uir e m e nts: 
J a p a n)
T h e f oll o wi n g c o u ntry -s p ecific 
i nf or m ati o n a n d st u dy c o n d uct 
c o nsi d er ati o ns f or O P V 1 1 6 9 1 0 
Pr ot oc ol A m e n d m e nt 5 …
S e cti o n 9. 2 R e g ul at or y a n d 
Et hi c al C o n si d er ati o n s, 
I n cl u di n g t h e I nf or m e d 
C o n s e nt Pr o c e s s
T h e st u dy will b e c o n d uct e d i n 
acc or d a nc e wit h “t h e Mi nist eri al 
Or di n a nc e o n t h e St a n d ar ds f or 
t h e C o n d uct of Cli nic al Tri als of 
M e dici n al Pr o d ucts ( M H W 
N otific ati o n N o. 2 8 d at e d 
2 7 M arc h 1 9 9 7)” a n d Arti cl e 1 4-3 
a n d 8 0 -2 of t h e P h ar m ac e utic al 
Aff airs L a w.
G S K will s u b mit t h e C T N t o t h e 
r e g ul at ory a ut h oriti es i n 
acc or d a nc e wit h Articl e 8 0 -2 of 
t h e P h ar m ac e utic al Aff airs L a w
b ef or e c o ncl usi o n …
T h e f oll o wi n g c o u ntry -s p ecific 
i nf or m ati o n a n dst u dy c o n d uct 
c o nsi d er ati o ns f or O P V 1 1 6 9 1 0 
Pr ot oc ol A m e n d m e nt 5 a n d 
Pr ot o c ol A m e n d m e nt 6 …
S e cti o n 9. 2 R e g ul at or y a n d 
Et hi c al C o n si d er ati o n s, 
I n cl u di n g t h e I nf or m e d C o n s e nt 
Pr o c e s s 
T h e st u dy will b e c o n d uct e d i n 
acc or d a nc e wit h “t h e Mi nist eri al 
Or di n a nc e o n t h e St a n d ar ds f or 
t h e C o n d uct of Cli nic al Tri als of 
M e dici n al Pr o d ucts ( M H W 
N otific ati o n N o. 2 8 d at e d 
2 7 M arc h 1 9 9 7)” a n d Articl e 1 4 -3 
a n d 8 0 -2 of t h e A ct o n S e c uri n g 
Q u alit y, Effi c a c y a n d S af et y of 
P h ar m a c e uti c al s, M e di c al 
D e vi c e s, R e g e n er ati v e a n d 
C el l ul ar T h er a p y Pr o d u ct s, G e n e 
T h er a p y Pr o d u ct s, a n d 
C o s m eti c s.
G S K will s u b mit t h e C T N t o t h e 
r e g ul at ory a ut h oriti es i n 
acc or d a nc e wit h Articl e 8 0 -2 of t h e 
A ct o n S e c uri n g Q u alit y, 
Effi c a c y a n d S af et y of 
P h ar m a c e uti c al s, M e di c al 
D e vi c e s, R e g e n er ati v e a n d 
C e ll ul ar T h er a p y Pr o d u ct s, G e n e 
T h er a p y Pr o d u ct s, a n d 
C o s m eti c s b ef or e c o ncl usi o n …
U p d at e d i nf or m ati o n

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 5
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 
1 1. 2. 2, 
( A p p e n dix 2 –
S o ut h K or e a; 
wit h cr oss -
r ef er e nc es
fr o m
a p plic a bl e
s ecti o ns 
wit hi n b o dy of
pr ot oc ol)
N A
A d diti o n of c o u nty -s p ecific 
r e q uir e m ents f or S o ut h K or e a: 
a d diti o n al scr e e ni n g pr oc e d ur es 
a n d excl usi o n crit eri a 
s p ecific ati o ns.
Pr ot oc ol m o dific ati o ns a n d
s u p pl e m e nt ary d et ails
r e q u est e d d uri n g r evi e w by 
t h e Mi nistry of F o o d a n d 
Dr u g S af ety.
S ecti o n 1 1. 6 
( A p p e n dix 6-
P e m p hi g us 
sev erity of 
cli nic al 
dis e as e 
sc or e)
C ol u m n: Or al Sc ori n g R o ws: 2, 
M o d er at e activity, a n d 3, S ev er e 
activity:
… d es q u a m ativ e gi n givitis …
C ol u m n: Or al Sc ori n g R o ws: 2, 
M o d er at e activity, a n d 3, S ev er e 
activity:
… d es q u a m ativ e ( er o si v e)
gi n givitis …
Cl arific ati o n t o f acilit a t e 
tr a nsl ati o ns.
S ecti o n 1 1. 1 5 
( A p p e n dix 1 5-
Pr ot oc ol 
ch a n g es)
N A
Li st of all c h a n g e s i n Pr ot o c ol 
A m e n d m e nt 6.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 6
Pr ot o c ol A m e n d m e nt 7:  2 5 A pril 2 0 1 6
A p plic a bl e t o all c o u ntri es a n d st u dy c e nt ers .  
A t t h e ti m e of t his a m e n d m e nt, 3 5 s u bj ects h a d b e e n r a nd o miz e d i n t h e st u dy.
** O P V 1 1 6 9 1 0 A m e n d m e nt 6 w as n ot i m pl e m e nt e d at a ny st u dy c e nt er. As a r es ult, c o n d uct of t h e st u dy f or 
all st u dy c e nt er s tr a nsiti o ne d fr o m A m e n d m e nt 5 dir ectly t o A m e n d m e nt 7 (i e, n o nc o ns ec utiv e n u m b eri n g) **
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Titl e p a g e 
N A
Pr ot oc ol a m e n d m e nt n u m b er, d at e, 
a n d r evisi o n c hr o n ol o gy.
A m e n d m e nt 7
Pr ot oc ol -
s p ecific 
d efi niti o ns; 
Pr ot oc ol 
s u m m ary, 
St u dy 
d esi g n; 
S ecti o n 3. 1
If B-c ell c o u nts h av e n ot 
r ec ov er e d by t h e W e ek 6 0 visit, 
s u bj ects n ot e nt erin g t h e 
ext e nsi o n st u dy will r e m ai n i n a n 
I n divi d u aliz e d F oll o w-u p P eri o d 
u ntil eit h er t h e C D 1 9 + B-c ell 
c o u nts or circ ul ati n g I g G l ev els 
ar e ≥L L N or b as eli n e l ev els (if 
< L L N) or u ntil 2 y e ars aft er t h e 
l ast d os e of i nv esti g ati o n al 
pr o d uct ( w hic h ev er c o m es f irst).
If B-c ell c o u nts h av e n ot 
r ec ov er e d by t h e W e ek 6 0 visit, 
s u bj ects n ot e nt eri n g t h e 
ext e nsi o n st u dy will r e m ai n i n a n 
I n divi d u aliz e d F oll o w-u p P eri o d 
u ntil b ot h t h e C D 1 9 + B-c ell 
c o u nts a n d circ ul ati n g I g G l ev els 
ar e ≥L L N or b as eli n e l ev els (if 
< L L N) or u ntil 2 y e ars aft er t h e 
l ast d os e of i nv esti g ati o n al 
pr o d uct ( w hic h ev er c o m es first).
B as e d o n disc ussi o n wit h 
i nv esti g at ors, crit eri a f or 
m ai nt ai ni n g s u bj ects i n t h e 
I n divi d u aliz e d F oll o w-u p 
P eri o d w er e m o difi e d t o 
all o w f or i m pr ov e d s af ety 
m o nit ori n g f oll o wi n g l ast 
d os e of i nv esti g ati o n al 
pr o d uct, w hil e f acilit ati n g t h e 
exit of s u bj ects fr o m t h e 
st u dy i n or d er t o pr o gr ess t o 
alt er n ativ e tr e at m e nt if 
n e e d e d.
S ecti o n 3. 1, 
Fi g ur e 3 - 2
M e et a ny of t h es e crit eri a:
 
C D 1 9 + B -c ells or I g G ≥L L N 
or b as eli n e ?
 
M e et ot h er crit eri a f or st u dy 
wit h dr a w al/ exit ?
 
2 y e ars aft er t h e l ast d os e ?
A N D H B V m o nit ori n g c o m pl et e (if 
a p plic a bl e) ?
M e et a ny of t h es e crit eri a:
 
C D 1 9 + B -c ells a n d I g G 
≥L L N or b as eli n e ?
 
M e et ot h er crit eri a f or st u dy 
wit h dr a w al/ exi t ?
 
2 y e ars aft er t h e l ast d os e ?
A N D H B V m o nit ori n g c o m pl et e (if 
a p plic a bl e) ?
S ecti o n 
3. 1. 3
If B-c ell c o u nts h av e n ot 
r ec ov er e d by t h e W e ek 6 0 visit, 
s u bj ects n ot e nt eri n g t h e 
ext e nsi o n st u dy ( O P V 1 1 7 0 5 9) will 
r e m ai n i n I n divi d u aliz e d F oll o w-u p 
u ntil: 
 
C D 1 9 + B -c ell c o u nts or
circ ul ati n g I g G l ev els ar e 
≥L L N or b as eli n e l ev els (if 
< L L N)
If B-c ell c o u nts h av e n ot 
r ec ov er e d by t h e W e ek 6 0 visit, 
s u bj ects n ot e nt eri n g t h e 
ext e nsi o n st u dy ( O P V 1 1 7 0 5 9) will 
r e m ai n i n I n divi d u aliz e d F oll o w-u p
u ntil: 
 
C D 1 9 + B -c ell c o u nts a n d
circ ul ati n g Ig G l ev els ar e 
≥L L N or b as eli n e l ev els (if 
< L L N)

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 7
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
S ecti o n 6, 
T a bl e 6 - 2
a. 
S u bj ects e nt eri n g t h e
i n divi d u aliz e d f oll o w-u p 
p eri o d c o nti n u e t o b e 
m o nit or e d ev ery 1 2 w e eks, 
u ntil C D 1 9 + B -ly m p h ocyt e 
c o u nts or I g G r ec ov er t o L L N 
or t o t h e s u bj ect’s B as eli n e 
v al u e (if < L L N) or if crit eri a 
f or st u dy wit h dr a w al ar e m et 
or f or a m axi m u m of 2 y e ars 
aft er t h e l ast d os e of 
of at u m u m a b S C.
a. 
S u bj ects e nt eri n g t h e 
In divi d u aliz e d F oll o w -u p 
P eri o d c o nti n u e t o b e 
m o nit or e d ev ery 1 2 w e eks, 
u ntil C D 1 9 + B -ly m p h ocyt e 
c o u nts a n d I g G r ec ov er t o 
≥L L N or t o t h e s u bj ect’s 
B as eli n e v al u e (if < L L N) or if 
crit eri a f or st u dy wit h dr a w al 
ar e m et or f or a m axi m u m of 
2 y e ars aft er t h e l ast d os e of 
of at u m u m a b S C.
B as e d o n disc ussi o n wit h 
i nv esti g at ors, crit eri a f or 
m ai nt ai ni n g s u bj ects i n t h e 
I n divi d u aliz e d F oll o w -u p 
P eri o d w er e m o difi e d t o 
all o w f or i m pr ov e d s af ety 
m o nit ori n g f oll o wi n g l ast 
d os e of i nv esti g ati o n al 
pr o d uct, w hil e f acilit ati n g t h e 
exit of s u bj ects fr o m t h e 
st u dy i n or d er t o pr o gr ess t o 
alt er n ativ e tr e at m e nt if 
n e e d e d.
S ecti o n 5. 3 
S p o ns or u n bl i n di n g f or a n alys es 
will occ ur aft er all s u bj ects h av e 
c o m pl et e d t h e W e ek 6 0 visit or
b e e n wit h dr a w n fr o m t h e 
tr e at m e nt p eri o d (s e e S ecti o n 
8. 3. 4) .
S p o ns or u n bli n di n g f or a n alys es 
will occ ur aft er all s u bj ects h av e 
c o m pl et e d t h e W e ek 6 0 visit, b e e n 
wit h dr a w n fr o m t h e tr e at m e nt 
p eri o d , or t h e st u d y h a s b e e n 
t er mi n at e d.
Giv e n t h e st u dy h a d b e e n 
t er mi n at e d, t h e Sp o ns or 
u n bli n d e d s u bj ects’ 
r a n d o miz e d tr e at m e nt 
assi g n m e nts t o pr ovi d e 
i nf or m ati o n f or t h e 
i nv esti g at ors’ c o nti n u e d 
m o nit ori n g of t h eir s u bj ects.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 8
Pr ot o c ol A m e n d m e nt 8 :  0 5 S e p 2 0 1 6
A p plic a bl e t o all c o u ntri es a n d st u dy c e nt ers .  
At t h e ti m e of t his a m e n d m e nt, 3 5 s u bj ects h ad b e e n r a n d o miz e d i n t h e st u dy.
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
G e n er al 
N A
Fr o m S ecti o n 1 t hr o u g h 
S ecti o n 9. 9, di d n ot a b br evi at e a 
t er m if it is us e d o nly o nc e.
D efi n e d a n a b br evi ati o n at t h e 
p oi nt of first us e i n t h e t ext.
D efi n e d a b br evi ati o ns us e d i n a 
t a bl e i n a t a bl e f o ot n ot e.
T r e at e d S ecti o n 1 t hr o u g h 
S ecti o n 9. 9 as t h e m ai n 
b o dy of t h e d oc u m e nt w h e n 
v erifyi n g a b brevi ati o n 
us a g e .
Titl e p a g e 
N A
Pr ot oc ol a m e n d m e nt n u m b er, d at e, 
a n d r evisi o n c hr o n ol o gy.
A m e n d m e nt 8
T hr o u g h o ut 
N A
All m e nti o ns of Gl ax o S mit h Kli n e / 
G S K c h a n g e d t o N ov artis. L e g al 
r e gist er e d a n d c o nt act a d dr ess es
u p d at e d .
T r a nsiti o n of pr ot oc ol
S p o ns or
Titl e p a g e; 
S p o ns or 
i nf or m ati o n 
p a g e ; 
Pr ot oc ol 
su m m ary
N A
N ov artis St u dy I D s a dd e d as 
f oll o ws: C or e St u dy: O P V 1 1 6 9 1 0 
( als o k n o w n as C O M B 1 5 7J 2 3 0 1 )
T r a nsiti o n of pr ot oc ol
S p o ns or ; N ov artis st u dy I D 
f or m at r e q uir e d f or N ov artis 
a d mi nistr ativ e p ur p os es.
N ov arti s st u dy I Ds a d d e d at 
first us a g e i n b ot h pr ot oc ol 
s u m m ary a n d m ai n t ext; 
G S K I D o nly us e d at 
s u bs e q u e nt i nst a nc es.
St u dy d esi g n; 
S ecti o n 3. 1; 
S ecti o n 3. 1. 3
N A
N ov artis St u dy I D s ad d e d as 
f oll o ws: Ext e nsi o n St u dy: 
O P V 1 1 7 0 5 9 ( also k n o w n as 
C O M B 1 5 7J 2 3 0 1 E 1 )
T r a nsiti o n of pr ot oc ol 
S p o ns or; N ov artis st u dy I D 
f or m at r e q uir e d f or N ov artis 
a d mi nistr ativ e p ur p os es.
N ov artis st u dy I Ds a d d e d at 
first us a g e i n b ot h pr ot oc ol 
s u m m ary a n d m ai n t ext; 
G S K I D o nly us e d at 
s u bs e q u e nt i nst a nc es.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 8 9
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
Pr ot oc ol -
s p ecific 
d efi niti o ns;
Pr ot oc ol 
su m m ary , 
St u dy d esi g n; 
S ecti o n 3. 1; 
Fi g ur e 3- 2, 
S ecti o n 3. 1. 3,
S ecti o n 6, 
T a bl e 6 -2; 
S ecti o n 5. 3
N A
Pr ot oc ol A m e n d m e nt 7 w as 
inc or p or at e d i n t h e f ull pr ot oc ol 
d oc u m e nt as p art of t h e 
A m e n d m e nt 8 u p d at es b ec a us e 
pr evi o usly o nly a s u m m ary of 
c h a n g es v ersi o n w as av ail a bl e.
Pr ot oc ol 
S u m m ary, 
St u dy D esi g n; 
S ecti o n 3. 1; 
S ecti o n 5. 7
S u bj ects c o m pl eti n g t h e st u dy a n d 
m e eti n g e ntry crit eri a will b e 
off er e d t h e o pti o n t o p artici p at e i n 
a n ext e nsi o n st u dy ( O P V 1 1 7 0 5 9), 
w hic h will st art aft er c o m pl eti o n of 
t he W e ek 6 0 visit.
A s t h e of at u m u m a b d e v el o p m e nt 
pr o gr a m i n t h e i n di c ati o n P V h a s 
b e e n t er mi n at e d, s u bj ects 
c o m pl eti n g t h e st u dy will n o 
l o n g er b e eli gi bl e t o p artici p at e i n 
t h e ext e nsi o n st u dy ( O P V 1 1 7 0 5 9).  
S u bj e ct s w h o w er e e nr oll e d i n 
t h e e xt e n si o n st u d y pri or t o 
pr o gr a m t er mi n ati o n m a y r e m ai n 
i n t h e e xt e n si o n st u d y u ntil e xit 
crit eri a ar e m et .
T ext w as u p d at e d b as e d o n 
t h e of at u m u m a b 
d ev el o p m e nt pr o gr a m i n t h e 
i n dic ati o n P Vh avi n g b e e n 
t er mi n at e d.
S ecti o n 6. 3. 6 
T o e ns ur e s u bj ect s af ety, e ac h 
pr e g n a ncy m ust b e r e p ort e d t o 
G S K wit hi n 2 w e eks of l e ar ni n g 
of its occ urr e nc e.
T o e ns ur e s u bj ect s af ety, e ac h 
pr e g n a n cy m ust b e r e p ort e d t o 
N o v arti s wit hi n 2 4 h o ur s of 
l e ar ni n g of its occ urr e nc e.
Tr a nsiti o n of pr ot oc ol 
S p o ns or   
S ecti o n 6. 3. 9 , 
T a bl e 6- 4
T y p e of 
E v e nt
Ti m e Fr a m e
Pr e g n a ncy 
2 w e eks
T y p e of 
E v e nt
Ti m e Fr a m e
Pr e g n a ncy 
2 4 h o ur s
S ecti o n 7 
A dv ers e ev e nts a n d c o nc o mit a nt 
m e dic ati o ns t er ms will b e c o d e d 
usi n g M e d D R A a n d a n i nt er n al 
v ali d at e d m e dic ati o n dicti o n ary, 
G S K Dr u g .
A dv ers e ev e nts a n d c o nc o mit a nt 
m e dic ati o ns t er ms will b e c o d e d 
usi n g t h e 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 ( M e d D R A ), 
t h e W orl d H e alt h Or g a niz ati o n 
Dr u g Di cti o n ar y , a n d a n i nt er n al 
v ali d at e d m e dic ati o n dicti o n ary.
U p d at e d t o pr ovi d e 
ex p a n d e d M e d D R A t er m at 
first us e a n d t o i ncl u d e t h e 
W orl d H e alt h Or g a niz ati o n 
Dr u g Dicti o n ary a n d t o 
r e m ove t h e G S K Dr u g 
s p ecific ati o n.
S ecti o n 1 0 
N A
Of at u m u m a b/ O M B 1 5 7/ G S K 1 8 4 1 1
5 7 I nv esti g at or’s Br oc h ur e (I B).  
V ersi o n 0 9.  D oc u m e nt n u m b er 
0 9 0 0 9 5 a 8 8 8 b 3f d 5 0.  
1 2 A pril 2 0 1 6
R ef er e nc e f or of at u m u m a b 
I nv esti g at or’s Br oc h ur e 
a d d e d t o pr ot oc ol b o dy 
r ef er e nc es i n S ecti o n 1 0. 
Cr oss -r ef er e nc es t o t h e 
I nv esti g at or’s Br oc h ur e 
hy p erli nk e d i n pr ot oc ol b o dy 
t o t h e cit ati o n i n t h e list of 
r ef er e nc es i n S ecti o n 1 0.

2 0 1 2 N 1 4 2 6 1 1
C O N FI D E N TI A L
N o v arti s
O P V 1 1 6 9 1 0
1 9 0
S e cti o n 
Ori gi n al T e xt
C h a n g e s
R ati o n al e
T hr o u g h o ut 
I nv esti g at or’s Br oc h ur e 
Inv esti g at or’s Br oc h ur e 
[ Of at u m u m a b/ O M B 1 5 7/ G S K 1 8 4
1 1 5 7 I n v e sti g at or’ s Br o c h ur e, 
2 0 1 6]
F urt h er d et ail a n d y e ar 
a d d e d t o I nv esti g at or 
Br oc h ur e r ef er e nc es f or 
cl arity a n d c o nsist e ncy wit h 
f or m at of ot h er r ef er e nc es.