A 2-year Follow-up Study to Assess Cognition and Health-related Quality of Life in Participants With Highly-active Relapsing Multiple Sclerosis, Having Participated in the CLARIFY MS Trial (CLARIFY MS Extension)
Phase: PHASE4
Conditions: Multiple Sclerosis
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1/ 6 6  
 
 
Cli nic al St u d y  Pr ot oc ol 
Title P a ge  
Cli nic al St u d y Pr ot oc ol Title:  
A 2 -year f oll o w -u p st u d y t o assess c o g niti o n a n d 
healt h -rel ate d q ualit y of life i n partici pa n ts wit h 
hi g hl y-acti ve rela psi n g m ulti ple scler osis, ha vi n g 
partici pate d i n t he C L A RI F Y M S trial 
St u d y N u m ber:  
M S 7 0 0 5 6 8 _ 0 1 5 8  
Pr ot oc ol V ersi o n : 
2 8 J u ne 2 0 2 1 / Versi o n 2. 0 
Merc k [C o m p o u n d ]: 
Ma ve ncla d
®  
Merc k Re gistere d C o m p o u n d N a m e i n 
J a p a n : 
N ot A p plica ble 
St u d y P h ase:  
I V 
S h ort Title:  
C o g niti o n a n d H R Q o L i n a d ults wit h 
hi g hl y- acti ve R M S i n Year 3 a n d 4 after i nitial 
Ma ve ncla d
®  d ose  
Acr o n y m or A b bre vi ati o n:  
C L A RI F Y M S E xt e nsi o n 
C o or di n ati n g I n vesti g at or:  
Pr of. 
, 
 
S p o ns or N a m e a n d Le g al Re gistere d 
A d dress:  
S p o ns or : 
Merc k H ealt hcare K G a A, Dar msta dt, Ger ma n y  
a n affiliate of Merc k K G a A, Dar msta dt, Ger ma n y 
Fra n kf urter Str. 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y 
 
Me dic al Res p o nsi ble:  
Na me:  
, M D, M Sc 
P h o ne: 
 
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:  
E u dra C T: 2 0 2 0- 0 0 3 8 7 4- 3 0  
Ke y w or ds  
Cla dri bi ne ta blets; patie nt -re p orte d o utc o m es; 
l o n g-ter m effects  
 
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
C CI

S u bst a n c e  c o d e:  N/ A         C o g niti o n  a n d  H R Q o L i n  a d ults  wit h  hi g hl y  a cti v e  R M S  i n  Y e a r  3  a n d  4 
aft e r i niti a l  M a v e n cl a d®  d os e  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C  O  N  F I  D  E  N  T I  A  L  
I  N  F  O  R  M  A  T I  O  N 
2/ 6 6  
 
 
P r ot o c ol  A m e n d m e nt  S u m m a r y  of  C h a n g es 
P r ot o c ol  Hist o r y 
 
V er si o n  N u m b er  
T y p e  
V er si o n  D at e  
1. 0  
Ori gi n al  Pr ot o c ol  
1 9 - A u g-2 0 2 0  
2. 0  
Gl o b al  A m e n d m e nt t o t h e 
O ri gi n al P r ot o c ol 
2 8- J u n -2 0 2 1  
P r ot o c ol  V e rsi o n [ 2. 0] ( 2 8- J u n e - 2 0 2 1) 
O v e r all  R ati o n al e f o r t h e  A m e n d m e nt  
 
S e cti o n  #  a n d  N a m e  
D e s cri pti o n  of  C h a n g e  
Bri ef  R ati o n al e  
S e cti o n  1. 3.  S c h e d ul e  of  A cti viti e s ; 
S e cti o n  4. 2.  S ci e ntifi c  R ati o n al e f or 
St u d y  D e si g n;  S e cti o n  8.  St u d y 
A s s e s s m e nt s  a n d  P r o c e d ur e s; 
S e cti o n  8. 1. 3.  C O VI D -1 9  S ur v e y; 
S e cti o n  9. 4. 3.  Ot h er  A n al y s e s  
A d diti o n  of  a  C O VI D -1 9 
S ur v e y f or  p arti ci p a nt s   
T o  c oll e ct  d at a  o n  t h e  p ot e nti al i m p act  of 
C O VI D -1 9  o n  t h e st u d y  e n d p oi nt s . 
S e cti o n  1. 3.  S c h e d ul e  of  A cti viti e s ; 
8. 1.  Effi c a c y  A s s e s s m e nt s  a n d 
Pr o c e d ur e s;  8. 1. 5. 1.  E x p a n d e d 
Di s a bilit y  St at u s  S c al e/   
 
 
 
 
 
 
S e cti o n  8. 3. 5.  Pr e g n a n c y  
A d diti o n  of  pr e g n a n c y 
r e p orti n g d et ail s  d uri n g t h e  g a p 
p eri o d  
D et ail s  of  pr e g n a n c y  o c c urri n g  d uri n g 
t h e  g a p  p eri o d  n e e d t o  b e  c oll e ct e d i n 
t h e a d v er s e  e v e nt ( A E)  p a g e  a n d 
r e p ort e d t o  Gl o b al P ati e nt  S af et y . 
T hr o u g h o ut  
Mi n or  e dit ori al  a n d  d o c u m e nt 
f or m atti n g r e vi si o n s 
Mi n or; t h er ef or e,  h a v e  n ot  b e e n 
s u m m ari z e d . 
 
- 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 2 1  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.  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3/ 6 6  
 
 
T a ble of C o nte nts  
Title Pa ge   
 .............................................................................................................. 1 
Ta ble of C o nte nts   .............................................................................................................. 3 
List of Ta bles   
 .............................................................................................................. 7 
List of Fi g ures  
 .............................................................................................................. 8 
1  
Pr ot oc ol S u m mar y ................................................................................ 9 
1. 1  
S y n o psis ................................................................................................9  
1. 2  
Sc he ma  ................................................................................................ 1 1 
1. 3  
Sc he d ule of A cti vities  ......................................................................... 1 1 
2  
I ntr o d u cti o n ......................................................................................... 1 5 
2. 1  
St u d y Rati o nale ................................................................................... 1 5  
2. 2  
Bac k gr o u n d ......................................................................................... 1 5  
2. 3  
Be nefit/ Ris k Assess me nt  .................................................................... 1 6 
3  
O bjecti ves a n d E n d p oi nts ................................................................... 1 7  
4  
St u d y Desi g n ....................................................................................... 2 2  
4. 1  
O verall Desi g n  .................................................................................... 2 2 
4. 2  
Scie ntific  Rati o nale f or St u d y Desi g n ................................................ 2 3 
4. 3  
J ustificati o n f or D ose .......................................................................... 2 4 
4. 4  
E n d of St u d y Defi niti o n ...................................................................... 2 4  
5  
St u d y P o p ulati o n ................................................................................. 2 4  
5. 1  
I n cl usi o n Criteria ................................................................................ 2 5 
5. 2  
E xcl usi o n Criteria  ............................................................................... 2 5 
5. 3  
Lifest yle C o nsi derati o ns ..................................................................... 2 5  
5. 4  
Scree n Fail ures  .................................................................................... 2 5 
6  
St u d y I nter v e nti o n(s) .......................................................................... 2 5  
6. 1  
St u d y I nter v e nti o n(s) A d mi nistrati o n  ................................................. 2 5 
6. 2  
St u d y I nter v e nti o n(s) Pre parati o n, Ha n dli n g, St ora ge, a n d 
Acc o u nta bilit y  ..................................................................................... 2 6 
6. 3  
Meas ures t o Mi ni mize Bias: St u d y I nter v e nti o n Assi g n me nt a n d 
Bli n di n g .............................................................................................. 2 6  
6. 4  
St u d y I nter v e nti o n C o m plia nce .......................................................... 2 6  
6. 5  
C o nc o mita nt T hera p y ......................................................................... 2 6  
6. 6  
D ose Selecti o n a n d M o dificati o n ........................................................ 2 7  
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
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 6  
 
 
6. 7  
St u d y I nter v e nti o n after t he E n d of t he St u d y .................................... 2 7  
7  
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici p a nt 
Disc o nti n uati o n/ Wit h dr a wal ............................................................... 2 7 
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n................................................ 2 7  
7. 2  
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y  ................... 2 7 
7. 3  
L ost t o F oll o w- U p ............................................................................... 2 8 
8  
St u d y Assess me nts a n d Pr oce d ures .................................................... 2 8  
8. 1  
Efficac y Assess me nts a n d Pr oce d ures  ................................................ 2 9 
8. 1. 1  
C o g niti o n ............................................................................................ 3 0  
 
 ...... 3 0 
8. 1. 2  
Healt h Relate d Q u alit y of Life  ........................................................... 3 1 
8. 1. 2. 1  
M ulti ple Scler osis Q ualit y of Life -5 4 I nstr u me nt  .............................. 3 1 
8. 1. 2. 2  
H os pital A n xiet y a n d De pressi o n Scale ............................................. 3 1  
8. 1. 3  
C O VI D - 1 9 S ur ve y .............................................................................. 3 2 
8. 1. 4  
E m pl o y me nt Stat us  ............................................................................. 3 2 
8. 1. 5  
Disa bilit y Assess me nts  ....................................................................... 3 2 
 
3 2  
 
3 3  
 
3 3  
 
3 3  
 
3 4  
 
. 3 4 
8. 1. 7  
Rela pses  .............................................................................................. 3 5 
8. 1. 7. 1  
Rela pse E val uati o n  ............................................................................. 3 5 
8. 1. 7. 2  
Pr oce d ure f or Rela ps e E val uati o n  ...................................................... 3 5 
 
... 3 6 
 
3 6  
 
3 6  
8. 1. 1 0  
Patie nt Diar y  ....................................................................................... 3 6 
8. 1. 1 1  
Retr os pecti ve Dat a C ollecti o n  ............................................................ 3 6 
8. 2  
Safet y Assess me nts a n d Pr oce d ures  ................................................... 3 7 
8. 2. 1  
P h ysical E xa mi nati o ns ........................................................................ 3 7  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5/ 6 6  
 
 
8. 2. 2  
Vital Si g ns  .......................................................................................... 3 7 
8. 3  
A d verse E v e nts a n d Seri o us A d verse E v e nts ..................................... 3 7  
8. 3. 1  
Ti me P eri o d a n d Fre q ue n c y f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E v e nt I nf or mati o n .................................................... 3 8  
8. 3. 2  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E v e nts ... 3 8  
8. 3. 3  
F oll o w- u p of A d v erse E v e nts a n d Seri o us A d vers e E ve nts ............... 3 9  
8. 3. 4  
Re g ulat or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ..... 3 9  
8. 3. 5  
Pre g na nc y  ........................................................................................... 3 9 
8. 3. 6  
Disease -Rel ate d E ve nts a n d/ or Disease -R elate d O utc o mes n ot 
Q ualif yi n g as A d verse E ve nts or Seri o us A d vers e E ve nts ................. 4 1  
8. 3. 7  
A d verse E v e nts of S peci al I nt erest  ..................................................... 4 1 
8. 4  
Treat me nt of O v er d ose  ....................................................................... 4 1 
8. 5  
P har mac o ki netics  ................................................................................ 4 1 
8. 6  
P har mac o d y na mics  ............................................................................. 4 1 
 
4 2  
 
4 2  
8. 9  
I m m u n o ge nicit y Assess me nts ............................................................ 4 3 
4 3  
4 3  
4 3  
9. 3  
P o p ulati o ns f or A nal yses .................................................................... 4 4  
9. 4  
Statistical A nal yses  ............................................................................. 4 4 
9. 4. 1  
Efficac y A nal yses  ............................................................................... 4 5 
9. 4. 2  
Safet y A nal yses  .................................................................................. 4 6 
9. 4. 3  
Ot her A nal yses  .................................................................................... 4 6 
9. 4. 4  
Se q ue nce of A nal yses  ......................................................................... 4 6 
1 0  
Refere n ces  ........................................................................................... 4 7 
1 1  
A p pe n dices ......................................................................................... 4 9  
A p pe n di x 1  
A b bre viati o ns ...................................................................................... 5 0  
A p pe n di x 2  
St u d y G o ver na nce ............................................................................... 5 2  
A p pe n di x 3  
A d verse E v e nts: Defi niti o ns a n d Pr oce d ures f or R ec or di n g, 
E val uati n g, F oll o w- u p, a n d Re p orti n g ................................................ 5 8  
 
6 4  
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

S u bst a nce c o de: N/ A  
C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6/ 6 6  
A p pe n di x 5  
C o ntrace pti o n ...................................................................................... 6 5  
A p pe n di x 6  
S p o ns or Si g nat ure Pa ge ........................................................................
A p pe n di x 7  
C o or di nati n g I n vesti gat or Si g nat ure Pa ge ...........................................
 
A p pe n di x 8  
Pri nci pal I n vesti gat or Si g nat ure Pa ge ................................................. 6  
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7/ 6 6  
 
 
List of T a bles  
Ta ble 1  
 O bjecti ves a n d E n d p oi nts .................................................................... 9 
Ta ble 2  
 Sc he d ule of A cti vities  ........................................................................ 1 2 
Ta ble 3  
 St u d y O bjecti ves ................................................................................ 1 8 
 
 
4 4  
Ta ble 5  
 A nal ysis P o p ulati o ns ......................................................................... 4 4 
Ta ble 6  
 A nal y sis of Efficac y E n d p oi nts ......................................................... 4 5 
Ta ble 7  
 Descri pti o n of Safet y A nal yses ......................................................... 4 6 
 
 
 
Gl o bal Versi o n I D: C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8/ 6 6  
 
 
List of Fi g ures  
Fi g ure 1: St u d y Sc he ma ..................................................................................................... 1 1  
 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9/ 6 6  
 
 
1  
Pr ot oc ol S u m m ar y  
1. 1  
S y n o psis  
Pr ot oc ol Title: A 2 -year f oll o w -u p st u d y t o assess c o g niti o n a n d healt h -relate d q ualit y of life i n 
partici pa nt s wit h hi g hl y-acti ve rela psi n g m ulti ple scler osis, ha vi n g partici pate d i n t he C L A RI F Y 
M S trial 
S h ort Title: C o g niti o n a n d H R Q o L  i n a d ults wit h hi g hl y-acti ve R M S i n Year 3 a n d 4 after i nitial 
Ma ve ncla d
®  d ose 
R ati o n ale: Hi g hl y- acti v e  rela psi n g  m ulti ple  scler osis  ( R M S)  is  c haract erize d  b y  ne ur ol o gical 
deteri orati o n, ca usi n g m ot or a n d c o g niti ve d ysf u n cti o n a n d i m pacti n g h ealt h relate d q u alit y of life 
( H R Q o L).  W hilst  t he  ra n d o mize d  c o ntr ol st u dies o n  cla dri bi ne  ta blets  ( Ma ve ncla d ® ) pr o vi de  a 
wealt h  of  i nf or mati o n  o n  cli nical  a n d  safet y  o ut c o mes,  t his  st u d y  will  a d d  t o  t he  e vi de nce  b y 
i n vesti gati n g  t he  l o n g-ter m  effect  (o v er 2 y ears  after  i nitia l treat me nt) o n  c o g niti o n  a n d 
patie nt -re p ort e d o utc o mes ( P R Os) a m o n g a d ults wit h hi g hl y-acti ve R M S.  
O bjecti ves a n d E n d p oi nts: T he pri mar y a n d sec o n dar y o bjecti ves a n d e n d p oi nts are pr o vi de d i n 
Ta ble 1 . 
T a ble 1  
 O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri mar y  
T o assess c o g niti ve i m pair me nt i n 
partici pa nts wit h hi g hl y -acti ve 
rela psi n g m ulti ple scler osis 
(R M S ), ha vi n g partici pat e d t o t he 
C L A RI F Y M S trial, at 4 years 
after i nitial d ose of cla dri bi ne 
ta blets 
Perce nta g e  of p artici pa nt s  wit h n o  or m i nimal  decli ne  i n 
c o g niti ve  f u ncti o n,  d efi ne d as   an  i m pr o ve d 
or  sta ble  
S y m b ol Di git M o dalities Test ( S D M T) sc ore  or a decli ne 
of 4 p oi nts  or less  i n t he S D M T sc ore, at 4 years  aft er i nitial 
d ose of cla dri bi ne ta blets ( M 4 8) c o m pare d t o S D M T sc ore 
pri or  t o  i nitial  d ose  of cla dri bi ne ta blets ( C L A RI F Y  M S 
trial Baseli ne ) 
Sec o n dar y  
T o assess  healt h r elate d q ualit y of 
life (H R Q o L ) i n partici pa nts wit h 
hi g hl y-acti ve R M S, ha vi n g 
partici pate d i n t he C L A RI F Y M S 
trial, at 4 years after i niti al d ose 
of cla dri bi ne ta blets 
•  C ha n ge i n H R Q o L as meas ure d b y t he M ulti ple 
Scler osis Q ualit y of Life - 5 4 Q uesti o n naire (M S Q o L -
5 4) p h ysical a n d me ntal healt h  sc ores at 4 years after  
i nitial d ose of cla dri bi ne ta blets ( M 4 8) c o m pare d t o  
pri or t o i nitial d ose of cla dri bi ne ta blets ( C L A RI F Y 
M S trial Baseli ne ) 
•  C ha n ge i n H R Q o L as meas ure d b y M S Q o L - 5 4 
p h ysical a n d me ntal healt h sc ores at 4 y ears after  
i nitial d ose of cla dri bi ne ta blets ( M 4 8) c o m pare d t o 
M 2 4 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 /6 6  
 
 
H R Q o L = H e alt h r el at e d q u alit y of lif e; S D M T = S y m b ol Di git M o d aliti e s T e st; M S Q o L -5 4 = M ulti pl e S cl er o si s Q u alit y of 
Lif e 5 4 Q u e sti o n n air e ; R M S= R el a p si n g M ulti pl e S cl er o si s.  
O ver all  Desi g n: T his  is t he e xte nsi o n  st u d y  t o  t he 2- year C L A RI F Y  M S trial t o  o bser ve 
partici pa nts d uri n g t he t hir d a n d f o urt h year  after t he i nitial cla dri bi ne ta blet d ose; n o cla dri bi ne 
ta blets will be  a d mi nistere d d uri n g t he e xte nsi o n st u d y peri o d . At t he e xt e nsi o n st u d y Baseli ne, 
data  will  b e  c ollecte d  r etr os pecti vel y fr o m  t h e p ote ntial tra nsiti o n g a p  peri o d  b et wee n  t he 
C L A RI F Y M S trial a n d C L A RI F Y M S E xte nsi o n st u d y (i.e., bet wee n M 2 4 a n d e xte nsi o n st u d y 
B aseli ne). I n a d diti o n, partici pa nts will atte n d visits f or assess me nts at  the e xt e nsi o n  st u d y Baseli ne  
( pla n ne d t o c oi nci de wit h or b e as near t o M 2 4 as p ossi ble t o mi ni mize t he tra nsiti o n ga p  peri o d), 
M 3 6 at 3 6 m o nt hs/ 3 years after  i nitial d ose of cla dri bi ne ta blets, a n d  M 4 8  at 4 8 m o nt hs/ 4 years 
after i nitial d ose of cla dri bi ne ta blets. 
Discl os ure  St ate m e nt:  T his will  be  a n  o pe n  la bel,  si n gle  ar m,  e x pl orat or y,  m ultice nter, 
retr os pecti ve a n d pr os pecti ve, 2- year P has e  I V st u d y. T he  p ur p os e of t he st u d y is t he e val uati o n 
of t he eff ect of a treat me nt f or hi g hl y-acti ve R M S . 
N u m ber of Ar ms: 1  
Bli n di n g:  N o t a p plica ble 
N u m ber of P artici p a nts: De p e n di n g o n t h e dr o p -o ut rate of t he p are nt st u d y , it is e x pecte d t h at 
u p t o a ma xi m u m of 3 8 0 partici pa nts will be e nr olle d i nt o t he e xte nsi o n st u d y. Ass u mi n g a dr o p -
o ut rate o ver t he c o urse of t he e xte nsi o n st u d y of 1 0 % t o 2 0 %, it is e x pecte d t o ac hie ve a ma xi m u m 
of 3 0 0 t o 3 4 0 e val ua ble p artici pa nts f or t he e xte nsi o n st u d y.  
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: T he e xte nsi o n st u d y will c o ver a 2- year p eri o d i n 
w hic h t he partici pa nts will n ot be treate d wit h cla dri bi ne ta blets, w hic h were a d mi nistere d  i n t he 
C L A RI F Y M S trial .  
I n v ol ve m e nt of S peci al C o m mittee (s): Yes 
A Steeri n g C o m mittee ( S C) will be esta blis he d; t he S C  C harter will be i n place t hat descri bes t he 
S C  res p o nsi bilities.  T he  S C  is  a  m ulti disci pli nar y  gr o u p  of  l ea d st u d y I n v esti gat ors,  me dical 
e x perts, a n d S p o ns or’s pers o n nel, w h o,  c ollecti vel y, ha ve t he sci e ntific, me di cal, a n d cli nical st u d y 
ma na ge me nt e x peri e nce t o desi g n, c o n d uct a n d e val uate t he st u d y. T he S C pr o vi des a d vice a n d 
rec o m me n dati o ns r e gar di n g t he desi g n, t he c o n d uct, a n d t he e val uati o n of t he st u d y. T he S C is 
res p o nsi ble f or safe g u ar di n g t he i nterests of partici pa nts  a n d f or t he c o n d uct of t he st u d y. 
 
 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 /6 6  
 
 
1. 2  
Sc he m a  
A sc he ma of t he st u d y desi g n , i ncl u di n g b ot h C L A RI F Y M S ( pare nt st u d y) a n d C L A RI F Y M S 
E xte nsi o n (e xte nsi o n st u d y), is prese nte d b el o w. 
Fi g ure 1: St u d y S c he m a  
 
 
N ote:  M 3 6 a n d M 4 8 will be pla n ne d re lati ve t o C L A RI F Y M S Baseli ne; a p ote ntial dela y  i n M 2 4 (i.e., the Fi nal St u d y 
Visit  of t he C L A RI F Y M S trial ) d ue t o a dela y i n  t he i nitiati o n of t he sec o n d-year cla dri bi ne  ta blet treat me nt d oes n ot 
affect t he ti mi n g of M 3 6 a n d M 4 8 . 
Baseli ne of t he e xte nsi o n st u d y will i ncl u de retr os pecti ve data c ollecti o n fr o m t he p ote ntial tra nsiti o n ga p (i.e., peri o d 
bet wee n M 2 4 a n d C L A RI F Y M S E xte nsi o n B aseli ne)  a n d pr os pecti ve assess me nts.  
1. 3  
Sc he d ule of Acti vities  
T he r ec o m me n de d or der of t he asses s me nts is as pr o vi de d i n t he Sc he d ule of Acti vities  (T a ble 2 ). 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 after i niti al M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 /6 6  
 
 
T a ble 2  
 Sc he d ule of Acti vities  
A s s e s s m e nt s & Pr o c e d ur e s  
A s s e s s m e nt P eri o d  
N ot e s  
B a s eli n e  
M 3 6  
E n d of 
St u d y/ M 4 8  
U n s c h e d ul e d 
Vi sit s 
E arl y Di s -
c o nti n u ati o n 
Vi sit  
St u d y m o nt h (fr o m i niti al a d mi ni str ati o n of 
cl a dri bi n e  t a bl et s) 
B et w e e n 
C L A RI F Y M S 
Fi n al Vi sit 
( M 2 4) a n d 
M 3 6  
3 6  
4 8  
2 4 -4 8  
 
 
Vi sit wi n d o w  
± 2 8 d a y s  
± 2 8 d a y s  
 
 
I nf or m e d C o n s e nt 
X 
 
 
 
 
 
I n cl u si o n/ e x cl u si o n crit eri a 
X 
 
 
 
 
 
D e m o gr a p h y  
X 
 
 
 
 
 
M e di c al hi st or y  
X 
 
 
 
 
F or m e di c al hi st or y, o nl y s e ri o u s 
a d v er s e e v e nt s ( S A E s) w hi c h ar e 
o n g oi n g fr o m t h e C L A RI F Y M S tri al 
will b e r e c or d e d  ( a s d e s cri b e d i n 
S e cti o n  8. 3. 1 )  
C o n c o mit a nt m e di c ati o n s a n d pr o c e d ur e s  
X 
X  
X  
X  
X  
B a s eli n e d at a will b e c oll e ct e d 
r etr o s p e cti v el y fr o m t h e tr a n siti o n 
g a p b et w e e n C L A RI F Y M S Fi n al 
Vi sit ( M 2 4) a n d C L A RI F Y M S 
E xt e n si o n B a s eli n e f or a n y 
c o n c o mit a nt m e di c ati o n s t h at m a y 
h a v e b e e n i niti at e d i n t h at ti m e 
p eri o d  
C o g niti v e F u n cti o n  
 
 
 
 
 
 
 
 
 
H R Q o L  
M ulti pl e S cl er o si s Q u alit y of Lif e 
5 4  - I n str u m e nt ( M S Q o L-5 4)  
 
X 
X  
 
X  
 
 
 
 
 
 
 
 
 
C O VI D -1 9 S ur v e y  
 
X 
X 
 
X 
 
E m pl o y m e nt St at u s  
 
 
X 
 
X 
 
Gl o bal Versi o n I D: C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 after i niti al M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 /6 6  
 
 
A s s e s s m e nt s & Pr o c e d ur e s  
A s s e s s m e nt P eri o d  
N ot e s  
B a s eli n e  
M 3 6  
E n d of 
St u d y/ M 4 8  
U n s c h e d ul e d 
Vi sit s 
E arl y Di s -
c o nti n u ati o n 
Vi sit  
S af et y A s s e s s m e nt s  
P h y si c al e x a mi n ati o n  
 
X  
X  
X  
X  
 
Vit al si g n s  
 
X 
X 
X  
X 
 
A d v er s e e v e nt r e p orti n g  
X 
X 
X 
X  
X 
B a s eli n e d at a will b e c oll e ct e d 
r etr o s p e cti v el y fr o m t h e tr a n siti o n 
g a p b et w e e n C L A RI F Y M S Fi n al 
Vi sit ( M 2 4) a n d C L A RI F Y M S 
E xt e n si o n B a s eli n e f or a n y A E s a n d 
S A E s t h at m a y h a v e o c c urr e d i n t h at 
ti m e p eri o d 
Di s a bilit y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R el a p s e r e p ort  
X 
X 
X 
 
X 
B a s eli n e d at a will b e c oll e ct e d 
r etr o s p e cti v el y fr o m t h e tr a n siti o n 
g a p b et w e e n C L A RI F Y M S Fi n al 
Vi sit ( M 2 4) a n d C L A RI F Y M S 
E xt e n si o n B a s eli n e f or a n y r el a p s e s 
t h at m a y h a v e o c c urr e d i n t h at ti m e 
p eri o d  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI

CCI
CCI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 /6 6  
 
 
2  
I ntr o d ucti o n 
C la dri bi ne ta blets (Ma ve ncla d
® ) are a p pr o ve d  ( E ur o pea n  Me dici nes  A ge nc y  a p pr o val  o n 
2 5 A u g ust 2 0 1 7) f or t he treat me nt of hi g hl y -acti v e rela psi n g m ulti ple scler osis ( R M S ) i n a d ults. 
Detaile d i nf or mati o n o n t he c he mistr y, p har mac ol o g y, efficac y, a n d safet y of  cla dri bi ne ta blets is 
i n t he S u m mar y of Pr o d uct C haract eristics (S m P C ). 
2. 1  
St u d y R ati o n ale  
Hi g hl y- acti ve  R M S   is  c haract erize d  b y  ne ur ol o gical deteri orati o n  ca usi n g m ot or  a n d  c o g niti ve 
d ysf u ncti o n  a n d i m pacti n g healt h  relate d  q ualit y  of  life  ( H R Q o L ) (J o nes  2 0 1 6). W hilst  t he 
ra n d o mize d c o ntr ol st u di es o n cla dri bi ne ta blets pr o vi de a wealt h of i nf or mati o n o n cli nical a n d 
safet y  o utc o mes, t here  is  a  call  f or P hase  I V st u dies t o m o nit or l o n g -ter m  effects  of  se q ue ntial 
disease - m o dif yi n g t her a pies (Derf uss 2 0 2 0 ).  
T h is st u d y will  a d d t o  t he  e vi de n ce  b y  i n vesti g ati n g  t he  l o n g-ter m  effect  (o ver 2  y ears  after 
i nitiati o n  of  treat me nt) o n  c o g niti o n  a n d patie nt -re p orte d  o utc o mes (P R Os ) a m o n g  a d ults  wit h 
hi g hl y- acti ve R M S . T his  e xte nsi o n st u d y will c ollect  2-year  f oll o w-u p data  t o t he C L A RI F Y M S 
trial till u p t o 4 years after i nitial d ose of cl a dri bi ne ta blets t o  e x pl ore t he l o n g-ter m  effects  of 
cla dri bi ne ta blet a d mi nistrati o n.  
F or f urt her i nf or m ati o n o n st u d y rati o nale, p lease refer t o Secti o n 4. 2 . 
2. 2  
B ac k gr o u n d  
M ulti ple  scler osis  ( M S)  is  a  c hr o ni c,  i nfla m mat or y,  pr o gressi ve,  de m y eli nati n g  disease  of  t he 
ce ntral n er v o us s yste m a n d is t he m ost c o m m o n ca use of seri o us n e ur ol o gi cal disa bilit y i n y o u n g 
a d ults (Prz y be k 2 0 1 5 ). T he disease c o urs e of M S is heter o ge n e o us a n d u n pre dicta ble re q uiri n g 
c hr o nic  tr eat me nt  a n d  r e g ular  me di cal  m o nit ori n g  b y  n u mer o us  met h o ds  s uc h  as, ma g netic 
res o na nce i ma gi n g (M RI ) t hat was desi g ne d f or t he i n vesti gati o n, dia g n osis a n d ma na ge me nt of 
patie nt s wit h M S (Oreja - G ue var a 2 0 1 5). 
S o me  patie nt s  e x perie nce  a  hi g hl y-acti ve  diseas e  c o urse  wit h  ra pi d  a n d  earl y  disa bilit y  ofte n 
heral de d  b y  hi g h  rela pse  rates  a n d  earl y  m ot or,  cere bellar  a n d/ or  c o g niti ve  d ysf u ncti o n 
(Hirst  2 0 0 8).  Earl y  i nitiati o n  of  effecti ve  i m m u n ot hera p y  is  c o nsi dere d  t o  be  i m p orta nt  i n  t his 
gr o u p  of patie nt s  i n  or der  t o  pre ve nt  a g gressi ve  disease  pr o gressi o n  a n d  se vere  disa bilit y 
acc u m ulati o n ( D u b e y 2 0 1 5 ).  
Des pite  t he  r ece nt  a p pr o vals  of  se veral  ne wer  t h era pies,  t he  treat me nt  b ur de n  of  M S  re mai ns 
si g nifica nt. W hile  cli nical st u dies de m o nstrate e vi de nce f or t he efficac y of ne w t hera pies , t hese 
st u dies are ofte n of a li mite d d urati o n  a n d ma y n ot ca pt ure l o n g-ter m o utc o mes  (L ucc h etta  2 0 2 0). 
L o n g- ter m st u dies are nee de d t o esta blis h t he cli nical be nefits as well as t he p ote ntial i m pact o n 
c o g niti ve i m pair me nt a n d  H R Q o L b y ne w dr u gs i n M S patie nts. 
It h as bee n d e m o nstrate d t hat treat me nt wit h cla dri bi ne ta blets i n 2 s h ort c o urses o ver 2 c o nsec uti ve 
years  has  c o nsiste ntl y  s h o w n  r o b ust  cli nicall y  a n d  statisticall y  si g nifica nt  be nefits  i n patie nt s 
acr oss t he s pectr u m o f Rela psi n g Re mitti n g M ulti ple Scler osis (earl y t o late sta ges, treat me nt naï ve 
or e x perie n ce d patie nt s) (Gi o va n n o ni 2 0 1 0 ; Leist 2 0 1 4 ). I n p artic ular, it w as f o u n d t hat treat me nt 
wit h cla dri bi ne ta blets res ulte d i n si g nifica nt i m pr o ve me nts i n cli nical a n d ra di ol o gical efficac y 
Gl o bal Versi o n I D: C CI

S u bst a n c e  c o d e:  N/ A         C o g niti o n  a n d  H R Q o L i n  a d ults  wit h  hi g hl y  a cti v e  R M S  i n  Y e a r  3  a n d  4 
aft e r i niti a l  M a v e n cl a d®  d os e  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C  O  N  F I  D  E  N  T I  A  L  
I  N  F  O  R  M  A  T I  O  N 
1 6 /6 6  
 
 
o ut c o m es,    wit h  si g nifi c a ntl y    m or e  p ati e nt s  r e m ai ni n g  fr e e  fr o m  r el a ps e,  fr e e  fr o m   3 - m o nt h 
s ust ai n e d E x p a n d e d  Dis a bilit y  St at us  S c al e ( E D S S )  pr o gr essi o n, a n d fr e e fr o m  M RI l esi o n  a cti vit y 
o v er  9 6  w e e ks  c o m p ar e d t o  pl a c e b o  (Gi o v a n n o ni  2 0 1 0 ).  
Effi c a c y  d at a fr o m t h e  C L A RI T Y tri al s h o w e d  a  st atisti c all y si g nifi c a nt  l o w er a n n u ali z e d r el a ps e 
r at e ( A R R), hi g h er  pr o p orti o n  of  p ati e nt s r el a ps e-fr e e  o v er  9 6 w e e ks,  hi g h er  pr o p orti o n  of  p ati e nt s 
fr e e  of  s ust ai n e d  dis a bilit y  o v er  9 6 w e e ks ,  a n d   l o n g er  ti m e  t o  3-m o nt h   E D S S  pr o gr essi o n  i n 
p ar tici p a nts  r e c ei vi n g   cl a dri bi n e  t a bl ets  3. 5  m g/ k g   c o m p ar e d   t o  p ar tici p a nt s   o n   pl a c e b o  
(Gi o v a n n o ni  2 0 1 0 ).  In  a d diti o n,  cl a dri bi n e  t a bl ets    w er e  st atisti c all y  si g nifi c a ntl y  s u p eri or  t o 
pl a c e b o  wit h r e g ar d t o  n u m b er s  a n d r el ati v e r e d u cti o n  of  T 1  G d + l esi o ns,  a cti v e  T 2 l esi o ns,  a n d 
c o m bi n e d  u ni q u e  a cti v e  ( C UA ) l esi o ns as  d e m o nstr at e d i n  br ai n  M RI  o v er t h e  e ntir e  9 6  w e e ks  of 
t h e st u d y (C o mi  2 0 1 3 ). 
2. 3  
B e n efit/ Ris k  Ass ess m e nt  
T h e  pri m ar y  ai m  of t his  st u d y is t o  ass ess  c o g niti o n  a n d  H R Q o L  o v er t h e t hir d  a n d  f o urt h  y e ar 
aft er  i niti al  a d mi nistr ati o n  of  cl a dri bi n e  t a bl ets.    R es ults  fr o m  t his  st u d y    m a y  b e  of  b e n efit  t o 
p ati e nts  wit h  M S  a n d  cli ni ci a ns  b y  h el pi n g t o i nf or m f ut ur e tr e at m e nt  a p pr o a c h es  a n d tr e at m e nt 
d e cisi o n - m a ki n g. 
T h e  b e n efit /ris k r el ati o ns hi p  w as c ar ef ull y c o nsi d er e d i n t h e  pl a n ni n g  of t his e xt e nsi o n st u d y.  M or e 
d et ail e d i nf or m ati o n  a b o ut t h e  k n o w n  a n d  e x p e ct e d  b e n efits  a n d  ris ks  a n d  r e as o n a bl y  e x p e ct e d 
a d v ers e  e v e nts  ( A Es)  of cl a dri bi n e t a bl ets  m a y  b e f o u n d i n  S e cti o n  4. 2  a n d t h e  S m P C . Als o,  d uri n g 
t h e C L A RI F Y  M S tri al ,  st u d y p arti ci p a nts r e c ei v e d   cl a dri bi n e t a bl ets,  w hi c h w er e  c o nsi d er e d t o 
h a v e  a  p ositi v e  b e n efit /ris k  pr ofil e t h at s u p p orte d  t h eir us e i n t his  p arti ci p a nt  gr o u p.  Mi ni m al ris k 
t o  p arti ci p a nts is  e x p e ct e d si n c e  p arti ci p a nts  e nr oll e d i n t his st u d y  will  n ot  b e r e c ei vi n g  a n y st u d y 
tr e at m e nt; t h e c l a dri bi n e t a bl ets tr e at m e nt  c o urs e is t o  b e  c o m pl et e d  u n d er t h e  st u d y  pr ot o c ol of 
t h e C L A RI F Y  M S tri al,  a n d  p a rtici p a nts  will  r e c ei v e r o uti n e  cli ni c al c ar e  o v er t h e  e xt e nsi o n st u d y 
p eri o d.  T h e  C L A RI F Y  M S  E xt e nsi o n st u d y  will  b e   of a n  i nt er v e nti o n al n at ur e,  b e c a us e  of  t h e  M RI 
s c a ns, bl o o d  dr a ws,  a n d  P R Os,  as  p er  st u d y  pr ot o c ol . T h es e  a d diti o n al  di a g n osti c  or  m o nit ori n g 
pr o c e d ur es  d o  n ot  p os e  m or e t h a n  mi ni m al ris k  or  b ur d e n t o t h e s af et y  of t h e  p arti ci p a nts c o m p ar e d 
t o  n or m al  cli ni c al  pr a cti c e.  
Bl o o d  dr a ws  m a y  c a us e  dis c o mf ort,  br uisi n g , a n d  v er y r ar el y i nf e cti o n  at t h e sit e  w h er e t h e s ki n is 
p u n ct ur e d  b y t h e  n e e dl e.  P ati e nts  m a y  als o  e x p eri e n c e  di z zi n ess,  n a us e a  or f ai nti n g  d uri n g  bl o o d 
s a m pli n g.  H o w e v er, i n  g e n er al t h es e r e a cti o ns  ar e  mil d t o  m o d er at e  a n d  will r es ol v e  o n t h eir  o w n.  
B as e d  o n t h e  a v ail a bl e  cli ni c al  a n d s af et y  d at a t o  d at e, t h e  c o n d u ct  of t h e st u d y,  as  s p e cifi e d i n t his 
pr ot o c ol, is  c o nsi d er e d j ustifi a bl e. 
Gl o bal Versi o n I D: C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 
after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 7 /6 6  
 
 
3  
O bjecti ves a n d E n d p oi nts  
T he st u d y o bjecti ves a n d t heir li n ke d e n d p oi nts are descri be d i n  Ta ble 3 . F or t he statistical as pects 
of t he e n d p oi nts, ref er t o Secti o n  9. 4 . 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 after i niti al M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 8 /6 6  
 
 
T a ble 3  
 St u d y O bjecti ves  
O bjecti ves  
E n d p oi nts  
Pri mar y  
T o assess c o g niti ve i m pair me nt i n  partici pa nts 
wit h  hi g hl y-acti ve R M S, ha vi n g partici pate d 
i n t he C L A RI F Y M S trial, at 4 years after 
i nitial d ose of cla dri bi ne ta blets 
Perce nta g e of partici pa nt s wit h n o or m i ni mal decli ne i n c o g niti ve f u ncti o n, defi ne d 
as a n i m pr o ve d or sta bl e S y m b ol Di git M o dalities Test ( S D M T ) sc orea or a decli ne 
of 4 p oi nts or less i n t he S D M T sc ore, at 4 years after i nitial d ose of cla dri bi ne 
ta blets ( M 4 8) c o m pare d t o S D M T sc ore pri or t o i nitial d ose  of cla dri bi ne ta blets 
( C L A RI F Y M S Baseli ne ) 
Sec o n dar y  
T o assess healt h r elate d q ualit y of life 
(H R Q o L ) i n partici pa nt s wit h hi g hl y-acti ve 
R M S , ha vi n g partici pate d i n t he C L A RI F Y 
M S trial, at 4 years aft er i nitial d ose of 
cla dri bi ne ta blets 
•  C ha n ge i n H R Q o L as meas ure d b y M ulti ple Scler osis Q ualit y of Life 
5 4 Q uesti o n naire ( M S Q o L - 5 4) p h ysical a n d m e ntal healt h  sc ores at 4 years 
after i nitial d ose of cla dri bi ne  ta blets ( M 4 8) c o m p are d t o pri or t o  i nitial d ose of 
cla dri bi ne ta blets ( C L A RI F Y M S Baseli ne )   
•  C ha n ge i n H R Q o L as meas ure d b y M S Q o L - 5 4 p h ysical a n d me ntal healt h 
sc ores at 4 years  after i nitial d ose of cla dri bi ne ta blets ( M 4 8) c o m pare d t o M 2 4  
 
T o assess t he l o n g -ter m ( 4 years) s afet y a n d 
t olera bilit y of cla dri bi ne ta blets 
•  Occ urre nces of a d v erse e ve nts ( A Es) a n d s eri o us a d verse e v e nts ( S A Es) d uri n g 
t he t hir d a n d f o urt h year after i nitial d ose of cla dri bi ne ta blets 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 after i niti al M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 9 /6 6  
 
 
O bjecti ves  
E n d p oi nts  
Gl o bal Versi o n I D: 
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 after i niti al M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 0 /6 6  
 
 
O bjecti ves  
E n d p oi nts  
Gl o bal Versi o n I D: 
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 4 after i niti al M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 1 /6 6  
 
 
O bjecti ves  
E n d p oi nts  
f 
Vi s u o s p ati al M e m or y T e st -R e vi s e d; C V L T -II= C alif or ni a V er b al L e ar ni n g T e st -II; 
 
; H R Q o L = H e alt h  r el at e d  q u alit y  of  lif e; 
; M S = M ulti pl e  S cl er o si s;  M S Q o L -5 4 = M ulti pl e 
S cl er o si s  Q u alit y  of  Lif e  5 4  Q u e sti o n n air e;
 R M S = R el a p si n g  M ulti pl e  S cl er o si s;   S A E =S eri o u s  a d v er s e  e v e nt; 
; 
.  
 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2 /6 6  
 
 
4  
St u d y Desi g n  
4. 1  
O ver all Desi g n  
•  T his will  be a n  o pe n  la bel,  si n gle  ar m,  e x pl orat or y, m ultice nter , retr os pecti ve  a n d 
pr os pecti ve, 2- y ear P has e I V exte nsi o n st u d y , of p artici pa nts wit h hi g hl y- acti ve R M S w h o 
c o m plete d t he C L A RI F Y M S trial ( E u dra C T n o.: 2 0 1 7- 0 0 2 6 3 2- 1 7).  
•  T he  C L A RI F Y M S trial was a si n gle ar m, o pe n la bel, m ultice nte r, 2-year P hase I V st u d y 
of partici pa nts w h o recei ve d cla dri bi ne ta blets f or 2 years, wit h o ne treat me nt c o urse of 
2 wee ks at t he be gi n ni n g of eac h year. T he Fi nal St u d y Visit of t he  C L A RI F Y M S trial 
( M 2 4) is pla n ne d 1 2 m o nt hs after t he i nitiati o n of t he sec o n d -year treat me nt ; i nitiati o n of 
t he sec o n d-y ear treat me nt is  pla n ne d 1 2 m o nt hs after i nitial d ose of cla dri bi ne ta blets, b ut 
c o ul d be dela y e d d ue t o, f or i nsta nce, l y m p h oc yte c o u nt bel o w e x pecte d ra n ges.  
•  T he e xte nsi o n st u d y i n v ol ves t he f oll o w- u p of p artici pa nts f or a n a d diti o nal 2- year peri o d  
( u ntil  4  years after  i nitial  a d mi nistrati o n  of cla dri bi ne ta blets),  d uri n g w hic h  t he 
partici pa nts are n ot tr eate d wit h cla dri bi ne t a blets. T he ai m is t o i ncl u de partici pa nts fr o m 
c o u ntries wit h at least 2 0 partici pa nts e nr olle d i n t he C L A RI F Y M S trial or sites wit h at 
least 1 0 partici pa nts e nr olle d i n t he C L A RI F Y M S trial. 
•  T he e xte nsi o n  st u d y Bas eli ne will be  pl a n ne d as near t o M 2 4 as p ossi ble; t he e xte nsi o n 
st u d y Baseli ne ma y  als o  be  t he  sa me visit  as M 2 4. At Baseli ne ,  data  will  be  c ollecte d 
retr os pecti vel y fr o m t he p ote ntial tra nsiti o n ga p peri o d bet wee n M 2 4 a n d C L A RI F Y M S 
E xte nsi o n B aseli ne, a n d  pr os pecti ve dat a will be c ollecte d as p er Sc he d ul e of Acti vities  
(Secti o n 1. 3 ). I nf or me d  c o nse nt  f or  partici pati o n  i n  t he  e xte nsi o n  st u d y  nee ds  t o  be 
o btai ne d bef or e a n y assess me nts w hic h are s p ecific t o  t he e xte nsi o n st u d y.  
•  Partici pa nt s will atte n d visits f or assess me nts, i ncl u di n g t he e xte nsi o n st u d y Baseli ne , M 3 6 
at 3 6 m o nt hs/3 years  si nce i nitial d ose of cla dri bi ne ta blets, a n d M 4 8 at 4 8 m o nt hs/ 4 years  
si nce i nitial d ose of cla dri bi ne ta blets. T he visits s h o ul d  be pla n n e d as cl os e t o t he yearl y 
date as p ossi ble, b ut as a ma xi m u m,  fall wit hi n a wi n d o w of ± 2 8 da ys. A p artici pa nt  ma y 
ret ur n  f or  a n U nsc he d ul e d  Visit  at  t he  discreti o n  of  t he  I n v esti gat or  t o  u n der g o  f urt h er 
e val uati o ns.  T he  data  fr o m  Sc he d ule d  a n d U ns c he d ule d  Visits will  be  c ollecte d  i n  t he 
electr o nic case re p ort f or m ( eC R F ).  
•  I n  t he  e v e nt  of  earl y  dis c o nti n uati o n  fr o m  t he e xte nsi o n  st u d y,  t he  parti ci pa nt will  be 
i n vite d  t o ret ur n  f or  t he  Earl y Disc o nti n uati o n  V isit  f or  fi nal  assess me nt. I n  cas e  t he 
partici pa nt is n ot willi n g t o or ca n n ot ret ur n t o t he site f or t he Earl y Disc o nti n uati o n Visit,  
a tele p h o ne call will be  or ga nize d t o o btai n t he reas o n f or wit h dra w al a n d A E re p orti n g. 
•  T he  sc he m a  a n d  visit  sc he d ules  f or  efficac y  a n d  safet y  assess me nts  are  det aile d  i n 
Secti o ns  1. 2  an d  1. 3 . 
•  T he st u d y ai ms t o e nr oll t he first partici pa nt i n Q 1 2 0 2 1 a n d ha ve t h e last partici pa nt’s visit 
i n Q 4 2 0 2 3. 
•  A Scie ntific Steeri n g C o m mittee ( S C ) will be esta blis he d t o e ns ure t h at t he st u d y meets 
scie ntific sta n dar ds (Refer t o  A p pe n di x 2 ). 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 3 /6 6  
 
 
4. 2  
Scie ntific R ati o n ale f or St u d y Desi g n  
T he treat me nt b ur de n of M S is si g nifica nt a n d f urt her e vi de nce f or t he l o n g-ter m effect of ne w 
t hera pies is nee de d ( Derf uss 2 0 2 0 ; L ucc hetta 2 0 2 0 ). This e xte nsi o n st u d y of t he C L A RI F Y M S 
trial will c o ntri b ute t o t he k n o wle d ge o n t he l o n g-ter m effect a n d safet y  of cla dri bi ne ta blets f or 
t he t hir d a n d f o urt h y ear after i nitiati o n of treat me nt, f oc usi n g o n c o g niti o n a n d H R Q o L, a m o n g 
a d ults wit h hi g hl y- acti ve R M S .  
Cla dri bi ne ta blets treat me nt  has  a  ma xi m u m  d urati o n of  2 0  da ys  i n 2 years,  after  w hic h 
partici pa nt s  are t o be m o nit o re d acc or di n g t o t he S m P C  f or a n a d diti o nal 2 years  (treat me nt -
free). T he  desi g n  of  t his e xte nsi o n st u d y  is  base d  o n t his cla dri bi ne  t a blet  treat me nt-free 
m o nit ori n g peri o d, wit h t he pa rtici pants visiti n g I n vesti gat ors as part of  r o uti ne cli nical practice ; 
m ost assess me nts are p art of r o uti ne cli nical practice,
 
 
  
T he pri mar y o bjecti v e of t his st u d y is t o assess c o g niti o n i n partici pa nts wit h hi g hl y -acti ve R M S  
at 4 years aft er i nitial d os e of cl a dri bi ne ta blets . Partici pa nts wit h hi g hl y- acti ve R M S are at hi g h 
ris k f or earl y c o g niti ve i m pair me nt. T he pre val e n ce of c o g niti ve i m pair me nt i n M S is re p orte d 
t o be ar o u n d 4 3% t o 7 0 %. C o g niti ve i m pair me nt has a detri me nt al effect o n t he li ves of M S 
patie nts  b y  re d uci n g  s ocial  acti vities,  i ncreasi n g  p h ysical  de pe n de nce,  retar di n g  pr o gress  i n 
re ha bilitati o n, a n d affecti n g e ver y da y life acti vities  (La n g d o n 2 0 1 0 ). 
T o  assess  c o g niti ve  f u ncti o n  o ver  t h e  st u d y  peri o d, an  e x pert  c o ns e ns us  c o m mittee  of 
ne ur ol o gists  a n d  ne ur o ps yc h ol o gists,  wit h  e xte nsi ve  researc h  a n d  cli nical  e x perie n ce  of  M S 
c o g niti o n, ha ve r ec o m me n de d 
 
. T he 
 is a u ni versall y acce pte d assess me nt f or c o g niti ve f u ncti o n i n M S t hat 
ta kes a s h ort ti me t o a d mi nister, is hi g hl y se nsiti ve a n d relia ble, a n d h ealt hcare pr ofessi o nals ca n 
easil y be trai ne d t o a d mi nister it, w hereas q u alifie d ne ur o ps yc h ol o gists are re q uire d f or ot her 
si milar assess me nts  (Be ne dict 2 0 1 2 ). T he 
; a  
 c o m p o ne nt has bee n c orrelate d t o 
 (Batista  2 0 1 2 ). T h e  
  is  c ollecte d  r o uti n el y  i n  M S  care  i n  all 
partici pati n g c o u ntries, w hile t he ot her c o m p o ne nts of  
 are n ot, as t he y ha ve n ot bee n 
vali date d  yet  i n  s o me  of  t he  partici pati n g  c o u ntries  (i ncl u di n g  A ustria,  t he  Net herla n ds,  a n d 
De n mar k).  
T he sec o n d ar y o bjecti ve of t his st u d y is t o assess H R Q o L i n partici pa nts wit h hi g hl y-acti ve R M S  
at 4 years after i nitial d os e of cla dri bi ne ta blets . T he H R Q o L  of patie nts  wit h M S is l o wer t ha n 
patie nt s wit h a n y ot her c hr o nic c o n diti o ns, i ncl u di n g isc he mic h eart disease, T y pe- 2 dia b etes, 
a n d  Cr o h n’s  disease (Or me  2 0 0 7 ). T he M ulti ple  Scler osis  Q ualit y  of  Life  5 4  Q uesti o n naire 
(M S Q o L - 5 4) is a n i deal q uesti o n naire t o assess H R Q o L  i n M S patie nts o ver a peri o d of ti me, 
beca use it ca n a d dress t he i m pact of t he l o w b ur de n of treat me nt of cla dri bi ne ta blets i n o verall 
H R Q o L , w hic h  c o vers  m ulti ple  d o mai ns,  i ncl u di n g  r ole  li mitati o ns,  b o dil y  pai n, p h ysical 
f u ncti o n, e m oti o nal well bei n g, e ner g y, healt h perce pti o ns, s ocial f u n cti o n, c o g niti ve f u ncti o n, 
healt h distress, se x ual f u ncti o n, c ha n ge i n healt h, a n d o verall q ualit y of life.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 8 7 5 5 0 _ 6 7 4 8 4 7 1
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 5 /6 6  
 
 
Pr os pecti ve a p pr o v al of pr ot oc ol de viati o ns t o i ncl usi o n a n d e xcl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d. 
Bef ore perf or mi n g a n y st u d y assess me nts t hat are  n ot part of t he partici pa nt’s r o uti ne me dical 
care, t he I n vesti gat or will c o nfir m t hat t he partici pa nt or t he partici pa nt’s le gal re pres e ntati ve 
has pr o vi de d writte n i nf or me d c o nse nt, as i n dicate d i n  A p pe n di x 2 . 
5. 1  
I ncl usi o n Criteri a 
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y: 
1.  Partici pa nts ha vi n g partici pate d i n t he C L A RI F Y M S trial, w h o  
a. Ha ve  at least C L A RI F Y M S Baseli ne data o n S D M T  
b.  Recei ve d at least a si n gle d ose of cla dri bi ne t a blets i n t he C L A RI F Y M S trial  
c. C o m plete d t he Fi nal St u d y Visit ( M 2 4) of t he C L A RI F Y M S trial. 
2.  Ca pa ble of gi vi n g  si g ne d i nf or me d c o ns e nt, as i n dicate d i n  A p p e n di x 2 , w hic h i ncl u des 
c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he i nf or me d c o nse nt f or m 
(I C F) a n d t his pr ot oc ol. 
5. 2  
E xcl usi o n Criteri a  
Partici pa nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y: 
1.  Partici pa nt  is  c o nsi dere d  b y  t he  I n vesti gat or  a n d  S p o ns or ,  f or  a ny  reas o n,  t o  be  a n 
u ns uita ble ca n di date f or t he st u d y. 
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce  
2.  Partici pati o n i n ot her st u dies/trials.  
5. 3  
Lifest yle C o nsi der ati o ns  
N ot a p plica ble.  
5. 4  
Scree n F ail ures  
I n di vi d uals w h o d o n ot meet t he criteria f or parti ci pati o n i n t his st u d y (scree n fail ure) ma y n ot 
be rescree n e d.   
6  
St u d y I nter ve nti o n(s)  
N ot a p plica ble.  
6. 1  
St u d y I nter ve nti o n(s) A d mi nistr ati o n  
N ot a p plica ble.  
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 6 /6 6  
 
 
6. 2  
St u d y  I nter ve nti o n(s)  Pre p ar ati o n,  H a n dli n g,  St or a ge,  a n d 
Acc o u nt a bilit y  
N ot a p plica ble.  
6. 3  
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g  
N ot a p plica ble.  
6. 4  
St u d y I nter ve nti o n C o m pli a nce  
N ot a p plica ble.  
6. 5  
C o nc o mit a nt T her a p y  
Rec or d  i n  t he case  re p ort  f or m  ( C R F ) all  c o n c o mita nt  t hera pies  (e. g.,  m e dici nes  or  n o n dr u g 
i nter ve nti o ns) use d fr o m t he ti me t he partici pa nt si g ns t he i nf or me d c o ns e nt u ntil c o m pleti o n of 
t he  st u d y,  i ncl u di n g  a n y  c ha n ges.  F or  pres cri pti o n  a n d  o ver-t he-c o u nt er  me dici nes,  vacci nes, 
vita mi ns,  a n d  her bal  s u p ple me nts,  rec or d  t he  n a me,  reas o n  f or  use,  d ates  a d mi nistere d,  a n d 
d osi n g i nf or mati o n.  I n a d diti o n, t he f oll o wi n g c o nc o mita nt t hera pies will be rec or d e d i n t he C R F 
as well: 
•  C o nc o mita nt  t hera pies  t hat  are  li n ke d  t o  a  s eri o us  a d verse  e vent  ( S A E ),  w hic h were 
i nitiate d  d uri n g  t he  C L A RI F Y  M S  trial,  a n d  are  o n g oi n g  at  t he  ti me  of  e nr olli n g  (i.e., 
si g ni n g t he i nf or me d c o nse nt) i n t he e xte nsi o n st u d y. 
•  C o nc o mita nt t hera pies t hat were i nitiate d after t he Fi nal St u d y Visit of t he C L A RI F Y M S 
trial ( M 2 4) a n d pri or t o e nr olli n g (i.e., si g ni n g t he i nf or me d c o nse nt) i n t he e xte nsi o n st u d y . 
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n c o nc o mita nt or pri or t h era p y. 
T here are n o r estricti o ns re gar di n g c o nc o mita nt t hera pies t hat a p artici pa nt ca n be o n d uri n g t he 
st u d y peri o d; partici pa nts will be treate d at t he dis creti o n of t he I n v esti gat or.  
•  Disease -relate d: All c o n c o mita nt me dicati o ns use d f or c o n diti o ns / s y m pt o ms relate d t o M S 
(f or e x a m ple, pai n, f ati g ue or wea k ness, i nc o or di n ati o n, bla d der d ysf u ncti o n, s pasticit y). 
•  Me dical hist or y rel ate d: All c o nc o mita nt me dicati o n s use d f or a me dical c o n diti o n alrea d y 
re p orte d i n t he partici pa nt's me dical hist or y (f or e xa m ple, a n y f or m of pai n, es peciall y l o w er  
bac k pai n a n d h ea dac he, de pressi o n et c.) or fa mil y hist or y ( pri mar y hea d ac h e, i ns o m nia etc.).  
•  Self -me dicati o n:  As  t his  is  a n  o ut p atie nt st u d y,  s pecial  care  will  be  t a ke n  t o  q u esti o n 
partici pa nt s o n a n y self-me dicati o n,  a n d t h e y will be as ke d t o res p o n d a b o ut t he details of t he 
a d mi nistrati o n of t he d oses a n d t he c o nc o mita nt me dicati o ns i n a diar y. T he use of a n y her bal 
or nat ural pr o d uct s, or ot her " h o me re me dies" is all o we d. H o we v er, t h e use of t hese pr o d u cts, 
a n d  t he  use  of  vita mi ns,  n utriti o nal  s u p ple me nts  a n d  all   t he ot her  c o nc o mita nt  me dici nal 
pr o d ucts s h o ul d als o be n ote d i n a diar y. 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 7 /6 6  
 
 
•  Rela pse  ma na g e me nt:  I n  case  of  n e ur ol o gical  e v e nts  relate d  t o  M S,  wit h  rela pse  criteria 
( Secti o n 8. 1. 7. 1 ), treat me nt will be at t he discreti o n of t he I n vesti gat or, f oll o wi n g l ocal g o o d 
me dical practice a n d i nter nati o nal g ui deli nes.  
•  Disease reacti vati o n: I n t he cas e of dis ease reacti v ati o n, f urt her disease- m o dif yi n g treat me nt 
will be at t he discreti o n of t he I n vesti gat or.  
•  Pr o hi bite d me dici nes: As per  S m P C  f or cla dri bi ne ta blets. 
6. 6  
D ose Selecti o n a n d M o dific ati o n  
N ot a p plica ble.  
6. 7  
St u d y I nter ve nti o n after t he E n d of t he St u d y  
N ot a p plica ble.  
 
7  
Disc o nti n u ati o n  of  St u d y  I nter ve nti o n  a n d  P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al  
7. 1  
Disc o nti n u ati o n of St u d y I nter ve nti o n  
N ot a p plica ble.  
7. 2  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y  
•  A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me, at his/ her  o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he I n vesti gat or f or safet y, be ha vi oral, c o m plia nce, 
or a d mi nistrati ve reas o ns. 
•  A partici pa nt will be wit h dra w n fr o m t he st u d y if t he partici pa nt e nr olls i n a n ot her st u d y. 
•  At  t he  ti me  of  disc o nti n ui n g  fr o m  t he  st u d y, if  p ossi ble,  a Disc o nti n uati o n  Visit  will  be 
c o n d ucte d, as liste d i n t he Sc he d ule of A cti vities  ( Secti o n 1. 3 ). The Sc he d ule of Acti vities  
s pecifies  the  data  t o  c ollect  at  st u d y  disc o nti n uati o n  a n d  f oll o w -u p,  a n d  a n y  a d diti o nal 
e val uati o ns  t hat  n ee d  t o  be  c o m plete d.  If  a  p h ysical  visit  is  n ot  p ossi ble,  a n  o pti o n  f or  a 
tele p h o ne call is pr o vi de d, t o o btai n reas o n f or disc o nti n uati o n a n d t he safet y assessme nt at 
least. 
•  If t he p artici pa nt wit h dr a ws c o nse nt f or f ut ure i n v ol ve me nt i n t he st u d y, a n y data c ollecte d 
u p t o t hat p oi nt ma y still be use d,  b ut n o f ut ure data ca n be ge nerate d, a n d a n y bi ol o gical 
sa m ples c ollecte d will be destr o ye d, u nl ess t he I n vesti gat or o btai ns per missi o n t o retai n a n d 
e val uate t he s a m ples . 
•  A partici pa nt has t he ri g ht at a n y ti me t o re q uest destr ucti o n of a n y bi ol o gical sa m ples ta ke n. 
T he I n vesti gat or will  d oc u me nt t his i n t he site st u d y rec or ds. 
•  P artici pa nts w h o  are dis c o nti n ue d/ wit h dra w n fr o m t he st u d y will n ot be  re place d. 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 8 /6 6  
 
 
•  T he I n v esti gat or will sec ure t he safet y of t he st u d y partici pa nts a n d ma k e e ver y atte m pt t o 
c ollect data.  
7. 3  
L ost t o F oll o w -U p  
A  partici pa nt  will  be  c o nsi dere d  l ost  t o  f oll o w -u p  if  he  or  s he  re p eate dl y  fails  t o  ret ur n  f or 
Sc he d ule d Visits a n d is u na ble t o be c o ntacte d b y t he st u d y site. 
T he f oll o wi n g acti o ns will  be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y 
visit:  
•  T he site will  atte m pt t o c o ntact t he partici pa nt a n d resc he d ul e t he misse d visit as s o o n as 
p ossi ble,  c o u nsel  t he  partici pa nt  o n  t he  i m p orta nce  of  mai ntai ni n g  t he  assi g ne d  visit 
sc he d ule a n d ascertai n if t he partici pa nt wa nts t o or s h o ul d c o nti n ue i n t he st u d y. 
•  Bef ore a partici pa nt is dee me d “l ost t o f oll ow- u p” , t he I n vesti gat or or d esi g nee will  ma k e 
e ver y eff ort t o re gai n c o ntact wit h t he partici pa nt: 1) w h ere p ossi ble, ma k e 3 tel e p h o ne 
calls;  2) if  necessar y,  s e n d  a  certifie d  letter ( or  a n  e q ui vale nt  l ocal  met h o d)  t o  t he 
partici pa nt’s last k n o w n maili n g a d dress, a n d 3) if a partici p a nt has gi ve n t he a p pr o priat e 
c o nse nt,  c o ntact  t he  partici pa nt’s  ge neral  practiti o ner  f or  i nf or mati o n.  T hese  c o ntact 
atte m pts will  be d oc u me nte d i n t he partici pa nt’s me dical rec or d. 
•  If t he partici pa nt c o nti n u es t o be u nreac h a ble, he/s he will be dee me d as “l ost t o f oll o w -
u p”. 
8  
St u d y Assess me nts a n d Pr oce d ures  
•  St u d y  assess me nts  a n d  pr oce d ures  a n d  t heir  ti mi n g  are  s u m marize d  i n  t h e  Sc he d ule  of 
Acti vities  (Secti o n  1. 3 ). 
•  N o  pr ot oc ol wai vers or e xe m pti o ns are all o we d. 
•  I m me diat e saf et y c o n cer ns are disc usse d wit h t he S p o ns or i m me diatel y u p o n occ urre nce 
or a ware ness.   
•  A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifi e d i n t h e Sc he d ule of 
Acti vities , is esse ntial a n d re q uire d f or st u d y c o n d uct. 
•  All  scree ni n g  e val u ati o ns will  be  c o m plete d  a n d  re vie we d  t o  c o nfir m  t hat  p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T he In vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nts scree ne d, t o c o nfir m eli gi bilit y, a n d if a p plica ble, rec or d 
reas o ns f or scr ee ni n g fail ure. 
•  Pri or  t o  perf or mi n g  a n y  st u d y  assess me nts  t hat  are  n ot  part  of  t he  p artici pa nt’s  r o uti ne 
me dical  care,  t he  I n vesti gat or  will  o btai n  writte n  i nf or me d  c o nse nt  as  s pecifie d  i n  
A p pe n di x 2 . 
•  Pr oce d ures c o n d ucte d as p art of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d c o u nt) 
a n d o btai ne d bef ore si g ni n g of t he I C F ma y be use d f or scree ni n g or b as eli ne p ur p oses 
pr o vi de d t he pr o ce d ur es met t he pr ot oc ol -s pecifie d criteria a n d were p erf or me d wit hi n t he 
ti me fra me defi ne d i n t he Sc he d ule of A cti vities . 
Gl o bal Versi o n I D: C CI

C CI
C CI
C CI

CCI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 1 /6 6  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 1. 2  
H e alt h R el ate d Q u alit y of L ife  
8. 1. 2. 1  
M ulti ple S cler osis Q u alit y of Life- 5 4  I nstr u me nt  
T he M S Q o L -5 4 q uesti o n naire will  be c o m plete d b y t he partici pa nt s o n t he ta blet at t he site . T he 
M S Q o L -5 4  is  a m ulti di me nsi o nal  healt h -relate d  q ualit y  of  life  meas ure  t hat  c o m bi nes  b ot h 
ge neric  a n d  M S -s p ecific  ite ms  i nt o  a  si n gle  i nstr u me nt (Vic kre y  1 9 9 5 ; Vic kre y  1 9 9 7 ).  T h e 
M S Q o L -5 4 q uesti o n naire was de vel o pe d t o meas ure H R Q o L i n patie nts wit h M S. It is c o m p ose d 
of 5 4 ite ms a n d is a c o m bi nati o n of t he S F-3 6 as well as a n a d diti o nal 1 8 disease -s pecific ite ms 
s uc h as fati g ue a n d c o g niti ve f u ncti o n. Vali date d tra nslate d versi o ns will be use d i n a p plica ble 
c o u ntries.  
 
 
 
 
 
 
 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 2 /6 6  
 
 
 
 
 
 
 
8. 1. 3  
C O VI D -1 9 S ur ve y  
T he C O VI D -1 9 S ur v e y will c ollect i nf or mati o n o n:  
•  P artici pa nts’ p ote ntial i nfecti o n (s) wit h C O VI D -1 9  si nce t he be gi n ni n g of t he pa n de mic 
a n d t he se verit y of t he s y m pt o ms 
•  Infect i o ns a n d/ or  m ortalit y  d ue  t o  C O VI D - 1 9 i n  t he  partici pa nts’  fa mil y  a n d  s ocial 
e n vir o n me nt 
•  P ote ntial  q uara nti ne peri o ds a n d l oc k d o w ns  
•  Partici pa nts ’ per cei ve d i m pact of l oc k d o w ns o n pr ofessi o nal a n d s o cial acti vities  
•  Partici pa nts’ stress le vel relate d t o l oc k d o w n a n d ma n dat or y s ocial restricti o ns  
8. 1. 4  
E m pl o y me nt St at us  
T he I n vesti gat or  will  c ollect  t he  partici pa nt’s  e m pl o y ment  stat us  t o  classif y  i n  o ne  of  t he   6 
a vaila ble e m pl o y me nt c o n diti o ns: U ne m pl o ye d, Sic k lea v e, E m pl o ye d/ part ti me, E m pl o ye d/f ull 
ti me, E d ucati o n, H o me ma ker. 
8. 1. 5  
Dis a bilit y Assess me nts  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 3 /6 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 4 /6 6  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Gl o bal Versi o n I D: 
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 5 /6 6  
 
 
8. 1. 7  
Rel a pses  
I n t his pr ot oc ol, s y m pt o ms a n d si g ns of rela pse or w orse ni n g of M S si nce t he pre vi o us visit will 
us uall y be ca pt ure d i n t he c o nte xt of t he efficac y assess ment a n d  rec or d e d o n t he rela ps e m o d ule 
of t he e C R F. T heref ore, s y m pt o ms, rela pses or w orse ni n g of M S will n ot be c o nsi dere d as A Es 
n or ca pt ure d o n t he A E m o d ule of t he e C R F u nless c o nsi dere d p ossi bl y or pr o ba bl y rel ate d t o 
cla dri bi ne ta blets (i.e. w orse ni n g is n ot c o nsiste nt wit h t he a ntici pate d nat ural pr o gressi o n of t he 
disease).  
8. 1. 7. 1  
Rel a pse E v al u ati o n  
All t he f oll o wi n g criteria are t o be met f or esta blis hi n g a n M S cli nical rela pse  (i.e., q ualif yi n g 
rela pse): 
1.  Ne ur ol o gical  a b n or malit y,  eit her  n e wl y  a p peari n g  or  re -a p p eari n g,  wit h  a b n or malit y  
s pecifie d b y b ot h 
a. Ne ur ol o gical a b n or malit y se parat e d b y at least 3 0 da ys fr o m o nset of a prece di n g  
cli nical e ve nt,  a n d  
b.  Ne ur ol o gical a b n or malit y lasti n g f or at least 2 4 h o urs 
2.  A bse nce of fe v er or k n o w n i nfecti o n (fe ver wit h te m perat ure > 3 7. 5° C / 9 9. 5 ° F) 
3.  O bjecti ve  ne ur ol o gical  i m pair me nt,  c orrelati n g  wit h  t he 
partici pa nt ’s  re p orte d 
s y m pt o ms, defi ne d as eit her   
a. I n crease i n at least o ne of t he f u ncti o nal s yste m sc ores of t he E D S S, or 
b.  I n crease of t h e t otal E D S S sc ore  
T he occ urr e nce of parest hesia, fati g ue, me ntal s y m pt o ms, a n d/ or ve getati ve s y m pt o ms wit h o ut 
a n y a d diti o nal s y m pt o m will n ot be classifie d as a n M S cli nical rela pse.  
8. 1. 7. 2  
Pr oce d ure f or Rel a pse E v al u ati o n  
T he partici pa nt  will be i nstr ucte d t o i m me diatel y c o ntact t he treati n g p h ysicia n if he/s he de vel o ps 
ne w or re -occ urri n g or w orse ni n g ne ur ol o gical (i n cl u di n g vis ual) s y m pt o ms. At eac h Sc he d ule d 
Visit , t he  patie nt  diar y  will  be re vie we d,  a n d t h e  partici pa nt will  be  as k e d  w het her  a n y  s uc h 
s y m pt o ms ha ve occ urr e d.  
U p o n  re p orti n g  s y m pt o ms  i n dicati ve  of  a  rel a pse,  t he  I n vesti gat or  will  assess  w het her  t he 
s y m pt o ms  occ urre d i n  t he  pres e nce  of  fe ver  or  i nfecti o n  (i n  case  of  a n  u nsc he d ule d  p h o n e-
c o ntact, t he tr eati n g p h ysicia n ma y si m pl y as k t he partici pa nt ). If fe ver or i nfecti o n is e xcl u d e d, 
t he I n vesti gat or m ust arr a n ge f or a ne ur ol o gical e xa mi nati o n as s o o n as p ossi ble, at t he latest 
wit hi n 7 da ys f oll o wi n g t he re p orti n g of t h e e ve nt. If fe v er or i nfecti o n ca n n ot be e xcl u de d, t he 
ne ur ol o gical e xa mi nati o n b y t he I n vesti gat or  will ha ve t o  be  p ost p o ne d u ntil t he fe ver or t he 
i nfecti o n ha ve ceas e d ( pr o vi de d, t hat t he s y m pt o ms i n dicati ve of a rela pse are still prese nt). 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 6 /6 6  
 
 
Base d  o n  t he  res p ecti ve  E D S S  sc ores,  i n  c o nj u ncti o n  wit h  t he  res ults  fr o m  pre vi o us 
e xa mi nati o ns, t he I n v esti gat or will assess w het her t he E D S S criteri o n f or a rela pse d uri n g t he 
c o urse of t he st u d y is f ulfille d. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 1. 1 0  
P atie nt Di ar y  
T he partici pa nts will be pr o vi de d wit h access t o a diar y t o rec or d det ails o n A Es  a n d c o nc o mita nt 
me dicati o n s a n d pr oce d ures . T h e partici pa nt s will recei ve i nstr ucti o ns re g ar di n g t he filli n g o ut 
of t he diar y. 
T he partici pa nt’s diar y e ntries m ust be re vie w e d b y t he st u d y c o or di nat or(s)/ n urse(s) wit h t he 
partici pa nt  t o  clarif y  a n y  discre p a ncies  a n d  e n s ure  pr o p er  c o m pleti o n.  T his  re vie w  m ust  be 
c o m plete d  at  eac h  visit  a n d  t he  re vie w  rec or d e d  i n  t he  p artici pa nt’s  cli nic  visit  n otes.  T he 
a p p oi nte d desi g nee will e nter i n t he e C R F w hat eac h partici pa nt rec or ds o n his/ her f or m a n d a n y 
i nf or mati o n t hat is o btai ne d after s u bse q ue nt q uesti o ni n g of t he partici pa nts. 
8. 1. 1 1  
Retr os pecti ve D at a C ollecti o n  
Pre vi o us meas ure me nts of efficac y assess me nts, perf or me d as part of t h e C L A RI F Y M S trial, 
will be retrie ve d i n t he a nal ysis p hase.   
Gl o bal Versi o n I D: 
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 7 /6 6  
 
 
8. 2  
S afet y Assess me nts a n d Pr oce d ures  
T he  safet y  pr ofile  of cla dri bi ne  ta blets  will  be  assesse d  t hr o u g h  t he  rec or di n g,  re p orti n g  a n d 
a nal ysis of b aseli ne me di cal c o n diti o ns, A Es, p h ysical e xa mi nati o n fi n di n gs, a n d vital si g ns.  At 
eac h St u d y Visit ( Secti o n 1. 3 ), the partici pa nt will be q uerie d o n c ha n g es i n his or her  disease  
c o n diti o n a n d t he patie nt diar y will be re vie we d f or a n y A Es t hat ma y ha ve occ urre d bet wee n 
t he visits. C o m pre he nsi ve assess me nt of a n y  p ot e ntial t o xicit y  e x perie nce d b y eac h partici pa nt 
will be c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. 
T he I n vesti gat or will re p ort a n y A Es, w h et her o bser ve d b y t he I n vesti gat or or re p orte d b y t he 
partici pa nt; t he r e p orti n g peri o d  is s pecifie d i n Secti o n 8. 3. 1 . All A Es a n d S A Es m ust be re p ort e d 
o n t he a p pr o priate eC R F pa ge as des cri be d i n A p pe n di x 3 . M ore i n f or mati o n ca n be f o u n d i n 
A p pe n di x 3  an d i n t he C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns pr o vi de d b y t he S p o ns or. 
8. 2. 1  
P h ysic al E x a mi n ati o ns   
•  At  t he  discreti o n  of  t he  p h ysicia n, a c o m plete  or  brief  p h ysical  e x a mi nati o n  will  be 
perf or me d:  
•  A c o m plete p h ysical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he 
Car di o vasc ular, Res pirat or y, Gastr oi ntesti nal a n d Ne ur ol o gical s yste ms.  
•  A brief p h ysical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, 
l u n gs, car di o vasc ular s yste m, a n d a b d o me n (li ver a n d s plee n). 
•  A b n or mal res ults will be d oc u me nte d i n t he C R F.  
•  I n v esti gat ors  will  pa y  s pecial  atte nti o n  t o  cli nical  si g ns  relate d  t o  pre vi o us  seri o us 
ill nesses. 
8. 2. 2  
Vit al Si g ns  
Vital si g ns will be meas ure d i n a s e mi -s u pi ne p ositi o n after 5 mi n utes rest a n d will i ncl u de b o d y 
te m perat ur e, s yst olic a n d diast olic bl o o d press ure, p ulse, a n d res pirat or y rat e. 
8. 3  
A d verse E ve nts a n d Seri o us A d verse E ve nts  
•  I n t his secti o n, “st u d y i nter ve nti o n” refers  t o cla dri bi ne ta blets (i.e., t he st u d y i nter ve nti o n 
of t he C L A RI F Y M S pare nt st u d y) si nce n o st u d y i nter ve nti o n is a d mi nistere d i n t his 
st u d y. 
•  T he defi niti o ns of a n A E a n d a S A E  are i n A p pe n di x 3 .  
•  T he I n v esti gat or a n d a n y q ualifie d desi g nees (e. g., S u b-I n v esti gat ors) are res p o nsi ble f or 
detecti n g, d oc u me nti n g, a n d rec or di n g e v e nts t hat meet t he d efi niti o n of a n A E or S A E. 
T he I n vesti gat or re mai ns res p o nsi ble f or f oll o wi n g u p A Es t hat are seri o us or t hat ca use d 
t he partici pa nt t o disc o nti n ue t he st u d y, as s pecifi e d i n Secti o n  8. 3. 3 . 
•  Re q uests  f or  f oll o w -u p  will  us uall y  be  ma d e  via  t he St u d y  M o nit or, alt h o u g h  i n 
e xce pti o nal  cir c u msta nces  t he gl o bal  patie nt  safet y  de part me nt  ma y  c o ntact  t he 
I n v esti gat or directl y t o o btai n f urt her i nf or m ati o n or t o disc uss t he e ve nt. 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 8 /6 6  
 
 
8. 3. 1  
Ti me  Peri o d  a n d  Fre q ue nc y  f or  C ollecti n g  A d verse  E ve nt 
a n d Seri o us A d verse E ve nt I nf or m ati o n  
•  
All S A Es will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil M 4 8 ( E n d of St u d y Visit ) or 
Earl y  Disc o nti n uati o n  Visit  at  t he  ti me  p oi nts  s pecifie d  i n  t h e Sc he d ul e  of  Acti vities  
( Secti o n 1. 3 ).  Be y o n d  t his  re p orti n g  peri o d,  a n y  ne w  u ns olicite d  S A Es  t hat  t he 
I n v esti gat or s p o nta ne o usl y re p orts t o t he S p o ns or will be c ollecte d a n d pr o cesse d.   
•  
All A E s will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil M 4 8 ( E n d of St u d y Visit ) or 
Earl y Disc o nti n uati o n Visit at t he ti me p oi nts s pecifie d i n t he Sc he d ule of Acti vities. 
•  
T he date of t he last pr oce d ure acc or di n g t o t he C L A RI F Y M S trial (i.e., t he C L A RI F Y 
M S e xit date) a n d t he d at e of si g ni n g i nf or me d c o nse nt f or t he  C L A RI F Y M S  E xte nsi o n 
st u d y (i.e., t he C L A RI F Y M S E xte nsi o n e nr oll me nt date) are i m p orta nt t o deter mi ne h o w 
A Es/ S A Es wil l be rec or d e d a n d re p orte d: 
•  S A Es wit h a n o nset d ate pri or t o t he C L A RI F Y M S e xit date a n d are o n g oi n g o n t he 
C L A RI F Y  M S 
E xte nsi o n  e nr oll me nt  date  wil l  be  rec or de d  o n  t h e  Me dical 
Hist or y/ C urre nt Me dical C o n diti o ns C R F. If t he e ve nt w orse ns, a ne w S A E will be 
rec or d e d o n t he A E C R F pa ge a n d re p orte d as s p ecifie d i n  A p pe n di x 3 . N o n -seri o us 
A Es  w hic h  are  o n g oi n g  at  t he  C L A RI F Y  M S  e xit  date  will   n ot  be rec or de d  i n  t he 
C L A RI F Y M S  E xte nsi o n st u d y. 
•  A E/ S A Es  wit h  a n  o nset  date  after  t he  C L A RI F Y  M S  e xit  date  a n d  bef ore  t he  
C L A RI F Y  M S   Exte nsi o n  e nr oll me nt  date  will  be  c ollecte d  retr os p ecti v el y  (after 
o btai ni n g i nf or me d c o nse nt) a n d rec or de d o n  t he A E C R F pa g e f or t he C L A RI F Y M S  
E xte nsi o n st u d y.  
•  A Es/ S A Es wit h a n o nset date aft er t he  C L A RI F Y M S  Exte nsi o n e nr oll me nt date will 
be rec or de d o n t he A E C R F pa ge f or t he C L A RI F Y M S  E xte nsi o n st u d y. 
•  
All  S A Es  will  be  rec or de d  a n d  re p orte d  t o  t he  S p o ns or  o r  desi g nee  i m me diatel y  a n d 
u n der  n o  circ u msta nce  will  t his  e xcee d  2 4  h o urs,  as  i n dicate d  i n  A p pe n di x  3 .  The 
I n v esti gat or will s u b mit a n y u p date d S A E dat a t o t he S p o ns or wit hi n 2 4 h o urs of it bei n g 
a vaila ble usi n g t he sa me pr oce d ure t hat was us e d f or t he i nitial re p ort. 
•  
I n v esti gat ors  are  n ot  o bli gate d  t o  acti vel y s olicit  A Es  or  S A Es after  t he  e n d  of  st u d y 
partici pati o n. H o w e ver, if t he In vesti gat or l ear ns of a n y S A E, i ncl u di n g a deat h, at a n y 
ti me  after  a  partici pa nt  has  been  disc har ge d  fr o m  t he  st u d y,  a n d  he/s he  c o nsi ders  t he 
e ve nt  t o  be  r eas o na bl y  relate d  t o  t he  st u d y  i nter ve nti o n s or  st u d y  parti ci pati o n,  t he 
I n v esti gat or will  pr o m ptl y n otif y t he S p o ns or. 
8. 3. 2  
Met h o d  of  Detecti n g  A d verse  E ve nts  a n d  Seri o us  A d verse 
E ve nts  
At eac h  St u d y Visit, t he p artici pa nt will be q ueri e d o n c ha n ges i n his or h er c o n diti o n. I n a d diti o n, 
t he partici pa nts will be as ke d t o  rec or d A Es  i n a c o nti n u o us ma n ner i n t heir patie nt diar y. 
Care will be ta k e n n ot t o i ntr o d uce bias w h e n detecti n g A Es a n d/ or S A Es. O pe n -e n d e d a n d n o n -
lea di n g  ver bal  q u esti o ni n g  of  t he  partici pa nt  is  t he  preferre d  m et h o d  t o  i n q uire  a b o ut  A E 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 9 /6 6  
 
 
occ urr e nces.  
It is i m p orta nt t hat eac h A E re p ort i ncl u de  a des cri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates a n d ti mes w he n it is i m p orta nt t o assess t he ti me of A E o nset relati ve t o t h e 
rec or d e d  tr eat me nt  a d mi nistrati o n  ti me),  its  se verit y,  its  ca usal  rel ati o ns hi p  wit h cla dri bi n e  
ta blets,  a n y  ot her  p ote ntial  ca usal  fact ors,  a n y  treat me nt  gi ve n  or  ot her  acti o n  ta ke n,  a n d  its 
o utc o me. I n a d diti o n, seri o us cases s h o ul d be i de ntifie d, a n d t he a p pr o priat e seri o us ness criteria 
s h o ul d be d oc u me nte d.  
T he  met h o d  of  rec or di n g,  e val uati n g,  a n d  assessi n g  ca usalit y  of  A E s a n d  S A Es a n d  t he 
pr oce d ur es f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are i n  A p pe n di x 3 . 
8. 3. 3  
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts  
After t he i nitial A E/ S A E re p ort, t he In v esti gat or is re q uire d t o pr o acti vel y f oll o w eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts. All S A Es  will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt 
is  ot her wise  e x plai ne d,  or  t he  p artici pa nt  is  l ost  t o  f oll o w-u p  (as  defi ne d  i n  Secti o n 7. 3 ). 
Reas o na ble  atte m pts  t o  o btai n  t his  i nf or mati o n will  be  ma de  a n d  d oc u me nte d.  It  is  als o  t he 
I n v esti gat or’s r es p o nsi bilit y t o e ns ure t hat a n y necessar y a d diti o nal  t hera pe utic meas ures  a n d 
f oll o w-u p  pr oce d ur es  are  perf or me d.  F urt her  i nf or mati o n  o n  f oll o w -u p  pr oce d ures  is  i n  
A p pe n di x 3 . 
8. 3. 4  
Re g ul at or y  Re p orti n g  Re q uire me nts  f or  Seri o us  A d verse 
E ve nts  
P r o m pt n otificati o n b y t he I n v esti gat or t o t he S p o ns or of a n S A E ( partic ularl y life-t hreate ni n g 
a n d deat hs) is ess e ntial s o t hat le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of 
partici pa nts a n d t he safet y of a st u d y i nter ve nti o n u n der c li nical i n vesti gati o n are met.  
T he S p o ns or has  a le g al res p o nsi bilit y t o n otif y  b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y  a ge n cies  a b o ut  t he  safet y  of a  st u d y  i nter ve nti o n  u n der  cli nical  i n vesti gati o n.  T he 
S p o ns or will c o m pl y wit h c o u ntr y -specific re g ulat or y re q uire me nts relati n g t o safet y re p orti n g 
t o t he re g ulat or y a ut h orit y, I nstit uti o nal Re vie w B oar ds (I R B)/I n de p e n de nt Et hics C o m mittees 
(I E C), a n d I n v esti gat ors. 
I n di vi d ual  Case  Safet y  Re p orts will  be  pre pare d  f or  s us pecte d  u ne x p ecte d  seri o us  a d verse 
reacti o ns  ( S U S A R)  acc or di n g  t o  l ocal  re g ulat or y  re q uire m e nts  a n d S p o ns or  p olic y  a n d 
f or war de d t o In vesti gat ors, as necess ar y.  
A n In v esti gat or w h o recei ves a n I n di vi d ual Case Safet y Re p ort descri bi n g a S U S A R or ot her 
s pecific  safet y  i nf or mati o n (e. g.,  E mer gi n g  Safet y  Iss ue  Re p ort,  s u m mar y  or  listi n g  of 
S A Es/ S U S A Rs)  fr o m  t he  S p o ns or  will  re vie w  a n d  t he n  file  it  al o n g  wit h  t he S m P C  in  t he 
I n v esti gat or’s  Site  File  a n d  will  n otif y  t he  I R B/I E C,  if  a p pr o priate  acc ordi n g  t o  l ocal 
re q uire me nts. 
8. 3. 5  
Pre g n a nc y  
•  Details of all pre g n a ncies i n fe male partici pa nts will be c ollecte d fr o m si g ni n g of t he I C F 
u ntil M 4 8  ( E n d  of  St u d y  Visit )  or  Earl y  Disc o nti n uati o n  Visit,  as  per  t he  Sc he d ule  of 
Acti vities  ( Secti o n 1. 3 ). Base d o n k n o w n p har m ac ol o gical effects of cla dri bi ne ta blets a n d 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 0 /6 6  
 
 
mec ha nis m of acti o n , n o pre g na nc y data fr o m fe m ale part ners of male p arti ci pa nts will be 
c ollecte d d uri n g t his st u d y si nce n o cla dri bi ne t a blet treat me nt is a d mi nistere d.  
•  If a pre g n a nc y is re p orte d, t he  I n v esti gat or will i nf or m t he S p o ns or  wit hi n 2 4 h o urs of 
lear ni n g of t h e pr e g na nc y a n d will f oll o w t he pr oce d ures s p ecifie d b el o w f or  c ollecti o n of 
pre g na nc y i nf or mati o n. 
•  A b n or mal  pre g na n c y  o utc o mes  (e. g.,  s p o nta n e o us  a b orti o n,  fetal  deat h,  still birt h, 
c o n ge nital a n o malies, ect o pic pre g na n c y) are c o nsi dere d S A Es. 
•  Pre g na ncies wit h a n o nset date after t he C L A RI F Y M S e xit date a n d bef ore t he C L A RI F Y 
M S E xte nsi o n e nr oll me nt date will be c ollecte d retr os pecti vel y after o btai ni n g i nf or me d 
c o nse nt f or t he C L A R I FY M S  E xte nsi o n st u d y. T he pre g n a nc y, of w hic h t he I n vesti gat or 
lear ne d  at  e nr oll me nt, s h o ul d  be  re p orte d  t o  t he  S p o ns or wit hi n  2 4  h o urs  after  patie nt 
si g ne d i nf or me d c o nse nt f or C L A RI F Y M S E xte nsi o n st u d y. 
 
C ollecti o n of Pre g n a nc y I nf or m ati o n 
Pre g na nc y r ele va nt i nf or mati o n o n male partici pa nts wit h fe male part ners will n ot be c ollecte d 
d ue t o la pse of m ore t h a n 6 m o nt hs si nce t he last d ose of cla dri bi ne t a blets.  
Fe male Partici pa nts w h o bec o me pre g na nt : 
•  T he In v esti gat or  will  c ollect  pre g na nc y  i nf or m ati o n  o n  a n y  fe male  partici pa nt  w h o 
bec o mes pre g n a nt w hile s he is i n t he st u d y or if s he beca me pre g na nt d uri n g t he ga p peri o d 
bet wee n C L A RI F Y M S Fi nal Visit ( M 2 4) a n d C L A RI F Y  M S E xte nsi o n Baseli ne. T he 
i nitial i nf or mati o n will be rec or d e d o n t he A E C R F pa ge a n d s u b mitte d t o t he S p o ns or 
usi n g t he a p plica ble p a per re p ort f or m . T he re p ort s h o ul d be s u b mitte d wit hi n t he  ti meli nes 
descri be d a b o ve . 
•  T he  partici p a nt  will  be  f oll o we d  t o  det er mi ne  t he  o utc o me  of  t he  pre g na nc y .  T he 
In v esti gat or will c ollect f oll o w - u p i nf or mati o n o n t he partici pa nt a n d t h e ne o nate, a n d t h e 
i nf or mati o n will be f or w ar de d t o t h e S p o ns or. G e nerall y, f oll o w -u p will n ot be re q uire d 
f or  l o n ger  t ha n  6  t o  8  wee ks  b e y o n d  t he  esti mate d  deli ver y  date.  A n y  ter mi nati o n  of 
pre g na nc y will be r e p ort e d, re g ar dless of fet al stat us ( prese n ce or a bse n ce of a n o malies) 
or i n dicati o n f or t he pr o ce d ure. 
•  W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na nc y c o m plicati o n 
or electi ve ter mi nati o n of a pr e g na n c y f or me dical reas o ns will be re p ort e d as a n A E or 
S A E  a n d rec or de d i n t he e C R F . 
•  A s p o nta ne o us a b orti o n ( occ urri n g at < 2 2 wee ks gestati o nal a ge) or still birt h ( occ urri n g at 
> 2 2 wee ks gestati o nal a g e) is al wa ys c o nsi dere d t o be a n S A E a n d will be re p o rte d as s uc h. 
•  A n y p ost -st u d y pre g n a nc y relate d S A E c o nsi dere d reas o n a bl y rel ate d t o cl a dri bi ne ta blets 
b y t he In vesti gat or will b e re p orte d t o t he S p o ns or as s pecifie d i n Secti o n 8. 3. 4 . W hile t he 
I n v esti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y partici pa nts, 
he or s he ma y lear n of a n S A E t hr o u g h s p o nta ne o us re p orti n g. 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 1 /6 6  
 
 
•  A n y  fe male  partici pa nt  w h o  bec o mes  pre g n a nt  w hile  partici pati n g  i n  t he  st u d y ma y 
c o nti n ue i n t he st u d y, as n o st u d y treat me nt is i n v ol ve d, a n d t he assess me nts are eit her part 
of r o uti ne me dical care , n o n-i n vasi ve P R Os, or n o n -e xte nsi ve bl o o d sa m ples . I n a d diti o n, 
partici pa nts  w h o  s witc h  t o  a n y  ot her diseas e -m o dif yi n g  dr u g ,  a p pr o pri ate  safet y  a n d 
c o ntrace pti o n meas ures will be f oll o we d as per t he ne w disease -m o dif yi n g dr u g ’s S m P C 
a n d l ocal cli nical pr actice.   
 
8. 3. 6  
Dise ase -Rel ate d  E ve nts  a n d/ or  Dise ase -Rel ate d  O utc o mes 
n ot Q u alif yi n g as A d verse E ve nt s or Seri o us A d verse E ve nt s 
T he f oll o wi n g diseas e -r elate d e ve nts are c o m m o n i n partici pa nts wit h hi g hl y- acti ve R M S  a n d 
ca n be seri o us/life-t hreat e ni n g: 
•  S y m pt o ms a n d si g ns of rela pse or w orse ni n g of M S 
Beca use  t hese  e v e nts  ar e  t y picall y  ass ociate d  wit h  t he  disease  u n der  st u d y , t he y  will  n ot  be 
re p orte d acc or di n g t o t he sta n dar d pr ocess f or e x pe dite d re p orti n g of A Es a n d S A Es e ve n t h o u g h 
t he e ve nt m a y meet t he d efi niti o n of an A E or  S A E. T hese e ve nts will be rec or de d o n t he rela pse 
m o d ule of t he e C R F  pa g e  wit hi n 1 5 da ys after t h e visit.  
H o we ver,  if  eit her  of  t h e  f oll o wi n g  c o n diti o ns  a p plies,  t he n  t he  e ve nt will  be  rec or de d  a n d 
re p orte d as a n S A E (i nstea d of a disease -relate d e v e nt): 
•  T he e ve nt is, i n t he In vesti gat or’s o pi ni o n, of great er i nte nsit y, fre q ue n c y, or d urati o n t ha n 
e x pecte d f or  t he i n di vi d ual partici pa nt (i.e., w ors e ni n g n ot c o nsiste nt wit h t he a ntici pate d 
nat ural pr o gr essi o n of t he disease). 
O R  
•  T he I n vesti gat or c o nsi ders t hat t here is a reas o n a ble p ossi bilit y t hat t he e ve nt was relate d 
t o st u d y i nter ve nti o n. 
8. 3. 7  
A d verse E ve nts of S peci al I nterest  
N ot a p plica ble.  
8. 4  
Tre at me nt of O ver d ose  
N ot a p plica ble.  
8. 5  
P h ar m ac o ki netics  
N ot a p plica ble.  
8. 6  
P h ar m ac o d y n a mics  
N ot a p plica ble.  
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 2 /6 6  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
Gl o bal Versi o n I D: 
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 3 /6 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
8. 9  
I m m u n o ge nicit y Assess me nts 
N ot a p plica ble.  
9  
St atistic al C o nsi der ati o ns  
T he  statistical  a nal yses  descri be d  i n  t his  secti o n  will  be  perf or me d  as  f urt her  o utli ne d  i n  t he 
I nte grate d  A n al ysis  Plan (I A P),  w hic h  will  be  fi nalize d  pri or  t o  data bas e  l oc k  a n d  will  be 
i ncl u de d i n t he C S R  f or t his pr ot oc ol.  
St u d y data will be i nte grate d wit h st u d y data fr o m t he C L A RI F Y M S trial as re q uire d t o perf or m 
t he statistical a nal yses. 
C o nti n u o us varia bles will b e s u m marize d usi n g d es cri pti ve statistics , i.e., n u m ber of p artici pa nts, 
n u m ber of partici pa nts wit h missi n g a n d n o n -missi n g val ues, mea n, sta n d ar d de viati o n, me dia n, 
2 5 t h Perce ntile, 7 5 t h Perce ntile ( Q 1 -Q 3), mi ni m u m, a n d ma xi m u m. Q ualitati ve varia bles wil l be 
s u m marize d b y c o u nts a n d perce nt a ges. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 4 /6 6  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. 3  
P o p ul ati o ns f or A n al yses  
T he a nal ysis p o p ulati o n are s pecifi e d i n Ta ble 5 . T he fi nal decisi o n t o e xcl u de partici pa nts fr o m 
a n y a nal ysis p o p ulati o n will be ma de pri or t o dat a base l oc k . 
T a ble 5  
 A n al ysis P o p ul ati o ns 
A n al y si s S et 
D e s cri pti o n  
S cr e e ni n g S et  
All p arti ci p a nt s  w h o pr o vi d e d i nf or m e d c o n s e nt f or t h e e xt e n si o n st u d y  
F ull A n al y si s S et ( F A S)  
T h e F A S will i n cl u d e all eli gi bl e p arti ci p a nt s  
S af et y  A n al y si s  P o p ul ati o n  
T h e S af et y  A n al y si s  S et  will i n cl u d e all p arti ci p a nt s fr o m t h e S cr e e ni n g S et w h o 
r e c ei v e d at l e a st o n e d o s e of cl a dri bi n e t a bl et s 
F A S = F ull a n al y si s s et . 
 
T he efficac y  a nal yses will be perf or me d o n t he F ull A nal ysis Set ( F A S ). All safet y a n al yses will 
be perf or me d o n t he Saf et y A nal ysis P o p ulati o n.  
9. 4  
St atistic al A n al yses  
T he st u d y is e x pl or at or y i n nat ure. A c o ntr ol of t he p ote ntial T y pe-I- err or i nflati o n ca us e d b y 
m ulti ple e n d p oi nts a n d m ulti ple testi n g is n ot i m ple me nte d.  
Para meter esti mates wit h ass ociate d 9 5 % c o nfi de n ce i nter vals will be re p ort e d, as a p plica bl e .  
T he st u d y dataset c o m prises of m ulti ple o utc o me assess me nts ma de f or eac h partici pa nt  o ver a 
2 4- m o nt h peri o d. T h eref ore, d ue t o t he l o n git u di n al nat ure of t h e dat a a n d t he le n gt h y f oll o w - u p 
peri o d, it is li kel y t h at missi n g o utc o me data will be prese nt d u e t o l oss t o f oll o w-u p. Patter ns 
Gl o bal Versi o n I D: C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 5 /6 6  
 
 
a n d de grees of missi n g ness will be s u m marize d a n d will tri g ger t he a p pr oac h t o deal wit h missi n g 
data.  
9. 4. 1  
Effic ac y A n al yses  
T he efficac y a n al yses ar e descri be d i n  Ta ble 6 . All efficac y a nal yses will be perf or me d o n t he 
F A S p o p ulati o n.  
T a ble 6  
 A n al ysis of Effic ac y E n d p oi nts 
E n d p oi nt  
St ati sti c al A n al y si s M et h o d s  
Pri m ar y 
T h e pr o p orti o n o f p arti ci p a nt s wit h n o d e cli n e or a m a xi m al d e cli n e of 4 p oi nt s i n S D M T s c or e 
at M 4 8 will b e d e s cri b e d u si n g a 9 5 % c o nfi d e n c e i nt er v al c o m p ut e d a c c or di n g t o Wil s o n’ s 
s c or e m et h o d.  
A l o gi sti c r e gr e s si o n wit h at l e a st a g e a n d B a s eli n e E D S S i n cl u d e d a s c o v ar i at e s will b e 
p erf or m e d a s s e n siti vit y a n al y si s. F urt h er f a ct or s or c o v ari at e s t o pr e di ct di s e a s e pr o gr e s si o n 
m a y b e a d d e d a s a p pr o pri at e.  
I n or d er t o i n v e sti g at e t h e r o b u st n e s s of r e s ult s of t h e pri m ar y effi c a c y a n al y si s wit h r e s p e ct t o 
mi s si n g v al u e s, a d diti o n al s e n siti vit y a n al y s e s will b e c o n d u ct e d b y a p pl yi n g m ulti pl e 
i m p ut ati o n t e c h ni q u e s. T h e i m p a ct of diff er e nt a s s u m pti o n s wit h r e g ar d s t o mi s si n g p att er n s 
will b e i n v e sti g at e d.  
S e c o n d ar y  
T h e diff er e n c e s i n M S Q o L -5 4 p h y si c al a n d m e nt al h e alt h s c or e s at M 4 8  will b e a s s e s s e d 
u si n g r e p e at e d mi x e d -eff e ct s  li n e ar r e gr e s si o n, a c c o u nti n g  f or cli ni c all y r el e v a nt f a ct or s  (e. g. , 
a g e a n d E D S S) , wit hi n -p arti ci p a nt c orr el ati o n , a n d p o ol e d c e nt er c orr el ati o n . 
E sti m at e s f or t h e m e a n diff er e n c e i n s c or e s b et w e e n s p e cifi e d ti m e p oi nt s will b e r e p ort e d, 
wit h a 9 5 % c o nfi d e n c e i nt er v al a n d 2- si d e d p -v al u e.  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
. 
 
 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
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 /6 6  
 
 
 
 H R Q o L =  
H e alt h  r el at e d  q u alit y  of  lif e; I A P= I nt e gr at e d a n al y si s  pl a n;  M S = M ulti pl e  s cl er o si s; M S Q o L -5 4 = M ulti pl e  S cl er o si s 
Q u alit y  of  Lif e  5 4  Q u e sti o n n air e;
 
 
9. 4. 2  
S afet y A n al yses  
T he saf et y a n al yses are d escri be d i n  Ta ble 7 . All s afet y a nal yses will be perf or me d o n t he Safet y 
A nal ysis  P o p ulati o n. A Es  a n d  S A Es  will  be c o d e d  usi n g  Me dical  Dicti o nar y  of  Re g ulat or y 
Acti vities (Me d D R A ). 
T a ble 7  
 Descri pti o n of S afet y A n al yses 
E n d p oi nt  
St ati sti c al A n al y si s M et h o d s  
Pri m ar y 
N ot a p pli c a bl e  
S e c o n d ar y  
N ot a p pli c a bl e  
 
 
 
 
 
 
. 
A E = A d v er s e e v e nt; M e d D R A = M e di c al Di cti o n ar y of R e g ul at or y A cti viti e s; S A E = S eri o u s a d v er s e e v e nt . 
9. 4. 3  
Ot her A n al yses  
Partici pa nt s’ de m o gra p hic fact ors a n d e xte nsi o n st u d y B aseli ne cli nical c h aract eristics will be 
s u m marize d.  
T he  data  c ollect e d  wit h  t he  C O VI D -1 9  S ur ve y  will  be  a nal yze d  as  a d diti o nal  e x pla nat or y 
varia bles t o t he efficac y a nal yses b y p ossi ble i m pacts of t he pa n d e mic.  
As  t he  e xte nsi o n St u d y  Visits  are  i nitiate d  2 years  after  t he  i nitial  treat me nt  wit h  cla dri bi ne  
ta blets, it ca n n ot be e xcl u de d t hat a s pecific t y pe of partici pa nt fr o m t he C L A RI F Y M S trial is 
a vaila ble  f or  f oll o w -u p.  A  p ote ntial  selecti o n  bias  will  be  e val uate d  b y  c o m pari n g  t he 
c haracteristics of t he p artici pa nts fr o m t he C L A RI F Y M S trial a n d t he partici pa nts i ncl u de d i n 
t his st u d y.  
9. 4. 4  
Se q ue nce of A n al yses  
Fi nal a nal yses will be perf or me d at  t he e n d of st u d y. I n a d diti o n,  i nteri m a nal ysis at e xte nsi o n 
st u d y Baseli ne or M 3 6 ma y be perf or me d. 
 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

S u bst a n c e  c o d e:  N/ A         C o g niti o n  a n d  H R Q o L i n  a d ults  wit h  hi g hl y  a cti v e  R M S  i n  Y e a r  3  a n d 
4  aft e r i niti a l  M a v e n cl a d®  d os e  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C  O  N  F I  D  E  N  T I  A  L  
I  N  F  O  R  M  A  T I  O  N 
4 7 /6 6  
 
 
1 0  
R ef e r e n c e s  
A m at o  M P,  P ort a c ci o  E,  G or etti  B  et  al.  R el e v a n c e  of  c o g niti v e  d et eri or ati o n i n  e arl y r el a psi n g -
r e mitti n g  M S:  a  3-y e ar f oll o w - u p st u d y. M ult  S cl er .  2 0 1 0; 1 6( 1 2): 1 4 7 4- 8 2. 
B atist a   S,    Zi v a di n o v    R,    H o o gs    M  et  al.  B as al  g a n gli a,  t h al a m us  a n d  n e o c orti c al  atr o p h y 
pr e di cti n g sl o w e d  c o g niti v e  pr o c essi n g i n  m ulti pl e s cl er osis. J  N e ur ol.  2 0 1 2; 2 5 9( 1): 1 3 9- 4 6. 
 
 
B e n e di ct  R H,  M orr o w  S,  R o d g ers  J,  et  al.  C h ar a ct eri zi n g  c o g niti v e  f u n cti o n  d uri n g  r el a ps e i n 
m ulti pl e s cl er osis.  M ult  S cl er.  2 0 1 4;  2 0( 1 3): 1 7 4 5- 5 2. 
C o o k  K F,  B a m er  A M,  R o d d e y  T S  et  al .  A  P R O MI S f ati g u e  s h ort f or m f or  us e  b y i n di vi d u als 
w h o  h a v e  m ulti pl e s cl er osis.  Q u al.  Lif e  R es .  2 0 1 2; 2 1( 6): 1 0 2 1- 3 0. 
C o mi    G,   C o o k  S D,    Gi o v a n n o ni    G  et  al.    M RI  o ut c o m es    wit h  cl a dri bi n e  t a bl ets  f or    m ulti pl e 
s cl er osis i n t h e  C L A RI T Y st u d y. J  N e ur ol.  2 0 1 3; 2 6 0: 1 1 3 6 – 4 6. 
D erf uss  T,  M e hli n g  M,  P a p a d o p o ul o u  A,  et  al.  A d v a n c es i n  Or al I m m u n o m o d ul ati n g  T h er a pi es 
i n  R el a psi n g  M ulti pl e  S cl er osis.  L a n c et  N e ur ol.  2 0 2 0; 1 9( 4): 3 3 6- 4 7. 
D u b e y  D,  C a n o  C A,  St u v e  O. I ntr a ct a bl e  a n d  hi g hl y  a cti v e r el a psi n g  m ulti pl e s cl er osis  –  r ol e  of 
al e mt u z u m a b.  N e ur o ps y c hi atr  Dis  Tr e at .  2 0 1 5; 1 1: 2 4 0 5 – 1 4. 
E M A/ 4 2 4 7 1 5/ 2 0 1 7.  P R A C  c o nfir ms r estri cti o ns  o n t h e  us e  of li n e ar  g a d oli ni u m  a g e nts.  B e n efit -
ris k  b al a n c e  of  c ert ai n li n e ar  g a d oli ni u m  a g e nts  n o l o n g er f a v o ur a bl e.  7 J ul y  2 0 1 7. 
Gi o v a n n o ni  G,  C o mi  G,  C o o k  S  et  al.  A  pl a c e b o -c o ntr oll e d tri al  of  or al  cl a dri bi n e f or r el a psi n g 
m ulti pl e s cl er osis.  N  E n gl J  M e d.  2 0 1 0; 3 6 2( 5): 4 1 6- 2 6. 
Hirst    C L,  P a c e    A,  Pi c k ers gill   T P  et  al.    C a m p at h   1-H  tr e at m e nt  i n  p ati e nts    wit h  a g gr essi v e 
r el a psi n g r e mitti n g  m ulti pl e s cl er osis. J  N e ur ol.  2 0 0 8; 2 5 5( 2): 2 3 1- 8. 
J o n es  E,  Pi k e J,  M ars h all  T  et  al . Q u a ntif yi n g t h e  R el ati o ns hi p  B et w e e n I n cr e as e d  Dis a bilit y  a n d 
H e alt h   C ar e   R es o ur c e    Utili z ati o n,  Q u alit y  of   Lif e,    W or k  Pr o d u cti vit y,   H e alt h   C ar e   C osts  i n 
P ati e nts  Wit h  M ulti pl e  S cl er osis i n t h e  U S.  B M C  H e alt h  S er v  R es.  2 0 1 6; 1 6: 2 9 4. 
K urt z k e  J F.  R ati n g  n e ur ol o gi c i m p air m e nt i n  m ulti pl e  s cl er osis:  A n  e x p a n d e d  dis a bilit y  st at us 
s c al e ( E D S S).  N e ur ol o g y.  1 9 8 3; 3 3( 1 1): 1 4 4 4- 5 2. 
L a n g d o n  D.  C o g niti v e i m p air m e nt i n  m ulti pl e  s cl er osis – r e c e nt  a d v a n c es  a n d  f ut ur e  pr os p e cts. 
E ur  N e ur ol  R e v.  2 0 1 0; 5: 6 9- 7 2. 
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 8 /6 6  
 
 
Leist T P, C o mi G, Cree B A et al. Effect of oral 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 n cet Ne ur ol . 2 0 1 4; 1 3( 3): 2 5 7- 6 7. 
L ucc hetta R C, Le o n art L P, G o nçal ves M V M et al. Relia bilit y i n l o n g -ter m cli nical st u dies of 
disease -m o dif yi n g  t hera pies  f or  rela psi n g -re mitti n g  m ulti ple  scler osis:  A  s yste matic  re vie w. 
P L o S O ne. 2 0 2 0; 1 5( 6):e 0 2 3 1 7 2 2. 
Mat hi o wetz V, We b er K, Kas h ma n N et al . A d ult N or ms f or t he Ni ne H ole Pe g Test of Fi n ger 
De xterit y. O TJ R . 1 9 8 5; 5: 2 4- 3 3. 
Ma ve ncla d 1 0 m g ta blets. S u m mar y of Pr o d uct C haract eristics. Merc k E ur o pe B. V. 2 2 A u g ust 
2 0 1 7. 
Accesse d  
fr o m:  
htt ps:// w w w.e ma.e ur o p a.e u/e n/ d oc u me nts/ pr o d uct -
i nf or mati o n/ ma ve ncla d-e par- pr o d u ct-i nf or mati o n _ e n. p df. Accesse d o n: 3 1 Ma y 2 0 2 0.  
M otl R W, C o he n J A, B e ne dict R, et al. V ali dit y of t he ti me d 2 5-f o ot w al k as a n a m b ulat or y 
perf or ma n ce o utc o m e me as ure f or m ulti ple scler osis. M ult Scler J. 2 0 1 7; 2 3( 5): 7 0 4- 1 0. 
Oreja -G ue vara  C.  O v er vie w  of  ma g n etic  res o n a nce  i ma gi n g  f or  ma na ge me nt  of  rela psi n g 
re mitti n g m ulti ple scler osis i n e ver y da y practice. E ur J Ne ur ol. 2 0 1 5; 2 2 S u p pl 2: 2 2- 7. 
Or me M, Kerri ga n J, T y as D, et al . T h e effect of disease, f u n cti o nal stat us, a n d rela ps es o n t he 
utilit y of pe o ple wit h m ulti ple scler osis i n t he U K. Val ue Healt h. 2 0 0 7; 1 0( 1): 5 4- 6 0. 
Prz y be k J, G niat k o ws ka I, Mir o ws ka -G uzel D  et al. E v ol uti o n of dia g n ostic criteria f or m ulti ple 
scler osis. Ne ur ol N e ur oc hir P ol. 2 0 1 5; 4 9( 5): 3 1 3- 2 1. 
R o vira  A,  A u ger  C.  R ole  of  C o ntrast -e n ha n ce d  Ma g netic  Res o na nce  I ma gi n g  i n  M ulti ple 
Scler osis. E ur Ne ur ol Re v. 2 0 1 2; 7( 3): 1 8 1- 8. 
Ster n A F. T he h os pital a n xiet y a n d de pressi o n scale. Occ u p Me d ( L o n d) . 2 0 1 4; 6 4( 5): 3 9 3- 4. 
St oja n o v  A ,  Mal o ba bic  M,  Mil ose vic V  et  al., 
Ps yc h ol o gical  stat us  of  patie nts  wit h 
rela psi n g-r e mitti n g  m ulti ple  scler osis  d uri n g  c or o na vir us  disease-2 0 1 9  o ut brea k .  M ult  Scler 
Relat Dis or d. 2 0 2 0; 4 5: 1 0 2 4 0 7 
Str o ber L, De L uca J, Be ne dict R H et al, M ulti ple Scler osis O utc o me Assess me nts C o ns orti u m 
( M S O A C). S y m b ol di git m o dalities test: a v ali d cli nical trial e n d p oi nt f or meas uri n g c o g niti o n 
i n m ulti ple scler osis. M ult Scler J . 2 0 1 9; 2 5( 1 3): 1 7 8 1- 9 0. 
Vic k re y BG , Ha ys R D, Har o o ni R et al. A healt h-relate d q u alit y of life meas ure f or m ulti ple 
scler osis. Q ual Life Res . 1 9 9 5; 4( 3): 1 8 7- 2 0 6. 
Vic kre y B G, Ha ys R D, Ge n o vese BJ et al. C o m paris o n of a ge n eric t o disease -tar gete d h ealt h-
relate d q ualit y- of-life meas ures f or m ulti ple scler osis. J Cli n E pi de mi ol. 1 9 9 7; 5 0( 5): 5 5 7- 6 9. 
Wats o n T M, F or d E, W ort hi n gt o n E, et al. V ali dati o n of m o o d meas ures f or pe o ple wit h m ulti ple 
scler osis. I nt J M S Care . 2 0 1 4; 1 6( 2): 1 0 5- 9. 
Zi g m o n d  A S,  S nait h  R P.  T he  h os pital  a n xiet y  a n d  de pressi o n  scal e.  Acta  ps yc hiatrica 
sca n di na vica. 1 9 8 3; 6 7( 6): 3 6 1- 7 0. 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 9 /6 6  
 
 
1 1  
A p pe n dices  
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 0 /6 6  
 
 
A p pe n di x 1  A b bre vi ati o ns  
 
 
  
A E  
A d verse E v e nt  
 
 
 
 
B V M T -R  
Brief Vis u os patial Me m or y Test -Re vise d  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C R F  
Case R e p ort F or m  
C S R  
Cli nical S t u d y R e p ort 
C U A  
C o m bi ne d U ni q ue A cti ve 
C V L T -II 
Calif or nia Ver b al Lear ni n g Test -II 
e C R F 
Electr o nic C ase R e p ort F or m  
E D C  
Electr o nic D ata C a pt ure  
 
 
F A S  
F ull A nal ysis S et 
G C P  
G o o d Cli nical Practice  
 
 
 
 
H R Q o L  
Healt h R elate d Q u alit y of L ife 
I C H 
I nter nati o nal C o u ncil f or Har m o nizati o n  
I C F 
I nf or me d C o nse nt F or m 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
I S M P 
I nte grate d St u d y Ma na g e me nt Pla n 
 
 
Me d D R A  
Me dical Dicti o nar y of Re g ulat or y Acti vities  
 
 
M S  
M ulti ple S cler osis 
M S Q o L -5 4  
M ulti ple Scler osis Q ualit y of Life -5 4 Q u esti o n naire  
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 8 7 5 5 0 _ 6 7 4 8 4 7 1
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 1 /6 6  
 
 
 
 
P R O  
Patie nt -R e p orte d O utc o me  
 
 
R M S  
Rela psi n g M ulti ple S cler osis 
S A E  
Seri o us A d verse E v e nt  
S A R S -C o V -2  
Se vere A c ute R es pirat or y S y n dr o me C or o na vir us 2  
S C  
Steeri n g C o m mittee  
 
 
S m P C  
S u m mar y of Pr o d uct C haracteristics  
S U S A R  
S us pecte d U ne x p ecte d S eri o us A d vers e Reacti o ns  
 
  
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 2 /6 6  
 
 
A p pe n di x 2  St u d y G o ver n a nce  
Fi n a nci al Discl os ure  
I n v esti gat ors  a n d  S u b-I n vesti gat ors  will  pr o vi de  t he  S p o ns or  wit h e n o u g h,  acc urate  fi na n cial 
i nf or mati o n, as r e q ueste d, f or t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial certificati o n 
or discl os ure state me nts t o t he a p pr o priate re g ulat or y a ut h orities. T his i nf or mati o n is re q uire d 
d uri n g t he st u d y a n d f or 1 year after c o m pleti o n of t he st u d y. 
I nf or m e d C o nse nt Pr ocess 
•  T he I n vesti gat or or his/ her re pr ese ntati ve will e x pl ai n t he nat ure of t he st u d y t o t he partici pa nt 
or his/ her le g all y a ut h orize d re prese nt ati ve (w h ere all o we d b y l ocal la ws a n d re g ulati o ns)  a n d 
a ns wer all q uesti o ns o n t he st u d y.  
•  Partici pa nts will  be i nf or me d t hat t heir partici pati o n is v ol u ntar y. 
•  Partici pa nts  or  t heir  le gall y  a ut h orize d  re prese ntati ve (w here  all o we d  b y  l ocal  la ws  a n d 
re g ulati o ns) will  be  re q uire d  t o  si g n  a  state me nt  of  i nf or me d  c o ns e nt  t hat  meets  t h e 
req uire me nts of 2 1 C F R 5 0; l ocal  re g ulati o ns; I nter nati o nal C o u ncil f or Har m o nizati o n (I C H) 
g ui deli nes;  Healt h  I ns ur a nce  P orta bilit y  a n d  Acc o u nta bilit y  Act  ( HI P A A)  re q uire me nts, 
w here  a p plica bl e;  a n d  t he 
I nstit uti o nal  Re vie w  B oar d/I n de p e n de nt  Et hics  C o m mittee 
(I R B/I E C) or st u d y ce nter. 
•  T he me dical r ec or d will  i ncl u de a state m e nt t hat writte n i nf or me d c o ns e nt w as o btai ne d bef ore 
t he partici pa nt was e nr olle d i n t he st u d y a n d t he date t he writte n c o ns e nt was o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt will  als o si g n t he i nf or me d c o nse nt f or m 
(I C F). 
•  If t he I C F is u p dat e d d uri n g t heir partici p ati o n i n t he st u d y, partici pa nts will  be re -c o nse nte d 
t o t he m ost c urre nt, a p pr o ve d versi o n. 
•  A c o p y of t h e I C F(s) will  be pr o vi de d t o t h e partici pa nt or t he p artici pa nt’s l e gall y a ut h orize d 
re pres e ntati ve. 
•  T he ori gi nal si g ne d a n d date d c o nse nt will re mai n at t he I n vesti gat or’s site a n d will  be safel y 
arc hi ve d  s o  t hat  it  ca n  be  r etrie ve d  at  a n y  ti me  f or  m o nit ori n g,  a u diti n g  a n d  i ns pecti o n 
p ur p oses. 
D at a Pr ot ecti o n 
•  T he  S p o ns or  will  assi g n  a  u ni q ue  i de ntifier  t o  partici pa nts  after  o btai ni n g  t heir  i nf or me d 
c o nse nt. If p ossi ble , eac h partici pa nt will be assi g ne d t he sa m e i de ntifier as i n t he C L A RI F Y 
M S trial . A n y partici pa nt rec or ds or datas ets t hat are tra nsferre d t o t he S p o ns or will c o ntai n 
t he i de ntifier o nl y; partici pa nt na mes or a n y i de ntifia ble i nf or mati o n will n ot be tra nsferre d. 
•  T he S p o ns or will  i nf or m partici pa nts t hat t heir pers o nal st u d y-relate d d ata will be use d per 
l ocal data pr otecti o n a n d pri vac y la ws. T he l e vel of discl os ure will  als o b e e x plai ne d t o t he 
partici pa nt  a n d pre g na nt part ners (if a p plica bl e), w h o will be re q uire d t o gi ve c o nse nt f or t heir 
data t o be use d, as s p ecifi e d i n t he i nf or me d c o ns e nt. 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 3 /6 6  
 
 
•  T he  partici p a nt s will  be  i nf or me d t h at t heir me di cal rec or ds m a y be e xa mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n n el, b y a p pr o priate 
I R B/I E C  me m bers,  a n d  b y  re g ulat or y  a ut h orit y  i ns pect ors.  All  s uc h  pers o ns  will  strictl y 
mai ntai n partici pa nts’ c o nfi de ntialit y.  
St u d y A d mi nistr ati ve  
S p o ns or 
•  T he  S p o ns or  of  t his  e xte nsi o n  st u d y  is  Merc k  K Ga A,  Fra n kf urter  Strasse  2 5 0,  6 4 2 9 3 
Dar msta dt, Ger ma n y. 
•  Sites ,  t hat  partici pate d  i n  t he  C L A RI F Y  M S trial, fr o m  E ur o pe  (i n cl u di n g  t he  f oll o wi n g 
c o u ntries:  A ustria,  Czec h  Re p u blic,  De n mar k,  Fra nce,  H u n gar y,  It al y,  P ola n d,  Sl o va kia, 
S pai n,  a n d  t he  Net herla n ds)  will  be  a p pr oac he d  f or  partici pati o n  i n  t his e xte nsi o n  st u d y. 
A b o ut 6 5 sites are e x p ect e d t o partici pate.  
•  T he C o or di nati n g I n vesti gat or liste d o n t he title pa ge r e prese nts all I n v esti gat ors f or d ecisi o ns 
a n d  disc ussi o ns  o n  t his  st u d y,  per  I C H  G o o d  Cli nical  Practice   (G C P ).  T he  C o or di nati n g 
I n v esti gat or will pr o vi de e x pert me dical i n p ut a n d a d vice o n t he st u d y desi g n a n d e xec uti o n 
a n d is res p o nsi ble f or t he re vie w a n d si g n off of t h e cli nical st u d y re p ort ( C S R ). 
T he st u d y will a p p ear i n t he f oll o wi n g cli nical st u dies re gistries: E U Cli nical Trials Re gister, 
Cli nical Trials. g o v, a n d nati o nal re gistries as per l ocal re g ulati o ns. 
Scie ntific Steeri n g C o m mittee  
•  A  Steeri n g  C o m mittee  ( S C)  will  be  esta blis he d  t o  e ns ure  t hat  t he  st u d y  meets  scie ntific 
sta n dar ds. T he S C  C harter will be i n place t hat d escri bes t he S C res p o nsi bilities. T he S C is a 
m ulti disci pli nar y gr o u p of lea d st u d y I n v esti gat ors, me dical e x perts, a n d S p o ns or’s pers o n nel, 
w h o, c ollecti vel y, ha v e t he scie ntific, me di cal, a n d cli nical st u d y ma na ge me nt e x perie n ce t o 
desi g n, c o n d uct a n d e v al ua te t he st u d y. T he S C pr o vi des a d vice a n d rec o m me n dati o ns wit h 
re gar d t o t he desi g n, t he c o n d uct, a n d t he e val uati o n of t he st u d y. T he S C is res p o nsi ble f or 
safe g uar di n g t he i nterests of partici pa nts  a n d f or t h e c o n d uct of t he st u d y. 
C o ntr act rese arc h or g a n iz ati o n 
•  C o ntract res ear c h or g a nizati o n s ( C R Os) a n d v e n d ors will be i n v ol ve d i n  s o me as pects of t his 
st u d y wit h o versi g ht b y t he S p o ns or. D etails of s u c h str uct ures a n d ass oci ate d pr oce d ures will 
be defi ne d i n a s e par ate I nte grate d St u d y Ma na g e me nt Pla n (I S M P).  
Re g ul at or y a n d Et hic al C o nsi der ati o ns 
•  T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he pr ot oc ol a n d t he f oll o wi n g: 
•  C o nse ns us  et hical  pri nci ples  deri ve d  fr o m  i nter nati o nal  g ui deli nes,  i ncl u di n g  t he 
Declar ati o n  of  Helsi n ki  a n d  C o u ncil  f or  I nter nati o nal  Or ga nizati o ns  of  Me dical 
Scie nces ( CI O M S) I nter n ati o nal Et hical G ui deli nes  
•  A p plica ble I C H G C P G ui deli nes  
•  A p plica ble la ws a n d re g ulati o ns 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 4 /6 6  
 
 
•  T he  I n vesti gat or will  s u b mit  t he  pr ot oc ol,  pr ot oc ol  a me n d me nts  (if  a p plica ble),  I C F, 
I n v esti gat or Br oc h ure, a n d ot her rele va nt d oc u me nts (e. g., a d vertise me nts) t o a n I R B/I E C a n d 
t he I R B/I E C will  re vie w a n d a p pr o ve t h e m bef ore t he st u d y is i nitiate d. 
•  A n y pr ot oc ol a me n d me nts (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g a n d 
re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n g es, e x ce pt f or c h a n ges necessar y t o 
eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. W he n a p plica bl e, a me n d me nts will be 
s u b mitte d t o t he a p pr o priate Healt h A ut h orities. 
•  T he I n vesti gat or will be r es p o nsi ble f or t he f oll o wi n g: 
•  Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or m ore 
fre q ue ntl y per t he I R B’s/I E C’s re q uire m e nts, p olicies, a n d pr o ce d ures. 
•  N otif y i n g  t he  I R B/I E C  of seri o us  a d vers e  e ve nts  (S A Es ) or  ot her  si g nifica nt  safet y 
fi n di n gs, as re q uire d b y I R B/I E C pr oce d ures. 
•  Pr o vi di n g o versi g ht of t he st u d y c o n d uct at t he site a n d a d here nce t o re q uire me nts of 
2 1  C F R,  I C H  g ui deli nes,  t he  I R B/I E C,  E ur o pea n  re g ulati o n  5 3 6/ 2 0 1 4  f or  cli nical 
st u dies (if a p plica ble), a n d all ot her a p plica ble l o cal re g ulati o ns. 
•  T he pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n will be s u b mitte d or n otifie d t o t he Healt h 
A ut h orities i n acc or d a nce wit h all l ocal a n d nati o nal re g ulati o ns f or eac h site. 
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts  
•  I ns ura nce c o v er a ge will be pr o vi de d f or eac h c o u ntr y partici pati n g i n t h e st u d y. I ns ura n ce 
c o n diti o ns will  meet g o o d l ocal sta n dar ds, as a p plica ble. 
Cli nic al St u d y Re p ort  
•  After st u d y c o m pleti o n, t he S p o ns or will write a C S R  i n c o ns ultati o n wit h t he C o or di nati n g 
I n v esti gat or, Pri nci pal I n vesti gat or (f or si n gle ce nter st u dies), a n d a n y SC or ot her rele v a nt 
st u d y-a p p oi nte d c o m mittees or gr o u ps. 
P u blic ati o n  
•  T he r es ults of t his st u d y ma y be  p u blis he d or prese nte d at scie ntific meeti n gs. If t his is 
f oresee n,  t he  I n vesti gat or  a gr ees  t o  s u b mit  all  m a n uscri pts  or  a bstracts  t o  t he  S p o ns or 
bef ore  s u b missi o n.  T his  all o ws  Merc k K G a A t o  pr otect  pr o prietar y  i nf or mati o n  a n d  t o 
pr o vi de c o m me nts.  
•  T he  S p o ns or  will  c o m pl y  wit h  t he  re q uire me nts  f or  p u blicati o n  of  st u d y  res ults.  Per 
sta n dar d e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p ort p u blicati o n of 
m ultice nter  st u dies  o nl y  i n  t heir  e ntiret y  a n d  n ot  as  i n di vi d ual  site  data.  I n  t his  cas e,  a 
C o or di nati n g I n vesti gat or will be desi g nate d b y a gree me nt. 
•  A ut h ors hi p will be deter mi ne d b y a gree me nt a n d i n li ne wit h I nter n ati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire m e nts. 
 
Gl o bal Versi o n I D: C CI

CCI
CCI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 6 /6 6  
 
 
•  S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t h e partici pa nt a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. 
•  T he I n vesti gat or will  kee p a pa per or electr o nic fil e ( me dical file a n d ori gi n al me dical rec or ds) 
at  t he  site  f or  eac h  st u d y  partici pa nt.  T he  file will  i de ntif y  eac h  p artici pa nt,  c o ntai n  t he 
f oll o wi n g de m o gra p hic a n d me dical i nf or mati o n f or t he partici pa nt, a n d will  be as c o m plete 
as p ossi ble: 
•  Partici pa nt’s f ull na me, d ate of birt h, se x, hei g ht, a n d wei g ht 
•  Me dical hist or y a n d c o n c o mita nt diseases 
•  Pri or a n d c o nc o mita nt t h era pies (i n cl u di n g c ha n g es d uri n g t he st u d y) 
•  St u d y i de ntifier (i.e., t he S p o ns or’s st u d y n u m ber) a n d partici pa nt’s st u d y n u m ber 
•  Dates of e ntr y i nt o t he st u d y (i.e., si g nat ure d ate o n t he i nf or m e d c o ns e nt) a n d eac h visit 
t o t he site 
•  A n y me dical e x a mi nati o ns a n d cli nical fi n di n gs pre defi n e d i n t he pr ot oc ol 
•  All A Es  
•  Date t hat t he partici p a nt left t he st u d y, i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m t he 
stu d y. 
•  All s o urce data will  be file d (e. g., C T or M RI sca n i ma ges, E C G rec or di n gs, a n d la b orat or y 
res ults).  Eac h  d oc u m e nt will  ha ve  t he  partici pa nt  n u m ber  a n d  t he  pr oce d ure  date;  i deall y, 
pri nte d b y t he i nstr u me nt use d f or t he pr oce d ure. As necessar y, me dical e val uati o n of t hese 
rec or ds will  be perf or me d, d oc u me nte d, si g ne d a n d date d b y t he I n vesti gat or. 
•  Data r ec or d e d o n pri nte d or electr o ni c C R Fs t hat are tra ns cri be d fr o m s o urce d oc u me nts will  
be  c o nsiste nt  wit h  t he  s o urce  d o c u me nts  or  t h e  discre p a ncies will  be  e x plai ne d.  T h e 
I n v esti gat or ma y nee d t o re q uest pre vi o us m e dical rec or ds or tra nsfer rec or ds, de pe n di n g o n 
t he st u d y. Als o, c urre nt me dical rec or ds will  be a vaila ble.  
•  T he St u d y M o nit ors will use pri nt o uts of electr o nic files f or s o urce d ata v erificati o n. T h ese 
pri nt o uts will  be si g ne d a n d date d b y t he I n vesti gat or a n d ke pt i n t he st u d y file. 
•  S o urce  d o c u me nts are st ore d  at  t he  site  f or  t he  l o n gest  p ossi ble  ti me  per mitte d  b y  t he 
a p plica ble  re g ulati o ns,  a n d/ or  as  per  I C H  G C P  g ui deli nes,  w hic he ver  is  l o n ger.  T he 
I n v esti gat or e ns ures t hat n o destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he Sp o ns or’s 
writte n a p pr o val. 
•  Defi niti o n of w hat c o nstit utes s o urce data is fo u n d i n t he I S M P. 
St u d y a n d Site St art a n d Cl os ure  
First Act of Recr uit me nt  
•  T he st u d y start date is t he date w h e n t he cli nical st u d y will be o pe n f or recr uit me nt. 
•  T he first act of re cr uit me nt is w he n t he first site is o pe ne d a n d will be t he st u d y start date. 
St u d y Cl os ure a n d Site Ter mi nati o n 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 7 /6 6  
 
 
•  T he S p o ns or reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y ti me a n d 
f or a n y reas o n. St u d y sites will be cl ose d u p o n st u d y c o m pleti o n. A st u d y site is c o nsi dere d 
cl ose d w he n all re q uir e d d oc u me nts a n d st u d y s u p plies ha ve bee n c ollecte d a n d a Site Cl os ure 
Visit  has bee n c o m plete d.  
•  T he I n vesti gat or ma y i nitiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use a n d  
e n o u g h n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n. 
•  Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n v esti gat or ma y i ncl u de: 
•  Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he I R B/I E C 
or l ocal H ealt h A ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes 
•  I n a de q uat e recr uit me nt of partici pa nts b y t he I n v esti gat or 
•  Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d 
•  If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he S p o ns or will  pr o m ptl y i nf or m t he 
I n v esti gat ors,  t he  I E Cs/I R Bs,  t he  re g ulat or y  a ut h orities,  a n d  a n y  c o ntract  res earc h 
or ga nizati o n(s) use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y 
t he a p plica ble re g ulat or y re q uire me nts. T he I n vesti gat or will pr o m ptl y i nf or m t he partici pa nts 
a n d ass ure a p pr o pri ate partici pa nt t hera p y a n d/ or f oll o w- u p. 
 
 
 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 8 /6 6  
 
 
A p pe n di x 3 
A d verse  E ve nts:  Defi niti o ns  a n d  Pr oce d ures  f or  Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g  
I n t his secti o n, “st u d y i nter ve nti o n” refers t o cla dri bi ne ta blets (i.e., t he st u d y i nter ve nti o n of t he 
C L A RI F Y M S pare nt st u d y) si nce n o st u d y i nter v e nti o n is a d mi nistere d i n t his st u d y. 
A E Defi niti o n  
A E Defi niti o n  
•  A n A E is a n y u nt o war d me dical occ urre n ce i n a patie nt or cli nical st u d y partici pa nt, 
te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her c o nsi dere d relate d t o 
t he st u d y i nter ve nti o n or n ot.  
•  A n A E ca n t h eref ore b e a n y u nfa v ora bl e a n d u ni nt e n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e xacer bate d) te m p orall y ass ociate d 
wit h t he use of st u d y i nter ve nti o n. F or s ur gi cal or dia g n ostic pr oce d ures, t h e 
c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is c o nsi dere d as t he A E rat her t ha n t he 
pr oce d ur e itself . 
E ve nts Meeti n g  t he A E Defi niti o n 
•  A n y a b n or mal la b or at or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts (e. g., E C G, ra di ol o gical sca ns, vital si g ns meas ure me nts), 
i ncl u di n g t h ose t hat w orse n fr o m Baseli ne, c o nsi dere d cli nicall y si g nifica nt i n t he 
me dical a n d scie ntific j u d g me nt of t he I n vesti gat or (i.e., n ot relat e d t o pr o gressi o n of 
u n derl yi n g disease). 
•  E xacer bati o n of a c hr o ni c or i nter mitte nt pre-e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
•  Ne w c o n diti o ns detect e d or dia g n ose d after st u d y i nter ve nti o n a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve bee n prese nt bef ore t he start of t he st u d y. H o we ver, as t he st u d y 
i nter ve nti o n (cla dri bi ne t a blets) was a d mi nistere d d uri n g t he pare nt st u d y, o nl y ne w 
c o n diti o ns n ot detecte d/ dia g n ose d d uri n g t he pare nt st u d y nee d t o be c ollecte d. 
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g- dr u g i nteracti o n. 
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y 
i nter ve nti o n or a c o n c o mita nt me dicati o n.  
•  “ Lac k of efficac y” or “fail ure of e x pecte d p har mac ol o gical acti o n” p er se will n ot be 
re p orte d as a n A E or a S A E. H o we v er, t he si g ns, s y m pt o ms, a n d/ or cli nical se q uelae 
res ulti n g fr o m lac k of efficac y will be re p orte d as a n A E or a S A E if t h e y f ulfill t he 
defi niti o n of a n A E or S A E. 
E ve nts N O T  Meeti n g t he A E Defi niti o n  
•  U nless j u d ge d b y t he I n v esti gat or t o be m ore se v ere t ha n e x p ecte d  f or t he p artici pa nt’s 
c o n diti o n, a n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs, ot her a b n or mal safet y 
assess me nts t hat are ass o ciate d wit h t he u n derl yi n g disease, t he diseas e/ dis or der bei n g 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 9 /6 6  
 
 
st u die d, or e x pect e d pr o gressi o n, si g ns, or s y m pt o ms of t he disease/ dis or der bei n g 
st u die d. 
•  Me dical or s ur gical pr oce d ure ( e. g., e n d os c o p y, a p pe n dect o m y): t he c o n diti o n t hat lea ds 
t o t he pr oce d ur e is t he A E. 
•  Sit uati o ns i n w hic h a n u nt o war d me dical o cc urre n ce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital). 
•  A ntici pate d da y -t o- d a y fl uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t h e st u d y t hat d o n ot w orse n. 
A E/ S A Es O bser ve d i n Ass oci ati o n wit h Dise ase Pr o gressi o n  
Pr o gressi o n  of  t he  disease/ dis or der  bei n g  st u di e d  assesse d  b y  meas ure me nt  of  lesi o ns  o n 
ra di o gra p hs  or  ot her  met h o ds  as  well  as  ass ociate d  cli nical  si g ns  or  s y m pt o ms  (i ncl u di n g 
la b orat or y  a b n or malities)  will  n ot  be  re p orte d  as  A Es/ S A Es,  u nless  t he partici pa nt’s  ge neral 
c o n diti o n is m ore se vere t ha n e x p ecte d f or t he his/ her c o n diti o n a n d/ or u nless t he o utc o me is 
fatal wit hi n t he A E  re p orti n g peri o d, as defi ne d i n Secti o n 8. 3. 1 . 
S y m pt o ms  a n d  si g ns  of  rela pse  or  w orse ni n g  of  M S  si nce  t he  pre vi o us  visit  will  us uall y  be 
ca pt ure d i n t he c o nte xt of t he efficac y assess me nt, a n d rec or de d o n t he rel a pse m o d ule of t he 
e C R F. T heref ore, s y m pt o ms, rela pses or w orse ni n g of M S will n ot be c o nsi dere d as A Es u nless 
c o nsi dere d p ossi bl y or pr o ba bl y relat e d t o cla dri bi ne ta blets (i.e. w orse ni n g is n ot c o nsiste nt wit h 
t he a ntici pate d nat ur al pr o gressi o n of t he diseas e). 
S A E Defi niti o n  
If a n  e ve nt  is  n ot  a n  A E  per t he defi niti o n  a b o ve,  t he n  it  ca n n ot  be  a n  S A E  e ve n  if  seri o us 
c o n diti o ns are met (e. g., h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y, deat h 
d ue t o pr o gressi o n of dis ease). 
 
A S A E is defi ne d as a n y u nt o w ar d me dic a l occ urre nce t h at, at a n y d ose: 
a.  Res ults i n de at h  
b.  Is life-t hre at e ni n g 
T he  ter m  'life -t hreate ni n g'  i n  t he  defi niti o n  of  'seri o us'  refers  t o  a n  e v e nt  i n  w hic h  t he 
partici pa nt was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h, if it were m ore se vere.  
c. 
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n 
•  I n g e ner al, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n d etai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer g e nc y w ar d f or o bser vati o n 
a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ysicia n’s office or 
o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es. If a 
c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he e ve nt is 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A  
C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 0 /6 6  
seri o us. W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was necessar y, t he 
A E will  be c o nsi dere d s eri o us. 
•
H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n
fr o m B aseli ne is n ot  c o nsi dere d a n A E.
•
H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d pr ol o n gati o n of
a n elect i ve h os pitalizati o n (i.e., u n desira ble effects of a n y a d mi nistere d treat me nt) m ust
be d oc u me nte d a n d re p orte d as S A Es.
d.
Res ults i n persiste nt dis a bilit y/i nc a p acit y
T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal l ife 
f u ncti o ns. 
T his defi niti o n is n ot  i nte n de d t o i ncl u de e x perie n ces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, n a usea, v o miti n g, diarr hea, i nfl ue nza, a n d 
acci de nt al tra u ma ( e. g., s prai ne d a n kle) w hic h ma y i nterfere wit h or pre v e nt e ver y da y life 
f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n. 
e. 
Is a c o n ge nit al a n o m al y/ birt h defect
f.  
Ot her sit u ati o ns:
•
Me dical or scie ntifi c j u d g me nt will  be e xercis e d i n deci di n g w het her S A E re p orti n g is
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be
i m me diatel y life-t hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he
partici pa nt or ma y r e q uir e me dical or s ur gi cal i nter ve nti o n t o pre ve nt o ne of t he ot her
o utc o mes liste d i n t he a b o ve defi niti o n. T hese e v e nts are us uall y c o nsi dere d as seri o us.
•
E xa m ples of s uc h e v e nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt i n a n
e mer ge n c y r o o m or at h o me f or aller gi c br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns
t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n d e nc y or dr u g a b use.
A n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a dia g n ostic pr oce d ure  is als o c o nsi dere d 
a n S A E f or r e p orti n g p ur p oses, as s pecifi e d bel o w f or re p orti n g S A Es. 
Rec or di n g a n d F oll o w - Up of A E a n d/ or S A E  
A E a n d S A E Rec or di n g  
•
W he n a n A E/ S A E o cc urs, it is t he res p o nsi bilit y of t he In v esti gat or t o re vi e w all
d oc u me ntati o n (e. g., h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics re p orts)
relate d t o t he e v e nt.
•
T he In vesti gat or will t he n rec or d all rele v a nt A E/ S A E i nf or mati o n i n t he C R F.
•
As nee de d, t h e S p o ns or  ma y as k f or c o pies of certai n me dical rec or ds (e. g., a ut o ps y
re p orts, s u p ple me ntal la b re p orts, d oc u me nts o n m e dical hist or y/c o nc o mita nt
me dicati o ns, disc har ge l etters), as s u p p orti n g s o urce d oc u me nt ati o n. All partici pa nt
i de ntifiers, e xce pt t he partici pa nt n u m ber, will be re dacte d o n t h ese c o pies b ef ore
s u b missi o n t o t he S p o ns or.
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 1 /6 6  
 
 
•  
T he In vesti gat or will atte m pt t o esta blis h a dia g n osis of t h e e ve nt base d o n si g ns, 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n. W he ne ver p ossi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E. 
•  
S pecific g ui da nce is i n t he C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns.  
 
Assess m e nt of I nte nsit y  
T he In vesti gat or will assess t he i nte nsit y of eac h A E a n d S A E re p orte d d uri n g t he st u d y a n d 
assi g n it t o 1 of t he f oll o wi n g cate g ories: 
•  Mil d: A n e ve nt t hat is easil y t olerate d b y t he parti ci pa nt, ca usi n g mi ni mal disc o mf ort a n d 
n ot i nterferi n g wit h e ver y da y acti vities. 
•  M o derate: A n e ve nt t hat ca uses s ufficie nt disc o mf ort a n d i nterferes wit h n or mal 
e ver y da y acti vities.  
•  Se vere: A n e v e nt t hat pre ve nts n or mal e ver y d a y acti vities.  D o n ot c o nf use a n A E t hat is 
assesse d as se v er e wit h a S A E . Se vere is a cate g or y use d t o rate t he i nte nsit y of a n e ve nt; 
b ot h A Es a n d S A Es ca n be assesse d as se vere.  
A n e ve nt is defi ne d as “seri o us” w he n it meets at least 1 of t he pre defi ne d criteria s pecifie d 
i n t he defi niti o n of a n S A E, N O T w he n it is rate d as se vere. 
 
 
Assess m e nt of C a us alit y  
•  
T he I n vesti gat or will ass ess t he relati o ns hi p bet w ee n st u d y i nter ve nti o n a n d eac h 
A E/ S A E occ urr e nce:  
•  
U nrelate d: N ot r eas o na bl y relate d t o  t he st u d y i nter ve nti o n. A E c o ul d n ot me dicall y 
( p har mac ol o gicall y/cli nicall y) be attri b ute d t o t he st u d y i nter ve nti o n. A reas o na ble 
alter nati ve e x pl a nati o n will  be a vaila ble.  
•  
Relate d: Reas o na bl y r elate d t o t he st u d y i nter ve nti o n. A E c o ul d me dicall y 
( p har mac ol o gicall y/cli nicall y) be attri b ute d t o t he st u d y i nter ve nti o n. 
•  
A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g g est a ca us al relati o ns hi p, rat her t ha n a rel ati o ns hi p ca n n ot be 
r ule d o ut. 
•  
T he I n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  
•  
Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t h e e ve nt t o st u d y i nter ve nti o n 
a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate d. 
•  
T he I n vesti gat or will als o c o ns ult t he I n v esti gat or Br oc h ure (I B) a n d/ or Pr o d uct 
I nf or mati o n, f or mar kete d pr o d ucts, i n his/ her ass ess me nt. 
•  
F or eac h A E/ S A E, t he I n vesti gat or will  d oc u me nt i n t he me dical n otes t hat he/s he has 
revie we d t h e A E/ S A E a n d assesse d ca usalit y. 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 2 /6 6  
 
 
•  
T here ma y b e sit uati o ns w he n a n S A E has o cc urre d , a n d t he I n v esti gat or h as mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he S p o ns or or its desi g nee.  T o meet t he 
re p orti n g ti meli ne, t he ca usalit y assess me nt is n ot re q uire d f or t he i nitial re p ort. 
•  
T he I n vesti gat or ma y c ha n ge his/ her ca us alit y assess me nt after c o nsi deri n g f oll o w - u p 
i nf or mati o n a n d se n d a S A E f oll o w- u p re p ort wit h t he u p date d ca usalit y assess me nt. 
•  
T he ca us alit y assess me nt is o ne of t he crite ria use d w he n deter mi ni n g re g ulat or y 
re p orti n g re q uir e me nts. 
 
F oll o w- u p of A Es a n d S A Es  
•  T he In vesti gat or will perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal meas ure me nts 
a n d/ or e val uati o ns, as me dicall y i n dicate d or as re q ueste d b y t he S p o ns or t o el uci date t he 
nat ure a n d/ or ca usalit y of t he A E or S A E, as f ull y as p ossi ble. T his ma y i ncl u de 
a d diti o nal la b orat or y tests or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or 
c o ns ultati o n wit h ot her healt h care pr ofessi o nals. 
•  Ne w or u p d ate d i nf or mati o n will be rec or d e d i n t he ori gi nall y c o m plete d C R F. 
•  T he I n vesti gat or will s u b mit a n y u p date d S A E data t o t he S p o ns or wit hi n 2 4 h o urs of 
recei pt of t h e i nf or mati o n. 
Re p orti n g of S A Es  
S A E Re p orti n g b y  a n Electr o nic D at a C ollecti o n T o ol  
•  
T he pri mar y mec ha nis m f or re p orti n g a n S A E t o t he S p o ns or or its desi g nee will be t he 
electr o nic d ata c ollecti o n t o ol.  
•  
If t he electr o nic s yste m is u na vaila ble, t he n t he sit e will use t he pa per S A E data 
c ollecti o n t o ol, s pecifie d bel o w, t o re p ort t he e ve nt wit hi n 2 4 h o urs. 
•  
T he site will e nter t he S A E data i nt o t he electr o nic s yste m as s o o n as it bec o mes 
a vaila ble.  
•  
After t he st u d y is c o m plete d at a site, t he electr o ni c data c ollecti o n t o ol will be ta ke n 
off -li ne t o pre v e nt t he e ntr y of ne w d ata or c ha n ges t o e xisti n g data. 
•  
If a site r ecei v es a r e p ort of a ne w S A E fr o m a stu d y partici pa nt or recei v es u p date d 
data o n a pr e vi o usl y re p orte d S A E after t he electr o nic data c ollecti o n t o ol h as bee n 
ta ke n off-li ne, t h e n t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m or t o t he 
S p o ns or’s safet y de p art m e nt. 
•  
B y e xce pti o n, a n S A E ( or f oll o w - u p i nf or mati o n) ma y be re p orte d b y tele p h o ne.  T he 
site will c o m plete t he electr o nic S A E data e ntr y i m me diatel y t hereafter. 
S A E Re p orti n g b y a P a per F or m  
•  
S A E re p orti n g o n a pa p er re p ort f or m is use d as a bac k -u p met h o d f or a n El ectr o nic 
data Ca pt ure ( E D C ) s yste m fail ure. T h e f or m i ncl u des  c o m pleti o n i nstr ucti o ns f or t he 
I n v esti gat or, na mes, a d dr esses, a n d tele p h o n e a n d fa x n u m bers. All i nf or mati o n fr o m 
t he pa per f or m will  be tra nscri be d i nt o t he electr o nic f or m as s o o n as t he s yste m 
bec o mes a v aila ble.  
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A       C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 3 /6 6  
 
 
•  
Facsi mile tra ns missi o n (f a x t o mail) of t he pa p er f or m or a n y f oll o w -u p i nf or mati o n is 
t he pref err e d met h o d f or tra ns missi o n a n d will be d o ne wit hi n 2 4 h o urs t o t he S p o ns or 
or its desi g nee. 
•  
I n rar e cir c u msta nces a n d i n t he a bse nce of facsi mile e q ui p me nt, n otificati o n b y 
tele p h o ne is acce pta ble wit h a c o p y of t he f or m se nt b y o ver ni g ht mail or c o urier 
ser vice. 
•  
I nitial n otificati o n via tel e p h o ne d oes n ot re place t he nee d f or t he I n v esti gat or t o 
c o m plete a n d si g n t he f or m  wit hi n 2 4 h o urs after b ec o mi n g a ware of t h e e v e nt. 
•  
A d diti o nal d oc u me nts (e. g. la b orat or y re p orts, a ut o ps y re p ort, h os pital disc har ge letter) 
a n d rele v a nt pa ges fr o m t he C R F ma y be re q uire d i n a d diti o n (e. g. me dical hist or y, 
c o nc o mita nt me dicati o n). T he data pr o vi d e d will  be c o nsiste nt wit h t he i nf or mati o n i n 
t he C R F. 
Re p orti n g of Pre g n a ncies  
•  Pre g na nc y will  be r e p ort e d usi n g t he a p plica ble p a per re p ort f or m. 
•  T he a p plica ble  p a per re p ort  f or m will be  use d t o re p ort if a n a b n or mal o utc o me of t he 
pre g na nc y o cc urs a n d t he c hil d/fet us s ustai ns a n e ve nt. 
•  Facsi mile tra ns missi o n (f a x t o mail) of t he pa p er f or m or a n y f oll o w - u p i nf or mati o n is 
t he pref err e d met h o d f or tra ns missi o n a n d will be d o ne wit hi n 2 4 h o urs t o t he S p o ns or or 
its desi g nee. 
 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A  
C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 4 /6 6  
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI

S u bst a nce c o de: N/ A  
C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti a l M a ve ncl a d®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 5 /6 6  
A p pe n di x 5 
C o ntr ace pti o n  
Acc or di n g  t o  cla dri bi ne  ta blets  ( Ma ve ncla d ® )  S m P C,  t here  are  n o  re q uire me nts  re gar di n g 
c o ntrace pti o n t hat a p pl y after 6 m o nt hs si nce t he  last d ose. At t he m o me nt of e nr oll me nt i n t he 
C L A R I F Y M S E xt e nsi o n st u d y, partici pa nts will h a ve c o m plete d treat me nt, wit h a la ps e of m ore 
t ha n 6 m o nt hs si nce t he last d ose of cla dri bi ne ta blets. 
Gl o bal Versi o n I D: C CI

S u bst a nce c o de: N/ A
C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S i n Ye ar 3 a n d 
4 after i niti al M a ve ncl a d ® d ose
M S 7 0 0 5 6 8 _ 0 1 5 8
C O N F I D E N T I A L
I N F O R M A T I O N
6 6/ 6 8
A p pe n di x 6
S p o ns or Si g n at ure P a ge
St u d y Title:
A 2 - year f oll o w-u p st u d y t o assess c o g niti o n a n d 
healt h -rel ate d q ualit y of life i n partici pa nts 
wit h 
hi g hl y -acti ve rela psi n g 
m ulti ple 
scler osis, 
ha vi n g 
partici pate d i n t he C L A RI F Y M S trial
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:
2 0 2 0 - 0 0 3 8 7 4- 3 0
Cli nic al St u d y Pr ot oc ol Versi o n:
2 8 J u ne 2 0 2 1/ Versi o n 2. 0
I a p pr o ve t h e desi g n of t he cli nical st u d y:
_ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
, M D, M Sc
F u ncti o n/ Title:
, 
Gl o b al 
Me dical 
Affairs, 
Ne ur ol o g y 
& 
I m m u n ol o g y
I nstit uti o n:
Merc k H ealt hcare K Ga A
A d dress:
Fra n kf urterstr asse 2 5 0. 6 4 2 9 3, Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
F a x n u m ber:
N ot A p plica ble
E- m ail a d dress:
_
_
3 0. 6. 2 0 2 1
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
C CI

Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
P P D
C CI

S u bst a nce c o de: N/ A  
C o g niti o n a n d H R Q o L i n a d ults wit h hi g hl y acti ve R M S  i n Ye ar 3 a n d 
4 after i niti al M a ve ncl a d ®  d ose  
M S 7 0 0 5 6 8 _ 0 1 5 8 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 8 /6 8  
A p pe n di x  8 
Pri nci p al I n vesti g at or  Si g n at ure Pa ge  
St u d y Title:  
A  2 -year  f oll o w -u p  st u d y  t o  assess  c o g niti o n  a n d 
healt h -rel ate d  q ualit y  of  life  i n  partici pa nts  wit h 
hi g hl y- acti ve  rela psi n g  m ulti ple  scler osis,  ha vi n g 
partici pate d i n t he C L A RI F Y M S trial  
Re g ul at or y  A ge nc y  I de ntif yi n g 
N u m bers:  
2 0 2 0- 0 0 3 8 7 4- 3 0 
Cli nic al St u d y Pr ot oc ol Versi o n:  2 8  J u ne 2 0 2 1 / Versi o n 2 . 0 
Site N u m ber:  
I a m r es p o nsi ble f or t he c o n d uct of t he st u d y at t his site a n d u n dersta n d a n d will c o n d uct it per 
t he cli nical st u d y pr ot oc ol, a n y a p pr o v e d pr ot o c ol a me n d me nts, I C H G C P ( T o pic E 6) a n d all 
a p plica ble H ealt h A ut h orit y re q uire me nts a n d nati o nal la ws. 
I als o u n d ersta n d t hat H ealt h A ut h orities ma y re q uire t he S p o ns ors of cli nical st u dies t o o btai n 
a n d s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I n vesti gati o nal Me dici nal Pr o d uct 
a n d a n y ot h er fi n a ncial ti es wit h t he S p o ns or. T h e S p o ns or will use a n y s u c h i nf or mati o n s olel y 
f or c o m pl yi n g wit h t h e r e g ulat or y r e q uire me nts. T heref ore, I a gree t o s u p pl y t he S p o ns or wit h 
a n y necessar y i nf or m ati o n re g ar di n g o w n ers hi p i nterest a n d fi na n cial ties i ncl u di n g t h ose of m y 
s p o use a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y t o meet Healt h A ut h orit y 
re q uire me nts. 
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_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Si g nat ure 
Date of Si g nat ure 
N a m e, ac a de mic de gree:  
F u ncti o n/ Title:  
I nstit uti o n: 
A d dress:  
Tele p h o ne n u m ber:  
F a x n u m ber:  
E -m ail a d dress:
Gl o bal Versi o n I D: C CI