Clinical trial NCT04776213
Conditions: Multiple Sclerosis
Keywords: Multiple sclerosis Health related quality of life Mavenclad® Relapsing Multiple Sclerosis Cladribine Cognitive impairment cognition Fatigue
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Start date: 2021-02-23; Completion date: 2023-06-20
Enrollment: 280 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study was the evaluation of the effect of a treatment for highly-active relapsing multiple sclerosis (RMS). This was the extension study to CLARIFY MS (NCT03369665), to assess cognitive impairment and health related quality of life (HRQoL) in participants with highly active RMS, at 4 years after initial dose of Mavenclad® tablets.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Mavenclad®
Intervention descriptions: intervention 1: This low interventional extension study involves the follow up of participants in the parent study. The participants were followed up for an additional 2 year period (until 4 years after initial administration of Mavenclad® tablets), during which the participants were not treated with Mavenclad®, as per European Medicines Agency (EMA) label of Mavenclad®.

Protocol documents:
Prot_000.pdf: 
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 
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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 
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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 
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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  
 
 
 
 
 
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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: 
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Gl o bal Versi o n I D: 
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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. 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
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

SAP_001.pdf: 
M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 0   
 
 
I nte gr ate d A n al ysis Pl a n 
St u d y N u m ber:  
M S 7 0 0 5 6 8 _ 0 1 5 8  
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 -relate d 
q ualit y  of  life  i n  parti ci 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 
St u d y P h ase:  
I V 
Merc k C o m p o u n d : 
Ma ve ncla d ®  
Pr ot oc ol V ersi o n:  
2 8 J u ne 2 0 2 1/ Versi o n 2. 0  
I nte gr ate d A n al ysis Pl a n 
A ut h or : 
 
C o or di n ati n g A ut h or  
 
, M er c k 
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
, M er c k  
 
F u n cti o n  
E diti n g A ut h or( s) / D at a A n al y st( s)  
 
 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n : 
2 5 A u g ust 2 0 2 3 / Versi o n 2. 0 
I nte gr ate d A n al ysis Pl a n 
Re vie wers : 
 
F u n cti o n  
N a m e  
 
 
M e di c al  R e s p o n si bl e 
 
Cli ni c al Tri al L e a d er/ Cli ni c al 
R e s e ar c h M a n a g er  
 
 
 
 
 
 
 
 
 
C o nfi de nti al  
T his d o c u me nt is t h e pr o p ert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o n e of its affiliate d c o m p a nies.  
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or p art - be p asse d o n, re pr o d u ce d, p u blis h e d or use d wit h o ut 
e x press p er missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p y ri g ht © [2 0 2 3]  b y Merc k K G a A, D a r mst a dt, Ger m a n y o r its affili ate. All ri g hts reser v e d.  
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I N F O R M A T I O N 
2/ 7 0   
 
 
A p pr o v al  P a ge  
 
I nte gr ate d A n al ysis Pl a n f or I nteri m An al ysis : M S 7 0 0 5 6 8 _ 0 1 5 8 
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 h ealt h-rel ate d q ualit y of life i n partici p a 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  
A p pr o val of t h e I A P b y all Merc k Data A nal ysis Res p o nsi ble has t o be d oc u me nte d wit hi n 
E D M S via e Si g nat ur e. Wit h t he a p pr o val, t h e Merc k res p o nsi ble f or eac h of t he a nal ysis als o 
ta kes res p o nsi bilit y t hat all re vie wers’ c o m me nts are a d dresse d a d e q uatel y. 
B y usi n g e Si g nat ure, t he si g nat ure will a p pear at t he e n d of t he d o c u me nt. 
 
 
 
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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 0   
 
 
1  
T a ble of C o nte nts  
 
A p pr o val Pa ge  
2  
1  
Ta ble of C o nte nts .................................................................................. 3  
2  
List of A b bre viati o ns a n d Defi niti o n of Ter ms .................................... 6  
3  
M o dificati o n Hist or y  ............................................................................ 9 
4  
P ur p ose of t he I nte grate d A nal ysis Pla n ............................................. 1 0  
5  
O bjecti ves a n d E n d p oi nts ................................................................... 1 1  
6  
O ver vie w of Pla n ne d A n al yses  ........................................................... 1 5 
6. 1  
I nteri m A nal ysis .................................................................................. 1 5 
6. 2  
Fi nal A nal ysis  ..................................................................................... 1 5 
7  
C ha n ges t o t he Pla n ne d A nal yses i n t he Cli nical St u d y Pr ot oc ol ...... 1 5  
8  
A nal ysis Sets a n d S u b gr o u ps .............................................................. 1 6  
8. 1  
Defi niti o n of A nal ysis Sets  ................................................................. 1 6 
8. 2  
S u b gr o u p Defi niti o n a n d Para meteri zati o n ........................................ 1 7  
9  
Ge ner al S pecificati o ns f or Data A n al yses  .......................................... 1 8 
9. 1  
Defi niti o n of Baseli ne a n d C ha n ge fr o m Baseli ne ............................. 1 9  
9. 2  
Defi niti o n of Visit Dates  ..................................................................... 1 9 
9. 3  
Defi niti o n of D urati o n ........................................................................ 1 9  
9. 4  
Defi niti o n of start of C O VI D - 1 9 pa n d e mic ........................................ 1 9 
9. 5  
Visit ti mi n g wit h res pect t o C O VI D - 1 9 pa n d e mic ............................. 1 9 
9. 6  
C o n versi o n Fact ors ............................................................................. 2 0  
9. 7  
Ti me Wi n d o w ..................................................................................... 2 0  
9. 8  
St u d y peri o d ........................................................................................ 2 1  
9. 9  
I m p utati o n of Missi n g D ata ................................................................ 2 2 
9. 1 0  
Data Ha n dli n g i n case of P Ds ............................................................. 2 3  
9. 1 1  
C o variates a n d Stratificati o n Fact ors  .................................................. 2 3 
1 0  
St u d y Partici pa nts ............................................................................... 2 3  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns ............................... 2 3  
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M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 0   
 
 
1 0. 2  
Pr ot oc ol De viati o ns / E xcl usi o n fr o m A nal ysis Sets .......................... 2 5  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De viati o ns ............................................................ 2 5 
1 0. 2. 2  
Reas o ns Lea di n g t o t he E xcl usi o n fr o m a n A nal ysis Set ................... 2 6  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  ............................. 2 6 
1 1. 1  
De m o gra p hics ..................................................................................... 2 6  
1 1. 2  
Me dical Hist or y  .................................................................................. 2 7 
1 1. 3  
Ot her Baseli ne C haracteristics  ............................................................ 2 7 
1 2  
Pre vi o us or C o nc o mita nt T hera pies/ Pr oce d ures ................................. 2 7  
1 3  
St u d y I nter v e nti o n: C o m plia nce a n d E x p os ure .................................. 2 8  
1 4  
Efficac y A nal yses  ............................................................................... 2 8 
1 4. 1  
Pri mar y E n d p oi nt: N o or mi ni mal decli ne i n c o g niti ve f u ncti o n at 
Year 4 Visit  ......................................................................................... 2 9 
1 4. 1. 1  
Pri mar y O bjecti ve: Deri vati o n a n d a nal ysis of t he pri mar y 
e n d p oi nt .............................................................................................. 2 9  
1 4. 1. 2  
Se nsiti vit y A nal yses of t he pri mar y e n d p oi nt ..................................... 3 0  
1 4. 2  
Sec o n dar y E n d p oi nts .......................................................................... 3 5  
1 4. 2. 1  
Sec o n dar y E n d p oi nt: M S Q o L- 5 4 C ha n ge at Year 4 Visit fr o m 
Baseli ne  ............................................................................................... 3 5 
1 4. 2. 2  
Sec o n dar y E n d p oi nt: M S Q o L- 5 4 C ha n ge at Year 4 Visit fr o m 
C L A RI F Y M S Year 2 Visit  ................................................................ 3 7 
 
.. 3 8 
 
3 8  
 
4 0  
 
4 1  
 
. 4 3 
 
4 5  
 
4 7  
 
4 9  
 
5 1  
 
 .. 5 2 
 
5 3  
 
5 4  
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C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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I N F O R M A T I O N 
5/ 7 0   
 
 
 
5 5  
 
5 6  
 
. 5 7 
1 5  
Safet y A nal yses  .................................................................................. 5 9 
1 5. 1  
A d verse E v e nts  ................................................................................... 5 9 
1 5. 1. 1  
All A d verse E v e nts  ............................................................................. 5 9 
1 5. 1. 2  
A d verse E v e nts Lea di n g t o Disc o nti n uati o n of St u d y I nter ve nti o n ... 6 1  
1 5. 2  
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E v e nts  ................................................................................... 6 1 
1 5. 2. 1  
Deat hs  ................................................................................................. 6 1 
1 5. 2. 2  
Seri o us A d verse E v e nts ...................................................................... 6 1  
1 5. 2. 3  
Ot her Si g nifica nt A d vers e E ve nts ...................................................... 6 1  
1 5. 3  
Cli nical La b orat or y E val uati o n ........................................................... 6 2  
1 5. 4  
Vital Si g ns  .......................................................................................... 6 2 
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns ............................................ 6 3  
1 6  
A nal ysis of Ot her E n d p oi nts ............................................................... 6 3  
1 6. 1  
C O VI D - 1 9 S ur ve y .............................................................................. 6 3 
 
6 4  
 
 
6 4  
1 6. 4  
Baseli ne C haracteristics C o m pare d t o Pare nt St u d y  .......................... 6 4 
1 7  
Refere n ces  ........................................................................................... 6 5 
1 8  
A p pe n dices ......................................................................................... 6 7  
1 8. 1  
A p pe n di x 1: U p date d List of D M Ds f or C L A RI F Y M S E xte nsi o n 
St u d y ................................................................................................... 6 7  
 
6 9  
1 8. 3  
A p pe n di x 3: Preferre d ter ms f or selecti o n of A Es ass ociate d t o 
L y m p h o pe nia ...................................................................................... 7 0  
 
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I N F O R M A T I O N 
8/ 7 0   
 
 
S A F  
Safet y A nal ysis Set  
S C R  
Scree ni n g A n al ysis Set  
S D  
Sta n dar d De viati o n  
S E  
Sta n dar d Err or  
S F -3 6  
3 6 -Ite m S h ort F or m S ur v e y 
 
 
S M Q  
Sta n dar dise d Me d D R A Q uer y  
S O C  
S yste m Or ga n Class  
 
 
 
  
 
 
 
 
 
 
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 
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M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n  
T he  p ur p ose  of  t his  I nt e grate d  A nal ysis  Pla n  (I A P) is  t o  d oc u me nt  t ec h nical  a n d  detaile d  
s pecificati o ns f or t he a n al ysis of data c ollecte d f or pr ot oc ol M S 7 0 0 5 6 8 _ 0 1 5 8. Res ults of t he 
a nal yses descri be d i n t his I A P will be i ncl u de d i n t he cli nical st u d y re p ort. A d diti o nall y, t he 
pla n ne d a nal yses i de ntifie d i n t his I A P ma y be i ncl u de d i n re g ulat or y s u b missi o ns or f ut ure 
ma n uscri pts. A n y p ost -h oc, or u n pla n ne d a nal yses perf or me d t o pr o vi de res ults f or i ncl usi o n i n 
t he C S R b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearl y i de ntifie d i n t he C S R. 
T he I A P is base d u p o n Secti o n 9 ( Statistical c o nsi derati o ns) of t he st u d y pr ot oc ol a n d pr ot oc ol 
a me n d me nts a n d is pre p are d i n c o m plia nce wit h I C H E 9. It d escri b es a n al yses pla n ne d i n t he 
pr ot oc ol a n d pr ot oc ol a m e n d me nts. 
T he  a nal yses  d escri b e d  i n  t his  I A P  will  als o  i ncl u de  data  fr o m  t he  C L A RI F Y  M S  trial  
(C L A RI F Y M S st u d y M S 7 0 0 5 6 8 _ 0 0 2 1 , referre d t o as t he pare nt st u d y i n t he c urre nt d oc u me nt). 
T heref ore, t he st u d y pr ot oc ol a n d pr ot oc ol a me n d me nts of t he C L A RI F Y M S trial, as well as t he 
C L A RI F Y M S I A P V 5, will als o be refere nce d, w here a p plica ble.  W he n a nal ysis datasets fr o m 
pare nt  st u d y  will  be  utilize d,  n o  se parate  re m o val  of  data,  n ot  s pecifi call y  re q uire d  f or  t he  
a nal ysis of t he C L A RI F Y M S E xte nsi o n St u d y, will be d o ne. 
T he  w or di n g  us e d  i n  t his  I A P  is  c h ose n  t o  b est  matc h  t he  res pecti ve  w or di n g  i n  t he  st u d y  
pr ot oc ol te m plate, t he C S R te m plate, C DI S C re q uire me nts a n d s pecial re q uire me nts f or ta ble 
la y o uts. T heref ore, t he f oll o wi n g a p pr oac h is use d: 
Ge ner all y, t he ter m ‘ partici pa nt’ will be use d i nstea d of ‘s u bject’ or ‘ patie nt’. H o we v er, i n t a bles 
a n d listi n gs t he ter m ‘s u bject’ will be us e d t o matc h C DI S C re q uire m e nts, e xce pt f or i n -t e xt 
ta bles w here ‘ p artici pa nt’ will be use d t o matc h t he C S R a n d pr ot oc ol te m plates. Si milarl y, t he 
ter m ‘st u d y i nter ve nti o n’ will be use d i n t his d oc u me nt i nstea d of ‘treat m e nt’ t o matc h pr ot oc ol 
a n d  C S R  te m plates,  h o we ver,  ta bles  a n d  listi n gs  will  use  ‘treat me nt’  f or  bre vit y  reas o ns.  
E xce pti o ns fr o m t his r ule are c o m m o nl y use d ter ms li ke “ o n -treat me nt”, “treat me nt-e mer g e nt”, 
“treat me nt  p olic y”,  “s u bject -years”,  “ b y -s u bject ”,  or  na mes  of  e C R F  pa ges  li ke  “ Treat me nt  
Ter mi nati o n” pa g e.  
 
 
 
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M a ve ncl a d ® 
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C O N F I D E N T I A L  
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5  
O bjecti ves a n d E n d p oi nts  
 
O bj e cti v e s  
E n d p oi nt s  
I A P s e cti o n 
Pri m ar y  
T o a s s e s s c o g niti v e i m p air m e nt i n 
p arti ci p a nt s  wit h hi g hl y -a cti v e R M S, 
h a vi n g p arti ci p at e d  i n t h e C L A RI F Y 
M S tri al, at 4 y e ar s  aft er  i niti al d o s e of 
cl a dri bi n e t a bl et s   
•  
P er c e nt a g e of p arti ci p a nt s wit h n o or mi ni m al 
d e cli n e i n c o g niti v e f u n cti o n, d efi n e d a s a n i m pr o v e d 
or st a bl e S y m b ol Di git M o d aliti e s T e st ( S D M T) s c or e 
or a d e cli n e of 4 p oi nt s or l e s s i n t h e S D M T s c or e, at 
4 y e ar s aft er i niti al d o s e of cl a dri bi n e t a bl et s ( M 4 8) 
c o m p ar e d t o S D M T s c or e pri or t o i niti al d o s e of 
cl a dri bi n e t a bl et s ( C L A RI F Y M S B a s eli n e)  
1 4. 1  
S e c o n d ar y  
T o a s s e s s h e alt h r el at e d q u alit y of lif e  
( H R Q o L) i n p arti ci p a nt s wit h hi g hl y-
a cti v e  R M S, h a vi n g p arti ci p at e d i n t h e 
C L A RI F Y  M S tri al, at 4 y e ar s aft er 
i niti al d o s e of cl a dri bi n e t a bl et s  
•  
C h a n g e i n H R Q o L  a s m e a s ur e d b y 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 ( M S Q o L -
5 4) p h y si c al h e alt h s c or e s at 4 y e ar s  aft er i niti al 
d o s e of cl a dri bi n e t a bl et s ( M 4 8) c o m p ar e d t o pri or t o 
i niti al d o s e of cl a dri bi n e t a bl et s ( C L A RI F Y M S 
B a s eli n e)  
•  
C h a n g e i n H R Q o L a s m e a s ur e d b y 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 ( M S Q o L -
5 4) m e nt al h e alt h s c or e s at 4 y e ar s  aft er i niti al d o s e 
of cl a dri bi n e t a bl et s ( M 4 8) c o m p ar e d t o pri or t o i niti al 
d o s e of  cl a dri bi n e t a bl et s ( C L A RI F Y M S B a s eli n e)  
•  
C h a n g e i n H R Q o L a s m e a s ur e d b y M S Q o L -5 4 
p h y si c al h e alt h  s c or e s at 4 y e ar s aft er i niti al d o s e of 
cl a dri bi n e t a bl et s ( M 4 8) c o m p ar e d t o M 2 4  
•  
C h a n g e i n H R Q o L a s m e a s ur e d b y M S Q o L -5 4 
m e nt al h e alt h  s c or e s at 4 y e ar s aft er i niti al d o s e of 
cl a dri bi n e t a bl et s ( M 4 8) c o m p ar e d t o M 2 4  
1 4. 2  
 
T o a s s e s s t h e l o n g -t er m (4  y e ar s ) 
s af et y a n d t ol er a bilit y of cl a dri bi n e 
t a bl et s 
•  
O c c urr e n c e s of a d v er s e e v e nt s ( A E s) a n d s eri o u s 
a d v er s e e v e nt s ( S A E s) d uri n g t h e t hir d a n d f o urt h 
y e ar aft er i niti al d o s e of cl a dri bi n e t a bl et s  
1 5  
 
 
 
 
 
 
 
 
 
 
 
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I N F O R M A T I O N 
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O bj e cti v e s  
E n d p oi nt s  
I A P s e cti o n 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
O bj e cti v e s  
E n d p oi nt s  
I A P s e cti o n 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 /7 0   
 
 
O bj e cti v e s  
E n d p oi nt s  
I A P s e cti o n 
Gl o bal Versi o n I D: C CI
C CI
C CI


CCI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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I N F O R M A T I O N 
1 6 /7 0   
 
 
•  As data  f or  a  C O VI D -1 9  s u r ve y was  a d de d  t o  t he  C S P  a me n d me nt  Secti o n  8. 1. 3  
c orres p o n di n g o bjecti ve a n d e n d p oi nt was a d d e d acc or di n gl y. 
•  I n t his I A P descri pti ve s u m maries of 
 
will be descri b e d  bas e d o n ra w s c ores .  
 a nal ysis usi n g a n Ass ess me nt Ce ntre 
A p plicati o n Pr o gra m mi n g I nterface platf or m ma y  be perf or me d as a p ost -h oc a nal ysis.  
•  T he f oll o wi n g c orr elati o n a nal ysis are d escri b e d as e n d p oi nts as descri be d i n t he Cli nical 
St u d y Pr ot oc ol, b ut ma y  be perf or m e d as p ost -h oc a nal ysis a n d will n ot be descri be d i n 
t his I A P: 
 
 
 
 
 
. 
 
8  
A n al ysis Sets a n d S u b gr o u ps  
8. 1  
Defi niti o n of A n al ysis Sets  
Scree ni n g A n al ysis Set ( S C R)  
T he Scree ni n g a nal ysis set i ncl u des all partici pa nts w h o si g ne d t he i nf or me d c o nse nt f or t he 
E xte nsi o n St u d y. 
F ull A n al ysis Set ( F A S)  
T he f ull a nal ysis set will i ncl u de all eli gi ble (see C S P Secti o n 5. 1 f or defi niti o n of eli gi bilit y 
criteria) p artici pa nts , f or w h o m a n y Visit data has bee n c ollect e d after e n d date of C L A RI F Y M S 
Year 2  Visit  ( M o nt h 2 4 Visit). 
S afet y A n al ysis Set ( S A F)  
T he Safet y A nal ysis Set will  i ncl u de all partici pa nts fr o m t he S C R w h o recei ve d at least o ne 
d ose of cla dri bi ne t a blets i n t he C L A RI F Y M S trial . 
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
 
 
 
A n al yses per A n al ysis Set  
U nless ot her wise s pecifie d, all efficac y a nal ys es will be p erf or me d o n t he F A S a n d all safet y 
a nal yses will be perf or m e d o n t he S A F.   
If n ot state d ot her wise, dis p ositi o n of partici pa nts will be s u m marize d o n t he S C R , pre vi o us a n d 
c o nc o mita nt me dicati o ns a n d t he a nal yses o n de m o gra p hics a n d ot her b aseli ne c haracteristics 
will be perf or me d b ase d o n t he F A S. 
8. 2  
S u b gr o u p D efi niti o n a n d P ar a meteriz ati o n  
S u b gr o u p a nal yses will be perf or me d o n selecte d efficac y e n d p oi nts as d efi ne d i n S ecti o n 1 4 .  
T he f oll o wi n g s u b gr o u ps will be defi ne d: 
Pre vi o us  ( pri or  t o  p a re nt  st u d y  B aseli ne) tre at me nt  wit h  Dise as e  M o dif yi n g  Dr u gs  
( D M Ds):  
•  D M D pre -tr eate d: Partici pa nts will be cate g orize d as D M D pre-treat e d if t he y ha ve ta k e n 
D M Ds a n y ti me bef or e st art of st u d y me dicati o n ( C L A RI F Y M S Baseli ne).  
•  Pre -treat me nt n aï ve: all p artici pa nts n ot classifie d as D M D pre-treate d.  
Details of t he defi niti o n of t his s u b gr o u p are s pecifie d i n C L A RI F Y M S I A P V 5.  
Q u alif yi n g  rel a pse st at us i n p are nt st u d y :  
•  A n y q ualif yi n g rela pses i n pare nt st u d y.  
•  N o q ualif yi n g rela pses i n pare nt st u d y. 
T he pri mar y a n al ysis  will be re peate d f or t his s u b gr o u p. 
 
 
 
. 
 
Gl o bal Versi o n I D: C CI
C CI
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M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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I N F O R M A T I O N 
1 8 /7 0   
 
 
 
 
 
 
 
 
 
 
 
 
9  
Ge ner al S pecific ati o ns f or D at a A n al yses  
U nless ot her wise s pecifi e d, c o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics, 
i.e., t he  n u m ber  of  partici pa nts  wit h  missi n g  a n d  n o n- missi n g  val ues  ( n),  mea n,  sta n dar d  
de viati o n, me dia n, 2 5t h perce ntile ( Q 1) a n d 7 5t h p erce ntile ( Q 3), mi ni m u m, a n d ma xi m u m.  
Q ualitati ve varia bles will be s u m marize d b y fre q u e nc y c o u nts a n d p erce nta ges.  
U nless  ot her wise  state d  t he  calc ulati o n  of  pr o p orti o ns  will  be  base d  o n  t he  n u m ber  of  
partici pa nts of t h e a n al ysis set of i nterest. T heref ore, c o u nts of missi n g o bser vati o ns will b e 
i ncl u de d i n t he de n o mi nat or a n d prese nt e d as a s e parate cate g or y. 
Descri pti ve statistics b y n o mi nal V isit or ti me p oi nt will i ncl u de o nl y data fr o m sc he d ule d V isits. 
U nsc he d ule d V isits will be i ncl u de d i n t he deri v ati o n of baseli ne or w orst o n-treat me nt val ues. 
 A c o ntr ol of t h e p ote ntial t y pe -I-err or 
i nflati o n  ca use d  b y  m ulti ple  e n d p oi nts  a n d  m ulti ple  testi n g  is  n ot  pla n ne d  f or  t his  st u d y. If 
c o nfi de nce  i nter vals  ( CI) ar e  t o  be  calc ulat e d,  t hese  will  be  t w o -si de d  wit h  a  c o nfi de n ce  
pr o ba bilit y of 9 5 %, u nless ot her wise s pecifie d i n t his I A P. 
St u d y data will be i nte gr ate d wit h st u d y data fr o m t he C L A RI F Y M S tri al as re q uire d t o perf or m 
t he statistical a nal yses, i.e., st u d y data u p t o M 2 4 Visit is i nte grate d fr o m t he C L A RI F Y M S trial. 
If n ot s pecifie d  ot her wise, all listi n gs will o nl y i ncl u de data c ollecte d i n t he E xte nsi o n  St u d y , 
i ncl u di n g t he ga p peri o d bet 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 . 
Listi n gs  re gar di n g  de m o gra p hic  a n d  o t her  Baseli ne  c haracteristics  will  i ncl u de  data  fr o m  
C L A RI F Y M S Baseli ne.  
If data fr o m p are nt st u d y are us e d, all r ul es fr o m pare nt st u d y I A P still a p pl y f or t he a nal ysis of 
t hese data, e x ce pt alter nati ve r ules are e x plicitl y s pecifie d i n t his I A P. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
All a nal yses will be perf or me d usi n g S A S ® S oft ware v ersi o n 9. 4 or hi g her or R ( htt p:// w w w.r -
pr oject. or g/ ), V ersi o n 3. 6. 3 or hi g her as a p plica ble . 
 
9. 1  
Defi niti o n of B aseli ne  a n d C h a n ge fr o m B aseli ne  
If n ot s pecifie d ot her wis e, the Baseli ne is defi ne d as t he C L A RI F Y  M S Baseli ne t hat is s pecifie d 
i n Secti o n 9 of CL A RI F Y _ M S I A P V 5.   
A bs ol ute a n d per ce nt c h a n ges fr o m baseli ne are d efi ne d as : 
A bs ol ute c ha n ge = V isit val ue – Baseli ne val u e  
P erce nt c h a n ge = 1 0 0 * ( V isit val ue – B aseli ne val ue) / Baseli ne val ue 
T he Perce nta ge C ha n g e fr o m Baseli ne will be set t o missi n g f or partici pa nts wit h a zer o at 
Baseli ne.  
All c ha n ges t hat are defi ne d as c o m pari n g t o pri or i nitial d ose of cla dri bi n e ta blets will use t he 
C L A RI F Y M S Baseli ne as ref ere n ce.  
9. 2  
Defi niti o n of Visit D ates  
T he Visit start date is t he date of t he first assess me nt w hic h bel o n gs t o t he c orres p o n di n g V isit.  
T he Visit e n d date is t he date of t he last ass ess me nt w hic h bel o n gs t o t he c orres p o n di n g V isit. 
9. 3  
Defi niti o n of D ur ati o n  
D urati o n s i n d a ys will be calc ul ate d b y t he differe nce of start a n d st o p date + 1 (if n ot ot her wise 
s pecifie d). 
9. 4  
Defi niti o n of st art of C O VI D -1 9 p a n de mic  
T he start of C O VI D -1 9 pa n de mic will be defi ne d b y c o u ntr y as t he earliest date of eit her t he date 
of t he first deat h fr o m C O VI D -1 9 o cc urre d i n eac h c o u ntr y acc or di n g t o t he p u blis he d data b y 
E ur o pea n
 Ce ntre
 f or
 Disease
 Pre ve nti o n
 a n d
 C o ntr ol
 o n
 2 6 t h 
J u ne
 2 0 2 0
 
(htt ps:/ w w w.ec dc. e ur o pa.e u/e n/ p u blicati o ns- data/ d o w nl oa d-t o da ys- d ata - ge o gra p hic-distri b uti o n -
c o vi d- 1 9-cases-w orl d wi de ) or 1 1t h Marc h 2 0 2 0 ( w he n t he W orl d H ealt h Or ga nizati o n [ W H O ] 
declar e d C O VI D - 1 9 pa n de mic).  
9. 5  
Visit ti mi n g wit h res pect t o C O VI D -1 9 p a n de mic  
A V isit is defi ne d t o be perf or me d after t he start of C O VI D -1 9 pa n de mic if t he V isit e n d date is 
greater t ha n t he start of C O VI D -1 9 p a n de mic dat e.  
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
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M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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I N F O R M A T I O N 
2 0 /7 0   
 
 
9. 6  
C o n versi o n F act ors  
T he  f oll o wi n g  c o n versi o n  fact ors  will  be  us e d  t o  c o n vert  da ys  i nt o  m o nt hs  or  years  f or  all  
o bser vati o ns e xce pt V isit relate d dat es:  
1 m o nt h = 3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys. 
9. 7  
Ti me W i n d o w 
•  Da y 1 is t he da y of start of st u d y me dicati o n at C L A RI F Y M S Baseli ne  Visit , t he da y 
bef ore is D a y - 1 ( n o Da y 0 is defi ne d). 
•  St u d y da y is defi ne d relati ve t o Da y 1. 
T he Visit sc he d ule i n t he E xte nsi o n St u d y is defi ne d as f oll o ws: 
•  1 m o nt h = 3 0 da ys,  
•  1 year = 3 6 0 da ys,  
relati ve t o t he start date of t he C L A RI F Y M S Baseli ne  Visit.  
•  C L A RI F Y  M S E xte nsi o n Baseli ne Visit: T he V isit is pla n ne d t o c oi nci de wit h or be 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 , it ma y als o be t he sa me 
V isit as M 2 4. 
•  M o nt h 3 6 ( M 3 6) V isit: 3 years after D a y 1 ( ± 2 8 d a ys)  
•  M o nt h 4 8 ( M 4 8) Visit: 4 years after D a y 1 ( ± 2 8 d a ys) 
I n eac h a nal ysis, s h o ul d assess me nts be dela y e d, partici pa nts’ ass ess me nt data will be treate d as 
t h o u g h it occ urre d at t he ti me p oi nt s pecifie d (i.e., data c ollecte d o ut of V isit wi n d o ws will n ot be 
e xcl u de d or a dj uste d f or i n a n y a nal ys es) a n d i nfere n ces will be c o n d uct e d acc or di n gl y. T h us, 
f urt her ti me wi n d o ws will n ot be s pecifie d.  
All o bser vati o ns fr o m u nsc he d ule d Visits will be i ncl u de d o nl y i n t he a nal yses of V isit 
i n de pe n de nt s u m maries ( e. g., c o u nts of A Es, c o n c o mita nt me dicati o ns a n d pr oce d ures, rel a pse 
re p orti n g a n d E D S S) u nl ess f or t he last ass ess me nt a vaila ble. I n t his cas e t he missi n g earl y 
ter mi nati o n (E T ) Visit will be i m p ute d b y t he u nsc he d ule d Visit. 
If n ot s pecifie d ot her wis e, t he assess me nts of t he E T V isit will be ma p pe d t o t he n earest ne xt 
pla n ne d  p ost -baseli ne V isit  wit h  a  missi n g  assess me nt  bef ore  or  after  t he  E T   Visit  of  t he  
i n di vi d ual  assess me nt  f or  all  statistical  a nal yses  a n d  descri pti ve  s u m maries.  As  n ot  all  
assess me nts of t h e E T  ar e perf or me d at eac h V isit, t he differe nt assess me nts of t he E T  ca n b e 
assi g ne d t o diff er e nt V isits. If t he d urati o n (i n d a ys) bet w ee n t he E T   Visits a n d t w o missi n g 
pla n ne d V isits are e q u al, t he n t he assess me nt will be assi g ne d t o t he later V isit. 
 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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I N F O R M A T I O N 
2 1 /7 0   
 
 
9. 8  
St u d y  peri o d  
T he f oll o wi n g st u d y peri o ds are defi ne d: 
Treat me nt Peri o d  (i. e., P are nt St u d y Peri o d ): see C L A RI F Y M S  I A P V 5  f or defi niti o n. 
 
Ga p Peri o d:  
•  Start = Visit e n d date of M 2 4 Visit + 1  
•  E n d: E xte nsi o n St u d y Baseli ne Visit start date  
Year 3 Visit  Peri o d:  
•  Start = Visit e n d date of M 2 4 Visit + 1  
•  E n d = Visit e n d date of M 3 6 Visit 
Year 4 Visit  Peri o d:  
•  Start = Visit e n d date of M 3 6 Visit + 1  
•  E n d = Visit e n d date of M 4 8 Visit 
 
Year 3 Visit a n d Year 4 Visit Peri o d (i.e., E xte nsi o n St u d y Peri o d ): 
•  Start  = Visit e n d date of M 2 4 Visit + 1  
•  E n d = Visit e n d date of M 4 8 Visit 
 
After start of st u d y me di cati o n u ntil e n d of Year 3 Visit Peri o d: 
•  Start  = Start of st u d y me dicati o n (see C L A RI F Y M S I A P V 5  f or defi niti o n) 
•  E n d = Visit e n d date of M 3 6 Visit 
After start of st u d y me dicati o n u ntil e n d of Year 4 Visit Peri o d (i.e., P are nt a n d E xte nsi o n 
St u d y Peri o d ): 
•  Start  = Start of st u d y me dicati o n (see C L A RI F Y M S I A P V 5  f or defi niti o n) 
•  E n d  = Visit e n d date of M 4 8 Visit 
I n case of missi n g M 4 8 Visit or earl y disc o nti n uati o n bef ore a n E n d of Peri o d defi ne d a b o ve, t he 
Visit e n d date of E T Visit will be use d t o re place t he c orres p o n di n g E n d date, or t he st u d y 
disc o nti n uati o n date will be use d if t he E T Visit w as n ot perf or m e d.  
I n case of missi n g M 3 6 Visit, t he Visit e n d date of M 3 6 Visit i n t he a b o ve defi niti o ns (i ncl u di n g 
Start  a n d  E n d)  will  be  re place d  b y  Clarif y  M S  Baseli ne  Visit  date  +  1 1 9 8 da ys  ( w hic h  is  
o btai ne d b y 1 0 8 0 ( 3 6 m o nt hs) + 9 0 ( 3 m o nt hs dela y all o we d f or F A S) + 2 8 ( Visit wi n d o w)), or 
t he Visit e n d date of E T Visit  if earlier, or date of disc o nti n uati o n if earlier a n d t he E T Visit was 
n ot perf or me d. 
 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
9. 9  
I m p ut ati o n of Missi n g D at a 
U nless ot her wise s pecifie d, all data will be e val u ate d as o bser v e d, a n d n o i m p utati o n met h o d f or 
missi n g val ues will be use d. 
I n all partici p a nt data listi n gs, i m p ute d val ues will be prese nte d, a n d i m p ute d i nf or mati o n will be 
fla g ge d. 
Missi n g  statistics,  e. g. , w he n  t he y  ca n n ot  b e  calc ulate d,  s h o ul d  b e  prese nte d  as  “ n d ”.  F or  
e xa m ple, if n = 1, t he m eas ure of v aria bilit y ( S D) ca n n ot be c o m p ute d a n d s h o ul d be pres e nte d as 
“ n d”.  
W here t a bles ar e pr ese nt e d o ver ti me, t he t otal n u m ber of partici p a nts wit h missi n g a n d n o n-
missi n g o bser vati o ns at eac h ti me - p oi nt s h o ul d reflect t he c o m plete p o p ulati o n. 
I n c o m plete or missi n g o nset dates of rela pses re p orte d at E xte nsi o n St u d y Baseli ne Visit  (i.e., 
rela pses e x p ecte d d uri n g ga p peri o d) will be i m p ut e d as f oll o ws:  
•  I n cases w h ere t he o nset date is c o m pletel y missi n g  t he o nset date will be re place d b y 
M 2 4 Visit + 1  
•  if o nset dat e is  partiall y missi n g b ut t he o nset m o nt h a n d year, or t he o nset year are e q ual 
t o t he M 2 4 Visit date t he n t he o nset date will be re place d b y M 2 4 Visit + 1 . 
•  I n all ot her cases t he missi n g o nset da y or missi n g o nset m o nt h will be re place d b y 1. 
I n c o m plete or missi n g o nset dates of rela pses re p orte d after E xte nsi o n St u d y Baseli ne Visit  will 
be i m p ute d as f oll o ws: 
•  I n cases w h ere t he o ns et date is c o m pletel y missi n g  t he o nset date will be re place d b y t h e 
E xte nsi o n St u d y Baseli ne Visit date + 1.  
•  if o nset dat e is partiall y missi n g b ut t he o nset m o nt h a n d year, or t he o nset year are e q ual 
t o  t he  E xte nsi o n  St u d y Baseli ne  Visit,  t he n  t he  o nset  date  will  be  re place d  b y  t he  
E xte nsi o n St u d y Baseli ne Visit date + 1 . 
•  I n all ot her cases t he missi n g o nset da y or missi n g o nset m o nt h will be re place d b y 1. 
 
I n c o m plete or missi n g o nset dates of A E re p ort e d d uri n g t he e xte nsi o n st u d y peri o d  will be 
i m p ute d as f oll o ws:  
•  I n case t h e o nset date is missi n g c o m pletel y or missi n g partiall y b ut t he o nset m o nt h a n d 
year, or t h e o nset year ar e e q ual t o t he M 2 4 Visit date t he n t he o nset dat e will be re place d 
b y t he M 2 4 Visit + 1 .  
•  I n all ot her cases t he missi n g o nset da y or missi n g o nset m o nt h will be re place d b y 1.  
•  I n c o m plete st o p dates will be re place d b y t he last da y of t he m o nt h (if da y is missi n g 
o nl y), if n ot res ulti n g i n a date later t ha n t h e date of partici pa nt ’s d eat h. I n t he latter case 
t he date of deat h will be use d t o i m p ute t he i nc o m plete st o p date.  
•  I n all ot her cases t he i nc o m plete st o p date will n ot be i m p ute d.  
 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
9. 1 0  
D at a H a n dli n g i n c ase of P Ds  
P D s i n t he e xte nsi o n st u d y will n ot be c o nsi dere d i n t he pla n ne d statistical a nal yses (i.e., all data 
will be a nal yze d i n d e pe n de nt fr o m a n y re p orte d P D). 
9. 1 1  
C o v ari ates a n d Str atific ati o n F act ors  
T he f oll o wi n g c o vari ates a n d stratificati o n fact ors will be defi ne d: 
 
U nless ot her wise s pecifie d, t hese fact ors will b e o btai ne d fr o m t he baseli ne i nf or mati o n of t he 
C L A RI F Y M S B aseli ne . 
A ge  
see C L A RI F Y  M S I A P V 5. 
E D S S at B aseli ne  
see C L A RI F Y  M S I A P V 5. 
P o ole d ce nters  
S o me c o u ntries ma y ha v e fe w eli gi ble partici pa nts o nl y. T heref ore, t he ce nters will be p o ole d 
t o get her i n ge o gra p hical gr o u ps b y c o u ntr y a n d a d diti o nall y De n mar k will be f urt her p o ole d 
t o get her wit h Net herla n ds. See C L A RI F Y M S I A P V 5 f or f urt her details. 
 
1 0  
St u d y P artici p a nt s 
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or re p orti n g partici pa nt dis p ositi o n a n d 
st u d y  i nter ve nti o n/st u d y disc o nti n uati o ns.  A d diti o nall y , pr oce d ures  f or  re p orti n g  pr ot oc ol  
de viati o ns are pr o vi d e d. 
1 0. 1  
Dis p ositi o n of P artici p a nt s a n d Disc o nti n u ati o ns 
T his secti o n descri bes p artici pa nt dis p ositi o n  i n t he E xte nsi o n St u d y.  
P artici pa nt  dis p ositi o n i n t his E xte nsi o n St u d y will be prese nte d f or t he S C R: 
•  T otal n u m ber of p artici pa nts scree n e d i n t he C L A RI F Y M S E xte nsi o n St u d y (i.e. 
partici pa nts w h o ga v e i nf or me d c o nse nt f or t he E xte nsi o n St u d y) 
•  N u m ber of partici pa nts w h o disc o nti n ue d i n t he scree ni n g p h ase b y t he mai n reas o n:  
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 /7 0   
 
 
o  S u bject  di d n ot meet all eli gi bilit y criteria  
o  Wit h dra wal b y s u bject 
o  Pr o gressi ve d isease 
o  A d verse e ve nt 
o  L ost t o f oll o w- u p 
o  Deat h  
o  Ot her  
•  N u m ber of eli gi ble partici pa nts i n t he E xte nsi o n St u d y, o verall a n d b y t he f oll o wi n g 
cate g ories:  
o  N u m ber a n d p erce nta ge of eli gi ble partici pa nts bef ore a n d after t he start of 
C O VI D - 1 9 pa n d e mic  
o  N u m ber a n d p erce nta ge of eli gi ble partici pa nts w h o c o m plete d t he st u d y 
o  N u m ber a n d p erce nta ge of eli gi ble partici pa nts w h o disc o nti n ue d t he st u d y, wit h 
t he pri mar y reas o n of dis c o nti n uati o n: 
 A d verse e ve nt  
 L ost t o f oll o w- u p 
 Pr ot oc ol n o n- c o m plia nce  
 Deat h  
 Pr o gressi ve disease  
 Wit h dra wal b y s u bject 
 Ot her  
o  S D M T c o m pleti o n stat us, i ncl u di n g reas o ns f or missi n g data 
o  M S Q o L - 5 4 c o m pleti o n stat us, i ncl u di n g reas o ns f or missi n g data 
T he d urati o n of ga p p eri o d bet wee n C L A R I F Y M S E n d of St u d y a n d C L A R I F Y M S  
E xte nsi o n St u d y Baseli ne will be s u m marize d usi n g t he f oll o wi n g classes: 
o  N o ga p (i.e., M o nt h 2 4 Visit a n d E xte nsi o n Baseli ne c oi nci de) 
o  D urati o n of ga p p eri o d < 1 m o nt h 
o  D urati o n of ga p p eri o d ≥ 1 m o nt h a n d < 3 m o nt hs  
o  D urati o n of ga p p eri o d ≥ 3 m o nt hs a n d < 6 m o nt hs  
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
o  D urati o n of ga p p eri o d ≥ 6 m o nt hs a n d < 9 m o nt hs  
o  D urati o n of ga p p eri o d ≥ 9 m o nt hs a n d ≤1 2 m o nt hs 
o  D urati o n of ga p p eri o d > 1 2 m o nt hs 
A d diti o nall y, d urati o n of ga p peri o d will be s u m marize d usi n g des cri pti ve statistics.  
Perce nta g es  will  be prese nte d  wit h  res pect t o t he n u m ber of eli gi ble partici p a nts . 
T he n u m ber of p artici pa nt s i n eac h a nal ysis set will be pr o vi de d o verall, b y re gi o n, b y c o u ntr y 
wit hi n re gi o n a n d b y site. 
T he f oll o wi n g partici pa nt  data listi n gs will be pr o vi de d: 
•  Listi n g of disc o nti n ue d partici pa nt s f or t he F A S , 
•  Listi n g of partici pa nts e x cl u de d fr o m t he A n al ysis Sets.  
 
1 0. 2  
Pr ot oc ol De vi ati o ns / E xcl usi o n fr o m A n al ysis Sets  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De vi ati o ns 
I m p ort a nt pr ot oc ol de viati o ns (I P Ds) are pr ot oc ol de viati o ns t hat mi g ht si g nifica ntl y affect t he 
c o m plete ness, acc urac y, a n d/ or r elia bilit y of t he st u d y data or t hat mi g ht si g nifica ntl y affect a 
partici pa nt ’s ri g hts, saf et y, or well- bei n g. 
I m p ort a nt pr ot oc ol de viati o ns will be i de ntifie d f or all partici pa nts b y eit her site m o nit ori n g, 
me dical r e vie w pr ocess es or pr o gra m mi n g a n d c o nfir me d pri or t o or at t he Data R e vie w M eeti n g 
at t he latest. 
A n y I P D is d oc u me nt e d i n S D T M datasets w h et her i de ntifie d t hr o u g h site m o nit ori n g, me dical 
re vie w  or  pr o gra m mi n g.  T he  m a na ge m e nt  of  pr ot oc ol  de viati o ns  is  o utsi de  of  t his  I A P  
d oc u me nt.  
T he f oll o wi n g s u m mar y ta bles a n d listi n gs of I P Ds will be pr o vi de d f or t he F A S:  
•  N u m ber a n d pr o p orti o n of partici pa nts wit h I P Ds b y classificati o n of I P Ds ( o verall a n d bas e d 
o n relati o ns hi p t o C O VI D- 1 9 pa n de mic),  
•  Listi n g of I P Ds (i ncl u di n g i nf or mati o n re gar di n g relati o ns hi p t o C O VI D- 1 9 pa n de mic). 
 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
1 0. 2. 2  
Re as o ns Le a di n g t o t he E xcl usi o n fr o m a n A n al ysis Set  
A fre q u e nc y ta ble, as w ell as a listi n g, or ga nize d acc or di n g t o reas o ns f or e xcl usi o n fr o m t he 
F A S will be pr o vi de d, if a p plica ble.  
P ossi ble reas o ns f or e x cl usi o n fr o m t he F A S i ncl u de: 
•  N ot f ulfill a n y of t he i ncl usi o n criteria  
o  Partici pa nts of t he C L A RI F Y M S trial w h o h a ve  at least C L A RI F Y M S baseli ne 
data o n S D M T 
o  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  
o  C o m plete d t he fi nal st u d y V isit ( M 2 4) of t he C L A RI F Y M S trial 
o  Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt 
•  Meet a n y of t he e xcl usi o n criteria  
o  Partici pa nt is c o nsi dere d b y t he I n vesti gat or, f or a n y reas o n, t o be a n u ns uita ble 
ca n di date f or t he st u d y 
o  Partici pati o n i n ot her st u dies/trials  
 
1 1  
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics  
If n ot state d ot her wise, t h e f oll o wi n g a nal yses will be perf or me d b ase d o n t he F A S o verall a n d/ or 
b y D M D s u b gr o u ps. 
1 1. 1  
De m o gr a p hics  
De m o gra p hic c h aracteristics will be s u m marize d descri pti vel y usi n g t he f oll o wi n g i nf or mati o n 
fr o m t he Scree ni n g/ Baseli ne Visit e C R F pa ges i n t he C L A RI F Y M S trial. 
T he de m o gra p hi c c haracteristics will be s u m marize d, a n d t he d ata will be prese nte d as s pecifi e d 
i n C L A RI F Y M S  I A P V 5 . 
T he f oll o wi n g partici pa nt data listi n g s usi n g C L A RI F Y M S Baseli ne data  will be pr o vi de d:  
•  De m o gra p hic Data ( e. g., C o u ntr y, Se x, Race, A g e, E D S S at Baseli ne, N u m ber of rela pses 
d uri n g last Y ear, i.e., b ef ore C L A RI F Y M S Baseli ne).  
I n a d diti o n, a ge at ti me of i nf or me d c o nse nt as c ollecte d fr o m t he “ De m o gra p hics” e C R F pa g e i n 
t he C L A RI F Y M S E xte nsi o n St u d y will be a d de d i n b ot h t he s u m mar y ta ble a n d t he listi n g. 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
1 1. 2  
Me dic al Hist or y  
T he  me dical  hist or y  will  be  s u m marize d  fr o m  t he  “ Me dical  Hist or y”  e C R F  pa ge  of  t he  
C L A RI F Y M S E X T E N SI O N Baseli ne , usi n g t he m ost rece nt Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A) versi o n at ti me of data base l oc k, preferre d ter m ( P T) as e ve nt cate g or y a n d 
s yste m or ga n class ( S O C) b o d y ter m as B o d y S yste m cate g or y. E ac h parti ci pa nt will be c o u nte d 
o nl y o nce wit hi n eac h P T or S O C. 
A d diti o nall y, als o t he me dical hist or y fr o m t he “ Me dical Hist or y” e C R F pa ge of t he C L A RI F Y 
M S Baseli ne , usi n g t he Me d D R A versi o n t hat has bee n a p plie d f or c o di n g of Me dical Hist or y i n 
t he pare nt st u d y, will be s u m marize d as w ell. 
Me dical hist or y will b e dis pla ye d i n ter ms of fre q ue nc y ta bl es: or dere d b y pri mar y S O C a n d P T 
i n al p ha betical or d er. 
1 1. 3  
Ot her B aseli ne C h ar acteristics  
, 
 C haracteristics a n d Vital Si g ns, will be prese nte d 
as s pecifie d i n C L A RI F Y M S I A P versi o n 5. 0.  
E D S S assess me nt at E xte nsi o n Baseli ne Visit was perf or me d f or al m ost all partici pa nts, 
re gar dl ess of w het h er t he y ha d a ga p p eri o d, a n d will be liste d o nl y. T he E D S S sc ores of 
partici pa nts w h o ha d a ga p peri o d will still be c o nsi dere d f or d eter mi ni n g disease pr o gressi o n, as 
pla n ne d i n t he C S P. 
 
 
 
1 2  
P re vi o us  or C o nc o mit a nt T her a pies/ Pr oce d ures   
 
Rele v a nt pre vi o us m e dic ati o ns at C L A RI F Y M S B aseli ne  will be s u m marize d  as s p ecifie d i n 
C L A RI F Y M S I A P  V 5 .  
C o nc o mit a nt m e dic ati o ns  are me dicati o ns, ot her t ha n st u d y me dicati o ns, w hic h are t a ke n b y 
partici pa nts after t he i nitial d ose of cla dri bi ne ta bl ets (i ncl u di n g t he st u d y peri o d of t he 
C L A RI F Y M S trial  a n d t he E xte nsi o n St u d y [ w hic h is i ncl u di n g t he ga p peri o d bet 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]). 
C o nc o mita nt me dicati o ns will be s u m marize d s e paratel y f or t h e st u d y p eri o d of t he C L A RI F Y 
M S trial  a n d t he E xte nsi o n St u d y peri o d.  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
Data will be us e d fr o m t he “ C o nc o mita nt me dicati o n” e C R F pa ge of t he C L A RI F Y M S trial a n d 
t he E xte nsi o n St u d y. All me dicati o ns e ntere d i nt o t he “ C o nc o mita nt me dicati o n” e C R F pa ge will 
be ass u me d t o be “c o nc o mita nt” irres pecti ve of t he act ual start a n d e n d d ates.  
A nat o mical T her a pe utic  C he mical classificati o n ( A T C )- 1st le vel  a n d  P T  will  be ta b ulate d  as  
gi ve n  fr o m  t he  W orl d  Healt h  Or ga ni zati o n  Dr u g  Dicti o nar y  (W H O -D D )  dicti o nar y. I n  case  
m ulti ple A T Cs are assi g n e d t o a dr u g, all A T C - 1st le vel will be use d f or re p orti n g. I n a d diti o n, all 
c o nc o mita nt me dicati o ns as w ell as c o nc o mita nt me dicati o ns gi ve n f or dis ease relat e d c o n diti o ns 
will be prese nte d b y P T a n d b y decreasi n g fre q ue n c y. 
T he  m ost  c urre nt  W H O -D D  dicti o nar y  versi o n  at  ti me  of C L A RI F Y  M S   E xte nsi o n  St u d y 
a nal ysis data b ase l oc k will be use d  o nl y f or C L A RI F Y M S E xte nsi o n St u d y . F or C L A RI F Y M S 
pare nt st u d y, t he versi o n of t hat has bee n use d f or c o di n g of c o nc o mita nt me dicati o ns will a p pl y . 
T he W H O -D D dicti o nar y use d f or c o di n g will be liste d as a f o ot n ote of c orres p o n di n g ta ble or 
listi n g.  
A d diti o nall y, a ll D M Ds w hic h ha ve bee n re p orte d f or t he st u d y peri o d of t he C L A RI F Y M S trial 
a n d t he C L A RI F Y M S E xte nsi o n St u d y peri o d will  be prese nte d  t o get her b y P T.  T he u p date d l ist 
of D M Ds  (see A p pe n di x 1 8. 1 ) will be use d t o i de ntif y D M D i n c o nc o mita nt me dicati o ns i n 
C L A RI F Y M S E xte nsi o n St u d y  i nstea d of t he pare nt st u d y D M D list (see C L A RI F Y M S I A P 
V 5) . List c o ul d f urt her b e u p date d bef ore d ata bas e l oc k.   
C o nc o mit a nt pr oce d ures  w hic h were u n derta ke n a n y ti me d uri n g t he E xte nsi o n St u d y Peri o d 
will be liste d b y partici pa nt.  
 
1 3  
St u d y Inter ve nti o n : C o m pli a nce a n d E x p os ure  
As  n o treat me nt is pr o vi de d i n t he E xte nsi o n S t u d y, partici pa nts’  c o m plia nce, a n d e x p os ure i n 
t he C L A RI F Y M S trial will be prese nt e d f or t he E xte nsi o n St u d y S A F  as defi ne d i n C L A RI F Y  
M S I A P  V 5.  
 
1 4  
Effic ac y A n al yses  
T he f oll o wi n g a nal yses will be perf or me d b ase d o n t he F A S. 
Descri pti ve  s u m mar y  statistics  will  be  prese nte d  f or  t he  a bs ol ute  val ues  a n d  t he  c ha n ges  fr o m  
baseli ne as a p plica ble, f or all efficac y e n d p oi nts at eac h V isit, f or t he F A S o verall a n d pre vi o us 
treat me nt wit h D M Ds s u b gr o u ps.  
Details a b o ut t he pres e ntati o n of c o nti n u o us a n d q ualitati ve varia bles are gi ve n i n Secti o n 9 . 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 9 /7 0   
 
 
F or t he d etaile d defi niti o n of c o variates a n d stratificati o n fact ors t hat are use d i n t he statistical 
m o dels see Secti o n 9. 1 1 .  
W here v er p ossi ble, all esti mate d res ults fr o m t h e statistical m o dels will be cal c ulate d wit h t he 
sa me o bser v e d mar gi n w hic h reflects t he p o p ul ati o n of t he w h ole c orres p o n di n g a nal ysis set, 
re gar dl ess of missi n g data (as des cri be d  i n C L A RI F Y M S I A P V 5). 
 
1 4. 1  
Pri m ar y  E n d p oi nt : N o  or  mi ni m al  decli ne  i n  c o g niti ve  
f u ncti o n at Ye ar 4 Visit  
T he pri mar y e n d p oi nt is t he perce nt a ge of partici pa nts wit h n o or mi ni mal decli ne i n c o g niti ve 
f u ncti o n, defi n e 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 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 after i nitial d ose of cla dri bi ne ta bl ets  
(i.e. at t he Year 4 Visit)  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). 
 
1 4. 1. 1  
Pri m ar y O bjecti ve: Deri v ati o n a n d a n al ysis of t he pri m ar y 
e n d p oi nt 
 
T he S D M T is a test of i nf or mati o n pr ocessi n g s pee d. It c o nsists of 9 a bstract s y m b ols. Eac h 
s y m b ol is paire d wit h a si n gle di git. T he partici pa nt is pr o vi de d wit h a “ ke y”, s h o wi n g eac h 
s y m b ol di git pair. I n a d diti o n, t he partici pa nts are s h o w n se veral r o ws of t he 9 s y m b ols, w hic h 
are  arra n g e d  pse u d o -ra n d o ml y,  wit h o ut  t he  di git.  Partici pa nts  are  as k e d  t o  v oice  t he  di git  
ass ociate d wit h eac h s y m b ol as ra pi dl y as p ossi ble f or 9 0 sec o n ds. T here is a si n gle o utc o me 
meas ure – t he S D M T sc ore ( 0-1 1 0) is t he n u m ber of c orrect res p o nses o ver t he 9 0 -sec o n d ti me 
s pa n (re g ar dless of t h e n u m ber of i nc orrect res p o nses). 
N o or mi ni mal decli ne i n c o g niti ve f u ncti o n is defi ne d as:  
•  Yes: C ha n ge fr o m C L A RI F Y M S Baseli ne i n S D M T ≥ -4 at Year 4  Visit  
•  N o: C ha n ge fr o m C L A RI F Y M S Baseli ne i n S D M T < - 4 at Y ear 4 Visit  
•  Missi n g: C L A RI F Y M S Baseli ne or M 4 8 Visit val ue is n ot a vaila ble  
 
T he pr o p orti o n of partici pa nts wit h n o decli ne or mi ni mal decli ne  i n S D M T sc ore at Year 4 Visit 
will be pr ese nte d t o get her wit h t h e 9 5 % c o nfi d e nce i nter v al c o m p ute d acc or di n g t o Wils o n’s 
sc ore met h o d.  
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 0 /7 0   
 
 
I n or der t o calc ul ate t he c o nfi de nce li mits acc or di n g t o Wils o n’s sc ore m et h o d i n S A S, t he o pti o n 
BI N O MI A L( C L = WI L S O N)  i n  t he  P R O C  F R E Q  ->  T A B L E S  state me nt  or  t he  o pti o n  
C L( T Y P E =sc or e)  i n t he P R O C S U R V E Y F R E Q  -> T A B L E S state me nt  ca n be use d . 
A n al y si s  
( A n al y si s 
S et) 
D eri v ati o n  
St ati sti c al A n al y si s M et h o d s  
 Mi s si n g d at a h a n dli n g  
Pri m ar y  e n d p oi nt: S u m m ar y of N o or Mi ni m al D e cli n e i n C o g niti v e F u n cti o n fr o m p ar e nt st u d y  B a s e li n e t o 
Y e ar 4 Vi sit  
Pri m ar y 
( F A S) 
 
N o or Mi ni m al D e cli n e i n 
C o g niti v e F u n cti o n at M o nt h 
4 8 Vi sit c o m p ar e d t o 
C L A RI F Y M S B a s eli n e.  
•  
D e s cri pti v e s u m m ar y st ati sti c s 
(i n cl u di n g 9 5 % c o nfi d e n c e 
i nt er v al f or pr o p orti o n s 
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 ) 
•  
F or e st pl ot s f or e sti m at e a n d 
9 5 % CI  
Mi s si n g v al u e s will b e 
i n cl u d e d i n t h e d e n o mi n at or 
a n d pr e s e nt e d a s a s e p ar at e 
c at e g or y.  
 
1 4. 1. 2  
Se nsiti vit y A n al yses of t he pri m ar y e n d p oi nt  
 
L o gistic Re gressi o n M o dels 
As a first se nsiti vit y a nal ysis t he pr o p orti o n of partici pa nts wit h n o decli ne or mi ni mal  decli ne i n 
S D M T sc ore at Year 4 Visit  will be a nal yze d wit h a l o gistic re gressi o n wit h a dj usti n g fact ors , 
S D M T at baseli ne,  a ge (i n years) a n d E D S S at Baseli ne ( ≤3, > 3).   
T he S D M T c ha n ges fr o m Baseli ne will als o be s u m marize d b y a  mi xe d effect li near a nal ysis f or 
re peat e d meas ur es f or t h e F A S. 
A d diti o nal S D M T cate g ories:  
I n a f urt her se nsiti vit y a nal ysis, t he c ha n ge fr o m C L A RI F Y M S Baseli ne i n S D M T at Year 4 
Visit  will be f urt her classifie d as  descri be d bel o w a n d s u m marize d wit h t he met h o ds as descri be d 
i n Secti o n 1 4. 1. 1 : 
•  I m pr o v e me nt: > 0 
•  Sta ble: 0  
•  Mi ni mal W orse ni n g: < 0 a n d ≥ - 4 
•  Maj or W orse ni n g: < - 4 
•  Missi n g: C L A RI F Y M S Baseli ne or Year 4 Visit  val ue is n ot a vaila ble 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
A n al y si s  
( A n al y si s S et) 
D eri v ati o n  
St ati sti c al A n al y si s M et h o d s  
Mi s si n g d at a h a n dli n g  
Pri m ar y  e n d p oi nt: N o or Mi ni m al D e cli n e i n C o g niti v e F u n cti o n fr o m p ar e nt st u d y  B a s eli n e t o Y e ar 4 Vi sit  
( S e n siti vit y A n al y si s) 
S e n siti vit y  
( F A S) 
N o or Mi ni m al D e cli n e i n 
C o g niti v e F u n cti o n at M o nt h 
4 8 Vi sit c o m p ar e d t o 
C L A RI F Y M S B a s eli n e.  
•  
L o gi sti c r e gr e s si o n:  
A dj u sti n g f a ct or s:  
•   
Ag e (i n y e ar s),  
•  
E D S S ( ≤3, > 3). 
•  
B a s eli n e S D M T s c or e  
E sti m at e d 
pr o b a bilit y  a n d 
c orr e s p o n di n g
 St a n d ar d
 
Err or s
 ( S E)
 will
 b e
 
pr e s e nt e d i n cl u di n g 2 -si d e d 
p- v al u e s a n d 9 5 % CI . 
•  
F or e st  pl ot s  f or  e sti m at e  
a n d 9 5 % CI  
U n k n o w n st at u s:  
P arti ci p a nt s  wit h  a n  u n k n o w n  
st at u s  will  b e  e x cl u d e d  fr o m  
t h e l o gi sti c r e gr e s si o n.  
Mi s si n g
 c o v ari at e
 or
 
str atifi c ati o n  i nf or m ati o n  will  
b e  i m p ut e d  a s  s p e cifi e d  i n  
S e cti o n 9. 1 1 . 
S e n siti vit y  ( F A S 
b y s u b gr o u p 
“ Pr e vi o u s 
tr e at m e nt wit h 
D M D s ”) 
N o or Mi ni m al D e cli n e i n 
C o g niti v e F u n cti o n at M o nt h 
4 8 Vi sit c o m p ar e d t o 
C L A RI F Y M S B a s eli n e.  
•  
L o gi sti c r e gr e s si o n:  
A dj u sti n g f a ct or s:  
•   
Ag e (i n y e ar s),  
•  
E D S S ( ≤3, > 3). 
•  
B a s eli n e S D M T s c or e  
E sti m at e d 
pr o b a bilit y  a n d 
c orr e s p o n di n g
 St a n d ar d
 
Err or s
 ( S E)
 will
 b e
 
pr e s e nt e d i n cl u di n g 2 -si d e d 
p- v al u e s a n d 9 5 % CI . 
F or e st  pl ot s  f or  e sti m at e  
a n d 9 5 % CI  
U n k n o w n st at u s:  
P arti ci p a nt s  wit h  a n  u n k n o w n  
st at u s  will  b e  e x cl u d e d  fr o m  
t h e l o gi sti c r e gr e s si o n.  
Mi s si n g c o v ari at e or 
str atifi c ati o n i nf or m ati o n will 
b e i m p ut e d a s s p e cifi e d i n 
S e cti o n 9. 1 1 . 
S e n siti vit y  
( F A S) 
C h a n g e fr o m C L A RI F Y M S 
B a s eli n e i n S D M T s c or e s at 
M o nt h I Vi sit, w h er e i = 1 2, 
2 4 a n d 4 8.  
Mi x e d -eff e ct s Li n e ar M o d el f or 
R e p e at e d M e a s ur e s ( M M R M) 
wit h t h e f oll o wi n g a dj u sti n g 
f a ct or s: 
•  
B a s eli n e S D M T s c or e,  
•  
A g e ( y e ar s), 
•  
E D S S at B a s eli n e ( ≤3, 
> 3), 
•  
Vi sit,  
•  
P o ol e d c e nt er  
•  
Wit hi n -s u bj e ct 
c orr el ati o n.  
E sti m at e d L e a st S q u ar e M e a n s 
( L S M e a n s) a n d c orr e s p o n di n g 
St a n d ar d Err or s ( S E) will b e 
pr e s e nt e d b y Vi sit i n cl u di n g 2 -
si d e d p -v al u e s a n d 9 5 % CI.  
 
•  
A n u n str u ct ur e d c o v ari a n c e 
m atri x will b e a s s u m e d f or 
t h e m o d el. If t h e m o d el 
d o e s n’t c o n v er g e a n 
alt er n ati v e c o v ari a n c e 
Mi s si n g o b s er v ati o n s at 
B a s eli n e:  
P arti ci p a nt s wit h a mi s si n g 
B a s eli n e s c or e will n ot b e 
i n cl u d e d i n t h e li n e ar m o d el. 
 
Mi s si n g p o st -B a s eli n e 
o b s er v ati o n s:  
Mi s si n g p o st -B a s eli n e 
a s s e s s m e nt s will n ot b e 
i m p ut e d. T h e r e p e at e d 
m e a s ur e m e nt m o d el h a n dl e s 
mi s si n g p o st -B a s eli n e 
a s s e s s m e nt s u n d er t h e 
a s s u m pti o n of Mi s si n g at 
R a n d o m ( M A R).  
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
A n al y si s  
( A n al y si s S et) 
D eri v ati o n  
St ati sti c al A n al y si s M et h o d s  
Mi s si n g d at a h a n dli n g  
str u ct ur e will b e u s e d 
i n st e a d. 
•  
F or e st pl ot s f or e sti m at e 
a n d 9 5 % CI  b y V i sit 
S e n siti vit y  ( F A S 
b y s u b gr o u p 
“ Pr e vi o u s 
tr e at m e nt wit h 
D M D s ”) 
C h a n g e fr o m C L A RI F Y M S 
B a s eli n e i n S D M T s c or e s at 
M o nt h I Vi sit, w h er e i = 1 2, 
2 4 a n d 4 8.  
Mi x e d -eff e ct s Li n e ar M o d el f or 
R e p e at e d M e a s ur e s ( M M R M) 
wit h t h e f oll o wi n g a dj u sti n g 
f a ct or s: 
•  
B a s eli n e S D M T s c or e,  
•  
A g e ( y e ar s),  
•  
E D S S at B a s eli n e ( ≤3, 
> 3), 
•  
Vi sit,  
•  
P o ol e d c e nt er  
•  
Wit hi n -s u bj e ct 
c orr el ati o n.  
E sti m at e d L e a st S q u ar e M e a n s 
( L S M e a n s) a n d c orr e s p o n di n g 
St a n d ar d Err or s ( S E) will b e 
pr e s e nt e d b y Vi sit i n cl u di n g 2 -
si d e d p -v al u e s a n d 9 5 % CI.  
 
A n u n str u ct ur e d c o v ari a n c e 
m atri x will b e a s s u m e d f or t h e 
m o d el. If t h e m o d el d o e s n’t 
c o n v er g e a n alt er n ati v e 
c o v ari a n c e str u ct ur e will b e 
u s e d i n st e a d.  
•  
F or e st pl ot s f or e sti m at e 
a n d 9 5 % CI  b y V i sit 
Mi s si n g o b s er v ati o n s at 
B a s eli n e:  
P arti ci p a nt s wit h a mi s si n g 
B a s eli n e s c or e will n ot b e 
i n cl u d e d i n t h e li n e ar m o d el. 
 
Mi s si n g p o st -B a s eli n e 
o b s er v ati o n s:  
Mi s si n g p o st -B a s eli n e 
a s s e s s m e nt s will n ot b e 
i m p ut e d. T h e r e p e at e d 
m e a s ur e m e nt m o d el h a n dl e s 
mi s si n g p o st -B a s eli n e 
a s s e s s m e nt s u n d er t h e 
a s s u m pti o n of Mi s si n g at 
R a n d o m ( M A R).  
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
A n al y si s  
( A n al y si s S et) 
D eri v ati o n  
St ati sti c al A n al y si s M et h o d s  
Mi s si n g d at a h a n dli n g  
Pri m ar y e n d p oi nt: S u m m ar y of N o or Mi ni m al D e cli n e i n C o g niti v e F u n cti o n fr o m p ar e nt st u d y B a s eli n e t o 
Y e ar 4 Vi sit ( S e n siti vit y A n al y si s)  
S e n siti vit y  ( F A S 
b y s u b gr o u p 
“R el a p s e st at u s 
i n p ar e nt st u d y”) 
N o or Mi ni m al D e cli n e i n 
C o g niti v e F u n cti o n at M o nt h 
4 8 Vi sit c o m p ar e d t o 
C L A RI F Y M S B a s eli n e.  
•  
D e s cri pti v e s u m m ar y 
st ati sti c s (i n cl u di n g 9 5 % 
c o nfi d e n c e i nt er v al f or 
pr o p orti o n s 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 ) 
•  
F or e st pl ot s f or e sti m at e 
a n d 9 5 % CI  
Mi s si n g v al u e s will b e 
i n cl u d e d i n t h e d e n o mi n at or 
a n d pr e s e nt e d a s a s e p ar at e 
c at e g or y.  
Pri m ar y e n d p oi nt: S u m m ar y of C h a n g e C at e g ori e s  i n C o g niti v e F u n cti o n fr o m p ar e nt st u d y B a s eli n e t o Y e ar 
4 Vi sit ( S e n siti vit y A n al y si s)  
S e n siti vit y  
( F A S) 
I m pr o v e m e nt, St a bl e, 
Mi ni m al W or s e ni n g a n d 
M aj or W or s e ni n g of 
C o g niti v e F u n cti o n at M o nt h 
4 8 Vi sit c o m p ar e d t o 
C L A RI F Y M S B a s eli n e.  
•  
D e s cri pti v e s u m m ar y 
st ati sti c s (i n cl u di n g 9 5 % 
c o nfi d e n c e i nt er v al f or 
pr o p orti o n s 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 ) 
•  
F or e st pl ot s f or e sti m at e 
a n d 9 5 % CI  
Mi s si n g v al u e s will b e 
i n cl u d e d i n t h e d e n o mi n at or 
a n d pr e s e nt e d a s a s e p ar at e 
c at e g or y.  
 
M ulti ple I m p utati o n  
I n or der t o e val uate t he r o b ust ness of t he ass u m pti o n a p plie d i n t he pri mar y a nal ysis t hat missi n g 
data are o bser ve d as missi n g at ra n d o m ( M A R), t he pri mar y a nal ysis will be re peate d a p pl yi n g a 
patter n mi xt ure m o del. If missi n g ness ca n be c o nsi dere d M A R (e. g. S D M T missi n g f or tec h nical 
reas o ns), dat a will be i m p ute d b y m ulti ple i m p utati o n ( MI) fr o m p ost-Baseli ne data w hile if it is 
c o nsi dere d as missi n g n ot at ra n d o m ( M N A R) (e. g. dr o p o ut d ue t o lac k of efficac y), d ata will be 
i m p ute d fr o m Baseli ne d ata.  
T he f oll o wi n g reas o ns f or missi n g S D M T res ults will be c o nsi dere d as M A R: 
•  S D M T missi n g at Baseli ne  
•  Partici pa nt disc o nti n ue d t he st u d y bef ore t he Year  4 Visit wit h pri mar y reas o n  
o  L ost t o f oll o w- u p 
o  A n y Pr ot oc ol n o n -c o m plia nce re p ort e d as “ Ot h er” a n d classifie d as n o n -relate d t o 
D M D  
o  A n y  pre g n a nc y  ( Disc o nti n uati o n  Reas o n  “ A d verse  E v e nt”  a n d  “ Pre g na nc y”  
re p orte d as A E lea di n g t o disc o nti n uati o n. 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
All ot her missi n g S D M T res ults will be ha n dle d as M N A R.  
T he f oll o wi n g pr oce d ure f or t he diff ere nt t y pes of missi n g data will be perf or me d:   
•  S D M T sc ores  missi n g at t he Baseli ne  Visit  will be i m p ute d fr o m t he distri b uti o n of 
a vaila ble S D M T sc or es at t he Baseli ne Visit .  
•  S D M T  sc ores  missi n g  at  a n y  p ost -Baseli ne Visit  t hat  are  c o nsi dere d  M A R  will  be  
i m p ute d fr o m t he distri b uti o n of a vaila ble S D M T sc ores of t he s a me p ost-Baseli ne Visit . 
•  S D M T  sc ores  missi n g  at  a n y  p ost -Baseli ne Visit  t hat  are  c o nsi dere d  M N A R  will  be  
i m p ute d fr o m t he distri b uti o n of S D M T sc ores of t he Baseli ne Visit   
MI met h o ds i n v ol ve t hr ee ste ps:  
I. 
I m p utati o n 
I m p utati o n  is  t he  ge ner ati o n  of  m ulti ple  c o pies  of  t he  ori gi nal  datas et  b y  re placi n g  missi n g  
S D M T sc ore val ues  at Year 1, Year 2 a n d Year 4 Visit  b y usi n g a n a p pr o priate st oc hastic m o del. 
T he missi n g data will be i m p ute d usi n g t he F ull y C o n diti o nal S pecificati o n ( F C S) met h o d. T he 
F C S met h o d is base d o n a n iter ati ve al g orit h m; at eac h iterati o n a n d f or eac h v aria ble of t he 
pre dicti o n  m o del,  t here  is  a  pre dicti o n  ste p  a n d  a n  i m p utati o n  ste p.  T he  m o dels  use d  f or  
i m p utati o n will be li near re gressi o n m o dels. A t otal of 1 0 i m p utati o ns will be perf or me d usi n g a 
see d of 1 2 3 4 5.  
T he i m p utati o n m o del will i ncl u de  a ge, E D S S a n d S D M T s c ore at p are nt st u d y bas eli ne or 
S D M T  at eac h pre vi o us p ost -baseli ne V isit, de pe n di n g o n t he assi g n me nt of missi n g data as 
M A R or M N A R .  
Fi nal i m p ute d val ues will be r o u n de d t o i nte ger val ues a n d c ut -offs will be a p plie d t o i m p ute d 
val ues o utsi de of t he n or mal ra n ge of 0 t o 1 1 0. 
II. 
A nal ysis 
T he a n al ysis ste p is perf or me d f or eac h of t he i m p ute d datasets. Si nce all i m p ute d datasets are 
c o m plete t here is n o n ee d t o b ot her wit h a n y missi n g data. 
T he classificati o n of t he S D M T sc ore (i ncl u di n g t he i m p ute d val ues) as n o decli ne or mi ni mal 
decli ne i n S D M T sc or e at Year 4 Visit  a n d t he calc ulati o n of t he relate d pr o p orti o ns wit h 9 5 % 
c o nfi de nce i nter val s c o m p ute d acc or di n g t o Wils o n’s sc ore met h o d , will be d o ne as d escri be d i n 
Secti o n 1 4. 1. 1 . 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
III. 
P o oli n g 
P o oli n g  is  t he  c o m bi nati o n  of  t he  differe nt  para meter  esti mates  acr oss  t he  m ulti ple  i m p ute d  
datasets  base d  o n  R u bi n’s  r ules  ( R u bi n,  1 9 8 7  ( 6))  t o  pr o d uce  a  u ni q ue  p oi nt  esti mate  a n d  
sta n dar d err or ta ki n g i nt o acc o u nt t he u n certai nt y of t he i m p utati o n pr ocess. 
T his se nsiti vit y a nal ysis will be a nal yze d f or t he F A S.  
A n al y si s  
( A n al y si s 
S et) 
D eri v ati o n  
St ati sti c al A n al y si s M et h o d s  
 Mi s si n g d at a h a n dli n g  
Pri m ar y  e n d p oi nt: S u m m ar y of N o or Mi ni m al D e cli n e i n C o g niti v e F u n cti o n fr o m p ar e nt st u d y  B a s eli n e t o 
Y e ar 4 Vi sit ( S e n siti vit y A n al y si s  – M ulti pl e I m p ut ati o n ) 
S e n siti vit y 
u si n g 
M ulti pl e 
I m p ut ati o n 
( F A S) 
 
N o or Mi ni m al D e cli n e i n 
C o g niti v e F u n cti o n at M o nt h 
4 8 Vi sit c o m p ar e d t o 
C L A RI F Y M S B a s eli n e.  
•  
D e s cri pti v e s u m m ar y st ati sti c s 
(i n cl u di n g 9 5 % c o nfi d e n c e 
i nt er v al f or pr o p orti o n s 
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 ) 
•  
F or e st pl ot s f or e sti m at e a n d 
9 5 % CI  
T h e M ulti pl e I m p ut ati o n 
Pr o c e d ur e a s d e s cri b e d i n 
S e cti o n 1 4. 1. 2  will b e a p pli e d 
t o h a n dl e mi s si n g d at a. 
 
1 4. 2  
Sec o n d ar y E n d p oi nts  
1 4. 2. 1  
Sec o n d ar y  E n d p oi nt:  M S Q o L -5 4  C h a n ge  at  Ye ar  4  Visit  
fr o m B aseli ne 
T he sec o n dar y e n d p oi nts are t he c ha n g es i n M S Q o L -5 4 p h ysical a n d me ntal healt h c o m p osite 
sc ores at Y ear 4 Visit c o m pare d t o C L A RI F Y M S Baseli ne.  
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 pecifi c ite ms i nt o a si n gle i nstr u me nt ( Vic kre y et al., 1 9 9 5; Vic kre y et al., 
1 9 9 7). T he M S Q o L -5 4 q uesti o n naire w as de v el o pe d t o meas ure H R Q o L i n partici pa nt s 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 u c h as fati g ue a n d c o g niti ve f u ncti o n. 
T he q uesti o n naires will b e s u m marize d i n 5 (c o m p osite) sc ores  
•  P h ysical healt h c o m p osite,  
•  Me ntal healt h c o m p osite,  
•  Satisfacti o n wit h se x ual f u ncti o n,  
•  C ha n ge i n healt h, 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
•  O verall q ualit y of life,  
w hic h will be deri ve d fr o m t he 1 2 s u bscales ( P h ysical f u ncti o n, R ole li mitati o ns -p h ysical, R ole 
li mitati o ns-e m oti o nal,  Pai n,  E m oti o nal  well -bei n g,  E ner g y/fati g ue,  H ealt h  perce pti o ns,  S ocial  
f u ncti o n, C o g niti ve f u ncti o n, Healt h distress, O verall q ualit y of life, Se x ual f u ncti o n) f oll o wi n g 
t he r ules s p ecifie d i n t he Sc ori n g Ma n ual ( Vic kre y 1 9 9 5). All sc ores ra n ge fr o m 0 % t o 1 0 0 %. 
1 0 0 % is t he best p ossi ble sc ore. 
T he sec o n d ar y  e n d p oi nt a nal ysis is f oc usi n g o n t he p h ysical a n d me ntal h ealt h c o m p osite sc ores 
w hile t he o ver all q ualit y of life will be a n al yze d as a tertiar y e n d p oi nt.  T he ot her c o m p osite 
sc ores a n d s u bs cales will n ot be a nal yze d statisticall y. 
T he o bser ve d res ults a n d c ha n g es fr o m C L A RI F Y M S Bas eli ne will b e ta b ulate d f or P h ysical 
healt h c o m p osite sc ore a n d Me ntal healt h c o m p osite  sc ore f or t he F A S.  
A d diti o nall y,  t he  c ha n g es  i n  M S Q o L -5 4  p h ysi cal  healt h  a n d  m e ntal  healt h  c o m p osite  fr o m  
C L A RI F Y M S Baseli ne will be classifie d as f oll o ws:  
•  C ha n ge i n M S Q o L- 5 4 sc ore fr o m Baseli ne < 5  
•  C ha n ge i n M S Q o L- 5 4sc ore fr o m Baseli ne ≥ 5  
I n a d diti o n, the y will be a nal yze d wit h a re peat e d mi xe d -effects li near m o del f or c h a n ge fr o m 
C L A RI F Y  M S  Baseli ne  t hat  will  ta ke  all  pla n ne d  i nter me diate  meas ure me nts  i nt o  acc o u nt 
w here b y a t w o-l e vel  (V isits  wit hi n  partici pa nt s) hierarc hical  m o del  is  s pecifie d  f or  re peat e d  
M S Q o L -5 4 P h ysical or Me ntal healt h c o m p osite sc ores  as d escri be d i n C L A RI F Y M S I A P V 5  
Secti o n 1 4. 1. 2 f or t he s e nsiti vit y a nal yses of t he pri mar y e n d p oi nts. 
A n al y si s  
( A n al y si s 
S et) 
D eri v ati o n  
St ati sti c al A n al y si s  M et h o d s  
Mi s si n g  d at a  h a n dli n g  
S e c o n d ar y  e n d p oi nt: C h a n g 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  fr o m p ar e nt st u d y B a s eli n e  
Vi sit  t o Y e ar 1, Y e ar 2, Y e ar 3 a n d Y e ar 4 Vi sit  
S e c o n d ar y  
( F A S) 
C h a n g e i n p h y si c al h e alt h  s c or e  
( M S Q o L-5 4)  b et w e e n C L A RI F Y 
M S B a s eli n e a n d C L A RI F Y M S 
M o nt h  1 2, C L A RI F Y M S M o nt h 
2 4, M o nt h 3 6 a n d M o nt h 4 8  Vi sit 
•  
M M R M  wit h t h e f oll o wi n g 
a dj u sti n g f a ct or s:  
•  
C L A RI F Y M S B a s eli n e  
s c or e,  
•   
A g e ( y e ar s), 
•   
E D S S ( ≤3, > 3), 
•  
Vi sit,  
•  
P o ol e d c e nt er,  
•  
Wit hi n -p arti ci p a nt  
c orr el ati o n.   
E sti m at e d L e a st S q u ar e 
M e a n s ( L S M e a n s) a n d 
Mi s si n g  v al u e s  at  C L A RI F Y -
M S B a s eli n e:  
P arti ci p a nt s  wit h   a mi s si n g  
M S Q o L  
a s s e s s m e nt  
at  
B a s eli n e will n ot b e i n cl u d e d i n 
t h e M M R M. 
Mi s si n g
 c o v ari at e
 or
 
str atifi c ati o n i nf or m ati o n will b e 
i m p ut e d
 a s
 s p e cifi e d
 i n
 
S e cti o n 9 . 
 
Mi s si n g  
p o st -B a s eli n e  
o b s er v ati o n s:  
C h a n g e i n m e nt al h e alt h  s c or e  
( M S Q o L-5 4)  b et w e e n C L A RI F Y 
M S B a s eli n e a n d C L A RI F Y M S 
M o nt h  1 2, C L A RI F Y M S M o nt h 
2 4, M o nt h 3 6 a n d M o nt h 4 8  Vi sit 
S e c o n d ar y  
( F A S b y 
s u b gr o u p 
“ Pr e vi o u s 
C h a n g e i n p h y si c al h e alt h  s c or e  
( M S Q o L-5 4)  b et w e e n C L A RI F Y 
M S B a s eli n e a n d C L A RI F Y M S 
M o nt h  1 2, C L A RI F Y M S M o nt h 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
A n al y si s  
( A n al y si s 
S et) 
D eri v ati o n  
St ati sti c al A n al y si s  M et h o d s  
Mi s si n g  d at a  h a n dli n g  
tr e at m e nt 
wit h 
D M D s”)  
 
2 4, M o nt h 3 6 a n d M o nt h 4 8  V i sit 
c orr e s p o n di n g St a n d ar d 
Err or s ( S E) will b e 
pr e s e nt e d b y Vi sit i n cl u di n g 
2- si d e d p -v al u e s a n d 9 5 % 
CI t h at ar e n ot a dj u st e d f or 
m ulti pl e t e sti n g d u e t o t h e 
e x pl or at or y n at ur e of t h e 
st u d y .  
•  
F or e st pl ot s f or e sti m at e 
a n d 9 5 % CI  b y V i sit 
Mi s si n g  
p o st -B a s eli n e  
a s s e s s m e nt s  
will  
n ot  
b e  
i m p ut e d.
 T h e
 r e p e at e d
 
m e a s ur e m e nt  m o d el  h a n dl e s  
mi s si n g  
p o st -B a s eli n e  
a s s e s s m e nt s  
u n d er  
t h e 
a s s u m pti o n  of  M A R.  
Mi s si n g S e x u al f u n cti o n 
s c or e s:  
S e e b el o w.  
C h a n g e i n m e nt al h e alt h  s c or e  
( M S Q o L-5 4)  b et w e e n C L A RI F Y 
M S B a s eli n e a n d C L A RI F Y M S 
M o nt h  1 2, C L A RI F Y M S M o nt h 
2 4, M o nt h 3 6 a n d M o nt h 4 8  Vi sit 
 
H a n dli n g of missi n g sc ores i n se x u al f u ncti o n: 
T he M S Q o L -5 4 q u esti o n naire h as bee n set -u p t o all o w o nl y s ki p pi n g of q uesti o ns 4 6 - 4 9 a b o ut 
t he Se x ual f u ncti o n b y selecti n g “ N ot a p plica bl e” as a n a ns w er. If m ore t ha n o ne q uesti o n i n t his 
part was a ns w ere d, t he S e x ual f u n cti o n sc ore will be calc ulate d acc or di n g t o t he sc ori n g m a n ual 
( Vic kre y 1 9 9 5), i.e. t he mea n of t he a ns were d q u esti o ns will be use d as s c ore. If o nl y o ne or n o 
q uesti o n  was  a ns were d,  t he  Se x ual  f u ncti o n  sc ore  will  be  i m p ute d  wit h  t he  a ns wer  of  t he  
Satisfacti o n wit h se x ual f u ncti o n sc ore. 
 
1 4. 2. 2  
Sec o n d ar y  E n d p oi nt : M S Q o L -5 4 C h a n ge  at  Ye ar  4  Visit  
fr o m C L A RI F Y M S Ye ar 2 Visit  
Bel o w  M S Q o L -5 4  relate d  sec o n dar y  e n d p oi nts will  be  assesse d  usi n g  re peate d  mi xe d -effects 
li near re gressi o n, acc o u nti n g f or cli nicall y rele va nt fact ors (e. g. a ge a n d E D S S at Year 2 Visit ), 
wit hi n partici pa nt c orrelati o n ( details as descri be d i n C L A RI F Y M S I A P V 5) , a n d p o ole d ce nter 
(see Secti o n 9  f or details). T he L S Mea ns will be calc ulate d wit h o bser ve d mar gi n w hic h reflects t he 
distri b uti o n of a ge, E D S S cate g ories at Year 2 Visit  a n d res pecti ve Year 2 Visit  c o m p osite sc ore of 
t he F A S. T he L S M ea ns wit h t he c orres p o n di n g sta n dar d err or, 9 5 % CI  a n d t w o-si de d p- val ue 
will be calc ulate d.  A n u nstr uct ure d c o vari a nce matri x will be ass u me d f or t h e m o del. If t h e 
m o del d oes n ot c o n ver g e  a varia nce c o m p o ne nts c o varia nce str uct ure will be use d. 
 
 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
A n al y si s  
( A n al y si s S et) 
D eri v ati o n  
St ati sti c al A n al y si s  M et h o d s  
Mi s si n g  d at a  h a n dli n g  
S e c o n d ar y  e n d p oi nt: C h a n g 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  fr o m p ar e nt st u d y Y e ar 2 Vi sit 
t o Y e ar 3 a n d Y e ar 4 Vi sit  
S e c o n d ar y  
( F A S) 
C h a n g e i n p h y si c al h e alt h  s c or e  
( M S Q o L-5 4)  b et w e e n C L A RI F Y 
M S M o nt h 2 4  a n d  M o nt h 3 6 a n d 
M o nt h 4 8  Vi sit 
R e p e at of s e c o n d ar y  e n d p oi nt 
a n al y s e s ( S e cti o n 1 4. 2. 1 ) 
R e p e at of s e c o n d ar y  
e n d p oi nt a n al y s e s 
( S e cti o n 1 4. 2. 1 ) 
C h a n g e i n m e nt al h e alt h  s c or e  
( M S Q o L-5 4)  b et w e e n C L A RI F Y 
M S M o nt h 2 4  a n d  M o nt h 3 6 a n d 
M o nt h 4 8  Vi sit 
S e c o n d ar y  
( F A S b y 
s u b gr o u p 
“ Pr e vi o u s 
tr e at m e nt wit h 
D M D s”)  
C h a n g e i n p h y si c al h e alt h  s c or e  
( M S Q o L-5 4)  b et w e e n C L A RI F Y 
M S M o nt h 2 4  a n d  M o nt h 3 6 a n d 
M o nt h 4 8  Vi sit 
C h a n g e i n m e nt al h e alt h  s c or e  
( M S Q o L-5 4)  b et w e e n C L A RI F Y 
M S M o nt h 2 4  a n d  M o nt h 3 6 a n d 
M o nt h 4 8  Vi sit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 5 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
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 /7 0   
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
1 5  
S afet y A n al yses  
T his Secti o n i ncl u des s pecificati o ns f or s u m mari zi n g safet y e n d p oi nts t hat are c o m m o n acr oss 
cli nical st u dies s uc h as a d verse e v e nts, la b orat or y tests a n d vital si g ns. 
Safet y a nal yses will be d o ne o n t he S A F a n d refl ect data c ollect e d d uri n g t he E xte nsi o n St u d y 
Peri o d . 
1 5. 1  
A d verse E ve nts  
T he defi niti o n of A E has bee n descri be d i n A p pe n di x 3 of t he st u d y pr ot oc ol. All a nal yses 
descri be d i n t his Secti o n will be base d o n re p orte d A Es d uri n g t he E xte nsi o n St u d y Peri o d.  
S A Es wit h a n o nset date 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 will 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. A listi n g c o m prisi n g all o n g oi n g S A Es fr o m t he C L A RI F Y M S trial 
will be prese nte d.  
Eac h partici pa nt will be c o u nte d o nl y o nce wit hi n eac h S O C or P T. If a partici pa nt e x perie n ces 
m ore t ha n o ne A E wit hi n a S O C or P T f or t he sa m e s u m mar y peri o d, o nl y t he A E wit h t he 
str o n gest relati o ns hi p or t he w orst se verit y, as a p pr o priate, will be i ncl u de d i n t he s u m maries of 
relati o ns hi p a n d se verit y.  
In c o m plete A E -ass ociat e d dates will be i m p ute d  as descri be d i n Secti o n 9. 9 . 
1 5. 1. 1  
All A d verse E ve nts  
All A Es re p orte d d uri n g t he E xte nsi o n St u d y Peri o d will be s u m marize d i n ter ms of fre q ue nc y 
ta bles usi n g Me d D R A (l atest versi o n a vaila bl e) P T as e ve nt cate g or y a n d Me d D R A pri mar y 
S O C b o d y ter m as B o d y S yste m cate g or y i n al p ha betical or der o verall a n d b y s u b gr o u ps, D M D 
pre -treate d a n d pre-treat me nt naï ve.  
U nless ot her wise state d a d verse e v e nts will be dis pla ye d i n ter ms of fre q ue nc y ta bles: P T a n d 
pri mar y S O C i n al p ha betical or der. O nl y t he hi g hest occ urre d se v erit y of a n A E b y P T a n d 
partici pa nts will be dis pla ye d i n s u m mar y ta bles b y se verit y. 
A d verse e ve nts rel ate d t o st u d y treat me nt are t h os e e ve nts wit h rel ati o ns hi p missi n g, u n k n o w n or 
relate d. 
T he f oll o wi n g fre q u e ncies of partici pa nts wit h a d v erse e v e nts  will be pre p are d.  
•  A n y A E,  
•  A n y st u d y treat me nt relat e d A Es,  
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
•  A n y seri o us A Es,  
•  A n y n o n-seri o us A Es,  
•  A n y st u d y treat me nt relat e d seri o us A Es,  
•  A n y A E b y se verit y ( mil d, m o derate, se v ere),  
•  A n y st u d y treat me nt relat e d A E b y se verit y ( mil d, m o derate, se v ere),  
•  A n y A Es lea di n g t o deat h ( A Es wit h o utc o me “fatal”),  
•  A n y st u d y treat me nt relat e d A Es lea di n g t o deat h ( A Es wit h o utc o me “fat al”),  
•  A n y A Es lea di n g t o st u d y disc o nti n uati o n, 
•  A n y st u d y treat me nt relat e d A Es lea di n g t o st u d y disc o nti n uati o n. 
T he details of t he ass ess me nt of i nte nsit y ( mil d, m o derate, se v ere) are des cri be d i n t he A p pe n di x 
3 of t he st u d y pr ot oc ol.  
S u m mar y  ta ble f or n o n- S A Es a p pl yi n g fre q u e nc y t hres h ol d of 5 % will be pr o vi de d b y S O C a n d 
P T.  
S u m mar y ta bles f or seri o us a n d n o n- S A Es a p pl yi n g fre q ue n c y t hres h ol d of 5 % s orte d b y 
decreasi n g fr e q ue nc y will be pr o vi de d b y P T. 
All A E b y w orst se verit y will be prese nte d b y S O C a n d P T. Missi n g se verit y will be prese nte d i n 
all se verit y gr o u ps. 
All A Es c ollecte d d uri n g t he E xte nsi o n St u d y Peri o d will be liste d b y partici pa nt .  
E x p os ure A dj uste d I nci de nce R ate  
E x p os ure a dj uste d  i nci d e nce rates  ( E AI R) are calc ulate d  as  n u m b er of partici pa nts wit h  A E  
di vi de d b y t he t otal ti me at ris k, w hic h is defi ne d as a s u m of t he i n di vi d ual ti mes i n years of all 
partici pa nts i n t he safet y p o p ulati o n fr o m start of E xte nsi o n St u d y P eri o d t o first o nset of A E or 
e n d of t h e E xte nsi o n St u d y P eri o d, w hic h e ver o cc urs first. T otal ti me at ris k ca n be e x presse d 
als o i n 1 0 0 s u bject- years.  
T he e xact P oiss o n 9 5 % c o nfi de nce i nter vals f or t h e E AI R are calc ulate d usi n g t he relati o ns hi p 
bet wee n t he P oiss o n a n d t he C hi-s q uare distri b uti o n ( Ul m, 1 9 9 0): 
𝐿𝐿𝐿𝐿𝐿𝐿=
𝜒𝜒2 𝑛𝑛,𝑎𝑎
2
2
2  × 𝑡𝑡, 
𝑈𝑈𝐿𝐿𝐿𝐿=
𝜒𝜒2 (𝑛𝑛+ 1 ),1 −𝑎𝑎
2
2
2  × 𝑡𝑡
, 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
w here t is t he s u m of t he i n di vi d ual ti mes i n years of all partici pa nts a n d n is t he n u m ber of 
partici pa nts wit h a s pecific A E f or t he E AI R, w hic h will be t he b asis f or t he n u m b er of t he 
de grees of fr ee d o m f or t he c hi -s q uar e q ua ntile f or t he u p per tail pr o ba bilit y χ 2.  
T he  i nci de nce  rat e  m ulti plie d  wit h  1 0 0  w o ul d  gi ve  t he  n u m ber  of  A Es  e x pect e d  i n  1 0 0  
partici pa nts wit hi n 1 year.  
E AI R  of A Es will be pr ese nte d o ver all, a n d b y S O C a n d P T. 
T he f oll o wi n g ta ble will be pr o vi de d: 
•  E x p os ure a dj uste d i nci de nce rat es of A Es b y S O C a n d P T. 
 
1 5. 1. 2  
A d verse  E ve nts  Le a di n g  t o  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.  
1 5. 2  
De at hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts  
1 5. 2. 1  
De at hs  
A n y st u d y disc o nti n uati o ns d ue t o deat h (see S ecti o n 1 5. 1. 2 ) a n d a n y A E l ea di n g t o deat h will be 
ta b ulate d (see Secti o n 1 5. 1. 1 ).  
A s u m mar y ta ble of o bser ve d Deat hs (fr o m “ St u d y Ter mi nati o n” e C R F p a ge) will be pr o vi de d 
t o get her wit h A Es wit h f atal o utc o me b y P T.  
1 5. 2. 2  
Seri o us A d verse E ve nts  
T he statistical a nal ysis a n d ta b ulati n g  of S A Es are defi ne d i n Secti o n 1 5. 1. 1 . I n a d diti o n, all 
S A Es will be liste d.   
1 5. 2. 3  
Ot her Si g nific a nt A d verse E ve nt s 
A Es ass oci ate d t o C O VI D- 1 9 
T he fre q ue n c y of A Es ass ociate d t o C O VI D -1 9 will be prese nte d. T he rele va nt e ve nts will b e 
i de ntifie d base d o n t he S M Q C O VI D- 1 9 ( n arr o w sc o pe) a n d will be prese nte d b y S O C a n d P T. 
A listi n g c o m prisi n g all C O VI D - 1 9 r elate d A E t er ms will be prese nte d.  
 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
A Es ass oci ate d t o C O VI D- 1 9 v acci nes 
T he fre q u e nc y of A Es ass ociate d t o C O VI D -1 9 v acci nes will be prese nte d.  
T he saf et y pr ofile of t h e i n vesti gati o nal treat me nt a n d vacci ne ma y o verla p. I n vesti gat ors are 
as ke d t o pr o vi de all A Es wit h p ote ntial C O VI D -1 9 vacci ne relate d ca us alit y A Es as part of 
i nf or mati o n  o n  “ Ca usalit y  fact ors  ot her  t ha n  st u d y  treat me nt”  a n d  t o  e nter  “ C O VI D 1 9  
vacci nati o n” as free te xt o n t he A E D T e C R F pa g e. Per t his classificati o n a f oc use d a n al ysis will 
be p ossi ble f or p ote ntial vacci nati o n ass o ciate d A Es. 
A listi n g c o m prisi n g all C O VI D -1 9 vacci nes relat e d A E ter ms will be prese nte d.  
A Es ass oci ate d t o L y m p h o pe ni a 
T he fre q u e nc y of A Es ass ociate d t o  L y m p h o pe nia will be prese nte d. T he rele va nt e ve nts will be 
i de ntifie d base d o n t he list of P T s i n A p pe n di x 1 8. 3  a n d will be prese nt e d b y S O C a n d P T. 
A listi n g c o m prisi n g all L y m p h o pe nia relat e d A E ter ms will be prese nte d.  
1 5. 3  
Cli nic al L a b or at or y E v al u ati o n  
N ot a p plica ble 
1 5. 4  
Vit al Si g ns  
T he ma xi m u m c ha n ges of vital si g n meas ure me nts fr o m C L A RI F Y M S Baseli ne t o E xte nsi o n 
St u d y P eri o d will be gr o u pe d as f oll o ws: 
H e art r at e i n cr e a s e fr o m b a s eli n e  
< 1 0 0 b p m; ≥ 1 0 0 b p m  
≤2 0 b p m, > 2 0 – 4 0 b p m, > 4 0 b p m  
H e art r at e d e cr e a s e fr o m b a s eli n e  
< 1 0 0 b p m; ≥ 1 0 0 b p m  
≤2 0 b p m, > 2 0 – 4 0 b p m, > 4 0 b p m  
S B P i n cr e a s e fr o m b a s eli n e  
< 1 4 0 m m H g; ≥ 1 4 0 m m H g  
≤2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g  
S B P d e cr e a s e fr o m b a s eli n e  
< 1 4 0 m m H g; ≥ 1 4 0 m m H g,  
≤2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g  
D B P i n cr e a s e fr o m b a s eli n e  
< 9 0 m m H g; ≥ 9 0 m m H g  
≤2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g  
D B P d e cr e a s e fr o m b a s eli n e  
< 9 0 m m H g; ≥ 9 0 m m H g,  
≤2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g  
F or eac h partici pa nt , t he w orst c ha n ge d uri n g t h e E xte nsi o n  St u d y  P eri o d will be c o nsi dere d. 
Missi n g val ues will be prese nte d as a se parate cate g or y.  
T he  f oll o wi n g  s u m maries  will  be  pre pare d  f or  vital  si g n  para meters  as  gr o u pe d  a b o ve  
c o nsi deri n g o nl y partici p a nt s wit h p ost-Baseli ne val ues:  
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
•  S u m mar y of Ma xi mal S hifts (c ha n ges i n cate g ories), 
•  Listi n g of hi g hest c ha n ge per partici p a nt . 
 
1 5. 5  
Ot her S afet y or T oler a bilit y E v al u ati o ns  
T he r es ults of t he p h ysi cal e xa mi nati o n will n ot b e pres e nte d i n a n y statistical a n al ysis or listi n g. 
A b n or malities occ urri n g or w orse ni n g d uri n g t he st u d y will be re p orte d as A E. 
 
1 6  
A n al ysis of Ot her E n d p oi nts  
1 6. 1  
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:  
•  Partici 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,  
•  I nfecti o ns a n d/ or m ort alit y d ue t o C O VI D-1 9 i n t h e 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, 
T he q uesti o n naire ite ms will  be descri pti vel y s u m marize d at Y ear 3 a n d Y ear 4 V isit f or t he 
F A S.  
N ote: At Year 3 as well as at Year 4 Visit partici pa nts c o ul d c o m plete a “ First S ur ve y” a n d a 
“ Sec o n d  S ur ve y”,  w hic h  c o ul d  lea d  t o  i nc o nsiste nt  e ntries.  I n  s uc h  cases  it  was  a gree d  t o  
s u m marize “ First S ur ve y ” f or Y ear 3 Visit a n d “ Sec o n d S ur ve y” f or Year 4 Visit. If t h e Year 3 
Visit data o n t he “ First S ur ve y” s h o ul d be missi n g b ut data f or Year 3 Visit is a vaila ble o n t he 
“ Sec o n d S ur ve y ”, t he n t his will be s u m marize d f or t he Year 3 Visit. T he sa me ca n be d o ne f or 
t he Year 4 Visit i n case t his data is missi n g o n t he “ Sec o n d S ur ve y ” b ut a vaila ble o n t he “ First 
S ur ve y”. 
 
 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
 
A n al y si s  
( A n al y si s S et) 
D eri v ati o n  
St ati sti c al A n al y si s  
M et h o d s  
Mi s si n g  d at a  h a n dli n g  
Ot h er e n d p oi nt s : C O VI D-1 9 s ur v e y at Y e ar 3 a n d 4 Vi sit   
T erti ar y  ( F A S) 
It e m s o n C O VI D-1 9 
q u e sti o n n air e at M 3 6 a n d 
M 4 8  
D e s cri pti v e s u m m ar y 
st ati sti c s  
N ot a p pli c a bl e  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 6. 4  
B aseli ne C h ar acteristics C o m p are d t o P are nt St u d y  
A  c o m paris o n  of  partici pa nt  baseli ne  a n d  bac k gr o u n d  c haract eristics  fr o m  p o p ulati o n  of  t he  
C L A RI F Y M S trial wit h p o p ulati o n of t he C L A RI F Y M S E X T E N SI O N trial  will be d o ne b y 
vis ual c o m paris o n. N o s p ecial statistical a nal ysis will be c o n d ucte d. 
 
Gl o bal Versi o n I D: C CI
C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
1 7  
Refere nces  
Ul m K. A si m ple met h o d t o calc ulat e t he c o nfi d e nce i nter val of a st a n dar dize d m ortalit y rati o. 
A merica n J o ur nal of E pi de mi ol o g y 1 9 9 0; 1 3 1( 2): 3 7 3- 3 7 5.  
VI C K R E Y, B. G. et al. C o m paris o n of a ge n eric t o disease -t ar gete d healt 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, v. 5 0, n. 5, p. 5 5 7 -6 9, Ma y 1 9 9 7. I S S N 0 8 9 5 - 
4 3 5 6. htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 9 1 8 0 6 4 8 visit.  
VI C K R E Y, Bar bar a G. M ulti ple scler osis q ualit y of life ( M S Q O L) -5 4 i nstr u me nt. L os A n geles: 
U ni versit y of Calif or nia, L os A n geles, 1 9 9 5.  
Par me nter,  B.  A.,  et  al.  T he  utilit y  of  re gressi o n -base d  n or ms  i n  i nt er preti n g  t h e  mi ni mal  
assess me nt of c o g niti ve f u ncti o n i n m ulti ple scler osis ( M A C FI M S). J. I nt. Ne ur o ps yc h ol. S oc. 
1 6, 6 – 1 6 ( 2 0 1 0). 
 
 
C li nical St u d y Pr ot oc ol, 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 u alit y 
of life i n partici p a nts wit h hi g hl y -acti ve rel a psi n g m ulti ple scler osis, ha vi n g partici pate d i n t h e 
C L A RI F Y M S trial; Versi o n 2. 0, 2 8 J u ne 2 0 2 1. 
Gi b b o ns  et  al.   A d va n ces  i n  A nal ysis  of  L o n git u di nal  Data.  A n n u al  Revie w  of  Cli nic al  
Psyc h ol o gy , 2 0 1 0, 6 , 7 9 – 1 0 7. htt ps:// d oi. or g/ 1 0. 1 1 4 6/a n n ure v.cli n ps y. 0 3 2 4 visit 0 8. 1 5 3 5 5 0 . 
I nte grate d A n al ysis  Pla n , A 2 -year Pr os pecti ve St u d y t o Assess Healt h -relate d Q ualit y of Life  i n 
S u bjects  wit h  Hi g hl y-acti ve Rela psi n g  M ulti ple  Scler osis  Treat e d wit h Ma v e ncla d ® ; 1 4 Dece m ber 
2 0 1 8 / Versi o n 2. 0 
Ke n war d, M. G., a n d J. H. R o ger. 1 9 9 7. S mall sa m ple i nfere n ce f or fi xe d effects fr o m restricte d 
ma xi m u m li keli h o o d. Bi o metrics  5 3: 9 8 3- 9 9 7. 
K urtz ke. Rati n g n e ur ol o gic i m pair me nt i n m ulti ple scler osis: A n e x pa n de d disa bilit y stat us scale 
( E D S S). Ne ur ol o gy , 1 9 8 3, 3 3 ( 1 1), 1 4 4 4 – 1 4 5 2. htt ps:// d oi. or g/ 1 0. 1 2 1 2/ w nl. 3 3. 1 1. 1 4 4 4 . 
 
K e n war d, M. G., a n d J. H. R o ger. 1 9 9 7. S mall sa m ple i nfere n ce f or fi xe d effects fr o m restricte d 
ma xi m u m  li keli h o o d. Bi o metrics  5 3: 9 8 3- 9 9 7. 
Gl o bal Versi o n I D: C CI
C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
Cli nical St u d y Pr ot oc ol, 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 u alit y 
of life i n partici p a nts wit h hi g hl y -acti ve rel a psi n g m ulti ple scler osis, ha vi n g partici pate d i n t h e 
C L A RI F Y M S trial; Versi o n 2. 0, 2 8 J u ne 2 0 2 1. 
I nte grate d A n al ysis  Pla n , A 2 -year Pr os pecti ve St u d y t o Assess Healt h -relate d Q ualit y of Life  i n 
S u bjects  wit h  Hi g hl y-acti ve Rela psi n g  M ulti ple  Scler osis  Treat e d wit h Ma v e ncla d ® ; 1 4 Dece m ber 
2 0 1 8 /  Versi o n 2. 0 Par m e nter, B. A., et al. T he utilit y of re gressi o n -base d n or ms i n i nter preti n g 
t he  mi ni mal  assess me nt  of  c o g niti ve  f u ncti o n  i n  m ulti ple  scler osis  ( M A C FI M S).  J.  I nt.  
Ne ur o ps yc h ol.  S oc.  1 6,  6 – 1 6  ( 2 0 1 0). Ul m  K.  A  si m ple  met h o d  t o  calc ulate  t he  c o nfi de n ce  
i nter val of a sta n d ar dize d m ortalit y rati o. A merica n J o ur n al of E pi de mi ol o g y 1 9 9 0; 1 3 1( 2): 3 7 3-
3 7 5.  
VI C K R E Y, B. G. et al. C o m paris o n of a ge n eric t o disease -t ar gete d healt 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, v. 5 0, n. 5, p. 5 5 7 -6 9, Ma y 1 9 9 7. I S S N 0 8 9 5 - 
4 3 5 6. htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 9 1 8 0 6 4 8 visit.  
VI C K R E Y, Bar bar a G. M ulti ple scler osis q ualit y of life ( M S Q O L) -5 4 i nstr u me nt. L os A n geles: 
U ni versit y of Calif or nia, L os A n geles, 1 9 9 5.  
 
 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 7 /7 0   
 
 
1 8  
A p pe n dices  
1 8. 1  
A p pe n di x  1:  U p d ate d List  of  D M Ds  f or  C L A RI F Y  M S  
E xte nsi o n S t u d y 
D M Ds  
 
Preferre d Ter m  
Ale mt uz u ma b ( Ca m pat h, Ma b Ca m pat h, 
Le mtra da)  
A L E M T U Z U M A B  
Cla dri bi ne ( Ma ve ncla d)  
C L A D RI BI N E  
Dacliz u ma b ( Zi n br yta)  
D A C LI Z U M A B  
Di met h yl f u marate ( Tecfi dera)  
DI M E T H Y L F U M A R A T E  
Dir o xi mel f u marate ( V u merit y)  
DI R O XI M E L F U M A R A T E  
Fi n g oli m o d ( Gile n ya)  
FI N G O LI M O D  
FI N G O LI M O D H Y D R O C H L O RI D E  
Glatira mer Acetate ( C o pa x o ne, Glat o pa)  
G L A TI R A M E R  
G L A TI R A M E R A C E T A T E  
I m m u n o gl o b uli ns  
I M M U N O G L O B U LI N H U M A N N O R M A L  
I M M U N O G L O B U LI N S  
I M M U N O G L O B U LI N S N O S  
I nterfer o n beta ( A v o ne x, Re bif, Betafer o n, 
E xta via, Ple gri d y, Betaser o n)  
I N T E R F E R O N  
I N T E R F E R O N B E T A  
I N T E R F E R O N B E T A-1 A  
I N T E R F E R O N B E T A-1 B  
P E GI N T E R F E R O N  
P E GI N T E R F E R O N B E T A -1 A  
Mit o xa ntr o ne ( N o va ntr o ne)  
MI T O X A N T R O N E  
MI T O X A N T R O N E H Y D R O C H L O RI D E  
Nataliz u ma b ( T ysa bri)  
N A T A LI Z U M A B  
N o n -a p pr o ve d i n vesti gati o nal D M Ds 
( m o n ocl o nal a nti b o dies, a nti S 1 P R, 
la q ui ni m o d etc)  
  
I N V E S TI G A TI O N A L D R U G  
L A Q UI NI M O D  
  
O PI CI N U M A B  
O T H E R A N TI N E O P L A S TI C A G E N T S  
  
Ocreliz u ma b ( Ocre v us)  
O C R E LI Z U M A B  
Ofat u m u ma b ( K esi m pta)  
O F A T U M U M A B  
Off -la bel i m m u n os u p pressa nts (azat hi o pri ne, 
m yc o p he n olate, c ycl o p h os p ha mi de)  
A Z A T HI O P RI N E  
C Y C L O P H O S P H A MI D E  
M E T H O T R E X A T E  
Oza ni m o d ( Ze p osia)  
O Z A NI M O D  
P o nesi m o d ( P o n v or y)  
P O N E SI M O D  
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
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 /7 0   
 
 
Rit u xi ma b  
RI T U XI M A B  
Si p o ni m o d ( Ma yze nt) 
SI P O NI M O D  
SI P O NI M O D F U M A R A T E  
Terifl u n o mi de ( A u ba gi o)  
T E RI F L U N O MI D E  
 
T he list ma y be e xte n de d d uri n g me dical re vi e w i n case t hat ne w or ot her D M Ds will be a p plie d 
d uri n g t he st u d y. 
F or cate g orizati o n i nt o D M D pre-tr eate d gr o u p, t he D M Ds liste d i n C L A RI F Y M S I A P V 5 was 
use d. Partici pa nts w h o ha ve ta ke n a n y of t he liste d D M Ds acc or di n g t o t he “ Rele va nt Pre vi o us 
Me dicati o n” e C R F p a ge of C L A RI F Y M S Baseli ne V isit will be cate g orize d as D M D pre-
treate d. All ot her p artici p a nts will be c o nsi dere d as pre-treat me nt naï ve. 
 
 
Gl o bal Versi o n I D: C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 9 /7 0   
 
 
 
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d ® 
C L A RI F Y M S E xte nsi o n  
M S 7 0 0 5 6 8 _ 0 1 5 8              Versi o n 2. 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 0 /7 0   
 
 
1 8. 3  
A p pe n di x 3: Preferre d ter ms f or selecti o n of A E s ass oci ate d 
t o L y m p h o pe ni a  
All P Ts gi ve n are base d o n Me d D R A versi o n 2 5. 1 a n d mi g ht be s u bject t o c ha n ge i n f ut ure 
Me d D R A versi o n. 
P Ts f or selecti o n of “ L y m p h o pe nia” 
Pref erre d C o de  
Pref erre d Ter m  
1 0 0 2 5 3 2 7  
L y m p h o pe nia  
1 0 0 0 7 8 3 9  
C D 4 l y m p h oc ytes decrease d  
1 0 0 0 7 8 4 3  
C D 4/ C D 8 rati o decrease d  
1 0 0 1 2 7 8 5  
Differ e ntial w hite bl o o d cell c o u nt a b n or mal  
1 0 0 2 5 2 5 2  
L y m p h oc yte c o u nt a b n or mal  
1 0 0 2 5 2 5 6  
L y m p h oc yte c o u nt decrease d  
1 0 0 5 1 3 1 3  
B -l y m p h oc yte c o u nt decrease d  
1 0 0 5 1 3 1 8  
T -l y m p h oc yte c o u nt decrease d 
1 0 0 5 2 2 3 1  
L y m p h oc yte per ce nta g e decrease d  
1 0 0 5 6 2 8 3  
C D 8 l y m p h oc ytes decrease d  
1 0 0 5 7 2 8 4  
T -l y m p h oc yte c o u nt a b n or mal 
1 0 0 6 3 2 9 3  
C D 4 l y m p h oc ytes a b n or mal  
1 0 0 6 3 3 3 7  
L y m p h oc yte per ce nta g e a b n or mal  
1 0 0 6 8 4 9 7  
Nat ural killer cell c o u nt decrease d  
1 0 0 6 8 5 0 0  
Nat ural killer T cell c o u nt decrease d  
1 0 0 7 1 5 4 3  
C D 8 l y m p h oc ytes a b n or mal  
1 0 0 7 2 7 9 8  
C D 4 l y m p h oc yte perce nta ge decrease d  
1 0 0 7 8 3 8 4  
C D 8 l y m p h oc yte perce nta ge decrease d  
1 0 0 7 8 5 8 9  
B -l y m p h oc yte c o u nt a b n or mal  
1 0 0 8 0 7 2 1  
B -cell a plasia  
1 0 0 8 3 9 3 4  
I di o pat hic C D 4 l y m p h oc yt o pe nia 
 
 
Gl o bal Versi o n I D: C CI


Si g nat ure Pa ge f or V V- C LI N- 3 4 4 5 2 8 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 3 4 4 5 2 8 v 1. 0
A p pr o val Tas k
Cli nical
2 8- A u g- 2 0 2 3 0 9: 3 3: 1 2 G M T + 0 0 0 0
Gl o bal Versi o n I D: C CI
P P D