Oral CLADribine in Patients That Change From First-line Disease Modifying Treatments for Multiple Sclerosis: a pROspective effectivenesS and Safety Study (CLAD CROSS)
Conditions: Multiple Sclerosis
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
N o n-l nt e r v e nti o n al St u d y P r ot o c ol 
St u d y P r ot o c ol N u m h e r 
M S 7 0 0 5 6 8 
0 0 7 0 
Titl e 
Or al 
C L A Dri bi n e i n p ati e nts t h at C h a n g e fr o m first-li n e 
Dis e as e 
M o dif yi n g 
Tr e at m e nts f or M ulti pl e 
S cl er osis: a 
p R Os p e cti v e eff e cti v e n ess a n d S af et y st u d y 
( C L A D C R O S S) 
P r ot o c ol v e rsi o n i d e ntifi e r 
2. 0 
P r ot o c ol D at e N e rsi o n 
7 A pril 2 0 2 1 / V ersi o n 2. 0 
R e pl a c es V e rsi o n 
v 1. 1 
A cti v e s u bst a n c e 
Cl a dri bi n e 
M e di ci n al p r o d u ct 
Cl a dri bi n e t a bl ets 
C O N FI D E N TI A L 
I N F O R M A TI O N 
1/ 5 1 
Gl o bal Versi o n I D: C CI

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Cl a d ri bi n e 
S p o ns o r 
R es e a r c h q u esti o n a n d 
o bj e cti v es 
M er c k H ell as s a. 
4 1- 4 5 Kifisi as A v e n u e, 1 5 1 2 3 
M ar o usi, At h e ns, Gr e e c e 
S p o ns or Le gal R e pr es e nt ati v e i n t h e E ur o p e a n U ni o n 
M er c k 
H e alt h c ar e K G a A, D ar mst a dt , G er m a n y, a n affili at e of 
M er c k K G a A, D ar mst a dt G er m a n y 
F r a n k f urt er Str ass e 2 5 0 
6 4 2 9 3 D ar mst a dt, G er m a n y 
T h e m ai n ai m is t o st u d y i n t h e rea l w orl d s etti n g t h e eff e cti v e n ess 
of Cl a dri bi n e t a blets i n t er ms of A R R ( A n n u ali z e d R e l a ps e R at e) 
a n d di s a bilit y pr o gr essi o n , i n p ati e nts w h o s witc h fr o m a first li n e 
D M D ( Dis e as e M o dif yi n g Dr u g) (I nt erf er o ns, Gl atir a m er A c et at e, 
T erifl u n or n id e , D M F ( D y m et h yl f u m ar at e)) . 
P ri m a r y O bj e cti v e: 
• 
T o st u d y t h e c h a n g e i n a n n u ali z e d r el a ps e r at e ( A R R) i n 
p ati e nts s wit c hi n g fr o m first-li n e D M Ds t o Cl a dri bi n e t a bl ets, 
b et w e e n t h e 1 2- m o nt h pr e- b as eli n e p eri o d a n d o v er t h e 1 2 
m o nt hs p eri o d b ef or e E n d of St u d y f oll o w- u p ( 2 y e ars) 
S e c o n d a r y O bj e cti v es: 
• 
T o ass ess c ha n g e i n a n n u ali z e d r el a ps e r at e ( A R R) i n p ati e nts 
s wit c hi n g fr o m first-li n e D M Ds t o Cl a dri bi n e t a bl ets, b et w e e n 
t h e 1 2- m o nt h pr e- b a s e li ne p eri o d a n d o v er t h e 1 2 m o nt hs 
p eri o d aft er i niti ati o n of Cl a dri bi n e t a bl ets ( 1 y e ar) 
• 
T o ass ess dis a bilit y pr o gr essi o n 1 
• 
T o ass ess dis a bi lit y i m pr o v e m e nt 1 
• 
T o ass ess s af et y of Cl a dri bi n e t a bl ets i n t h e real w orl d s etti n g, 
at t w o y e ars 
• 
T o ass ess Q u alit y of Lif e a n d tr e at m e nt s atisf a cti o n 
1 Disa bilit y pr o gressi o n is defi ne d as pr o gressi o n o n ;;;, I of 3 c o m p o ne nts ( E D S S, T 2 5 F W. a n d /or 9 1-l P T) c o nfir me d 
;;;,2 4 we e ks a part a n d wit h a ;;;, 2 0 % mi ni m u m t hres ho l d c ha n ge f or T 2 5 F W a n d 9 1-l P T. Pr o gressi o n o n E D S S is d efi ne d 
as at least I p oi nt i n t he E D S S sc ore or a n i ncrease of at least 1. 5 p oi nt s if t he baseli ne E D S S sc ore is 0. Disa bilit y 
I m pr o ve me nt is defi ne d as i m pr o ve me n t o n;;;, I of 3 c o m p o ne nt s ( ED S S, T 2 5 F W, a n d / or 9 H P T) c o nfir me d ;;;, 2 4 wee ks 
a part a n d wit h a ;;;, 2 0 % mi ni m u m thres h ol d c ha n ge f or T 2 5 F W a n d 91 ! P T. I m pr o ve me nt o n E D S S is defi ne d as a 
decrease i n E D S S b y at least I p oi nt ( 1. 5 p oi nts if baseli ne E D S S was 1. 5). T 2 5 F W a n d 9 H P T are o pti o nal a n d will 
be perf or m e d if d o ne as per r o uti ne practice. 
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C o u nt ri es of st u d y 
A ut h o r 
Cl a dri bi ne 
•  
T o ass ess tr e at m e nt a d h er e n c e 
• 
 
 
 
 
 
 
 
 
 
 
 
 
E M E A C o u ntri es ( E ur o p e, Mi d dl e E ast a n d Afri c a) 
 
 
 
 
P ost o d e: 
 
 
P h o n e: 
 
Fa x: 
 
E- m ail:
 
- C o nfi d e nti al -
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt , G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot - i n f ull or p art - b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y . C o p yri g ht © 2 0 1 9 b y M er c k 
K G a A, 
D ar m st a dt, 
G er m a n y, 
or it s s u b si di ar y . All ri g ht s r e s er v e d. 
C O N FI D E N TI A L 
I N F O R M A TI O N 
3/ 5 I 
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P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI

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9. 4 
 
9. 6 
9. 7 
9. 7. 1 
Cl a d ri bi n e 
T a ble of C o nt e nts 
T a bl e of C o nt e nts .................................................................................. 4 
List of A b br e vi ati o ns ............................................................................ 6 
R es p o nsi bl e P arti es ............................................................................... 8 
R es p o nsi bi liti es of t h e I n v esti g at or ...................................................... 9 
A bstr a ct ............................................................................................... I 0 
A m e n d m e nts a n d U p d at es .................................................................. 1 6 
M il est o n es ........................................................................................... 1 6 
R ati o n al e a n d B a c k gr o u n d .................................................................. 1 7 
M u lti pl e S c ler osis ............................................................................... 1 7 
M A V E N C L A D ® ( Cl a dri bi n e T a bl ets) 3. 5 m g/ k g ............................ 1 8 
E x p e ct e d c o ntri b uti o n of t his st u d y t o t h e k n o wl e d g e o n 
C l a dri bi n e t a blets i n R R M S ................................................................ 1 8 
R es e ar c h Q u esti o n a n d O bj e cti v es ..................................................... 1 8 
Pri m ar y O bj e cti v e ............................................................................... 1 9 
S e c o n d ar y O bj e cti v es ......................................................................... 1 9 
R es e ar c h M et h o ds ........................... .. .................................................. 2 0 
St u d y D esi g n ....................................................................................... 2 0 
D esi g n O v er vi e w ................................................................................ 2 0 
O ut c o, n es .................................... .. ................ ...................................... 2 1 
S etti n g ................................................................................................. 2 2 
S t u d y P o p ul ati o n ................................................................................. 2 2 
D efi nit i o n of St u d y C o h orts a n d D es cri pti o n of Tr e at m e nts .............. 2 3 
O bs er v ati o n P eri o d ............................ ................................................. 2 4 
Fr e q u e n c y of Ass ess m e nts ................................ .................................. 2 4 
Wit h dr a w al fr o m t h e St u d y ..... ........................................................... 2 9 
V ari a bl es ............................................................................................. 2 9 
D at a S o ur c e ......................................................................................... 3 0 
 
Data M a n a g e 1 n e nt ............................................................................... 3 1 
D at a A n al ysis ...................................................................................... 3 1 
A n al ysis S ets ....................................................................................... 3 1 
C O N F I D E N T I A L 
I N F O R M A TI O N 
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C
CI
C CI

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9. 7. 2 
9. 7. 3 
9. 7. 4 
9. 8 
9. 9 
9. 1 0 
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1 0 
I O. I 
1 0. 2 
11 
l l. 1 
1 1. 2 
1 1. 3 
I l. 4 
I l. 5 
1 1. 6 
1 2 
1 2.l 
1 2. 2 
1 3 
1 4 
Cl a d ri bi n e 
D eri v e d a n d Tr a nsf or m e d D at a ......................................................... . 3 1 
St atisti c al M et h o ds ... ........................................................................... 3 2 
S e q u e n c e of A n al ys es ......................................................................... 3 3 
Q u alit y C o ntr ol ................................................................................... 3 3 
Li mit ati o ns of t h e R es e ar c h M et h o ds ................................................. 3 3 
Ot h er As p e cts ...................................................................................... 3 3 
I n d e p e n d e nt Et hi cs C o m mitt e e or I nstit uti o n al R e vi e w B oar d .......... 3 3 
M o nit ori n g .......................................................................................... 3 4 
H e alt h A ut h oriti es .............................................................................. . 3 4 
Q u alit y Ass ur a n c e ............................................................................... 3 4 
Ar c hi vi n g ............................................................................................ 3 5 
Pr ot e cti o n of P ati e nts .......................................................................... 3 5 
S u bj e ct I nf or m ati o n a n d I nf or m e d C o ns e nt ....................................... 3 5 
S u bj e ct I d e ntifi c ati o n a n d Pri v a c y ...................................................... 3 5 
M a n a g e m e nt a n d R e p orti n g of A d v ers e E v e nts ................................. 3 6 
A d v ers e E v e nts ................................................................................... 3 6 
S e v erit y of A d v ers e E v e nts ......................... ....................................... 3 9 
C a us alit y Ass ess m e nt ......................................................................... 3 9 
R e c or di n g of A d v ers e E v e nts ............................................................. 3 9 
S af et y D at a C oll e cti o n f or R e p orti n g ................................................ . 4 0 
R e g ul at or y R e p orti n g t o t h e H e alt h A ut h oriti es ................................ . 4 2 
Pl a ns f or Diss e mi n ati n g a n d C o m m u ni c ati n g St u d y R es ults ............ . 4 3 
St u d y R e p ort ....................................................... ................................ 4 3 
P u bli c ati o n .......................................................................................... 4 3 
R ef er e n c es ........................................................................................... 4 4 
A p p e n di c es ......................................................................................... 4 6 
1 4 . 1 
Si g n at ur e P a g es a n d R es p o nsi bl e P ers o ns f or t he St u d y ................... . 4 7 
Si g n at ur e Pa ge - Pr ot o c ol L e a d .................................................................... .................... . 4 8 
Si g n at ur e P a g e - C o or di n ati n g I n v esti g at or .............................................................. ....... . 4 9 
Si g n at ur e P a g e - Pri n ci p al I n v esti g at or ............................................................................. 5 0 
S p o ns or R es p o nsi bl e P ers o ns n ot N a m e d o n t h e C o v er P a g e ........................................... 5 1 
C O N F I D E N TI A L 
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2 
A O L 
A D R 
A E 
A R 
A R R 
CI 
C N S 
C U A 
C R F 
C R O 
D M D 
D M F 
E D C 
E D S S 
E N C e P P 
E U 
G A 
G P 
G V P 
H C P 
! C F 
! E C 
I F N 
I N N 
I R B 
M A H 
M RI 
Cl a d ri bi n e 
Li st of A bb r e vi at io ns 
Acti vities of Dail y Li vi n g 
A d verse Dr u g Reacti o n 
A d verse E ve nt 
A d verse Reacti o n 
A n n ualize d Rela pse Rate 
C o nfi de nce I nter vals 
Ce ntral Ner v o us S yste m 
C u m ulati ve U ni q ue Acti ve 
Case Re p ort F or m 
C o ntract Researc h Or ga nizati o n 
Disease M o dif yi n g Dr u!!(s) 
D y met h y l Fu marate 
E lectr o nic Data Ca pt ure 
E x pa n de d Disa bilit y Stat us Scale 
E ur o pea n 
Net w or k 
of 
Ce ntres 
f or 
P har mac o vi gila nce 
E ur o pea n U ni o n 
Glatira mer Ac et a te 
Ge neral Practiti o ner 
G o o d P har mac o vi gila nce Practices 
Healt hcare Pr o vi der 
I nf or me d C o ns e nt F or m 
I nde pe n de nt Et hics C o m mittee 
I nterfer o n 
I nter nati o nal N o n pr o prietar y Na me 
I nstit uti o nal Re vie w B oa r d 
Mar k eti n g A ut h orizati o n H ol der 
Ma g netic Res o na nce I ma gi n g 
C O N FI D E N TI A L 
I  N F O R M A TI O N 
P har mac oe pi de mi ol o g y 
a n d 
6/ 5 1 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
M S 
R R M S 
R M P 
S A E 
S A P 
S m P C 
U S A 
T A R B 
T S Q M 
Cl a d ri bi n e 
M ulti pl e S cl er osis 
R el a psi n g R e mitti n g M ulti pl e Scl e r osis 
Ris k M a n a g e m e nt Pla n 
S eri o us A d v ers e E v e nt 
St atisti c al A n al ysis Pl a n 
S u m m ar y of Pr o d u ct C h ar a ct eristi cs 
U nit e d St at es of A m eri c a 
T h er a p e uti c Ar e a R e vi e w B o ar d 
Tr e at m e nt S atisf a cti o n Q u esti o n n air e f or M e di c ati o n 
C O N FI D E N TI A L 
I N F O R M A TI O N 
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L 0 4 A A 4 0 
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Cl a dri bi ne 
3 
R es p o nsi bl e P a r ties 
R es p o nsi bl e P a rti es 
C o o r di n ati n g ( P ri m a r y) 
I n v esti g at o r ( 
 
P r ot o c ol Le a d 
R C O Le a d 
C o nt a ct d et ails 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h o ne: 
 
E- m ail:
 
 
 
 
 
 
P h o ne: 
 
E- Mai 1:
 
 
 
 
 
 
P h o ne: 
 
E- M ail: 
 
C O N FI D E N TI A L 
I N F O R M A TI O N 
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Gl o bal Versi o n I D: C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
3. 1 
Cl a d ri bi n e 
R es p o nsi biliti es of t he I n v esti g at o r 
T h e I n v esti g at or is r es p o nsi bl e f or t h e c o n d u ct of t h e st u d y at his /h er sit e. H e/ S h e will e ns ur e t h at 
t he st u d y is p erf or m e d i n a c c or d a n c e wit h t h e pr ot o c ol a n d will e ns ur e t h e q u alit y a n d i nt e grit y of 
d at a, f oll o wi n g all a p pli c a bl e i nt er n ati o n al a n d n ati o n al g ui d eli n es. 
T his n o n-i nt er v e nti o n al st u d y will 
n ot i nt erf er e wit h tr e at m e nt pr es cri pti o n b y i n v esti g at ors. 
A c c or di n gl y, t h e I n v esti g at or will d e ci d e i n a d v a n c e t h e b est t h er a p e uti c str at e g y f or e a c h p ati e nt 
a c c or di n g t o c urr e nt pr a cti c e , r e g ar dl ess of t h e p ot e nti al p arti ci p ati o n of t his p ati e nt i n t h e st u d y. 
S u bs e q u e ntl y, if t h e pr es cri b e d tr e at m e nt is i n li ne wit h t h e st u d y pr ot o c ol, t h e I n v esti g at or will 
c o nsi d er t h e p os si bilit y of i n cl u di n g t h e p ati e nt i n t h e st u d y. 
T he I n v esti g at or is r es p o nsi bl e f or a d v ers e rea cti o n a n d/ or l a b or at or y a b n or m aliti es r e c or di n g a n d 
rep ort i n g, as s p e cifi e d i n S e cti o n 11 . 
C O N F I D E N T I A L 
I N F O R M A TI O N 
9/ 5 1 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
4 
Ti tle 
R ati o n a le a n d 
b a c k g r o u n d 
R es e a r c h q u esti o n 
a n d o b je cti v es 
Cl a dri bi ne 
A bst r a ct 
Or al 
C L A Dri bi n e 
m 
p ati e nts t h at C h a n g e 
fr o m first-li n e Dis e as e 
M o dif yi n g 
Tr e at m e nts 
f or 
M ulti pl e 
S cl er osis: 
a 
p R Os p e cti v e 
eff e cti v e n e ss a n d S af e t y st u d y 
( C L A D C R O S S) 
R e c e ntl y , t h e n u m b er of a v ail a bl e dis e as e- m o d if yi n g t h er a pi es f or 
tr e at m e nt of r el a psi n g-r e mitti n g M S ( R R M S) h as i n cr e as e d. H o w e v er , 
m a n y p ati e nts tr e at e d wit h t h es e a g e nts c o nti n u e t o e x p eri e n c e r el a ps es 
a n d dis e as e pr o gr essi o n . Cl a dri bi n e 
is a s y nt h eti c d e o x y a d e n osi n e 
a n al o g t h at a cts i n p eri p h er al tiss u es, e nt ers t h e C N S a n d is t a k e n u p b y 
l y mp h o c y t es a n d p h os p h or yl at e d b y d e o x y c yti di n e ki n as e, r es ulti n g i n 
t ar g et e d a n d s ust ai n e d r e d ucti o ns of t h e T a n d  B l y m p h o c yt es. I n t h e 
P h as e III C L A RI T Y st u d y tr e at m e nt wit h Cl a dri bi n e t a bl ets gi v e n i n 
s h ort c o urs es a n n u all y f or 2 y e ars si g nifi c a ntl y i m pr o v e d cli ni c al a n d 
M RI 
o ut c o m es. I n t h e P h as e Ill O R A C L E - M S st u d y, C l a dri bi n e 
si g nifi c a nt l y r e du c e d t h e ris k of cli ni c all y d efi nit e M S i n p ati e nts wit h a 
first cli ni c al d e m y eli n ati n g e v e nt c o m p ar e d wit h pl a c e b o. 
St u d y R ati o n al e: T h e m ai n ai m is t o st u d y i n t h e real w orl d s etti n g t h e 
eff e cti v e n ess of Cl a dri bi n e i n t er ms of A R R a n d dis a b ilit y pr o gr essi o n , 
i n p ati e nts th at s wit c h fr o m a first-li n e  d r u g (I nt erf er o ns, Gl atir a m er 
A c et at e, T eritl u n o mi d e , D M F). T h e P h as e Ill O N W A R D st u d y h as 
s h o w n a si g nifi c a nt r e d u cti o n i n A R R w h e n c o m p ari n g t h e pr e- b as eli n e 
tr e at m e nt p eri o d wit h the Cl a dri bi n e t a blets tr e at m e nt p eri o d. H o w e v er , 
t h e st u d y a llo w e d all I F Ns as pr e- b as eli n e tr e at me n ts a n d  p o o le d t h e m 
t o g et h er i n t h e a n al ysis . It w as als o n ot p o w er e d t o d et e ct diff er e n c es i n 
A R R a n d it di d n ot i n clu d e ot h er first li n e tr e at m e nts ( D M F a n d 
T erifl u n o mi d e) i n t h e a n al ysis. I n t h e c urr e nt st u d y w e w a nt t o e v al u at e 
t h e p ot e nti al r e d u cti o n 
111 A R R ass o ci at e d wit h 
Cl a dri bi n e t a bl ets 
tr e at m e nt, c o m p ar e d t o t h e p re-b as eli n e p eri o d , i n p ati e nts r e c ei vi n g 
first-li n e dis e as e- m o dif yi n g dr u gs , w h o s wit c h t o Cl a dri bi n e t a bl ets 
a c c or di n g t o t h e d e cisi o n of t h eir tr e ati n g p h ysi ci a n . 
T h e m ai n ai m is t o st u d y i n t h e real w orl d s etti n g t h e eff e cti v e n ess of 
Cl a dri bi n e t a bl ets i n t er ms of A R R a n d dis a bilit y pr o gr essi o n, i n p ati e nts 
w h o s wit c h fr o m a first-li n e dis e as e m o dif yi n g 
dr u g (I nt erf er o ns, 
Gl atir a m er A c et at e, T eritl u n o mi d e, D M F). 
P ri m a r y O bj e cti v e: 
• 
T o st u d y t h e c h a n g e i n a n n u ali z e d r el a ps e r at e ( A R R) i n p ati e nts 
s wit c hi n g fr o m first-li n e D M Ds t o Cl a dri bi n e t a bl ets, b et w e e n 
the 1 2- r n o nth pr e- b as e li n e p eri o d a n d o v er t h e 1 2 m o nt hs p eri o d 
b ef or e E n d of St u d y f oll o w- u p ( 2 y e ars) 
C  O N F I D E N TI A L 
I N F O R M A TI O N 
1 0 /5 1 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
St u d y D esi g n 
P o p ul ati o n 
Cl a dri bi ne 
S e c o n d a r y O bj e cti v es: 
• 
T o ass ess c h a n g e i n a n n u ali z e d r el a ps e r at e ( A R R) i n p ati e nts 
s wit c hi n g fr o m first-li n e D M Ds t o Cl a dri bi n e t a bl ets, b et w e e n 
t h e 1 2- m o nt h pr e- b as eli n e p eri o d a n d o v er t h e 1 2 m o nt hs peri o d 
aft er i niti ati o n of Cl a dri bi n e t a bl ets ( 1 y e ar) 
• 
T o 
ass ess dis a bilit y pr o gr essi o n . Dis a bilit y 
pr o gr essi o n 
1 s 
d efi n e d as pr o gr essi o n o n > 1 of 3 c o m p o n e nts ( E D S S, T 2 5 F W, 
a n d/ or 9 H P T) c o nfir m e d > 2 4 w e e ks a p art a n d wit h a > 2 0 % 
mi ni m u m t hr es h ol d c h a n g e f or T 2 5 F W a n d 9 H P T . T 2 5 F W a n d 
9 H P T ar e o pti o n al a n d will be p erf or m e d if d o n e as p er r o uti n e 
pr a cti c e. Pr o gr essi o n o n E D S S is d efi n e d as at l e ast 1 p oi nt i n 
t h e E D S S s c or e or a n i n cr e as e of at l e ast 1. 5 p oi nts if t h e b as eli n e 
E D S S s c or e is 0. 
• 
T o ass ess dis a bilit y i m pr o v e m e nt. Dis a bilit y I m pr o v e m e nt is 
d efi n e d as i m pr o v e m e nt o n > 1 of 3 c o m p o n e nts ( E D S S, 
T 2 5 F W, a n d/ or 9 H P T) c o nfir m e d > 2 4 w e e ks a p art a n d wit h a 
> 2 0 % mi ni m u m 
t hr es h ol d c h a n g e f or T 2 5 F W a n d 9 H P T. 
T 2 5 F W a n d 9 H P T ar e o pti o n al a n d will b e p erf or m e d if d o n e as 
p er r o uti n e pr a cti c e. I m pr o v e m e nt o n E D S S is d efi n e d as a 
d e cr e as e i n E D S S b y at l e ast I p oi nt ( 1 . 5 p oi nts if b as eli n e E D S S 
w as 1. 5). 
• 
T o ass ess s af et y of Cl a dri bi n e t a bl ets i n t h e r e al w orl d, at t w o 
y e ars 
• 
T o ass ess Q u alit y of Life a n d tr e at m e nt s atisf a cti o n 
• 
T o ass ess tr e at m e nt a d h er e n c e 
• 
 
 
 
 
 
 
 
 
 
 
 
T his is a pr os p e cti v e, n o n-i nt er v e nti o n al, m ulti c e nt er , P has e I V st u d y i n 
p ati e nts wit h a c o nfir m e d di a g n osis of R R M S w h o s wit c h e d fr o m first-
li n e D M Ds (I nt erf er o ns, Gl atir a m er A c et at e, T eritl u n o mi d e , D M F) t o 
tr e at m e nt wit h Cl a dri bi n e t a bl ets i n r o uti n e cli ni c al pr a cti c e. 
In cl usi o n C rit e ri a : 
1. 
P ati e nts m ust v ol u nt aril y gi v e writt e n i nf or m e d c o ns e nt. P ati e nts 
m ust 
rea d a n d f ull y u n d erst a n d t h e I nf or m e d C o ns e nt F or m 
(I C F) 
2. 
A d ult p ati e nts , M al e or f e m al e p ati e nts > 1 8 y e ars ol d 
C O N FI D E N TI A L 
I N F O R M A TI O N 
1 1 /5 1 
Gl o bal Versi o n I D: C CI
C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
O ut c o m es 
Cl a dri bi ne 
3. 
P ati e nts 
wit h 
c o nfir m e d di a g n osis of R el a psi n g- R e mitti n g 
M ulti pl e S cl er osis ( R R MS) di a g n os e d b y t h e tr e ati n g p h ysi ci a n 
a c c or d i n g t o a p pl ica b le cli ni c al pr a cti c e g ui d eli n es ( c urr e ntl y 
M c D o n al d 2 0 1 7 crit eri a), wit h hi g h dis e as e a cti vit y. 
4. 
P ati e nts s h o u l d h a v e b e e n tr e at e d wit h t h e s a m e first- li ne D M D 
(I nt erf er o ns, Gl atir a m er A c et at e, T eri fl u n o mi d e, D M F) a n d at a 
st a bl e d os e f or at l e ast o n e y e ar pri or t o s wit c h t o Cl a dri bi n e 
t a blets a n d s h o u l d h a v e b e e n pr es cri b e d Cl a dri bi n e tabl ets 
a c c or di n g t o t h e d e cisi o n of the tr e ati n g p h ysi ci a n a n d f or a n y 
r e as o n d e e m e d n e c ess ar y, pri or t o e nr o ll m e nt i n t h e st u d y. A n y 
w as h o ut 
p eri o d 
a n d/ or w as h o ut 
m et h o ds 
r e q u ire d b ef or e 
s wit c hi n g (s u c h as eli mi n ati o n of T crifl u n o mi d e) m ust h a v e b e e n 
c o n d u ct e d, a c c or di n g t o t h e d e cisi o n of t h e tr e ati n g p h ysi ci a n . 
5. 
R e q uir e d hist or y d at a s h o ul d be a v ail a bl e: 
-
M S 
d at a 
f or 
t h e 
12- m o nt hs 
pr e- b as eli n e 
p eri o d 
( a n n u al i z e d r el a ps e rate) 
-
M S M e di c ati o n Hist or y ( pri or D M Ds) 
6. 
F ulfil m e nt of t h e i n di c ati o n f or tr e at m e nt wit h Cl a dri bi n e t a bl ets 
p er st a n d ar d of c ar e i n a c c or d a n c e wit h t h e l o c al S m P C 
E x cl usi o n c rit e ri a: 
P ati e nts ar e n ot eli gi bl e f or t his st u d y if t h e y f ulfill a n y of t h e f oll o wi n g 
e x cl usi o n crit eri a: 
I. C o ntr ai n di c ati o ns t o us e of cl a dri bi n e t abl ets a c c or di n g t o t h e 
S u m m ar y of Pr o d u ct C h ar a ct eristi cs 
2. 
P ati e nts wit h 
his t or y of al c o h ol or dr u g a b us e t h at c o ul d 
p ot e nti all y i nt erf er e wit h t h eir p arti ci p ati o n i n t h e st u d y . 
3. 
P at i e nt t h at h a v e r e c ei ve d Cl a dri bi n e i n t h e p ast 
4. 
C o n c urr e nt p arti ci p ati o n i n a n i n v esti g ati o n al st u d y i n w hi c h 
p ati e nt ass ess m e nt a n d/ or tr e at m e nt m a y 
be di ct at e d b y a 
pr ot o c ol 
P ri m a r y E n d p oi nt 
Diff er e n c e i n A R R b et w e e n t h e pr e- b as eli n e 1 2- m o nt h p eri o d a n d o v er 
t h e 1 2 m o nt hs p eri o d b ef or e E n d of St u d y f oll o w- u p ( 2 y e ars). 
S e c o n d a r y E n d p oi nts 
• 
Diff er e n c e i n A R R b et w e e n t h e pr e- b as eli n e 1 2- m o nt h p eri o d 
a n d o v er t h e 1 2 m o nt hs p eri o d aft er st art of cl a dri bi n e ( 1 y e ar) 
C O N FI D E N TI A L 
I N F O R M A TI O N 
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Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
V a ri a bl es 
Cl a d ri bi n e 
• 
P er c e nt a g e of p ati e nts wit h 
6- m o nt h dis a bilit y pr o gr essi o n 
( E D S S, T 2 5 F W , 9- H P Tf 
at t he e n d of t h e st u d y f oll o w- u p 
p eri o d ( 2 y e ars) . 
• 
P er c e nt a g e of p ati e nts wit h 6- m o nt h dis a bilit y i m pr o v e m e nt 
( E D S S, T 2 5 F W , 9- H P T) 2 at t h e e n d of t h e st u d y f oll o w- u p 
peri o d ( 2 y e ars). 
• 
O c c urr e n c e of a d v ers e e v e nts a n d of s eri o us a d v ers e e v e nts. 
• 
Q u alit y of life ( M SI S- 2 9), Tr e at m e nt S atisf a cti o n ( T S Q M vi . 4) 
a n d 
 
• 
Tr e at m e nt a d h er e n c e , ass ess e d as p er c e nt a g e of cl a dri bi n e 
t a bl ets t a k e n v ers us pr es cri b e d d os e 
• 
D e m o gr a p hi cs 
• 
Me dic al Hist or y 
• 
M S hist or y 
• 
Pri or a n d c urr e nt M S m e di c ati o n 
• 
R e as o n f or s wit c hi n g fr o m  first li ne D M D t o Cl a dri bi n e t a bl ets 
• 
T h er a p y wit h Cl a dri bi n e T a bl ets ( d at e of a d mi nistr ati o n a n d 
n u m b er of t a bl ets t a k e n v ers us pr es cri b e d d os e) 
• 
P arti ci p ati o n i n a Cl a dri bi n e P ati e nt S u p p ort Pr o gr a m 
• 
R el a ps e C o u nt: A R R 
• 
Dis a bilit y test: E D S S, Ti m e d 2 5- F o ot W al k, 
9- H ol e P e g T est 
( E D S S Pl u s) 
• 
Q u alit y of life q u esti o n n air e:  M SI S- 2 9 
• 
 
• 
Tr e at m e nt S atisf a cti o n Q u esti o n n air e: T S Q M v 1. 4 
2 Dis a bilit y pr o gr essi o n is d efi n e d as pr o gr essi o n o n ;,, 1 of 3 c o m p o n e nts ( E D S S, T 2 5 F W. a n d /or 9 H P T) c o nfir m e d 
;,, 2 4 w e e ks a p art a n d wit h a ;,, 2 0 % mi ni m u m t hr es h ol d c h a n g e f or T 2 5 F W a n d 9 1-I P T. Pr o gr essi o n o n E D S S is d efi n e d 
as at least 1 p oi nt i n t h e E D S S sc or e or a n i n cr e as e of at l e ast 1. 5 p oi nts if t h e b as eli n e E D S S s c or e is 0. Dis a bilit y 
I m pr o ve m e nt is d efi n e d as i m pr o v e m e nt o n;,, I of 3 c o m p o n e nts ( E D S S, T 2 5 F W , a n d/ or 91 -I P T) c o nfir m e d ;,, 2 4 w e e ks 
a p art a n d wit h a ;,, 2 0 % mi ni m u m t hre s h ol d c h a n g e f or T 2 5 F W a n d 9 H P T . I m pr o v e m e nt o n E D S S is d efi n e d as a 
d e cr e as e i n E D S S b y at l e ast I p oi nt ( 1. 5 p oi nts if b as e li n e E D S S w as 1. 5). T 2 5 F W a n d 9 H P T ar e o pti o n al a n d will 
be p erf or m e d if d o n e as p er r o uti n e pr a cti c e. 
C O N FI D E N TI A L 
I N F O R M A TI O N 
1 3 /5 1 
Gl o bal Versi o n I D: C CI
C CI
C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
D at a S o u r c es 
 
D at a A n al ysis 
Cl a dri bi ne 
• 
S af et y [ S eri o us A d v ers e E v e nts ( S A Es), A d v ers e E v e nts of 
S p e ci al I nt er est ( A E SI) a n d A d v ers e Dr u g R e a cti o ns ( A D Rs)l 
D at a will be c oll e ct e d vi a a n el e ctr o ni c c as e r e p ort f or m (( e)- C R F) . I n 
a d diti o n, p a p er q u esti o n n air es will b e c o m pl et e d b y t h e s u bj e ct a n d the n 
will be tr a nsf erre d i nt o t h e ( e)- C R F. 
2 4 2 p ati e nts wit h c o nfir m e d di a g n osis of Hi g hl y A cti v e R el a psi n g-
R e mitti n g 
M ulti pl e 
S cl er osis 
( R R M S) will 
b e 
e nr oll e d 
i n t h e 
p arti ci p ati n g c o u ntri es. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All e n d p oi nts w i ll be pr es e nt e d b y d es cri pti v e st atisti cs f or B as eli n e, 12-
m o nt h , a n d E n d of St u d y ass ess m e nts. Ass ess m e nts d o n e at 6- m o nt h a n d 
1 8- m o nt hs will 
b e pr es e nt e d  si mi larl y. Q u a ntit ati v e 
( c o nti n u o us) 
v ari a b les will 
b e s u m m ari z e d wit h t h e use of d es cri pti v e st atisti c al 
m e as ur es fm e a n v al u e, st a n d ar d d e vi ati o n ( S D), m e di a n, mi n- m a x, QI-
C O N F I D E N TI A L 
I N F O R M A TI O N 
1 4 /5 1 
Gl o bal Versi o n I D: C CI
C CI
C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Mil est o n es 
Cl a dri bi ne 
Q 3]. Q u alit ati v e ( c at e g ori c al) v ari a bl es will be dis pl a y e d as fr e q u e n ci es 
a n d p er c e nt a g es ( N, %). 
T h e n or m alit y of distri b uti o ns will be e x a mi n e d usi n g t he S h a pir o- Wil k 
t est i n or d er t o d et er mi n e w h et h er or n ot t o use p ar a m etri c m et h o ds f or 
a n al ysis. 
P ri m a r y E n d p oi nt: Pr e-
a n d p ost- b as eli n e A R R ( 2 y e ars) will 
be 
c o m p ar e d b y A N O V A or Wil c o x o n 
si g n e d-r a n k t est if d at a is n ot 
n or m all y distri b ut e d. T h e 
9 5 % C o nfi d e n c e 
I nter val ( CI) f or t he 
diff er e n c e will als o be pr es e nt e d. 
F or S e c o n d a r y a n d e x pl o r at o r y e n d p oi nts t he f oll o wi n g c al c ul ati o ns 
a n d c o m p aris o ns will be p erf or m e d: 
-
Pr e- a n d p ost- b as eli n e A R R (l y e ar) will be c o m p ar e d 
b y A N O Y A or Wil c o x o n si g n e d-r a n k t est if d at a is n ot 
n or m all y distri b ut e d. T h e 9 5 % C o nfi d e n c e I nt er v al ( Cl) 
f or t h e diff er e n c e will als o be pr es e nt e d. 
-
F or all ot h er s e c o n d ar y e n d p oi nts , 9 5 % Cl 
will 
be 
c al c ul at e d f or t h e r es ult at e a c h ti m e p oi nt a n d f or t he 
diff er e n c es 
w h e n e v er 
a p pli c a bl e , usi n g 
a p pr o pri at e 
m et h o ds. 
 
 
 
 
 
 
 
 
 
 
 
 
 
First P ati e nt Si g n e d I C F: Q 4 2 0 1 9 
L ast P ati e nt Si g n e d I C F: Q 3 2 0 2 2 
L ast P ati e nt L ast Visit ( L P L V): Q 3 2 0 2 4 
Cli ni c al St u d y Re p ort: Q 2 2 0 2 5 
C O N FI D E N TI A L 
I N F O R M A TI O N 
1 5/ 5 1 
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C
CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
5 
Cl a d ri bi n e 
A m e n d m e nts a n d U p d ates 
Pr ot o c ol a m e n d m e nt 1: v ersi o n 1. 1 d at e d 3 1 M ar c h 2 0 2 0 
A d mi nistr ati v e c h a n g es i n cl u di ng u p d at e d S m P C l a n g u a g e a n d M er c k n a m e 
Pr ot o c ol a m e n d m e nt 2: v ersi o n 2 . 0 d at e d  7 A pril 2 0 2 1 
R e d u cti o n of t h e s a m pl e si z e 
A d d iti o n of t w o i nt eri m a n al ys es 
R e m ot e P R O c o m pl e ti o n all o w e d w h e n r e m ot e c o ns e nt is a ut h ori z e d 
E xt e nsi o n of t h e r e cr uit m e nt p eri o d 
A d mi nistr ati v e c h a n g es i n cl u di n g u p d at e d w or di n g t o Eli gi bilit y Crit eri a # 4 f or 
cl arit y 
6 
Mil est o n es 
Mil est o n e 
St art of d a t a c oll e cti o n 
E n d of d at a c oll e ct i o n 
Fi n al r e p ort of st u d y r es ults 
Pl a n ne d d at e 
Q 4 2 0 1 9 
Q 3 2 0 2 4 
Q 2 2 0 2 5 
C O N F I D E N T I A L 
I N F O R M A TI O N 
1 6 / 5 I 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
7 
7. 1 
R ati o n ale a n d B a c k g r o u n d 
M ulti pl e Scler osis 
M ulti pl e s cl er osis ( M S) is a c hr o ni c a ut oi m m u n e, i nfl a m m at or y n e ur ol o gi c al dis e as e of t h e ce ntral 
n er v o us s yst e m ( C N S) ( C al a br esi 2 0 0 4, H a us er 2 0 0 8). M S 
att a c k s t he m y eli n at e d a x o ns i n t he 
C N S , d estr o yi n g t h e m y eli n a n d t h e a x o ns t o v ar yi n g d e gr e es ( W ei ns h e n k er 1 9 9 6, Ol e k 2 0 1 1 ). 
T h e c o urs e of M S is h i g hly v ari e d a n d u n pr e di ct a bl e. I n m ost p ati e nts, t h e dis e as e is c h ar a ct eri z e d 
i niti all y b y e pis o d es of r e v ersi bl e n e ur ol o gi c al d efi cits, w hi c h ar e oft e n f oll o w e d b y pr o gr essi v e 
n e ur ol o gi c al d et eri or ati o n o v er ti m e. 
I n E ur o p e t h er e ar e m or e t h a n 6 0 0, 0 0 0 p ati e nts esti m at e d t o b e s uff eri n g fr o m M S, wit h a m e di a n 
pr e v al e n c e of I 0 0 c as es a n d a m e di a n i n ci d e n c e of 5 . 5 c as es p er I 0 0 ,0 0 0 ( B e z zi ni, 2 0 1 7), a n d 5 0 % 
of p ati e nts will n e e d he l p w al ki n g wit hi n 2 0 y e ars aft er t h e o ns et of t h e dis e as e ( Br o w n 2 0 I 9). 
T wi c e as m a n y w o m e n ar e aff e ct e d as m e n, a n d p ers o ns of N ort h er n E ur o p e a n d es c e nt a p p e ar t o 
b e at hi g h est ris k f or M S ( H a us er 2 0 0 8, Cr e e 2 0 0 7). T h e dis e as e is di a g n os e d o n t h e b asis of 
cli ni c al fi n di n gs a n d s u p p orti n g e vi d e n c e fr o m a n cill ar y t ests, s u c h as m a g n eti c r es o n a n c e i m a gi n g 
( M RI) of t h e br ai n a n d e x a mi n ati o n of t h e c er e b r os pin al fl ui d ( C S F). M S t y pi c all y pr es e nts i n 
a d ults 2 0 t o 4 5 y e ars of a g e ; o c c asi o n all y, it pr es e nts i n c hil d h o o d or late mi d dl e a ge ( Cr e e 2 0 0 7). 
T h e c a us e of M S is u n k n o w n, b ut it a p p e ars t o i n v ol v e a c o m bi n ati o n of g e n eti c s us c e pti bilit y a n d 
a n o n g e n eti c tri g g er, s u c h as a vir us, m et a b olis m, or e n vir o n m e nt al f a ct ors r es ulti n g i n a s elf-
s ust ai ni n g a ut oi m m u n e dis or d er t h at l e a ds t o r e c urr e nt i m m u n e att a c ks o n t h e C N S ( Cr e e 2 0 0 7) . 
N e ur ol o gists a gr e e t h at p ati e nts m a y be gr o u p e d i nt o f o ur m aj or c at e g ori es b as e d o n t h e c o urs e of 
dis e as e ( H a us er 2 0 0 8 , G ol d e n b er g 2 0 1 2): 
1. R el a psi n g-r e mitti n g M S: t h e m ost c o m m o n f or m, aff e cti n g a b o ut 8 5 % of M S p ati e nts. It 
is m ar k e d b y fl ar e- u ps (r el a ps es or e x a c er b ati o ns) of s y m pt o ms f oll o w e d b y p eri o ds of 
r e missi o n, w h e n s y m pt o ms i m pr o v e or dis a p p e ar. 
2. S e c o n d ar y pr o gressive M S : m a y 
d e v el o ps i n a p pr o xi m at el y 5 0 % of p ati e nts wit h 
r el a psi n g-r e mitti n g dis e as e wit hi n 2 0 y e ars of dis e as e pr o gr essi o n ( Br o w n 2 0 1 9) . F or m a n y 
p ati e nts, tr e at m e nt wit h dis e as e- m o dif yi n g a g e nts h el ps d el a y s u c h pr o gr essi o n. T h e 
dis e as e c o urs e c o nti n u es t o w ors e n wit h or wit h o ut p eri o ds of r e missi o n or l e v eli n g off of 
s y m pt o m s e v erit y ( pl at e a us). 
3. Pri m ar y pr o gr essi v e M S: aff e cts a p pr o xi m at el y I 0 % of M S p ati e nts. S y m pt o ms c o nti n u e 
t o w ors e n gr a d u all y fr o m t h e b e gi n ni n g. T h er e are n o r el a ps es or r e missi o ns, b ut t h er e ma y 
b e o c c asi o n al pl at e a us . T his f or m of M S is m or e r esist a nt t o t h e dr u gs t y pi c all y use d t o 
tr e at t h e dis e as e. C urr e ntl y o nl y o cr eli z u m a b has b e e n a p pr o v e d f or t h e tr e at m e nt of P P M S. 
4. 
Pr o gressive-rel a psi n g M S: a r ar e f or m, aff e cti n g f e w er t h a n 5 % of p ati e nts. It is 
pr o gr essi v e fr o m t h e st art, wit h i nt er mitt e nt fl ar e- u ps of w ors e ni n g s y m pt o ms al o n g t he 
w a y . T h er e ar e n o p eri o ds of r e missi o n. 
C O N FI D E N TI A L 
I N F O R M A TI O N 
I 7/51 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
7. 2 
Cl a d ri b i ne 
M A V E N C L A D ® ( Cl ad ri bi ne T a bl ets) 3. 5 m g/ k g 
R e c e ntl y , t h e n u m b er of a v a il abl e d is e as e- mo d if yi n g t h er a pi es f or tr e at m e nt ofr e la psi n g-r e mitti n g 
M S ( R R M S) has i n cr e as e d ( C arrit h ers 2 0 1 4, Wi n g er c h u k 2 0 1 4). H o w e v er, m a n y p ati e nts tr e at e d 
wit h t h es e a g e nts c o nti n u e t o e x p eri e n c e r el a ps es a n d dis e as e pr o gr essi o n ( Tsi v g o ulis 2 0 1 5, 
Ha dj i g e or gi o u 2 0 1 3, Tr a m a c er e 2 0 1 5) ; t h us, n e w tr e at m e nt o pti o ns ar e stil I r e q uir e d . Cl a dri bi n e , 
a s y nt h eti c d e o x y a d e n osi n e a n al o g t h at a cts i n p e ri p h er al tiss u es, e nt ers the C N S a n d is t a k e n u p 
b y l y m p h oc y tes a n d p h os p h or yl at e d b y d e o x y c yti di n e ki n as e, r es ulti n g i n t ar g et e d a n d s ust ai n ed 
r e d u cti o ns of th e T a n d B l y m p h o c yt es t h at are i m pli c at e d i n t h e p at h o g e n esis of M S ( L eist 2 0 1 1 ). 
I n t h e P has e II[ C L A RI T Y st u d y tr e at m e nt wit h Cl a dri bi n e t a blets gi v e n i n s h ort c o urs es a n n u all y 
f or 2 y e ars si g nifi c a ntl y i mpr o v e d cli ni c a l a n d M R I o ut c o m es ( Gi o v a n n o ni 2 0 1 0). L y m p h o p e ni a 
w as t h e m ost c o m m o nl y r e p ort e d a d v ers e e v e nt ( A E) ( C o o k 2 0 1 1 ). I n C L A R I T Y E xt e nsi o n , t h e 
c li nic a l b e n efits of 2 y e ars of tr e at m e nt wit h C l a dri bi n e t a blets w er e s h o w n t o be d ur a bl e, wit h o ut 
f urt h er a cti v e tr e at m e nt ( Gi o v a n n o ni 2 0 1 7). I n  th e O R A C L E- M S st u d y ,  C la dri bi n e tab l ets 
si g nifi c a ntl y r e d u c e d the ris k of cli ni c all y d efi nit e M S i n p ati e nts wit h a first cli ni c a l d e m y eli n ati n g 
e v e nt c o m p ar e d wit h pl a c e b o ( L eist 2 0 1 4) , w hil e i n t h e O N W A R D st u d y it f urt h er r e d u c e d th e 
A R R w h e n c o- a d mi nist er e d wit h I F N- B ( M o nta l b a n 2 0 1 8). 
7. 3 
E x pecte d c o nt ri b uti o n of t his st u d y t o t he k n o wle d ge o n Cl a d ri bi n e 
t a blets i n R R M S 
T h e m ai n ai m is t o st u d y i n t h e real w orl d s etti n g t h e eff e cti v e n ess of Cl a dri bi n e t a bl ets i n t er ms 
of A R R a n d dis a bilit y pr o gr essi o n, i n p ati e nts t h at s wit c h fr o m a first I i ne dr u g (I nt erf er o ns, 
G l atir a m er A c et at e , T erifl u n o mi d e , D M F). 
I n t h e C L A RI T Y st u d y a p pr o xi m at el y . 3 0 % of p arti ci p a nts w er e p r e-tr e at e d wit h I nt erf er o ns or 
G l atir a m er A c et at e . O n the ot h er h a n d, t h e O N W A R D st u d y h as s h o w n a si g nifi c a nt r e d u cti o n i n 
A R R w h e n c o m p ari n g t h e pr e- b as eli n e tr e at m e nt p eri o d w ith t h e Cl a dri bi n e t a bl ets tr e at m e nt 
p eri o d. H o w e v er, t h e st u d y all o w e d a ll I F N s as pr e- b as eli n e tr e at m e nts a n d p o ol e d t h e m t o g et h er 
i n t h e a n al ysis. It w as als o n ot p o w er e d t o d et e ct diff er e n c es i n A R R a n d it d i d n ot i n cl u d e ot h er 
first li ne tr e at m e nts (D M F a n d T erill u n o mi d e) i n t h e a n a l ysis. 
H er e we w a nt t o e v al u at e t h e r e d u cti o n i n A R R affor d e d b y Cl a dri bi n e t a bl ets, c o m p ar e d t o t h e 
pr e- b as eli n e p eri o d, i n p ati e nts tr e at e d wit h all first li n e dr u gs , w h o s wit c h t o Cl a dri bi n e t a bl ets 
a c c or di n g t o t h e d e cisi o n of t h eir tr e ati n g p h ysi ci a n. 
8 
Rese ar c h Q uest i o n a n d O bj e cti v es 
T h e m ai n ai m is t o st u d y i n t he r e al w orl d s etti n g t h e eff e cti v e n ess of Cl a dri bi n e t a blets i n t er ms 
of A R R a n d  d is a bilit y pr o gr essi o n, i n p ati e nts w h o s wit c h fr o m a first li n e dr u g (I nt erf er o ns, 
Gl atir a m er A c et at e , T erifl u n o mi d e, D M F) . 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
8. 1 
P ri m a r y O bje cti v e 
• 
T o st u d y t h e c h a n g e i n a n n u ali z e d r el a ps e r at e ( A R R) i n p ati e nts s wit c hi n g fr o m first-li n e 
D M Ds t o Cl a dri bi n e t a bl ets, b et w e e n t h e 1 2- m o nt h pr e- b as eli n e p eri o d a n d o v er t h e 1 2 
m o nt hs p eri o d b ef or e E n d of St u d y f oll o w- u p ( 2 y e ars) 
8. 2 
S e c o n d a r y O bj e cti v es 
• 
T o ass ess c h a n g e i n a n n u ali z e d r el a ps e r at e ( A R R) i n p ati e nts s wit c hi n g fr o m first-li n e 
D M Ds t o Cl a dri bi n e t a bl ets, b et w e e n t h e 1 2- m o nt h pr e- b as eli n e p eri o d a n d o v er t h e 1 2 
m o nt hs p eri o d aft er i niti ati o n of Cl a dri bi n e t a bl ets ( I y e ar) 
• 
T o ass ess dis a bilit y pr o gr essi o n. Dis a bilit y pr o gr essi o n is d efi n e d as pr o gr essi o n o n : > I of 
3 c o m p o n e nts ( E D S S, T 2 5 F W, a n d/ or 9 H P T) c o nfir m e d ; > 2 4 w e e ks a p art a n d wit h a 
; > 2 0 % mi ni m u m t hr es h ol d c h a n g e f or T 2 5 F W a n d 9 H P T. T 2 5 F W a n d 9 H P T are o pt i o nal 
a n d will b e p erf or m e d if d o n e as p er r o uti n e pr a cti c e. Pr o gr essi o n o n E D S S is d efi n e d as 
at l e ast I p oi nt i n t h e E D S S s c or e or a n i n cr e as e of at least 1. 5 p oi nts if t h e b as eli n e E D S S 
s c or e is 0. 
• 
T o ass ess dis a bilit y i m pr o v e m e nt. Dis a bilit y I m pr o v e m e nt is d efi n e d as i m pr o v e m e nt o n 
; > 1 of 3 c o m p o n e nts ( E D S S, T 2 5 F W, a n d/ or 9 H P T) c o nfir m e d ; > 2 4 w e e ks a p art a n d wit h 
a ;;;., 2 0 % mi ni m u m t hr es h ol d c h a n g e f or T 2 5 F W a n d 9 H P T. T 2 5 F W a n d 9 H P T are o pti o n al 
a n d will b e p erf or m e d if d o n e as p er r o uti n e pr a cti c e. I m pr o v e m e nt o n E D S S is d efi n e d as 
a d e cr e as e i n E D S S b y at le ast 1 p oi nt ( 1. 5 p oi nts if b as eli n e E D S S w as 1. 5). 
• 
T o ass ess s af et y of Cl a dri bi n e t a bl ets i n t h e real w orl d, at t w o y e ars 
• 
T o ass ess Q u al it y of Life a n d tr e at m e nt s atisf a cti o n 
• 
T o ass ess tr e at m e nt a d h er e n c e 
• 
 
 
 
E x pl or at or y O bj e cti v es 
• 
F or t h os e p ati e nts t h at t h e tr e ati n g p h ysi ci a ns d e ci d e t o pr es cri b e a n M RI at b as eli n e a n d/ or 
Y e ar 2: 
I. T o c o m p ar e M RI c h ar a ct eristi cs b et w e e n b as eli n e a n d Y e ars 1 a n d 2 
2. 
T o c o m p ar e M RI 
c h ar a ct eristi cs b et w e e n t h e 1 2- m o nt h pr e- b as eli n e a n d p ost-
b as eli n e r es ults ( Y e ars I a n d 2) 
• 
T o st u d y eff e cti v e n ess i n 5 s u b gr o u ps, d efi n e d 
a c c or di n g t o t h e pr e- b as eli n e D M D 
tr e at m e nt (I F N- B l a/ I F N- B I BI Gl atir a m er A c et at e , T erifl u n o mi d e, D M F). 
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C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
9 
9. 1 
9. 1. 1 
Cl a d ri bi n e 
R es e a r c h M et h o ds 
St u d y D esi g n 
D esi g n O v e r vi e w 
T his is a pr os p e cti v e , n o n-i nt er v e nti o n a l, m ulti c e nt er, P h as e I V st u d y i n p ati e nts wit h a c o nfir m e d 
dia g n osis of R R M S w h o s wit c h e d fr o m first-l i ne D M D tr e at m e nt (I nt erf er o ns, Gl atir a m er A c et at e, 
T erifl u n o mi d e , D M F) t o tr e at m e nt wit h Cl a d ri bi n e tabl ets i n r o uti n e cli ni c al pr a cti c e. 
N o st u d y s p e cifi c i nte r ve nti o n s w ill b e p erf or m e d o n t h e p ati e nts a n d t h ere wil l n ot b e a n y st u d y 
s p e cifi e d vi s its. Ass e ss m e nts pl a n n e d i n t his pr ot o c ol will b e a c c or di n g t o cli ni c al pr a cti c e . 
P at ie n ts wil l be e nr o lle d c o ns e c uti v e l y at st u d y s it es i n t he pa 1 1ici pati n g c o u ntri es. E a c h p ati e nt 
will be f o llo w e d f or t h e c o ur se of t h eir st a n d ar d Cl a dri bi n e tre at m e nt ( a p pr o xi m at el y 2 y e ars 
a c c or di n g t o cli ni c al pr a cti c e). 
Fi g ur e I pr o vi d es a sc h e m ati c o v e r vie w of t h e st u d y de s i g n. Fi g ur e 2 pr o vi d es a n o v er vi e w of the 
p ati e nt j o ur ne y w ithi n t h e st u d y. E nr ol m e nt m a y t a k e pl a c e fr o m t h e ti m e of cl a dri bi n e pr e scri pti o n 
u p u ntil t h e s e c o n d tr e at m e nt w e e k, i n t h e first tr e at m e nt y e ar. 
Pt s s w it c hi n g fr o m I nterf er o n, Gl atir a m er A c et at e, 
T erifl u n or ni d e or D M F. Pt s s h o ul d h a v e b e e n 
tr e at e d w it h t h e s a m e fir st-lin e D M D a n d at a st a bl e 
d o s e f or at l e a st o n e y e ar pri or t o s wi tc hi n g 
Cl a d ribi n e a l ets 
Si n gl e c o h ort st u d y 
S cr e e ni n g a 1 1 d R u n -i n e t c 
R e cr u itm e nt p eri o d = 2. 5 y e ar s 
O b s er v ati o n p e ri o d " 2 4 
o n t h s ( 2 y e a r s) 
Fi g u r e 1 - S c h e m ati c of S t u d y D esi g n 3 
3 Pt s: patie nts: I FN: I nte rfer o n; D M F: D y m et h y l f u m ara te; D M D: Disease M o diJ Yi n g Dr u g 
C O N F I D E N T I A L 
I N F O R M A T
I O N 
F i n al a n al y si s at 2 y e ar s ! 
II 
II 
2 0 / 5 1 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
Fir st pr e s cri pti o n 
Cl a dri bi n e 
j 
Fir st tr e at m e nt 
D e ci si o n t o s wit c h 
( m on ::~ : sv: a r l) 
t o Cl a dri bi n e 
1 
Fi r st- lin e D M D
* f or at l e a st o n e y e ar 
A R R 1 2 m o nt h s pr e- b a s eli n e p eri o d 
., I nt erf er o n, Gl atir a m er A c et at e, T erifl u n o mi d e, D M F 
j 
~ J _ _ __ ' E nr ~ ~n ~ ~ .'.:t u p 
, - -
t re at m e nt 
W e e k ( m o nt h 
2, v e ar 1 
~-,- _j 
Pr e-tr e at m e nt 
t e sti n g a s p er S m P C 
Fi g ure 2 - St u d y P ati e nt J o ur n e y 
9. 1. 2 
O ut c o m es 
9. 1. 2. 1 
P ri m a r y 
S e c o n d c o ur s e 
cl a dri bi n e Y e ar 2 
Pr e -tr e at m e nt j 
t e stin g a s p er 
S m P C~ 
A R R 1 2 m o nt h s p eri o d b ef or e 
e n d of st u d y f oll o w- u p 
Diff er e n c e i n A R R b et w e e n t h e pr e- b as eli n e 1 2- m o nt h p eri o d o v er t h e 1 2 m o nt hs p eri o d bef ore 
t he E n d of St u d y f oll o w- u p ( 2 y e ars) 4 . 
9. 1. 2 . 2 
S e c o n d a r y 
• 
Diff er e n c e i n A R R b et w e e n t h e pr e- b as eli n e 1 2- m o nt h p eri o d a n d o v er t h e 1 2 m o nt hs 
p eri o d aft er t h e st art of cl a dri bi n e ( I y e ar) 
• 
P er c e nt a g e of p ati e nts wit h 6- m o nt h dis a bilit y pr o gr essi o n 5 at t h e e n d of t h e st u d y f oll o w-
u p p eri o d ( 2 y e ars), m e as ur e d as E D S S, T 2 5 F W ( o pti o n al) a n d 9- H P T ( o pti o n al). 
4 R el a ps es will b e di a g n os e d b y t h e tr e ati n g p h ysi ci a ns , as p a r o uti n e cli ni c al pr a cti c e ; a t y pi c al d efi niti o n wit hi n t his 
c o nt e xt is t h e a p p e ar a n c e of n e w s y m pt o m s of t h e e x a c er b ati o n of pr e- e xi sti n g s y m pt o ms t h at ar e attri b ut e d t o M S 
a n d o c c ur o v er a mi ni m u m of 2 4 h o urs a n d s e p ar at e d fr o m a pr e vi o us att a c k b y at least 3 0 d a ys, i n t h e a bs e n c e of 
f e v er or i nf e cti o n. 
5 Dis a bilit y pr o gr essi o n is de fi n e d as pr o g r ess i o n o n ;;;, I of 3 c o m p o n e nts ( E D S S, T 2 5 F W , a n d /or 9 H P T) c o nfir m e d 
;;;, 2 4 w e e ks a p art a n d wit h a ;;;, 2 0 % mi ni m u m t hr es h ol d c h a n g e f or T 2 5 F W a n d 9 H P T. Pr o gr essi o n o n E D S S is d efi n e d 
C O N FI D E N TI A L 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
• 
Perce nta ge of patie nts wit h 6- m o n t h disa bilit y i m pr o ve me nt4 at t he e n d of t he st u d y f oll o w-
u p peri o d ( 2 years), meas ure d as E D S S, T 2 5 F W ( o pti o nal) a n d 9- H P T ( o pti o nal) 
• 
Occ urre nce of a d verse e ve nts a n d of seri o us a d verse e ve nts 
• 
Q u a lit y of I ife ( M SI S- 2 9) 
•  
Treat me nt Satisfacti o n ( T S Q M v 1. 4) 
• 
 
• 
Treat me nt a d here nce, assesse d as perce nta ge of cla dri bi ne ta blets ta ke n vers us prescri be d 
d ose 
9. 1. 2. 3 
E x pl o r at o r y 
• 
N u m ber of M RI lesi o ns ( T 2, Tl G d +, C U A) at baseli ne a n d years I a n d 2 
• 
C o m paris o n of t he n u m ber of M RI lesi o ns ( T 2, TI G d +, C U A) bet wee n t he pre- baseli ne 
1 2 m o nt hs a n d p ost- baseli ne res ults ( years I a n d 2) 
• 
A n e x p l orat or y s u b gr o u p a nal ysis will be c o n d ucte d o n effecti ve ness e n d p oi nts. wit h 5 
gr o u ps d efi ne d acc or di n g t o t he pre- baseli ne D M D treat me nt (I F N- 13 I a/ I F N- 13 1 13 I 
Glatira mer Acetate, Terifl u n o mi de, D M F) 
9. 2 
9. 2. 1 
S etti n g 
St u d y P o p ul ati o n 
T he st u d y p o p ulati o n will be i de ntifie d acc or di n g t o t he bel o w i ncl usi o n a n d e xcl usi o n criteria. 
F or i ncl usi o n i n the st u d y, all of t he f oll o wi n g i ncl usi o n criteria m ust be f ulfi lle d: 
I. Patie nts m ust 
v ol u ntaril y gi ve writte n 
i nf or me d c o nse nt. Patie nts m ust 
rea d a n d f ull y 
u n dersta n d the I nf or me d C o ns e nt F or m (! C F) 
2. 
A d ult patie nts, ma les or fe males patie nts 2': 1 8 years ol d. 
3. 
Patie nts wit h 
c o nfir me d dia g n osis of Rela psi n g- Re mitti n g 
M ulti ple 
Scler osis ( R R M S) 
dia g n os e d b y t he treati n g p h ysicia n acc or di n g t o a p plica b le cli nical practice g ui deli nes -
(c urre ntl y Mc D o nal d 2 0 1 7 criteria), wit h hi g h disease acti vit y. 
as at least I p oi nt i n t he E D S S sc ore or a n i ncrease of at leas t 1. 5 p oi nts if t he baseli ne E D S S sc ore is 0. Disa bilit y 
I m pr o ve me nt is defi n e d as i m pr o ve me nt o n ;;a, I of 3 c o m p o ne nts ( E D S S, T 2 5 F W, a n d/ or 9 H P T) c o nfir m e d ;;a, 2 4 wee ks 
a part a n d wit h a ;;a, 2 0 % mi ni m u m t hres h ol d c ha n ge Cor T 2 5 F W a n d 9 H P T . I m pr o ve me nt o n E D S S is d efi n e d as a 
decrease i n E D S S b y at least I p oi nt ( 1. 5 p oi nts if baseli ne E D S S was 1. 5). T 2 5 F W a n d 9 H P T arc o pti o nal a n d will 
be perf or me d if d o ne as per r o uti ne practice. 
C O N F I D E N T I A L 
I N F O R M A TI O N 
2 2 /5 1 
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C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
4. 
P ati e nts s h o ul d h a v e b e e n tr e at e d wit h t h e s a m e first-li n e D M D (I nt erf er o ns, Gl atir a m er 
A c et at e , T eritl u n o mi d e, D M F) a n d at a st a bl e d os e f or at l e ast o n e y e ar pri or t o s wit ch t o 
Cl a dri bi n e t a bl ets a n d s h o ul d h a v e b e e n pr es cri b e d Cl a dri bi n e t a bl ets, a c c or di n g t o t h e d e cisi o n 
of t he tr e ati n g p h ysi ci a n , pri or t o e nr oll m e nt i n t h e st u d y. A n y w as h o ut p eri o d a n d/ or w as h o ut 
m et h o ds r e q uir e d b ef or e s wit c hi n g (s u c h as eli mi n ati o n of T eritl u n o mi d e) m ust h a v e b e e n 
c o n d u ct e d, a c c or di n g t o t h e d e cisi o n of t h e tr e ati n g p h ysi ci a n. 
5. 
R e q uir e d hist or y d at a s h o ul d b e a v ail a bl e: 
• 
M S d at a f or t h e 1 2- m o nt hs pr e- b as eli n e p eri o d ( a n n u ali z e d r el a ps e r at e) 
• 
M S M e di c ati o n Hist or y ( pri or D M Ds) 
6. 
F ulfil m e nt of t h e crit eri a f or tr e at m e nt wit h 
Cl a dri bi n e t a bl ets p er st a n d ar d of c ar e 111 
a c c or d a n c e wit h t h e l o c al S m P C 
P ati e nts ar e n ot eli gi b le f or t his st u d y if t h e y f ulfill a n y of t he f oll o wi n g e x cl usi o n crit eri a: 
I. C o ntr ai n di c ati o ns 
t o us e of cl a dri bi n e t a bl ets a c c or di n g t o t h e S u m m ar y of Pr o d u ct 
C h ar a ct eristi cs 
2. 
P ati e nts wit h hist or y of al c o h ol or dr u g a b us e t h at c o ul d p ot e nti all y i nt erf er e wit h t h eir 
p arti ci p ati o n i n t he st u d y. 
3. 
P ati e nt t h at h a v e r e c ei v e d Cl a dri bi n e i n t h e p ast 
4. 
C o n c urr e nt p arti ci p ati o n i n a n i n v esti g ati o n al st u d y i n w hi c h 
p ati e nt ass ess m e nt a n d/ or 
tr e at m e nt m a y be di ct at e d b y a pr ot o c ol. 
9. 2. 2 
D efi niti o n of St u d y C o h orts a n d D es c ri pti o n of T r e at m e nts 
T his is a si n gl e c o h ort st u d y e nr olli n g all p ati e nts t h at s wit c h t o Cl a dri bi n e t a bl ets fr o m first-li n e 
D M Ds , a c c or di n g t o t h e d e cisi o n of t h e tr e ati n g p h ysi ci a n. P ati e nts s h o ul d h a v e b e e n u n d er 
tr e at m e nt wit h first-li n e D M Ds f or at l e ast o n e y e ar pri or t o s wit c hi n g (s e e S e cti o n 9. 2. 1) a n d 
s h o ul d h a v e b e e n pr es cri b e d t o Cl a dri bi n e t a bl ets pri or t o e nr oll m e nt ( b as eli n e visit). E nr oll m e nt 
m a y t a k e pl a c e fr o m t h e ti m e of cl a dri bi n e pr es cri pti o n u p u ntil t h e s e c o n d tr e at m e nt w e e k, i n t h e 
first tr e at m e nt y e ar. 
A ll eli gi bl e p ati e nts ar e tr e at e d wit h Cl a dri bi n e t a bl ets i n r o uti n e cli ni c al pr a cti c e. P ati e nts will 
r e c ei v e Cl a dri bi n e as p er t h e S m P C a n d t h e dis cr eti o n of t h eir tr e ati n g p h ysi ci a n. A c c or d i n g t o t h e 
S m P C, e a c h tr e at m e nt c o urs e c o nsists of 2 tr e at m e nt w e e ks , o n e at t h e b e gi n ni n g of t h e first m o nt h 
a n d o n e at t h e b e gi n ni n g of t h e s e c o n d m o nt h of t h e r es p e cti v e tr e at m e nt y e ar. E a c h tr e at m e nt 
w e e k c o nsists of 4 or 5 d a ys o n w hi c h a p ati e nt r e c ei v es 1 0 m g or 2 0 m g ( o n e or t w o t a bl ets) as a 
si n gl e d ail y d os e, d e p e n di n g o n b o d y w ei g ht. If n e c ess ar y, t h e tr e at m e nt c o urs e i n Y e ar 2 c a n be 
d el a y e d f or u p t o 6 m o nt hs t o all o w f or r e c o v er y of l y m p h o c yt es ( at l e ast 8 0 0 ce lls/ m m3). If t his 
r e c o v er y t a k es m or e t h a n 6 m o nt hs, t h e p ati e nt s h o ul d n ot r e c ei v e Cl a dri bi n e t a bl ets a n y m or e. I n 
p ati e nts w h er e cl a dri bi n e t a bl et tr e at m e nt w as d el a y e d, f oll o w- u p will r e m ai n 2 y e ars aft er 
e nr oll m e nt a n d will n ot be e xt e n d e d b y t h e p eri o d b y w hi c h tr e at m e nt w as d el a y e d. 
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L 0 4 A A 4 0 
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9. 2. 3 
Cl a d ri bi n e 
O bs e r v ati o n P e ri o d 
E a c h p ati e nt will be f oll o w e d fr o m t h e d at e t h e I nf or m e d C o ns e nt is si g n e d u ntil th e y ar e l ost t o 
f oll o w- u p, wi th dra wal of c o ns e nt, d e at h or t h e e n d of t h e d at a c oll e cti o n p eri o d, w hi c h e v er c o m es 
first. P ati e nts wi ll be f oll o w e d f or 2 4 m o nt hs fr o m first d os e of Cl a dri bi n e. F oll o w- u p wi ll c o nti n u e 
r e g ar dl ess of cl a dri b i ne t a bl ets dis c o nti n u ati o n f or 2 y e ars aft er first d os e or u ntil wit h dr a w al. 
9. 2. 4 
F r e q u e n c y of Ass ess m e nts 
A n o v er vi e w of the st u d y wit h a s u m m ar y of pl a n n e d ass ess m e nts is pr o vi d e d i n T a bl e I. 
C O N F I D E N T I A L 
I N F O R M A TI O N 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a dri bi n e 
T a bl e 1 - S c h e d ul e of Ass ess m e nts 
J n di ut h e m o nt h 
l nf or ml' d C o ns e nt 
l n cl usi o n/ cs cl usi o n c,it eri il 
D ci n o gr n p hi cs 
Rell" va nl me dic.ti hisl or y 
C o n c o mit a nt tr e ut m e n u 
M S mt di c ati o n hist or y 
M S D at a hist or y ( wi 1 hi n 1 2 m o nt hs 
pri or t o s wit c hi n g,-
T h n a p)' · wil h O a dri bi n c t a bl ets 
R e as o n f or s wit c hi n g fr o m first li ne 
0 1\ 1 0 t o Cl a dri bi nt la hlet!'I 
Dis a bilit y ( E D S S) 
Dis a bilit y ( 9fl P T) - o pti o n al 
Oisa bilil } ' ( T 2 5 F W) - o pti o n al 
Rela p se c o u nt 
E v al u ati o n of M RI (if a v ail a bl e) 
 
 
C oll e cti o n of tr e at m e nt s:,tisf a cti o u 
( T S Q M- 1. 4) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
_ _ _ _ _ _ , _ _ _ _ _ _ 1 1 _ _ _ _ _ _ 1 s, _ _ _ _ _ _ _ 2 4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S af et y n ~c or di n g a n d r~ p o 1·ti n g 
X 
X 
X 
X 
X 
a M S r el at e d data c o m pris e: 
M S Me d ic ati o n Hist or y : Disease m o dif yi n g d m g ( D M D ) 
M S 
Hi st ory . i n cl u di n g n u m b er of r ela ps es wit hi n 1 2 m o nt hs b ef or e i niti ati o n of Cl a dri bi n c t h er a py a n d n u m b er of n e w /e nl ar g e d M RI 
les i o ns ( Tl G d +. T 2 a n d C U A 
lesi o ns) m e as u re d 0 1 1 t he las t M R I pcrf o n n c d p er cli ni c al p r a cti c e he f ore i niti ati o n of C' la d ri bine l he r a py c o m p ar e d l o 1 2- m o nt h pr c- b ns eli n c M RI 
C O N FI D E N TI A L 
I N F O R M A TI O N 
2 5 i 5 I 
Gl o bal Versi o n I D: C CI
C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi ne 
As t his is a n o n-i nt er v e nti o n al st u d y, st u d y ass ess m e nts ar e p art of t h e r o uti n e pr a cti c e a n d r el at e d 
d at a will be c oll e ct e d d uri n g t h e visits i n li ne wit h t h e S m P C a n d as cli ni c all y i n di c at e d. P ati e nts 
will att e n d t h e sit es as p er r o uti n e pr a cti c e at t h e dis cr eti o n of t h e tr e ati n g p h ysi ci a n. T h er ef or e, 
the ti mi n g of t h e visits is a n a p pr o xi m ati o n . 
T h e first visit will b e t he b as eli n e visit. P ati e n ts w h o m e et all eli gi bilit y crit eri a a n d w h o si g n t h e 
I C F c a n be e nr oll e d i nt o th e st u d y. I n cl usi o n c a n o c c ur at t h e ti m e p oi nt of tr e at m e nt pr es cri pti o n 
wit h C l a dri bi n e t abl ets u p u ntil t h e s e c o n d tr e at m e nt w e e k of t h e first tr e at m e nt y e ar. B as eli n e d at a 
will b e c oll e ct e d at t h e ti m e of t h e visit. 
I n a d diti o n t o t h e b as eli n e d at a, d at a c oll e cti o n is pl a n n e d at 4 s u p pl e m e nt ar y visits a c c o r di n g t o 
r o uti n e pr actice: at m o nt h 6, 1 2 , 1 8 a n d 2 4 a p pr o xi m at el y . 
B as eli n e ass ess m e n ts ( V O) 
• 
D e m o gr a p h y: G e n d er, a g e, r a c e (if all o w e d p er l o c al r e g ul ati o n) 
• 
W ei g ht 
• 
R el e v a n t M e di c al 
Hist or y: 
M ali g n a n ci es 
( as m a n d at e d 
i n t h e S m P C), 
s e v er e a n d 
o p p ort u nisti c i nf e cti o ns 
• 
M S 
M e di c ati o n 
Hist or y: 
Dis e as e 
m o dif yi n g 
dr u g 
( D M D), 
i m m u n os u p pr essi v e/i m m u n o m o d ul at or y a g e nts ( ot h er t h a n D M D , s u c h as c orti c ost er oi d 
tr e at m e nt) 
• 
C o n c o mit a nt tre a t m e nts 
• 
R e as o n f or s wit c hi n g fr o m first li n e D M D t o Cl a d ri bi n e t a bl ets ( cli ni c al r el a ps es or dis a bilit y 
pr o gr essi o n, n e w or e n h a n ci n g M RI l esi o ns, or ot h er). 
• 
D at e of st art of t h er a p y wit h Cl a dri bi n e t a bl ets a n d n u m b er of t a bl ets t a k e n 
• 
P arti ci p ati o n i n a Cl a dri bi n e P ati e nt S u p p ort Pr o gr a m 
• 
M S 
d at a Hist or y , i n cl u di n g n u m b er of r el a ps es wit hi n 
1 2 m o nt hs 
b ef or e i niti ati o n of 
Cl a dri bi n e t h er a p y a n d n u m b er of n e w/ e nl ar g e d M RI l esi o ns ( Tl G d +, T 2 a n d C U A l esi o ns) 
m e a s ur e d o n t he last M RI p erf or m e d p er cli ni c al pr a cti c e wit hi n t h e l ast 1 2 m o nt hs b ef or e 
i niti ati o n of Cl a dri bi n e t h er a p y 
•  
MSI S- 2 9 Q u esti o n n air e: t o b e a ns w er e d b y th e s u bj e ct 
• 
E Q- 5 D- 3 L Q u esti o n n air e: t o b e a ns w er e d b y t h e s u bj e ct 
• 
E D S S, T 2 5 F W , 9- H P T , T 2 5 F W a n d 9 H P T ar e o pt i o n al a n d will be p erf or m e d if d o n e as pe r 
r o uti n e pr a cti c e. 
• 
S af e t y r e c or di n g a n d r ep orti n g 
•  
Up o n a v a ilabi lit y: M RI 
( Tl G d +, 
T 2 a n d C U A l esi o ns). T h es e ass ess m e nts ar e n ot 
m a n d at or y p arts of t his st u d y; h o w e v er, w e ki n d l y as k f or pr o vi di n g t h e s c or es i n c as e t h e 
t ests w er e c arri e d o ut d u e t o m e d ical r e as o ns or as p art of t h e cli ni c al r o uti n e. 
C O N F I D E N TI A L 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a dri bi ne 
Visit 1 ass ess m e nts ( VI, i n di c ati v e M o nt h 6) 
• 
T ot al n u m b er of r el a ps es w hil e i n st u d y, u p u ntil t his visit 
• 
D at e of a d mi nistr ati o n of t h er a p y wit h Cl a dri bi n e t a bl ets a n d n u m b er of t a bl ets t a k e n vers us 
pr es cri b e d d os e 
• 
C o n c o mit a nt tr e at m e nts 
• 
T S Q M- v 1. 4 Q u esti o n n air e: t o be a ns w er e d b y t he s u bj e ct 
• 
E D S S, T 2 5 F W, 9- H P T, T 2 5 F W a n d 9 H P T ar e o pti o n al a n d will be p erf or m e d if d o n e as per 
r o uti n e pr a cti c e 
• 
S af et y r e c or di n g a n d r e p orti n g 
• U p o n a v ail a bilit y: M RI (t ot al n u m b er of Tl G d +, T 2 a n d C U A l esi o ns). T h es e ass ess m e nts 
ar e n ot m a n d at or y p arts of t his st u d y; h o w e v er , w e ki n dl y as k f or pr o vi di n g t h e s c or es i n case 
t h e t ests w er e c arri e d o ut d u e t o m e di c al r e as o ns or as p art of t h e cli ni c al r o uti n e. 
Visit 2 ass ess m e nts ( V 2, i n di c ati v e M o nt h 1 2 ) 
• 
W ei g ht 
• 
C o n c o mit a nt tr e at m e nts 
• 
T ot al n u m b er of r el a ps es w hil e i n st u d y, u p u ntil t his visit 
• 
D at e of a d mi nistr ati o n of t h er a p y wit h Cl a dri bi n e t a bl ets a n d n u m b er of t a bl ets t a k e n vers us 
pr es cri b e d d os e 
• 
T S Q M- v l . 4 Q u esti o n n air e: t o be a ns w er e d b y t h e s u bj e ct 
• 
M SI S- 2 9 Q u esti o n n air e: t o be a ns w er e d b y t h e s u bj e ct 
• 
E Q- 5 D- 3 L Q u esti o n n air e: t o be a ns w er e d b y t h e s u bj e ct 
• 
E D S S, T 2 5 F W , 9- H P T, T 2 5 F W a n d 9 H P T ar e o pti o n al a n d will be p erf or m e d if d o n e as per 
r o uti n e pr a cti c e. 
• 
S af et y r e c or di n g a n d r e p orti n g 
• 
U p o n a v ail a bilit y: a n d M RI 
(t ot al n u m b er of Tl G d +, T 2 a n d C U A 
l esi o ns). T h es e 
ass ess m e nts ar e n ot m a n d at or y p arts of t his st u d y h o w e v er w e ki n dl y as k f or pr o vi di n g t he 
s c or es i n c as e t h e tests w er e c arri e d o ut d u e t o m e di c al r e as o ns or as p art of t h e cli ni c al 
r o uti n e. 
Visit 3 ass ess m e nts ( V 3, i n di c ati v e M o nt h 1 8) 
• 
T ot al n u m b er of r el a ps es w hil e i n st u d y, u p u ntil t his visit 
• 
D at e of a d mi nistr ati o n of t h er a p y wit h Cl a dri bi n e t a bl ets a n d n u m b er of t a bl ets t a k e n v ers us 
pr es c ri b e d d os e 
• 
C o n c o mit a nt tr e at m e nts 
• 
T S Q M- v 1. 4 Q u esti o n n air e: t o be a ns w er e d b y t h e s u bj e ct 
C O N FI D E N T I A L 
I N F O R M A T I O N 
2 7 / 5 1 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
• 
E D S S, T 2 5 F W, 9- H P T, T 2 5 F W a n d 9 1-l P T ar e o pti o n al a n d will be p erf or m e d if d o n e as p er 
r o uti n e pr a cti c e 
• 
S af et y r e c or di n g a n d r e p orti n g 
• 
 
 
 
Visit 4 ass ess m e nts ( V 4, i n di c ati v e M o nt h 2 4) 
• 
T ot al n u m b er of r el a ps es w hil e i n st u d y, u p u ntil t his visit 
• 
C o n c o mit a nt tr e at m e nts 
• 
T S Q M- v 1. 4 Q u esti o n n air e: t o b e a ns w er e d b y t h e s u bj e ct 
• 
M SI S- 2 9 Q u esti o n n air e: t o be a ns w er e d b y t h e s u bj e ct 
• 
E Q- 5 D- 3 L Q u esti o n n air e: t o be a ns w er e d b y the s u bj e ct 
• 
E D S S, T 2 5 F W, 9- H P T, T 2 5 F W a n d 9 1-l P T ar e o pti o n al a n d will be p erf or m e d if d o n e as p er 
r o uti n e pr a cti c e. 
• 
S af et y r e c ord i n g a n d r e p orti n g 
• 
 
 
 
A p ati e nt is c o nsi d er e d t o h a v e c o m pl et e d t h e st u d y aft er t h e y h a v e ha d a f o ll o w- u p visit at t h e 
e n d of t he o bs er v a ti o n p eri o d of 2 4 m o nt hs . St u d y ter mi n ati o n e arl ier th a n m o nt h 2 4 m a y o c c ur 
d u e t o l ost t o f o ll o w u p , i nf or m e d c o ns e nt wit h dr a w al or a n y ot h er r e as o ns as r e c or d e d. 
F oll o wi n g ass ess m e nts will be p erf or m e d at st u d y t er mi n ati o n, if t his i nf or m ati o n is a v ail a bl e : 
• 
W ei g ht 
• 
T ot al n u m b er of r el a ps es w hil e i n st u d y 
• 
T S Q M- v 1. 4 Q u esti o n n air e: t o be a ns w er e d b y t h e s u bj e ct 
• 
M SI S- 2 9 Q u esti o n n air e: t o be a ns w er e d b y the s u bj e ct 
• 
 
• 
E D S S, T 2 5 F W, 9- H P T, T 2 5 F W a n d 9 1-l P T ar e o pti o n al a n d wi ll be p erf or m e d if d o n e as p er 
r o uti n e prac tice. 
• 
Sa fet y re c or d i n g a n d r e p orti n g 
• 
U p o n a v ail a bilit y : M RI (t ot al n u m b er of Tl G d +, T 2 a n d C U A l esi o ns). T h es e ass ess m e nts 
are n ot m a n d at or y p arts of t his st u d y h o w e v er w e ki n dl y as k f or pr o vi di n g t h e s c or es i n c as e 
t h e t ests w er e c arri e d o ut d u e t o m e di c a l r e as o ns or as p art of t h e cli ni c al r o uti n e. 
F or p ati e nts l ost t o f oll o w u p o bs er v ati o ns will b e c e ns or e d a n d will be h a n dl e d as d efi n e d i n 
t h e S A P. L ost-t o f oll o w- u p is c o nfir m e d w h e n at le ast 3 d o c u m e nt e d att e m pts t o r e a c h o ut t h e 
C O N FI D E N TI A L 
I N F O R M A T I O N 
2 8 /5 1 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 0 0 7 0 
Cl a d ri bi n e 
p ati e nt h a v e b e e n m a d e. If a s u bj e ct is l ost t o f oll o w- u p, e v er y p ossi bl e eff ort m ust be m a d e b y 
st u d y c e nt er p ers o n n el t o c o nt a ct t h e s u bj e ct a n d d et er mi n e t h e r e as o n f or dis c o nti n u ati o n. T h e 
m e as ur es t a k e n t o f oll o w- u p m ust be d o c u m e nt e d. If a s u bj e ct dis c o nti n u es b ef or e c o m pl eti o n 
of st u d y pr o c e d ur es, t h e r e as o n f or dis c o nti n u ati o n m ust be d o c u m e nt e d i n t h e c as e r e p ort f or m 
( C R F) a n d s o ur c e d o c u m e nts. 
S af et y d at a ass ess m e nt 
• 
S af et y e v e nts ar e c oll e ct e d t hr o u g h o ut t h e st u d y as d es cri b e d i n S e cti o n 1 1. 5. 
9. 2. 5 
Wit h d r a w al fr o m t he St u d y 
P ati e nts m a y dis c o nti n u e fr o m t h e st u d y at a n y ti m e ( wit h dr a w c o ns e nt) . T h e r e as o n f or a n y st u d y 
dis c o nti n u ati o ns will b e c oll e ct e d, if a v ail a bl e. 
P ati e nts w h o dis c o nti n u e tr e at m e nt will c o nti n u e t o be f oll o w e d u ntil e n d of f oll o w- u p p eri o d 
r e g ar dl ess of tr e at m e nt st at us, u nl ess t h e y s wit c h t o a n ot h er D M D tr e at m e nt i n w hi c h c as e t h e y 
s h o ul d be wit h dr a w n fr o m t h e st u d y. 
9. 3 
V a ri a bl es 
• 
D e m o gr a p hi c d at a: G e n d er, a ge, r a c e (if all o w e d as p er l ocal r e g ul ati o n) 
• 
Ot h er B as eli n e Ass ess m e nts: W ei g ht 
• 
M e di c al hist or y, i n cl u di n g M S, m ali g n a n ci es, s e v er e a n d o p p ort u nisti c i nf e cti o ns 
• 
M S- M e di c ati o n hist or y: D M D, i m m u n os u p pr essi v e/i m m u n o m o d ul at or y a g e nts ( ot h er t h a n 
D M D, s u c h as c orti c ost er oi d tr e at m e nt) 
• 
T h er a p y wit h Cl a dri bi n e T a bl ets [ date of a d mi nistr ati o n a n d n u m b er of t a bl ets t a k e n v ers us 
pr es cri b e d d os e (tr e at m e nt a d h er e n c e)] 
• 
R e as o n f or s wit c hi n g fr o m first li ne D M D t o Cl a dri bi n e T a bl ets 
• 
P arti ci p ati o n i n a Cl a dri bi n e P ati e nt S u p p ort Pr o gr a m 
• 
C o urs e of dis e as e 
o 
R el a ps es 
o 
M RI d at a 
T 2 , Tl G d + a n d C U A l esi o n c o u nts 
o 
E D S S S c or e 
o 
T 2 5 F W (ti m e i n s e c o n ds, o pti o n al) 
o 
9- H P T (ti m e i n s e c o n ds, o pti o n al) 
• 
T S Q M- v 1. 4 V A S s c or e 
• 
M SI S- 2 9 s c or e 
C O N FI D E N TI A L 
I N F O R M A TI O N 
2 9/ 5 1 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
• E Q- 5 D- 3 L s c or e 
Cl a d ri bi n e 
• 
S af et y ( S eri o us A d v ers e E v e nts ( S A Es), A d v ers e E v e nts of S p e ci al I nt er est ( A E S!) a n d 
A d v er s e Dr u g R e a cti o ns ( A D Rs)) 
D eri v e d a n d tr a nsf or m e d d at a n e e d e d f or t h e a n al ysis ar e d es cri b e d i n S e cti o n 9. 7. 2 . 
9. 4 
D a t a S o u r c e 
T h e d at a t o be c oll e ct e d i n t h e st u d y will b e o bt ai n e d b y m e a ns of a n ( e) C R F. T h e d at a i n t h e 
( e) C R F sh o u l d be c o nsist e nt wit h t h e r el e v a nt s o urc e d o c u m e nts. F u rth er d et ails ar e pr o vi d e d i n 
S e cti o n 9. 6. 
P ati e nts wi ll c o m pl et e t he M SI S- 2 9 , E Q- 5 D- 3 L a n d T S Q M v 1. 4 q u esti o n n air es at t h e sit es a n d t h e 
i nf or m ati o n will b e tr a ns cri b e d i nt o t h e e C R F b y t h e i n v esti g at or sit e st aff. P ati e nts c a n c o m pl et e 
t h e M SI S- 2 9 a n d E Q- 5 D- 3 L r e m ot el y at b as eli n e w h e n 
r e m ot e c o ns e nt is p erf o n n e d a n d 
a ut h ori z e d i n the c o u ntr y. 
Pr e- b a se li n e d at a, liste d i n S e cti o n 9. 2. 4, will be o bt ai n e d fr o m p ati e nt r e c or ds a n d will be 
tr a ns cri b e d i nt o t h e e C R F b y t h e i n v esti g at or sit e st aff. 
9. 5 
St u d y Si z e 
2 4 2 p ati e nts wit h c o n fir m ed di a g n osis of Hi g hl y A cti v e R el a psi n g- R e mitti n g M ulti pl e S cl er osis 
( R R M S) will be e nr oll e d i n t h e p arti ci p ati n g c o u ntri es. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9. 6 
Cl a d ri bi n e 
D at a M a n a g e m e nt 
T h e m ai n p ur p os e of t h e ( e) CR F is t o o bt ai n d at a r e q uir e d b y t h e n o n-i nt er v e nti o n al st u d y pr ot o c ol 
i n a c o m pl et e, a c c ur at e, l e gi bl e a n d ti m el y m a n n er. T h e d at a i n t h e ( e) C R F s h o ul d be c o nsist e nt 
wit h t h e r el e v a nt s o ur c e d o c u m e nts . 
T he I nv esti g at or or d esi g n e e is r es p o nsi bl e f or e ns uri n g t h at t h e d at a c oll e ct e d i n t h e c o urs e of t his 
st u d y is a c c ur at e a n d d o c u m e nt e d a p pr o pri at el y o n all a p pli c a bl e f or ms. D at a will t h e n b e 
pr o c ess e d, e v al u at e d. a n d st or e d i n a n o n y m o us f or m i n a c c or d a n c e wit h a p pli c a bl e d at a pr ot e cti o n 
r e g ul ati o ns. T he I n v esti g at or m ust e ns ur e t h at t h e ( e) C R Fs a n d a n y ot h er ass o ci at e d d o c u m e nts 
f or w ar d e d t o S p o ns or or its d esi g n at e d or g a ni z ati o n c o nt ai n n o m e nti o n of a n y s u bj e ct n a m es . 
T h e d at a will be e nt er e d i nt o a v ali d at e d d at a b as e. T h e S p o ns or/ C R O or its d esi g n e e will b e 
r es p o nsi bl e f or d at a pr o c essi n g, i n a c c or d a n c e wit h t h e S p o ns or 's/ C R O's d at a m a n a g e m e nt 
pr o c e d ur es. D at a b as e l o c k will o c c ur o n c e q u alit y c o ntr ol a n d q u alit y ass ur a n c e pr o c e d ur es 
(i n cl u di n g S A E/ S A D R r e c o n cili ati o n) a n d c o di n g a cti viti es h a v e b e e n c o m pl et e d . P D F fil es of t h e 
( e) C R Fs will be pr o vi d e d t o t h e i n v esti g at ors at t h e c o m pl eti o n of t h e st u d y. 
9. 7 
D at a A n al ysis 
St atisti c al pr o gr a m mi n g a n d a n al ys es will be p erf or m e d usi n g S A S 9. 4 ( or hi g h er) . D et ail e d 
m et h o d ol o g y 
f or s u m m ar y a n d st atisti c al a n al ys es of d at a c oll e ct e d i n t his st u d y will 
be 
d o c u m e nt e d i n a st atisti c al a n al ysis pl a n ( S A P), w hi c h will b e fi n ali z e d pri or t o d at a b as e l o c k a n d 
will b e i n cl u d e d i n t h e cli ni c al st u d y r ep or t f or t his pr ot o c ol. T h e fi n al S A P will t a k e i nt o a c c o u nt 
a n y a m e n d m e nt t o t h e pr ot o c ol. 
All a n al ys es will be p erf or m e d o n p ati e nts w h o r e c ei v e d at l e ast o n e d o s e of Cl a dri bi n e t a bl ets 
f oll o wi n g e nr oll m e nt i n t h e st u d y. 
9. 7. 1 
A n a l ysis Sets 
F ull A n al ysis S et 
T h e F ull A n al ysis S et ( F A S) is d efi n e d as all t h e p ati e nts w h o pr o vi d e d i nf or m e d c o ns e nt a n d w h o 
r e c ei v e d at l e ast o n e d os e of Cl a dri bi n e. A s u b gr o u p a n al ysis will be c o n d u ct e d o n F A S , as 
d es cri b e d i n S e cti o n 9. 7 .3. 
9. 7. 2 
D e ri v e d a n d T r a nsf o r m e d D at a 
Missi n g 
i nf or m ati o n will b e c a pt ur e d f or q u a ntit ati v e as w ell as q u a lit ati v e v ari a bl es b y t h e 
c at e g or y '' Missi n g" i n t h e s u m m ar y st atisti cs. If t h er e ar e n o missi n g v al u es t his will be i n di c at e d 
b y " 0 " u nl ess ot h er wis e s p e cifi e d. D u e t o the lo n git uti n al n at ur e of t h e d at a a n d t h e l e n gt h y f oll o w-
u p p eri o d , it is p ossi bl e t h at missi n g o ut c o m e d at a will b e pr es e nt. P att er ns a n d d e gr e es of 
missi n g n ess will be s u m m ari z e d. I n g e n er al n o i m p uti o n of missi n g d at a will be d o n e. 
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Cl a dri bi ne 
9. 7. 3 
St atisti c al M et h o ds 
All e n d p oi nts will be pr es e nt e d b y d es c ri pti v e st atisti cs f or b as eli n e , 1 2- m o nt hs , a n d E n d of St u d y 
ass ess m e nts. Ass ess m e nts 
d o n e at 6- m o nt hs a n d 1 8- m o nt hs will 
b e pr es e nt e d si m ilarl y. 
Q u a ntit ati v e ( c o nti n u o us) v ari a bl es will be s u m m ari ze d wit h t h e us e of d es cri pti v e st atisti c al 
m e as ur es 
[ m e a n v al u e, st a n d ar d d e vi ati o n ( S D), m e di a n, 
mi n- m a x, 
Ql- Q 3]. 
Q u alit ati v e 
( c at e g ori c al) vari a bl es will b e d is pl a y e d as fr e q u e n ci es a n d p er c e nt a g es ( N, %). 
T h e n or m alit y of dist ri b uti o ns w i ll be e x a mi n e d usi n g t h e S h a pir o- Wil k t est i n or d er t o d et er mi n e 
w h et h er or n ot t o us e p ar a m etri c m et h o ds f or a n al ysis. 
P ri m a r y E n d p oi nt: Pre- a n d p ost- b as eli n e A R R will be c o m p ar e d b y A N O V A or Wi l c o x o n 
si g n e d-r a n k t est if data is n ot n or m all y distri b ut e d. T h e 9 5 % C o nfi d e n c e I nt er v al ( Cl) f or t h e 
diff er e n c e w ill be pr es e nt e d. 
If a p pr o pri at e , s e nsiti vit y a n a lys es will be d o n e t o d et er mi n e t h e i m p a ct of c o nf o u n di n g f a ct ors or 
t o d es cri b e t h e o ut c o m e f or s p e ci al s u bj e ct gr o u ps f ulfilli n g pr e d efi n e d crit eri a. D et ails will be 
d es cri b e d i n t h e S A P . 
F or S e c o n d a r y a n d e x pl o r at o r y e n d p oi nts t h e f o ll o wi n g c al c ul ati o ns a n d c o m p aris o ns will b e 
p erf or m e d: 
Pre- a n d p ost- b as eli n e A R R ( 1 y e ar) will b e c o m p ar e d b y A N O V A or Wil c o x o n 
si g n e d-r a n k t est if d at a is n ot n or m all y distri b ut e d. T h e 9 5 % C o nfi d e n c e I nt er v al 
( CI) f or t he diff er e n c e will b e pr es e nt e d. 
F or all ot h er s e c o n d ar y e n d p oi nts, 9 5 % CI will be c al c ul at e d f or t h e r es ult at e a c h 
ti m e p oi nt a n d f or t h e differ e n c es w h e n e v er a p pli c a bl e, usi n g a p pr o pri at e m et h o d s. 
I n t h e a n al ysis of 6- m o nt h dis a bilit y pr o gr essi o n/i m pr o v e m e nt E D S S , T 2 5 F W a n d 9- H P T v al u es 
m ust be o bt ai n e d at s e q u e nti al ti m e p oi nts , se p ar at e d b y 6- m o nt h i nt er v als. As T 2 5 F W a n d 9- H P T 
are o pti o n al a n d will be p erf or m e d if d o n e as p er r o uti n e pr a cti c e, missi n g v al u es m a y o c c ur a n d 
c o u l d lea d t o bi as i n t h eir a n al ysis. M et h o ds t o h a n dl e t his bi as iss u e will b e d es cri b e d i n d et ail i n 
S A P. 
A s u b gr o u p a n al ysis will 
b e c o n d u ct e d o n eff e cti v e n ess e n d p oi nts ( A R R at I a n d 2 y e ars, 
p er c e nt a g e of p ati e nts wit h 6- m o nt h dis a bilit y pr o gr essi o n a n d i m pr o v e m e nt), wit h 5 gr o u ps 
defi n e d a c c or di n g t o t h e pr e- b as eli n e D M D tr e at m e nt (I F N- B I a / I F N- B I B / G l atir a m er A c et at e, 
T eritl u n o mi d e, D M F) . 
 
 
 
 
 
 
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9. 7. 4 
Cl a d ri bi n e 
S e q u e n c e of A n al ys es 
M ai n  a n al ysis will be p erf or m e d o n c e all t h e p ati e nts c o m pl et e d t h e st u d y wit h t h e p ur p os e of 
e v al u ati n g all e n d p oi nts a n d d at a b as e is l o c k e d. T w o d es cri pti v e i nt eri m a n al ys es will 
be 
p erf or m e d, r es p e cti v el y w h e n 3 0 % a n d 6 0 % of t h e p ati e nts h a v e c o m p l et e d t h e 1 2- m o nt h f oll o w-
u p visit, t o als o o bs er v e pr e- b as eli n e A R R a n d t h e v ari a n c es a d h er e n c e wit h 
s a m pl e size 
ass u m pti o ns. A n al p h a a dj ust m e nt f or t h e m ulti pli cit y of t h e a n al ysis will be i ntr o d u c e d if t h e 
i nt eri m a n al ysis will lea d t o c h a n g e i n s a m pl e si z e str at e g y . T h e I nt eri m A n al ys es will be base d 
o n a s u bs et of m ai n a n al ysis o ut p uts a n d t h e  list will be d et ail e d i n t h e S A P. 
9. 8 
Q u alit y C o nt r ol 
Q u alit y c o ntr ol a cti viti es will i n cl u d e v erifi c ati o n of d at a a n d e ns ur e t h e d at a c oll e ct e d i n ( e) C R F 
is a c c ur at e, v ali d a n d i n a c c or d a n c e wit h t h e pr ot o c ol. 
9. 9 
Li mit ati o ns of t he R ese arc h M et h o ds 
T his st u d y is o p e n l a b el a n d o bs er v ati o n al , a n d t h er ef or e h as i n h er e nt li mit ati o ns i n t er ms of 
s us c e pti bilit y t o b ias, c o nf o u n di n g a n d r estri cti n g t h e a bilit y t o d efi n e c a us al ity. T h er e is li mite d 
c o ntr ol o v er p ati e nt ass ess m e nt as p ati e nt m o nit ori n g a n d di a g n osti cs ar e p er st a n d ar d of c ar e; n o 
a d diti o n al cli ni c al m o nit ori n g is g e n er all y c o n d u ct e d. P ati e nt s p e cifi c m et h o d ol o gi c al c h all e n g es 
s u c h as p ot e nti al bi as es fr o m p ati e nt s el e cti o n, l oss of p ati e nts t hr o u g h st u d y attriti o n, a n d o v er all 
p ati e nt r e c all ar e als o ot h er limit ati o ns. H o w e v er, o bs er v ati o n al st u d y str e n gt hs i n cl u d e t h at t h e y 
r efl e ct d ail y cli ni c al pr a cti c e m or e cl os el y t h a n r a n d o mi z e d c o ntr oll e d tri als, b ot h i n t er ms of t he 
h et er o g e n e o us p ati e nt p o p ul ati o ns t h at are i n cl u d e d, a n d t h e m e di c al 
i nt er v e nti o ns t h at t h e y 
r e c ei v e. R e al-lif e o bs er v ati o n al d at a is ess e nti al t o ass ess a n d i m pr o v e cli ni c al pr a cti c e w orl d wi d e 
a n d c o m pl e m e nt r a n d o mi z e d c o ntr oll e d tri als b y pr o vi di n g cli ni c all y-r el e v a nt, r e al- w orl d d at a a n d 
pr o vi d e c o nsi d er a bl e h e alt h e c o n o mi c i nf or m ati o n. 
9. 1 0 
9. 1 0. 1 
Ot h e r As p e cts 
I n d e p e n d e nt Et hi cs C o m mitt e e o r Instit uti o n al R e vi e w B o ar d 
Pri or t o c o m m e n c e m e nt of t h e st u d y at a gi v e n site , t h e pr ot o c ol will be s u b mitt e d t o g et h er wit h 
its ass o ci at e d d o c u m e nts (i nf or m e d c o ns e nt f or m , P R Os , et c ,) t o t h e r es p o nsi bl e I n d e p e n d e nt 
Et hi cs 
C o m mitt e e 
(I E C) 
f or 
its f a v or a bl e o pi ni o n /a p pr o v al. 
T h e 
writt e n 
f a v or a bl e 
o pi ni o n /a p pr o v al of t h e I E C will b e fil e d b y t h e I n v esti g at or a n d a c o p y will be s e nt t o t h e S p o ns or. 
T h e st u d y m ust n ot st art at a sit e b e f or e t h e S p o ns or has o bt ai n e d writt e n c o nfir m ati o n of f a v or a bl e 
o pi ni o n/ a p pr o v al fr o m t h e c o n c er n e d I E C. T h e I E C will be as k e d t o pr o vi d e d o c u m e nt ati o n of t h e 
d at e of t h e m e eti n g at w hi c h t h e f a v or a bl e o pi ni o n/ a p pr o v al w as gi v e n, a n d of t h e m e m b ers a n d 
v oti n g m e m b ers pr es e nt at t h e m e eti n g . Writt e n 
e vi d e n c e of f a v or a bl e o pi ni o n/ a p pr o v al t h at 
cl e arl y i d e ntifi es t h e st u d y , t h e pr ot o c ol v ersi o n , a n d t h e S u bj e ct I nf or m ati o n a n d C o ns e nt F or m 
v ersi o n r e vi e w e d s h o ul d be pr o vi d e d. W h er e 
p ossi bl e , c o pi es of t h e m e eti n g mi n ut es s h o ul d be 
o bt ai n e d . 
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A m e n d m e nts t o t h e pr ot o c ol will als o be s u b mitt e d t o t h e c o n c er n e d ! E C, b ef or e i m pl e m e nt ati o n 
i n c as e of s u bst a nti al ch a n g es. 
9. 1 0. 2 
M o nit o ri n g 
Ri s k b as e d m o nit ori n g will b e p erf or m e d f or t his st u d y . Ris k b as e d m o nit ori n g is t h e pr o c ess of 
e ns uri n g t h e q u alit y of cli n i c al st u di es b y i d e ntif yi n g, ass essi n g, m o nit ori n g a n d miti g ati n g t h e 
ris ks t h at c o ul d affe ct t h e q u alit y or s af et y of a st u d y . It c a n f a cil it at e effi ci e nt tri al d el i v er y wit h o ut 
c o m pr o misi n g p ati e nt s af et y or d at a q u a lit y. A S p o ns or or a n a p p oi nt e d C R O will i d e ntif y criti c al 
d at a a n d pr o c ess es , p erf or ms a ris k ass ess m e nt a n d t h en d e v el o ps a m o nit ori n g pl a n t h at f o c us es 
o n t h e i m p ort a nt a n d li kel y ris ks t o criti c al d at a a n d pr o c ess es. 
A S p o ns or or a n a p p oi nt e d C R O M o nit or will m ai nl y p erf or m 'r e m ot e' m o nit ori n g c alls at r e g ul ar 
i nt er v als. 
' O n sit e' visit s m a y be p erf or m e d , if r e q uir e d, at a n y ti me d uri n g t h e st u d y . F or h os pit als w h er e 
p ot e nti a l qu alit y ris ks are i d e ntifie d, o n-sit e visits c a n v erif y t h at t h e st u d y is b ei n g c arri e d o ut 
a c c or di n g t o t h e pr ot o c ol. 
M o nit ori n g 
o n-sit e visits will i n v ol v e c h e c ki n g of C R Fs a g ai nst ori gi n al p ati e nt r e c or ds a n d 
i d e ntifi c ati o n of a n y q u esti o ns or pr o b l e ms r el at e d t o st u d y c o n d u ct or d at a c oll e cti o n . 
I n v esti g at ors m ust th er ef or e e ns ur e t h at t h e M o nit or h as a c c ess t o r el e v a nt d o c u m e nts d uri n g 
m o nit ori n g visits, a n d  t h at t h e y a n d /or r el e v a nt sit e st aff m e m b ers ar e a v ail a bl e t o dis c uss a n y 
iss u es t h at m a y aris e. 
T h e st u d y M o nit or will s e n d m o nit ori n g r e p orts t o t h e S p o ns or . 
9. 1 0. 3 
H e alt h A ut h o riti es 
T h e pr ot o c ol will b e n otifi e d t o t h e N ati o n al H e alt h A ut h oriti es r e gist er i n a c c or d a n c e wit h t h e 
r e g ul ati o ns of ea c h c o u ntr y f or n o n-i nt er v e nti o n al st u di es. 
9. 1 0. 4 
Q u alit y Ass u r a n c e 
I n c o m pli a n c e wit h r e g ul at or y r e q uir e m e nts, t h e S p o ns or , a t hir d p art y o n b e h alf of t h e S p o ns or , 
r e g ul at or y a g e n ci es , or I E Cs m a y c o n d u ct q u alit y ass ur a n c e a u dits /i ns p e cti o ns at a n y ti m e d uri n g 
or f oll o wi n g a st u d y. T he I n v esti g at or m ust a gr e e t o a ll o w a u d it ors/i ns p e ct ors dir e ct a c c ess t o a ll 
st u d y-r el at e d d o c u m e nts , i n cl u di n g s o ur c e d o c u m e nts, a n d m ust a gr e e t o all o c at e his or h er ti m e 
a n d t h e ti m e of his or her st u d y st aff t o t h e a u dit ors/i ns p e ct ors i n or d er t o dis c uss fi n di n gs a n d 
iss u es. 
T he pr ot o c ol , eac h st e p of t h e d at a c a pt ur e pr o c e d ur e, a n d t h e h a n dli n g of t h e d at a , as w ell as t h e 
st u d y r e p ort, m a y be s u bj e ct t o i n d e p e n d e nt Cli ni c al Q u alit y Ass ur a n c e. A u d its m a y b e c o n d u ct e d 
at a n y ti m e d uri n g or aft er t h e st u d y t o e ns ur e t h e v ali dit y a n d i nt e grit y of t h e st u d y d at a. 
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9. 1 0. 5 
Cl a d ri bi n e 
A r c hi vi n g 
T h e ar c hi v e s h o ul d be m ai nt ai n e d f or t h e p eri o d s p e cifi e d b y l ocal r e g ul ati o ns, w h er e a p pli c a bl e. 
All ori gi n al s u bj e ct fil es ( m e di c al r e c or ds) m ust be st or e d at t h e sit e ( h os pit al, r es e ar c h i nstit ut e, 
or pr a cti c e) f or t h e l o n g est p ossi bl e ti m e p er mitt e d b y t h e a p pli c a bl e r e g ul ati o ns. I n t h e a bs e n c e of 
a p pli c a bl e r e g ul ati o ns, t he ar c hi v e s h o ul d be m ai nt ai n e d f or at l e ast 5 y e ars aft er t he fi nal st u d y 
r e p ort or t he first p u bli c ati o n of st u d y r es ults, w hi c h e v er c o m es later. I n a n y c as e, t he I n v esti g at or 
s h o ul d e ns ur e t h at n o d estr u cti o n of m e di c al r e c or ds is p erf or m e d wit h o ut t h e writt e n a p pr o v al of 
t h e S p o ns or. 
1 0 
1 0. 1 
P r ot e cti o n of P ati e nts 
S u bj e ct I nf o r m ati o n a n d I nf o r m e d C o ns e nt 
A n u n c o n diti o n al pr er e q uisit e f or a s u bj e ct's p arti ci p ati o n i n t h e st u d y is his/ h er writt e n i nf or m e d 
c o ns e nt. T h e s u bj e ct's writt e n i nf or m e d c o ns e nt t o p arti ci p at e i n t h e st u d y m ust be gi v e n b ef or e 
a n y st u d y-r el at e d a cti viti es are c arri e d o ut. 
A d e q u at e i nf or m ati o n m ust t h er ef or e be gi v e n t o t h e s u bj e ct b y t h e I n v esti g at or b ef or e i nf or m e d 
c o ns e nt is o bt ai n e d (a p ers o n d esi g n at e d b y t h e I n v esti g at or m a y gi v e t h e i nf or m ati o n, if p er mitt e d 
b y l ocal r e g ul ati o ns). A s u bj e ct i nf or m ati o n s h e et i n t h e l ocal l a n g u a g e will be pr o vi d e d b y t he 
S p o ns or f or t h e p ur p os e of o bt ai ni n g i nf or m e d c o ns e nt. I n a d diti o n t o pr o vi di n g t his writt e n 
i nf or m ati o n t o a p ot e nti al s u bj e ct, t h e I n v esti g at or or his/ h er d esi g n e e wil l i nf or m t he s u bj e ct 
v er b all y of all p erti n e nt as p e cts of t h e st u d y (t he l a n g u a g e use d i n d oi n g s o m ust be c h os e n s o t h at 
t h e i nf or m ati o n c a n be f ull y a n d r e a dil y u n d erst o o d b y l a y p ers o ns). D e p e n di n g o n n ati o n al 
r e g ul ati o ns, a p ers o n ot h er t h a n t h e I n v esti g at or m a y i nf or m t he s u bj e ct a n d si g n t h e I nf or m e d 
C o ns e nt F or m. 
T h e I nf or m e d C o ns e nt F or m m ust 
be si g n e d a n d p ers o n all y d at e d b y t h e s u bj e ct a n d t he 
I n v esti g at or. T h e si g n e d a n d d at e d d e cl ar ati o n of i nf or m e d c o ns e nt will r e m ai n at t h e I n v esti g at or's 
sit e, a n d m ust be s af el y ar c hi v e d b y t he I n v esti g at or. A c o p y of t h e si g n e d a n d d ate d i nf or m ati o n 
a n d c o ns e nt f or m s h o ul d be pr o vi d e d t o t h e s u bj e ct pri or t o p arti ci p ati o n. 
W h e n e v er 
i m p ort a nt n e w i nf or m ati o n b e c o m es a v ail a bl e t h at m a y be r el e v a nt t o t h e s u bj e ct's 
c o ns e nt, t he writt e n s u bj e ct i nf or m ati o n s h e et a n d a n y ot h er writt e n i nf or m ati o n pr o vi d e d t o 
p ati e nts will be r e vis e d b y t he S p o ns or a n d b e s u b mitt e d a g ai n t o t h e I E C/I R B f or r e vi e w a n d 
f a v or a bl e o pi ni o n. T h e a gr e e d, r e vis e d i nf or m ati o n will be f or w ar d e d t o e a c h s u bj e ct i n t he st u d y. 
T h e I n v esti g at or will e x pl ai n t h e c h a n g es t o t h e pr e vi o us v ersi o n. 
1 0. 2 
S u bj e ct I d e ntifi c ati o n a n d Pri v ac y 
A u ni q u e p ati e nt n u m b er will be assi g n e d t o e a c h s u bj e ct at i n cl usi o n. T his n u m b er will s er v e as 
t h e s u bj e ct's i d e ntifi er i n t he st u d y as well i n t h e st u d y d at a b as e. 
T h e I n v esti g at or m ust e ns ur e t h at t h e p ati e nts' a n o n y mit y is m ai nt ai n e d. O n t h e C R Fs or ot h er 
d o c u m e nts s u b mitt e d t o t h e S p o ns or, p ati e nts s h o ul d n ot be i d e ntifi e d b y t h eir n a m es, b ut b y t h eir 
C O N FI D E N TI A L 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a dri bi ne 
assi g n e d i d e ntifi c ati o n n u m b ers. If s u bj e ct n a m es ar e i n cl u d e d o n c o pi es of d o c u m e nts s u b mitt e d 
t o the S p o ns or, t h e n a m es ( e x c e pt f or i niti als) m us t b e o blit er at e d a n u t h e assi g n e d s u bj e ct n u m b ers 
a d d e d t o t h e d o c u m e nts . 
T h e I n v estig a t or s ho u l d k e e p a s e p ar at e l o g of p ati e nts' i d e ntifi c ati o n n u m b ers, n a m es, a d dr ess es , 
tel e p h o n e n u m b ers a n d h os pit al n u m b ers (if a p pli c a bl e). D o c u m e nts n ot f or s u b missi o n t o t he 
S p o ns or, s u c h as si g n e d I n f orm e d C o ns e nt F or ms , s h o ul d b e m ai nt ai n e d i n stri ct c o n fi d e n c e b y 
the I n v esti g at or. 
O nl y a ut h ori z e d p ers o ns will h a v e a c c ess t o i d e ntifi a bl e p ers o n al d et ails, if r e q uir e d  f or d at a 
v erifi c ati o n . T h e s u bj e ct ' s ori gi n a l m e di c al d at a th at ar e r e vi e w e d at t h e sit e d uri n g s o ur c e d at a 
v erifi c ati o n b y t h e M o nit or, 
a u dits , a n d H e alt h 
A ut h orit y 
i ns p e cti o ns wi ll be k e pt stri ctl y 
c o nfi d e nti al. T h e I n v esti g at or a gr e es t o pr o vi d e dir e ct a c c ess t o t h es e d o c u m e nts t o t h e S p o ns or 
a n d t o H e alt h A ut h orit y r e pr es e nt ati v es. T h e I n v esti g at or is r es p o nsi bl e f or r etri e vi n g i nf or m ati o n 
fr o m p ers o n a l m e d ical r e c or ds. 
Da ta pr ot e cti o n a n d pri v a c y r e g ul ati o ns will be o bs e r v e d i n c a pt uri n g, f or w ar di n g, pr o c essi n g, a n d 
st ori n g s u bj e ct d at a. P ati e nts will be i nf or m e d a c c or di n gl y, a n d will b e req u est e d t o gi v e t h eir 
c o ns e nt o n d at a h a n dli n g pr o c e d ur es i n a c c or d a n c e wit h n ati o n al r e g ul ati o ns. 
1 1 
1 1. 1 
M a n a g e m e nt a n d R e p o rti n g of A d v e rs e E v e nts 
A d v e rs e E ve nts 
A d v e rs e E v e nt ( A E) 
A n A E is a n y u nt o w ar d m e di c al o c c urr e n c e i n a p ati e nt or cli ni c al st u d y s u bj e ct a d mi nist er e d a 
p h ar m a c e uti c al pr o d u ct a n d \ V hic h d o es n ot n e c ess aril y h a v e a c a us al r el ati o ns h i p wit h t his 
tr e at m e nt. A n A E c a n t h er ef or e b e a n y u nf a v or a bl e a n d u ni nt e n d e d si g n (i n cl u di n g a n a b n or m al 
l a b or at or y fi nd i n g), s y m pt o m, or dis e as e t e m p or all y ass o ci at e d wit h t h e use of a m e d i ci n al 
pr o d u ct, w h et h er or n ot c o nsi d er e d r el at e d t o t h e m e di ci n al pr o d u ct. 
A d v e rse D r u g Re acti o n ( A D R) 
A n A D R is a r es p o ns e t o a m e di ci n al pr o d u ct w hi c h is n o xi o us a n d u ni nt e n d e d. 
R es p o ns e i n this c o nt e xt m e a ns t h at a c a us al r el ati o ns hi p b et w e e n a m e di ci n al pr o d u ct a n d a n A E 
is at l e ast a r e as o n a bl e p ossi bilit y. 
A D Rs m a y aris e fr o m use of t h e pr o d u ct wit hi n or o utsi d e t h e t er ms of t h e m ar k eti n g a u th ori z ati o n 
or fr o m o c c u p ati o n al e x p os ur e . C o n diti o ns of us e o utsi d e t h e m ar k eti n g a ut h ori z ati o n i n cl u d e off-
la bel use, o v er d os e , mis us e, a b u s e a n d m e di c ati o n err ors. 
Re p orts of S p e ci al Si t u ati o ns: P r e g n a n c y, o v e r d os e, off-l a b el us e, mis us e, m e di c ati o n e r r o r 
o r o c c u p ati o n a l e x p os u r e, l a c k of t h e r a p e uti c eff e cti v e n ess a n d ot h e rs 
C O N FI D E N TI A L 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a dri bi ne 
• 
Us e of a m e di ci n al pr o d u ct d uri n g pr e g n a n c y or br e astf e e di n g: r e p orts w h er e e m br y o , f et us or 
c hil d m a y h a v e b e e n e x p os e d t o m e di ci n al pr o d u cts ( eit h er t hr o u g h m at er n al e x p os ur e or 
tr a ns missi o n of a m e di ci n al pr o d u ct vi a s e m e n f oll o wi n g p at er n al e x p os ur e) 
• 
R e p orts of o v er d os e , a b us e, off-l a b el use, mis us e , m e di c ati o n err or or o c c u p ati o n al e x p os ur e 
• 
L a c k of t h er a p e uti c eff e cti v e n ess 
• 
Pr es cri pti o n err or/ dis p e nsi n g err or , e.g. d u e t o c o nf usi o n of i n v e nt e d n a m es of t h e m e di ci n al 
pr o d u cts 
• 
Dr u g i nt er a cti o n 
• 
S us p e ct e d tr a ns missi o n of a n i nf e cti o us a g e nt vi a a m e di ci n al pr o d u ct 
• 
Pr o d u ct c o m pl ai nts, i n cl u di n g f alsifi e d pr o d u ct or c o u nt erf eit 
R e p orts of s p e ci al sit u ati o n wit h n o ass o ci at e d a d v ers e r e a cti o n will n ot be s u b mitt e d t o t he 
a ut h orit ies as l C S Rs. T h e y will be c oll e ct e d a n d c o nsi d er e d i n t h e st u d y r e p ort or a n y i nt eri m 
r e p orts, as a p pli c a bl e. 
S e ri o us A d v e rs e E v e nt ( S A E)/ S e ri o us A d v e rs e D r u g Re acti o n ( S A D R) 
A n S A E/ S A D R is a n y A E/ A D R as d efi n e d a b o v e, w hi c h als o f ulfills at l e ast o n e of t he s eri o us n ess 
crit eri a b el o w: 
• 
R es ults i n d e at h 
• 
Is lif e-t hr e at e ni n g1 l 
• 
R e q uir es i n- p ati e nt h os pit ali z ati o n or pr ol o n g ati o n of e xisti n g h os pit ali z ati o n 
• 
R es ults i n p ersist e nt or si g nifi c a nt dis a bilit y /i n c a p a cit y 
• 
Is a c o n g e nit al a n o m al y /birt h d ef e ct 
• 
Is ot h er wis e c o nsi d er e d as m e di c all y i m p ort a nt2 l 
1 l Lif e-t hr e at e ni n g i n t hi s c o nt e xt r ef er s t o a r e a cti o n i n w hi c h t h e p ati e nt w a s at ri s k of d e at h at t h e ti m e of t h e 
r e a cti o n; it d o e s n ot r ef er t o a r e a cti o n t h at h y p ot h eti c all y mi g ht h a v e c a u s e d d e at h if m or e s e v er e . 
2 l M e di c al a n d s ci e ntifi c j u d g e m e nt s h o ul d b e e x er ci s e d i n d e ci di n g w h et h er ot h er sit u ati o n s s h o ul d b e c o n si d er e d a s 
s eri o u s r e a cti o n s, s u c h a s i m p ort a nt m e di c al e v e nt s t h at mi g ht n ot b e i m m e di at el y lif e t hr e at e ni n g or r e s ult i n d e at h 
or h o s pit ali z ati o n b ut mi g ht j e o p ar di s e t h e p ati e nt or mi g ht r e q uir e a n i nt er v e nti o n t o pr e v e nt o n e of t h e ot h er 
o ut c o m e s li st e d a b o v e . S u c h i m p ort a nt m e di c al e v e nt s s h o ul d b e c o n si d er e d a s s eri o u s. 
E x a m pl es of s u c h e v e nts ar e i nt e nsi v e tr e at m e nt i n a n e m er g e n c y r o o m or at h o m e f or all er gi c 
br o n c h os p as m, bl o o d d ys cr asi as or c o n v ulsi o ns t h at d o n ot r es ult i n h os pit ali z ati o n or d e v el o p m e nt 
of d e p e n d e n c y or a b us e. As a g ui d a n c e , t h e i m p ort a nt m e di c al e v e nt (I M E) t er ms list is i nte n de d 
t o be use d f or ass ess m e nt of s us p e ct e d a d v ers e r e a cti o ns (s e e E M A/ 2 0 7 8 6 5 /2 0 1 7) . 
A n y s us p e ct e d tr a ns missi o n vi a a m e di ci n al pr o d u ct of a n i nf e cti o us a g e nt is als o c o nsi d er e d a 
s eri o us a d v ers e r e a cti o n. 
A d v e rse E v e nts of S p e ci al I nterest ( A E SI) 
A n A E S! is a n A E of s ci e ntifi c a n d m e di c al c o n c er n s p e cifi c t o t h e s p o ns or's pr o d u ct or pr o gr a m , 
f or w hi c h o n g oi n g m o nit ori n g a n d r a pi d c o m m u ni c ati o n b y t h e I n v esti g at or t o t h e s p o ns or c a n be 
C O N FI D E N TI A L 
I N F O R M A TI O N 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a dri bi ne 
a p pr o pri at e. A E S !s f or m o nit ori n g s h o ul d t h e n be c oll e ct e d f oll o wi n g t h e pr o c e d ur e f or a n S A E 
d es cri b e d i n S e cti o n 1 1. 4. 
T h e st u d y-s p e cifi c data will b e r e gist er e d f or e a c h of t h e f oll o wi n g e v e nts a n d t h e k n o w n r el at e d 
risk f a ct ors: 
F or c o m pl et e a n d a c c ur at e i nf or m ati o n, t h e d at a c oll e ct e d o n t h es e pr e- d efi n e d e v e nts wi ll i n cl u d e 
as m u c h d et ail as p o ssi bl e t o c orr o b or at e di a g n osis , i n cl u di n g b ut n ot li mit e d t o hist o p at h ol o gi c 
r es ults, a n d r e l e v a nt l a b or at or y a n d i m a gi n g r es ults. 
M ali g n a n c y: 
A n y o c c urr e n c e of m ali g n a nt n e o pl as ms d uri n g t h e st u d y p eri o d . T h es e will be 
cl assifi e d o v er a ll a n d 
b y 
t y p e. M ali g n a n ci es 
will 
i ncl u d e all 
p h ysi ci a n- di a g n os e d 
a n d 
p at h o l ogi c a ll y 
c o nfir m e d 
s oli d 
t u m o urs 
(i n cl u di n g 
n o n- m el a n o m a 
s ki n 
c a n c er) 
a n d 
l y m p h o pr olif er ati v e/ h a e m at o p oi eti c n e o p lasti c dis e as es . B e ni g n t u m o urs will n ot b e c oll e ct e d. 
S e v e r e a n d/ o r s e ri o us i nf e cti o ns: T h e a b o v e m e nt i o n e d  4 c at e g ori es will f oll o w as : A n y 
o c c urr e n c e d uri n g t h e st u d y p eri o d, r e g ar dl ess of t h e c a us ati v e a g e nt a n d t h e d ur ati o n of i nf e cti o n, 
will be r e c or d e d . All of t h e f oll o wi n g will b e c o nsi d er e d: 
• 
B a ct eri al , vir al, f u n g al, p ar asiti c a n d pr ot o z o a( i nf e cti o ns 
• 
S e v er e a n d /or s eri o us i nf e cti o ns w i ll be d efi n e d b y t h eir m a n a g e m e nt or t h eir o ut c o m e: all 
i nf e cti o ns t h at r es ult i n d e at h or h os pit alis ati o n or r e q uir e t h e us e of i ntr a v e n o us tr e at m e nt 
( e. g. a nti bi oti cs) 
• 
O p p ort u nisti c i nf e cti o ns ar e d efi n e d as a n i n v asi v e i nf e cti o n c a us e d b y mi cr o or g a nis ms t h at 
ar e n or m all y n o n- p at h o g e ni c or r ar el y p at h o g e ni c i n i n di vi d u als wit h n or m al i m m u n e 
f u n cti o n or c a us e a n i nf e cti o n of a t y p e or s e v erit y n ot s e e n i n t h e n or m al h ost; o p p ort u ni stic 
i nf e cti o ns e x cl u d e h er p eti c i nf e cti o n 
• 
H er p es z ost er ( n ot c o nsi d er e d a n o p p ort u nisti c i nf e cti o n). O nl y s e v er e a n d /or s eri o us h er p es 
z ost er wi ll be c o ll e ct e d. 
T he d ur ati o n of i nf e cti o ns will be the diff er e n c e b et w e e n st art d at e a n d r e c o v er y d at e as r e p ort e d 
b y t h e tr e ati n g p h ysi ci a n . 
P ati e nts m a y c o nt rib u t e m or e t h a n I e pis o d e t o t his a n al ysis if, aft er r es ol uti o n as d efi n e d , a n ot h er 
i nfecti o n o c c urs . 
S e v e r e l ym p h o p e ni a: A n y o c c urr e n c e of s e v er e ( or w ors e) l y m p h o p e ni a d uri n g t h e st u d y p eri o d , 
cl assifi e d as Gr a d e ?: 3. As p er th e C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts ( C T C A E) 
( v 4.0 3 : J u n e 1 4, 2 0 1 0) fr o m t h e N ati o n al I nstit ut es of H e alt h , t h e gr a d es of l y m p h o p e ni a ar e 
d efi n e d b as e d o n l a b or at or y t est r es ults t h at i n di c at e a d e cr e as e i n n u m b er of ly m p h o c yt es i n a 
bl o o d s a m ple : 
• 
Gr a d e 3 (se v er e l y m p h o p e ni a): < 5 0 0 - 2 0 0 /m m 3; < 0. 5 - 0. 2 x I 0 9 / L 
• 
Gr a d e 4 (s eri o us I y m p h o p e ni a): < 2 0 0/ m m 3 ; < 0. 2 x  I 0 9 / L 
D u r ati o n of s e v e re Iy m p h o pe ni a: It is d efi n e d as t h e i nt er v al fr o m t h e fi n di n g of s e v er e 
ly m p h o p e ni a u ntil r es ol uti o n, w hi c h is t h e a c hi e v e m e nt of a C T C A E Gr a d e  I [r a n gi n g fr o m t h e 
C O N FI D E N TI A L 
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L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a dri bi ne 
l o w er li mit of n or m al ( L L N) t o 8 0 0 /m m 3] or n or m ali z ati o n ( a b o v e L L N i.e. n or m al l y m p h o c yt e 
c o u nt or C T C A E Gr a d e 0). P ati e nts m a y c o ntri b ut e m or e t h a n 1 e pis o d e t o t his a n al ysis if, aft er 
r es ol uti o n as d efi n e d, s e v er e l y m p h o p e ni a o c c urs a g ai n. T h e fr e q u e n c y of l y m p h o c yt e c o u nts i n 
p ati e nts wit h s e v er e l y m p h o p e ni a will be d es cri b e d wit h s p e ci al e m p h asis o n t h e n u m b er a n d 
ti mi n g of l y m p h o c yt e c o u nts i n r el ati o n t o Cl a dri bi n e t a bl ets d osi n g a n d d uri n g e pis o d es of s e v er e 
l y m p h o p e ni a. 
E v e nts n ot t o be c o nsi d e r e d as A d v e rs e E v e nts 
M e di c al c o n diti o ns pr es e nt at st u d y st art, t h at d o n ot w ors e n i n s e v erit y or fr e q u e n c y d uri n g t he 
st u d y ar e d efi n e d as B as eli n e M e di c al C o n diti o ns a n d are N O T t o be c o nsi d er e d A Es. 
1 1. 2 
S e v e rit y of A d v e rs e E v e nts 
I n v esti g at ors s h o ul d ass ess t h e s e v erit y/i nt e nsit y of a n y A E as f oll o ws: 
Mil d: 
M o d e r at e: 
Se vere: 
1 1. 3 
T h e s u bj e ct is a w ar e of t h e e v e nt or s y m pt o m, b ut t h e e v e nt or s y m pt o m is e asil y 
t ol er at e d. 
T h e s u bj e ct e x p eri e n c es s uffi ci e nt dis c o mf ort t o i nt erf er e wit h or r e d u c e his or 
h er us u al l e v el of a cti vit y . 
Si g nifi c a nt i m p air m e nt of f u n cti o ni n g: t h e s u bj e ct is u n a bl e t o c arr y o ut us ual 
a cti viti es. 
C a us alit y Ass ess m e nt 
I n v esti g at ors m ust ass ess t h e c a us al r el ati o ns hi p b et w e e n A Es a n d st u d y dr u g (i n cl u di n g a n y ot h er 
n o n- m e di ci n al pr o d u ct , r a di ati o n t h er a p y, et c.) c o nsi d eri n g t e m p or al r el ati o ns hi p b et w e e n t h e A E 
o ns et a n d st u d y dr u g a d mi nistr ati o n, s af et y pr ofil e of st u d y dr u g ( k n o w n A Rs) , t h e p ati e nt's 
c o n diti o n ( m e di c al hist or y , u n d erl yi n g dis e as e) , c o n c o mit a nt m e d i c ati o n, a n d st u d y pr o c e d ur es. 
R el at e d: 
S us p e ct e d t o b e r e as o n a bl y r el at e d t o a n y st u d y m e di c ati o n. 
N ot rel ate d: N ot s us p e ct e d t o be r e as o n a bl y r el at e d t o a n y st u d y m e di c ati o n .  A r e as o n a bl e 
alt er n ati v e e x pl a n ati o n m ust be pr o vi d e d . 
1 1. 4 
R e c o r di n g of A d v e rs e E v e nts 
T h e r e c or di n g p eri o d f or A Es b e gi ns , w h e n t h e s u bj e ct is i niti all y i n cl u d e d i n t he st u d y ( d at e of 
si g n at ur e of first i nf or m e d c o ns e nt) a n d c o nti n u es at l e ast e n d of t h e m a n d at or y s af et y-f oll o w- u p 
p eri o d at l ast st u d y visit. 
H o w e v er, as e nr oll m e nt m a y t a k e pl a c e fr o m t h e ti m e of cl a dri bi n e 
pr es cri pti o n u p u ntil t h e s e c o n d tr e at m e nt w e e k , i n t h e first tr e at m e nt y e ar, a n y A D Rs ass ess e d as 
r el at e d t o cl a dri bi n e b y t h e I n v esti g at or aft er t h e first d os e of cl a dri bi n e b ut b ef or e si g n at ur e of 
I nf or m e d C o ns e nt m ust be r e c or d e d i n t h e e C R F as w ell. 
All a d v ers e e v e nts, as s p e cifi e d a b o v e, o c c urri n g d uri n g t h e st u d y, m ust be d o c u m e nt e d b y t h e 
I n v esti g at or i n t h e e C R F, i n cl u di n g its d es cri pti o n, s eri o us n ess, s e v erit y ( gr a di n g), d ur ati o n ( o ns et 
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a n d r es ol uti o n d at es), ca usal r el ati o ns hi p, a n y ot h er p ot e nti a l c a us al f a ct ors, a cti o ns t a k e n wit h t h e 
st u d y dr u g (e. g. d os e r e d u cti o n, wit h dr a w al), r e quir e d tr e at m e nt a n d o ut c o m e of t h e A E. 
N ot e - Eve nt ter m ' De at h', ' Dis a bility' a n d ' H os pit aliz ati o n ' 
D e at h, dis a bilit y , a n d h os pit ali z ati o n ar e c o nsi d er e d o ut c o m es i n t h e c o nt e xt of s af et y r e p orti n g 
a n d n ot us u all y c o nsi d er e d A Rs/ A Es. T h er ef or e t h e pri m ar y c a us e of d e at h, dis a b ilit y or 
h os pit ali z ati o n s h o u l d be r e c or d e d a n d r e p ort e d as a n S A E /A R, a n d t h e o ut c o m e s h o ul d be 
r e c or d e d i n a s e p ar at e data fi el d. H o w e v er , a t er m f or t h e o ut c o m e wi ll be s el e cte d if it is t h e o nl y 
i nf or m ati o n re p ot 1e d or pr o vi d es si g nifi c a nt cli ni c al i nf or m ati o n. 
If d e at h o c c urs , t h e pri m ar y c a us e of d e at h or e v e nt le a di n g t o d e at h s h o ul d be r e c or de d a n d 
rep ort e d as a n S A E. '"F at al" will be r e c ord e d as t h e O U T C O M E of t his resp e cti v e e v e nt a n d n ot 
be as s e p ar at e e v e nt. O nl y , if n o c a us e of d e at h c a n be r e p ort e d (f or e x a m pl e , s u d de n d e at h , 
u n e x pl ai n e d d e at h), t he d e at h p er s e mi g ht t h e n b e r e p ort e d as a n S A E. 
Re p orts of S p e ci al Sit u ati o ns (s e e d efi niti o n) are a ls o t o be r e c or d e d i n t h e C R F f oll o wi n g t h e A E 
pr o c e d ur e, e v e n if o c c urri n g wit h o ut A E . 
P r e g n a n c y a n d B r e astf e e di n g. Pr e g n a n c y or br e astf e e di n g m ust be r e c or d e d i n t h e C R F a n d 
a d diti o n a ll y be r e p ort e d t o t h e S p o ns or i m m e di at el y ( wit hi n 2 4 h o urs of a w ar e n ess) b y usi n g 
s e p ar at e p a p er d at a c oll e cti o n f or ms f or pr e g n a n c y, i n d e p e n d e nt if a n A E w as r e p ort e d or n ot. T h e 
o ut c o m e of t h e pr e g n a n c y s h o ul d be f oll o w e d u p a n d re p o 1t e d t o t h e S p o ns or u ntil d eli v er y . 
W o m e n w h o b e c o m e pr e g n a nt u n d er t h er a p y wit h Cl a dri bi n e t a bl ets s h o u l d dis c o nti n u e tr e at m e nt. 
1 1. 5 
S afet y D at a C oll e cti o n f or Re p orti n g 
S afet y d at a c ollecti o n f or ms: 
T h e f oll o wi n g s af et y data c oll e cti o n f or ms ar e us e d i n t his st u d y: 
• 
( S eri o us) A d v ers e E v e nt Re p ort F or m 
• 
Pr e g n a n c y R e p ort F or m ( p a p er f or m) 
• 
P ar e nt- C hil d /F o et us A E R e p ort F or m ( p a p er f or m) 
• 
A d v ers e E v e nt of S pecial I nt er est ( A E SI) R e p ort F or m 
R e p o rt a bl e e v e n ts: 
T h e f oll o wi n g e v e nts are r e p ort a bl e t o t h e S af et y C h e c k D es k at C R O wit hi n 2 4 h o urs of 
a w ar e n ess: 
• 
All S A Es (relate d or u nr el at e d) ar e t o be r e p ort e d i n d e p e n d e nt of t h eir r el ati o ns hi p t o t h e st u d y 
dr u g via t h e e C R F or usi n g b a c k- u p p a p er f or ms i n c as e of e C R F o ut a g e 
• 
A Es of s p e ci al i nterest ( A E SI) ar e t o be r e p ort e d vi a t he e C R F or usi n g b a c k- u p p a p er f or ms i n 
c as e of e C R F o ut a g e 
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• 
Pr e g n a n c y or l a ct ati o n is t o be r e p ort e d b y usi n g t h e p a p er Pr e g n a n c y R e p ort F or m. 
• 
All e v e nts t h at o c c ur i n a C hil d/ F o et us of a pr e g n a nt w o m a n w h o w as e x p os e d t o t h e st u d y 
dr u g are t o be r e p ort e d b y usi n g t h e p a p er P ar e nt- C hil d/ F o et us R e p ort F or m 
S p e ci al sit u ati o ns (s e e d efi niti o n) s h o ul d be r e p ort e d b y usi n g t h e p a p er ( S eri o us) A d v ers e E v e nt 
R e p ort F or m b y i n di c ati n g w h et h er s eri o us or n ot 
N o n-s eri o us A D Rs ar e t o be r e p ort e d wit hi n 4 cal e n d ar d a ys vi a t h e e C R F or usi n g t h e p a p er 
( S eri o us) A d v ers e E v e nt R e p ort F or m i n c as e of e C R F o ut a g e. 
P r o c e d u r e f or S af et y D at a R e p o rti n g ( c o m pl eti o n a n d f o r w a r di n g): 
F or a n y n e w e v e nts t h at ar e list e d i n t h e s e cti o n a b o v e " R e p ort a bl e e v e nts", t he I n v esti g at or/ H C P 
will 
r e p ort t he e v e nt b y tr a ns mitti n g t h e S af et y D at a C oll e cti o n F or m i n E n glis h via t h e e C R F or 
via p a p er ( as d es cri b e d i n t he s e cti o n a b o v e) t o t h e S p o ns or vi a C R O S af et y C h e c k D es k . T h e 
I n v esti g at or m ust r es p o n d t o a n y re qu est b y C R O f or f oll o w- u p i nf or m ati o n, as n ot e d a b o v e f or 
i nitial r e p ort. C R O s h o ul d f or w ar d t h e f oll o w- u p i nf or m ati o n wit hi n 2 4 h o urs t o Gl o b al P ati e nt 
S af et y, as n ot e d a b o v e f or i niti al r e p orts . T h e s p o ns or h as t o m e et stri ct r e g ul at or y ti m eli n es 
ass o ci at e d wit h e x p e dit e d s af et y r e p orti n g o bli g ati o ns. 
 
 
 
 
 
 
 
 
T h e d at a e nt er e d o n t h e s af et y d at a c oll e cti o n f or ms m ust be c o nsist e nt wit h t h e i nf or m ati o n 
r e c or d e d i n t h e e C R F. If s o m e d at a ar e missi n g, t h e f or m s h o ul d be c o m pl et e d wit h t h e a v ail a bl e 
d at a a n d a f oll o w- u p r e p ort will be s e nt as s o o n as p ossi bl e. T h e mi ni m u m i nf or m ati o n t o be 
i ncl u de d i n t he i nitial r e p ort is t h e f oll o wi n g: 
• 
I n v esti g at or n a m e a n d c o nt a ct d et ails 
• 
S u bj e ct i d e ntifi c ati o n ( e. g., I D n u m b er, g e n d er, a g e) 
• 
Pr o d u ct (i n cl u di n g l ot/ b at c h n u m b er) 
• 
D es cri pti o n of S A E/ A D R/ fatal c as e/ S p e ci al sit u ati o n 
T h e r e p ort s h o ul d c o nt ai n c a us alit y a n d s eri o us n ess i nf or m ati o n (f or A Es) a n d m ust be si g n e d off 
b y t h e I n v esti g at or. 
W h e n 
A E 
i nf or m ati o n is c o m m u ni c at e d vi a t el e p h o n e, a writt e n/ E D C 
r e p ort m ust 
be s e nt 
i m m e di at el y wit hi n 2 4 h o urs t h er e aft er b y fa x or e- m ail. I n s u c h c as es t h e " cl o c k st art" f or c as e 
r e p orti n g t o Healt h A ut h oriti es is t he date a n d ti m e of t h e t el e p h o n e c o m m u ni c ati o n. 
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L 0 4 A A 4 0 
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E x p os u r e d u ri n g P r e g n a n c y 
All pr e g n a n ci es wit h a n esti m at e d c o n c e pti o n d at e i n t h e p eri o d fr o m t h e d at e of i nf or m e d c o ns e nt 
si g n at ur e ( wh ere a p p licabl e) u ntil t h e l ast p ost-tr e at m e nt s af et y visit , or as d efi n e d i n t h e p r ot o c ol, 
m ust be r e c or d e d b y c o n v e nti o n i n t h e A E p a g e /s e cti o n of  t he C R F. T he s a m e r ule a p p lies t o 
pr e g n a n ci es i n fe male p ati e nts a n d t o pr e g n a n ci es i n f e m al e p art n ers of m al e p ati e nts. T h e 
I n v esti g at or m ust n otif y the S p o ns or i n a n e x p e dit e d m a n n er of a n y pr e g n a n c y usi n g t h e Pr e g n a n c y 
R e p ort F or m , w hi c h m ust be tr a ns mitt e d a c c or di n g t o th e s a m e pr o c ess as d es cr ibe d f or S A E 
r e p orti n g. T h e S p o ns or m ust be n otifi e d a b o ut a n y pr e g n a n c y i n d e p e n d e nt w h et h er t he pr e g n a n c y 
is ass o ci at e d w ith a n A E or n ot. 
I n v esti g at ors m ust a cti v el y f oll o w u p, d o c u m e nt , a n d r e p ort t o t h e S p o ns or o n t h e o ut c o m e of all 
t h es e pr e g n a n ci es a n d de li v eri es e v e n if the s u bj e ct is wit h dr a w n fr o m t h e st u d y. If a n a b n or m al 
o ut c o m e o c c urs, t he r es p e cti v e s af et y d at a c oll e cti o n f or m ( Pr e g n a n c y R e p ort F or m, P ar e nt-
C hil d/ F o et us A E R e p ort F or m) is t o be c o m pl et e d a n d s e nt t o t he S p o ns or. 
P r o c e d u r e f or F oll o w- u p I nf o r m ati o n 
T h e I n v esti g at or m ust pr o m ptl y r es p o n d t o a n y re q u est b y C R O f or f oll o w- u p i nf or m ati o n or 
q u esti o ns fr o m t h e S p o ns or or d el e g at e , as n ot e d a b o v e f or i niti al r e p ort. S u c h r e q u ests wil l be s e nt 
t o t he I n v esti g at or via t he C R O S af et y C h e c k D es k . S A Es/ A D Rs / A E Sis a n d s p e ci al sit u ati o ns 
o c c u rri n g d uri n g t he st u d y m ust 
be m o nit or e d 
a n d f oll o w e d u p b y t h e I n v esti g at or u ntil 
st a bili z ati o n or u ntil t he o ut c o m e is k n o w n, u nl ess t h e s u bj e ct has a fatal o ut c o m e or is l ost t o 
f oll o w- u p. 
T he I n v esti g at or wi ll e ns ur e a n y n e c ess ar y a d diti o n al t h er a p e uti c m e as ur es 
a n d f oll o w- u p 
pr o c e d ur es ar e r e c or d e d a n d r e p ort e d vi a a f oll o w- u p r e p ort f or m. F or all s eri o us c as es /A D Rs/f at al 
c as es a n d s p e ci al sit u ati o ns a n d A E Sis missi n g i nf or m ati o n s u c h as o ut c o m e, c o nf o u n d ers, a n d 
c a us alit y is t o be pr o v i ded. A d diti o n all y, f oll o w- u p i nf or m ati o n of n o n-s eri o us a d v ers e dr u g 
r e a cti o ns m a y be re q uire d b y t h e S p o ns or f or m e di c al ass ess m e nt. R e as o n a bl e att e m pts t o o bt ai n 
f oll o w- u p i nf or m ati o n m ust b e m a d e a n d d o c u m e nt e d . 
R e p orti n g of a n y ne w i nf or m ati o n o n a pr e vi o usl y r e p ort e d e v e nt (f oll o w- u p) will f oll o w t h e 
pr o c e d ur es a n d ti m e li nes of t h e ori gi n al r e p ort. 
C R O s h o ul d f or w ar d t he f oll o w- u p i nf or m ati o n wit hi n 2 4 h o urs t o Gl o b al P ati e nt S af et y , as n ot e d 
a b o v e f or i nitial re p orts. T h e s p o ns or h as t o m e et stri ct r e g ul at or y ti m eli n es ass o ci at e d wit h 
e x p e dit e d s af et y r e p orti n g o bli g ati o ns. 
1 1. 6 
R e g ul at o r y R e p o rti n g t o t he H e alt h A ut h o riti es 
E x p e dit e d r e p orti n g of s eri o us A Es a n d n o n-s eri o us a d v ers e dr u g r e a cti o ns t o H e alt h A ut h oriti es 
is p erf or m e d b y t he S p o ns or b y the Gl o b al Dr u g S af et y d e p art m e nt, a c c or di n g t o a p p li c a bl e 
r e g ul ati o ns of p arti ci p ati n g c o u ntri es. 
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I n a d diti o n, t h e I n v esti g at or will 
c o m pl y wit h 
a n y a p pli c a bl e l o c al p h ar m a c o vi gil a n c e 
r e q uir e m e nts t o r e p ort a p pr o pri at e s af et y d at a, t o n ati o n al p h ar m a c o vi gil a n c e s yst e ms (e. g. Y ell o w 
C ar d S c h e m e i n U K), as r e q uir e d b y c o u ntr y s p e cifi c r e p orti n g r e q uir e m e nts. 
1 2 
1 2. 1 
Pl a ns f or Diss e mi n ati n g a n d C o m m u ni c ati n g St u d y Res ults 
St u d y R e p o rt 
T h e c o m pl et e d st u d y will be s u m m ari z e d i n a fi n al r e p ort t h at a c c ur at el y a n d c o m pl et el y pr es e nts 
t h e st u d y o bj e cti v es, m et h o ds, r es ults, li mit ati o ns of t h e st u d y, a n d i nt er pr et ati o n of t h e fi n di n gs. 
1 2. 2 
P u bli c ati o n 
T h e first p u bli c ati o n will be a p u bli c ati o n of t h e r es ults of t h e a n al ysis of t h e pri m ar y o ut c o m e(s) 
t h at will i n cl u d e d at a fr o m all st u d y sit es. 
T h e I n v esti g at or will i nf or m t h e S p o ns or i n a d v a n c e a b o ut a n y pl a ns t o p u blis h or pr es e nt d at a 
fr o m t he st u d y. A n y 
p u bli c ati o ns a n d pr es e nt ati o ns of t h e r es ults ( a bstr a cts i n j o ur n als or 
n e ws p a p ers, or al pr es e nt ati o ns , et c.), eit h er i n w h ol e 
or i n p art, b y i n v esti g at ors or t h eir 
r e pr es e nt ati v es will r e q uir e pr e-s u b missi o n r e vi e w a n d a p pr o v al b y t h e S p o ns or. 
T h e S p o ns or will n ot s u p pr ess or v et o p u bli c ati o ns, b ut m ai nt ai ns t h e ri g ht t o d el a y p u bli c ati o n i n 
or d er t o pr ot e ct i nt ell e ct u al pr o p ert y ri g hts. 
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Cl a d ri bi n e 
R ef e r e n c es 
Bezzi ni D., Batta glia M A. 
M u lti ple Sc ler osis E pi de mi ol o g y i n E ur o pe. I n: Asea A., Geraci F., 
Ka ur P. (eds) M ul ti ple Scler osis: Be nc h t o Be dsi de. A d va nces i n E x peri m e nta l Me dici ne 
a n d 
Bi ol o g y, 2 0 1 7; v ol 9 5 8. S pri n ger, C ha m. 
Br o w n J W L, C oles A H o rak o va D et al. Ass ociati o n of I nitial Disease- M o dif yi n g T he rap y Wit h 
Later C o n versi o n t o Sec o n dar y Pr o gressi ve M ulti ple Scler osis . J A M A . 2 0 1 9 ;  I 5; 3 2 1 ( 2) : 1 7 5- 1 8 7. 
Cala bresi P A. Dia g n osis a n d ma na ge me nt of m ulti ple scler osis. A m Fa m P h ysicia n. 
2 0 0 4; 7 0( 1 0): 1 9 3 5-- 4 4 . 
Carrit hers M D . U p d ate o n disease- m o dif yi n g treat me nts f or m ulti ple scler osis. Cli n T her. 2 0 14 
Dec 1; 3 6( 1 2): 1 9 3 8- 1 9 4 5. 
C o o k S, Ver mersc h P, C o mi G, et al. Safet y a n d t olera bilit y of Cla d ri bi ne ta blets i n m ulti ple 
scler osis : the C L A RI T Y ( C L A d Ri bi n e ta blets treati n g m ulti ple scler osis orall Y) st u d y. M ult Se ier 
2 0 1 1; 1 7: 5 7 8- 5 9 3. 
Cree B A C. M ulti ple 
scler osis. I n: Br ust J C M , e dit or. C urre nt Dia g n osis a n d Tr e at m e nt m 
Ne ur ol o g y . Ne w Y or k: La n ge Me dical B o o ks /Mc Gra w- Hill Me dical ; 2 0 0 7 . 
F o x RJ , Miller D H , P hilli ps J T et al. Place b o-c o ntr olle d p hase 3 st u d y of oral B G- 1 2 or glatira mer 
i n m ulti ple scler osis. N E n gl J Me d. 2 0 12 2 0; 3 6 7( 1 2): I 0 8 7- 9 7. 
Gi o va n n o ni G, C o mi G, C o o k S, et al. A place b o-c o ntr olle d trial of oral Cla dri bi ne f or rela psi n g 
m ulti ple scler osis. N E n gl J Me d 2 0 I 0; 3 6 2: 4 1 6-- 4 2 6. 
Gi o va n n o ni G, S oei ber g S ore nse n P, C o o k S, et al. Safet y a n d effecti ve ness of Cla dri bi ne ta blets 
i n patie nt s wit h rela psi n g-re mitti n g m ulti ple scler osis: res ults fr o m t he ra n d o mize d e xte nsi o n trial 
of t he C L A RI T Y st u d y. M u It S ei er E p u b 2 0 1 7 A u g I. d oi: I O. I l 7 7/l 3 5 2 4 5 8 5 1 7 7 2 7 6 0 3. 
G ol d e n ber g M M. M ulti ple scler osis re vie w. P T . 2 0 1 2 ;3 7( 3) : 1 7 5- 8 4 . 
Ha dji ge or gi o u G M , D o xa ni 
C, M ili g k os M, 
et al. A net w or k meta-a nal ysis 
of ra n d o mize d 
c o nt r o lle d trials f or c o m pa ri n g the effecti ve ness a n d safet y pr ofile of treat me nts wit h mar keti n g 
a ut h orizati o n f or rela psi n g m ulti ple scler osis . J Cli n P har m T h er. 2 0 1 3; 3 8: 4 3 3-- 4 3 9. 
Ha user S L , G o o d wi n D S . M ulti ple 
scler osis a n d ot her de m yeli nati n g diseases. I n: Fa uci A S , 
Bra u n w al d E, Kas per D L, Ha user S L, e dit ors. H arris o n's Pri nci ples of I nter nal Me dici ne. 
1 7t h e d. 
II. Ne w Y or k: Mc Gra w- Hill Me dical ; 2 0 0 8 . p p. 2 6 1 1- 2 6 2 1 . 
Leist T P , C o mi G, Cree B A C, et al. Effect of o ra l Cla dri bi ne o n ti me t o c o n versi o n t o cli nicall y 
defi nite m ulti ple scler osis i n patie nts wit h a first de m yeli nati n g e ve nt ( O R A C L E M S) : a p hase 3 
ra n d o mise d trial. La ncet Ne ur ol 2 0 1 4; 1 3: 2 5 7- 2 6 7 . 
C O N FI D E N TI A L 
I N F O R M A TI O N 
4 4/ 5 1 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
L eist T P, W eiss ert 
R. Cl a dri bi n e: m o d e of a cti o n a n d i m pli c ati o ns f or tr e at m e nt of m ulti pl e 
s cl er osis. Cli n N e ur o p h ar m a c ol 2 0 1 1 ;3 4: 2 8- 3 5 . 
M o nt al b a n 
X, L eist T P , C o h e n B A , M os es 
H, C a m p b ell J, Hi c ki n g C, D a n g o n d F. Cl a dri bi n e 
t a bl ets a d d e d t o I F N- P i n a cti v e r el a psi n g M S: 
T h e O N W A R D st u d y. N e ur al N e ur oi m m u n ol 
N e ur oi nfl a m m . 2 0 1 8 J ul 11 ;5( 5): e 4 7 7 . d oi: 1 0. 1 2 1 2/ N Xl. 0 0 0 0 0 0 0 0 0 0 0 0 0 4 7 7 . e C oll e cti o n 2 0 1 8 
Se p. 
Ol e k MJ . E pi d e mi ol o g y, ris k f a ct ors a n d cli ni c al f e at ur es of m ulti pl e s cl er osis i n a d ults. A v ail a bl e 
at: w w w. u pt o d at e. c o m/ c o nt e nts/ e pi d e mi ol o g y- a n d- cli ni c al-f e at ur es- of- m ulti pl e-s cl er osis-i n-
a d ults . A c c ess e d O ct o b er 3 1, 2 0 1 1 . 
Tr a m a c er e I, D el Gi o v a n e C, Sal a nt i G, 
D' A mi c o R, 
Fili p pi ni G. 
l m m u n o m o d ul at ors a n d 
i m m u n os u p pr ess a nts f or r el a psi n g-r e mitti n g m ulti pl e s cl er osis: a n et w or k m et a a n al ysis. C o c hr a n e 
D at a b as e S yst R e v 2 0 1 5: C d 0l 1 3 8 1. 
Tsi v g o ulis G, K ats a n os A H , Gri g ori a dis N, et al. T h e eff e ct of dis e as e m o dif yi n g t h er a pi es o n 
dis e as e pr o gr essi o n i n p ati e nts wit h r el a psi n g-r e mitti n g m ulti pl e s cl er osis: a s yst e m ati c r e vi e w a n d 
m et a- a n al ysis. P L o S O n e 2 0 1 5: 1 0: e 0 1 4 4 5 3 8. 
V er m ers c h P, G al a z k a A, D a n g o n d F et al. Effi c a c y of cl a dri bi n e t a bl ets i n hi g h dis e as e a cti vit y 
p ati e nts wit h r el a psi n g m ulti pl e s cl er osis: P ost h o c a n al ysis of s u b gr o u ps wit h a n d wit h o ut pri or 
dis e as e- m o dif yi n g dr u g tr e at m e nt. C urr M e d R es O pi n. 2 0 2 1 F e b 1; 1- 1 0. 
W ei ns h e n k er B C. E pi d e mi ol o g y of m ulti pl e s cl er osis . N e ur al Cli n . 1 9 9 6; 1 4 2 : 1- 3 0 8. 
Wi n g er c h u k O M, C art er J L. M ulti pl e s cl er osis: c urr e nt a n d e m er gi n g dis e as e- m o dif yi n g t h er a pi es 
a n d tr e at m e nt str at e gi es . M a y o Cli n Pr oc. 2 0 1 4 F e b; 8 9( 2): 2 2 5- 4 0. 
C O N FI D E N TI A L 
I N F O R M A TI O N 
4 5 /5 1 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
1 4 
Cl a d r ibi ne 
A p p e n di c es 
C O N F
I D E N T
I A L 
I N F O R M A T
I O N 
4 6 / 5 1 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
1 4. 1 
Cl a dri bi n e 
Si g n at ur e P a g es a n d R es p o nsi bl e P ers o ns f or t h e St u d y 
C O N FI D E N TI A L 
I N F O R M A TI O N 
4 7 /5 1 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
Si g n at ure P a ge - Pr ot oc ol Le a d 
St u d y Title: 
Or al C L A Dri bi n e i n p ati e nts t h at C h a n g e fr o m first-
li n e Dis e as e 
M o dif yi n g 
T r e at m e nts f or M ulti pl e 
S cl er osis: a p R O sp e cti v e eff e cti v e n ess a n d S af et y 
st u d y 
( C L A D C R O S S) 
St u d y Pr ot oc ol D at e/ Versi o n: 
7 A pril 2 0 2 1 I V ersi o n 2. 0 
Pr ot oc ol Le a d res p o nsi ble f or des i g ni n g t he n o n -i nter ve nti o n al st u d y: 
I a p pr o v e t h e d esi g n of t h e n o n-i nt er v e nti o n al st u d y: 
-
Si g n at ur e 
D at e of Si g n at ur e 
N a m e , a c a d e mi c de gree: 
 
F u n cti o n/ Titl e: 
 
I nstit uti o n: 
 
A d dr ess: 
 
T el e p h o n e n u m b er: 
 
E - m ail a d dr ess: 
 
C O N FI D E N TI A L 
I N F O R M A T I O N 
4 8 /5 1 
Gl o bal Versi o n I D: C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a dri bi ne 
Si g n at ure P a g e - C o o r di n ati n g I n v esti g at o r 
St u d y Titl e 
Or al C L A Dri bi n e i n p ati e nts t h at C h a n g e fr o m first-li n e 
Dis e as e M o dif yi n g Tr e at m e nts f or M ulti pl e S cl er osis: 
a p R Os p e cti v e eff e cti v e n ess a n d S af et y st u d y 
( C L A D C R O S S) 
St u d y P r ot o c ol D at e/ V e rsi o n 
7 A pril 2 0 2 1 / V ersi o n 2. 0 
l a p pr o v e t h e d esi g n of t h e n o n-i nt er v e nti o n al st u d y a n d I u n d erst a n d a n d will c o n d u ct t h e st u d y 
a c c or di n g t o t h e st u d y pr ot o c ol, a n y a p pr o v e d pr ot o c ol a m e n d m e nts, G o o d 
P h ar m a c o-
e pi d e mi ol o g y Pr a cti c es ( G P P) a n d all a p pli c a bl e H e alt h A ut h orit y r e q uir e m e nts a n d n ati o n al la ws. 
Si g n at ur e 
D at e of Si g n at ur e 
N  
d 
· d 
 
a m e, a c a e m 1c e gr e e: 
F u n cti o n I Titl e: 
I nstit uti o n: 
A d dr ess: 
T el e p h o n e n u m b er: 
E- m ail a d dr ess: 
 
 
 
 
 
 
 
 
 
 
 
C O N FI D E N TI A L 
I N F O R M A TI O N 
4 9/ 5 1 
Gl o bal Versi o n I D: C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
S i g n ature P a g e - Pri nci p al I n v esti g at o r 
St u d y Titl e 
St u d y Pr ot oc ol D at e/ V e rsi o n 
P ri n ci p al I n v esti g at or 
Or al C L A Dri bi n e i n p ati e nts t h at C h a n g e fr o m first-
li n e Dis e as e 
M o dif yi n g 
Tr e at m e nts 
f or M ulti pl e 
S cl er osis: a  p R Os p e cti v e eff e cti v e n ess a n d S af et y 
st u d y 
( C L A D C R O S S) 
7 A pril 2 0 2 1 / V ersi o n 2. 0 
I, t h e u n d ersi g n e d , a m r es p o nsi bl e f or t h e c o n d u ct of t h e st u d y at t his sit e a n d affir m t h at I 
u n d er st a n d a n d will c o n d u ct t h e st u d y a c c or di n g t o t h e st u d y pr ot o c ol , a n y a p pr o v e d pr ot o c ol 
a m e n d m e nts, G o o d P h ar m a c o- e pi d e mi ol o g y Pr a cti c es ( G P P) a n d all a p pli c a b le H e a lt h A ut h orit y 
r e q uir e m e nts a n d n ati o n al l a ws. 
I als o affir m t h at I u n d erst a n d t h at H e alt h A ut h oriti es m a y r e q uir e t h e S p o ns ors of t h e st u d y t o 
o bt ai n a n d s u p pl y d et ails a b o ut o w n ers hi p i nt er ests i n t h e S p o ns or or l n v esti g ati o n al M e di ci n al 
Pr o d u ct a n d  a n y ot h er fi n a n ci al ti es wit h t h e S p o ns o r. T h e S p o ns or will us e a n y s u c h i nf or m ati o n 
s o lel y f or the p ur p os e of c o m pl yi n g wit h t h e r e g ul at or y r e q uir e m e nts. I t h er ef or e a gr e e t o s u p p l y 
t h e S p o ns or wit h a n y n e c ess ar y i nf or m ati o n r e g ar di n g o w n ers hi p i nt er est a n d fi n a n ci al ti es 
i n cl u di n g th os e of m y s p o us e a n d d e p e n d e nt c hil dr e n, a n d t o pr o vi d e u p d at es as n e c ess ar y t o m e et 
H e a lt h A ut h orit y re q uir e m e nts . 
Si g n at ur e 
N a m e, a c a d e mi c d e g ree: 
F u n cti o n / Tit le: 
I nstit uti o n: 
A d dr ess: 
T el e p h o n e n u m b er: 
E- m ail a d dr ess : 
D at e of Si g n at ur e 
C O N FI D E N TI A L 
I N F O R M A TI O N 
5 0 /5 1 
Gl o bal Versi o n I D: C CI

L 0 4 A A 4 0 
M S 7 0 0 5 6 8 _ 0 0 7 0 
Cl a d ri bi n e 
S p o ns o r R es p o nsi bl e P e rs o ns n ot N a me d o n t he C o v e r P a g e 
N a m e , a c a d e mi c d e gr e e: 
 
F u n cti o n / Titl e: 
 
I nstit uti o n: 
 
A d dr ess: 
 
T el e p h o n e n u m b er: 
 
E- m ail a d dr ess: 
 
N a m e, a c a d e mi c d e gr e e: 
 
F u n cti o n/ Titl e: 
 
I nstit uti o n: 
 
A d dr ess : 
 
T el e p h o n e n u m b er: 
 
E- m ail a d dr ess: 
 
C O N FI D E N TI A L 
I N F O R M A TI O N 
51 /5 1 
Gl o bal Versi o n I D: C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D