Clinical trial NCT03369665
Conditions: Multiple Sclerosis
Keywords: Multiple sclerosis Mavenclad® Cladribine Health-related Quality of Life
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-06-20; Completion date: 2021-11-12
Enrollment: 485 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of the study was to assess the health-related quality of life (HRQoL) through the Multiple Sclerosis Quality of Life-54 Questionnaire (MSQoL-54) scale in highly-active relapsing multiple sclerosis (RMS) particpants treated with Mavenclad® for 2 years (24 months).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Mavenclad®
Intervention descriptions: intervention 1: Participants with Relapsing Multiple Sclerosis (RMS) received Mavenclad® 3.5 milligram per kilogram (mg/kg) of body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consisted of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective year.

Protocol documents:
Prot_000.pdf: 
Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 1 6  
 
 
Cli nic al Tri al Pr ot oc ol  
Cli nic al Tri al Pr ot oc ol N u m ber  
M S 7 0 0 5 6 8 _ 0 0 2 1  
Title  
A 2- year P r os p ecti ve St u d y t o A ssess H ealt h-relat e d 
Q ualit y  of  L ife  i n S u bjects wit h 
Hi g hl y -acti ve 
R ela psi n g 
M ulti ple 
Scler osis
 T reate d
 wit h
 
Ma ve ncla d
®  
P h ase  
I V 
I N D N u m ber 
N ot a p plica ble  
E u dr a C T N u m ber  
2 0 1 7 -0 0 2 6 3 2 -1 7  
C o or di n ati n g I n vesti g at or 
 
 
 
 
S p o ns or  
Merc k K ga A  
Fra n kf urter Str. 2 5 0  
6 4 2 9 3 Dar msta dt, Ger ma n y  
Me dical Res p o nsi ble:  
M o bile: 
  
Cli nic al Tri al Pr ot oc ol Versi o n  
1 4 Dece m b er  2 0 1 8 / Versi o n 2. 0 
Re pl aces Versi o n  
1. 0  
- C o nfi de ntial – 
T his d oc u me nt is t he pr o pert y of Mer c k K Ga A, D ar msta dt, Ger ma n y, or o ne of its s u bsi diaries. It is 
i nte n de d f or restricte d us e o nl y a n d ma y n ot – i n f ull or part – be passe d o n, re pr o d uce d, p u blis he d 
or  use d  wit h o ut  e x press  per missi o n  of  Merc k  K G a A,  Dar msta dt,  Ger ma n y,  or  its  s u bsi diar y. 
C o p yri g ht © 2 0 1 7 b y Merc k K G a A, Dar msta dt, G er ma n y, or its s u bsi diar y. All ri g hts res er ve d.  
Gl o bal Versi o n I D: 
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P P D


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E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 1 6  
 
 
Pr ot oc ol T a ble of C o nte nts  
Pr ot oc ol Ta ble of C o nte nts .................................................................................................. 2  
Ta ble of I n -Te xt Ta bles  ....................................................................................................... 7 
Ta ble of I n -Te xt Fi g ures  ...................................................................................................... 7 
List of A b br e viati o ns ........................................................................................................... 8  
1  
S y n o psis .............................................................................................. 1 0  
2  
S p o ns or, I n v esti gat ors a n d Trial A d mi nist rati ve Str uct ure ................ 1 4 
3  
Bac k gr o u n d I nf or mati o n  .................................................................... 1 4 
 
M ulti ple Scler osis  ............................................................................... 1 4 
 
Cla dri bi ne Ta blets ( Ma v e ncla d ® ) 3. 5/ k g ............................................ 1 5  
 
Safet y a n d T oler a bilit y of Ma ve ncl a d ®  .............................................. 1 5 
 
Be nefit -Ris k Assess me nt  ................................................................... 1 6 
 
Scie ntific Rati o nale f or Trial Desi g n  .................................................. 1 6 
3. 5. 1  
Q ualit y of lif e a n d Treat me nt Satisfacti o n  ......................................... 1 6 
3. 5. 2  
C o g niti o n a n d C orrelati o n wit h Brai n Atr o p h y .................................. 1 7  
3. 5. 3  
Ot her F u n cti o nal Scales  ...................................................................... 1 7 
4  
Trial O bjecti ves  .................................................................................. 1 8 
 
Pri mar y O bj ecti ve  ............................................................................... 1 8 
4. 1. 1  
Pri mar y E n d p oi nt ............................................................................... 1 8  
 
Sec o n dar y O bj ecti ve  ........................................................................... 1 8 
4. 2. 1  
Sec o n dar y E n d p oi nt ........................................................................... 1 8  
5  
I n v esti gati o nal Pla n ............................................................................ 1 9 
 
O verall Trial D esi g n a n d Pla n  ............................................................ 1 9 
 
Disc ussi o n of Trial Desi g n ................................................................. 2 0  
5. 2. 1  
I n cl usi o n of S pecial P o p ulati o ns ........................................................ 2 0 
5. 2. 2  
Steeri n g C o m mittee  ............................................................................ 2 1 
 
Selecti o n of Trial P o p ulati o n  .............................................................. 2 1 
5. 3. 1  
I n cl usi o n Criteria ................................................................................ 2 1 
5. 3. 2  
E x cl usi o n Criteria  ............................................................................... 2 2 
 
Criteria f or I nitiati o n of Trial Treat me nt  ............................................ 2 3 
5. 4. 1  
Criteria f or I nitiati n g a n d C o nti n ui n g T hera p y  .................................. 2 3 
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E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 1 6  
 
 
 
Criteria f or S u bject Wit h dra wal  ......................................................... 2 3 
5. 5. 1  
Wit h dra wal fr o m Trial T hera p y  ......................................................... 2 3 
5. 5. 2  
Wit h dra wal fr o m t he Tri al .................................................................. 2 4 
 
Pre mat ure Ter mi nati o n of t he Trial  .................................................... 2 4 
 
Defi niti o n of E n d of Trial ................................................................... 2 5  
 
Pla n ne d E xte nsi o n St u dies ................................................................. 2 5  
6  
I n v esti gati o nal Me dici nal Pr o d uct a n d Ot her Dr u gs Use d i n t he Trial 2 5 
 
Descri pti o n of t he I n v esti gati o nal Me di ci nal Pr o d u ct ........................ 2 5  
 
D osa ge a n d A d mi nistrati o n ................................................................ 2 5  
6. 2. 1  
P os ol o g y ............................................................................................. 2 5  
6. 2. 2  
Distri b uti o n of D ose ........................................................................... 2 6  
 
Assi g n me nt t o Treat me nt Gr o u ps ....................................................... 2 7  
 
N o n -i n vesti gati o nal Me dici nal Pr o d ucts t o be Use d .......................... 2 7 
 
C o nc o mita nt Me dicati o ns a n d T hera pi es ........................................... 2 7  
6. 5. 1  
Per mitte d Me dici nes  ........................................................................... 2 7 
6. 5. 2  
Pr o hi bite d Me dici nes .......................................................................... 2 8  
6. 5. 3  
Ot her I nter v e nti o ns  ............................................................................. 2 8 
6. 5. 4  
S pecial Preca uti o ns  ............................................................................. 2 8 
6. 5. 5  
Ma na ge me nt of S pecifi c A d verse E v e nts or A d verse Dr u g Reacti o ns 2 9  
 
Pac ka gi n g a n d La b eli n g of t he I n vesti gati o nal Me dici nal Pr o d uct .... 2 9  
 
Pre parati o n, H a n dli n g, a n d St ora ge of t he I n v esti gati o nal Me di ci nal 
Pr o d uct ................................................................................................ 2 9  
 
I n v esti gati o nal Me dici nal Pr o d uct Acc o u nta bilit y ............................. 2 9 
 
Assess me nt of I n vesti gati o nal Me dici nal Pr o d uct C o m plia nce ......... 3 0  
 
Bli n di n g .............................................................................................. 3 0  
 
E mer ge nc y U n bli n di n g  ....................................................................... 3 0 
 
Treat me nt of O v er d ose  ....................................................................... 3 0 
 
Me dical Care of S u bjec ts after E n d of Trial ....................................... 3 1 
7  
Trial Pr oce d ur es a n d Ass ess me nts  ..................................................... 3 1 
 
Sc he d ule of Assess me nts  .................................................................... 3 2 
7. 1. 1  
Scree ni n g ( M o nt h - 1 t o Baseli ne) ...................................................... 3 2  
7. 1. 2  
Rescree ni n g  ........................................................................................ 3 3 
7. 1. 3  
Treat me nt Peri o d  ................................................................................ 3 3 
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Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 1 6  
 
 
7. 1. 4  
Baseli ne Visit ( Visit 1)  ....................................................................... 3 3 
7. 1. 5  
M o nt h 2 Visit 2 ( ± 7 da ys) .................................................................. 3 4  
7. 1. 6  
M o nt h 6 Visit 3 ( ± 7 da ys) .................................................................. 3 5  
7. 1. 7  
M o nt h 1 2 Visit 4 ( ± 7 da ys) ................................................................ 3 5  
7. 1. 8  
M o nt h 1 4 Visit 5 ( ± 7 da ys) ................................................................ 3 6  
7. 1. 9  
M o nt h 1 8 Visit 6 ( ± 7 da ys) ................................................................ 3 6  
7. 1. 1 0  
Fi nal Visit/ Earl y Ter mi n ati o n/ M o nt h 2 4 Visit 7 ( ± 7 da ys)  ................ 3 7 
7. 1. 1 1  
U nsc he d ule d Visits ............................................................................. 3 8  
 
De m o gra p hic a n d Ot her Baseli ne C haracteristics  .............................. 3 8 
 
Efficac y Assess me nts  ......................................................................... 3 8 
7. 3. 1  
H R Q o L  ............................................................................................... 3 8 
7. 3. 2  
Treat me nt Satisfacti o n  ........................................................................ 3 9 
7. 3. 5  
M RI  .................................................................................................... 4 1 
 
Assess me nt of Safet y  .......................................................................... 4 4 
7. 4. 1  
A d verse E v e nts  ................................................................................... 4 5 
7. 4. 2  
Pre g n a nc y a n d I n Uter o Dr u g E x p os ure ............................................. 4 9  
7. 4. 3  
Cli nical La b or at or y Assess me nts  ....................................................... 5 0 
7. 4. 4  
Vital Si g ns, P h ysical E x a mi nati o ns, a n d Ot her Ass ess me nts ............ 5 0  
 
P har mac o ki netics  ................................................................................ 5 1 
 
Bi o mar kers  ......................................................................................... 5 1 
 
Ot her Assess me nts  ............................................................................. 5 1 
8  
Statistics  .............................................................................................. 5 1 
 
Ra n d o mizati o n .................................................................................... 5 2  
 
E n d p oi nts ............................................................................................ 5 2  
8. 3. 1  
Pri mar y E n d p oi nt(s) ........................................................................... 5 2  
8. 3. 2  
Sec o n dar y E n d p oi nt ........................................................................... 5 2  
Gl o bal Versi o n I D: C CI
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E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 1 6  
 
 
 
A nal ysis Sets  ...................................................................................... 5 3 
 
Descri pti o n of Statistical A nal ys es  ..................................................... 5 3 
8. 5. 1  
Ge ner al C o nsi derati o ns ...................................................................... 5 3  
8. 5. 2  
A nal ysis of Pri mar y E n d p oi nts........................................................... 5 4  
8. 5. 3  
A nal ysis of Sec o n dar y a n d
.................................. 5 4 
 
I nteri m a n d A d diti o nal Pla n ne d A nal yses .......................................... 5 5 
9  
Et hical a n d Re g ulat or y As pects  ......................................................... 5 5 
 
Res p o nsi bilities of t he I n vesti gat or  .................................................... 5 5 
 
S u bject I nf or mati o n a n d I nf or me d C o nse nt ....................................... 5 5  
 
S u bje ct I d e ntificati o n a n d Pri vac y  ..................................................... 5 6 
 
E mer ge nc y M e dical S u p p ort a n d S u bject Car d  ................................. 5 6 
 
Cli nical Trial I ns ura nce a n d C o m pe nsati o n t o S u bjects .................... 5 7  
 
I n d e pe n de nt Et hics C o m mittee or I nstit uti o nal Re vie w B oar d .......... 5 7 
 
Healt h A ut h orities  .............................................................................. 5 7 
1 0  
Trial Ma na ge m e nt  .............................................................................. 5 7 
 
Case Re p ort F or m Ha n dli n g ............................................................... 5 7  
 
S o urce Data a n d S u bject Files  ............................................................ 5 8 
 
I n v esti gat or Site File a n d Arc hi vi n g .................................................. 5 8 
 
M o nit ori n g, Q ualit y Ass ura nce a n d I ns pecti o n b y Healt h A ut h orities 5 9  
 
C ha n ges t o t he Cli nical Trial Pr ot oc ol  ............................................... 5 9 
 
Cli nical Trial Re p ort a n d P u blicati o n P olic y  ..................................... 5 9 
1 0. 6. 1  
Cli nical Trial Re p ort  ........................................................................... 5 9 
1 0. 6. 2  
P u blicati o n  .......................................................................................... 5 9 
1 1  
Refere n ces Cite d i n t he T e xt  .............................................................. 6 1 
1 2  
A p pe n dices ......................................................................................... 6 5  
 
A p pe n di x 1: Sc he d ule of Assess me nts ............................................... 6 5  
 
A p pe n di x 2: M S Q o L- 5 4 S C A L E  ....................................................... 6 7 
 
A p pe n di x 8: T S Q M v 1. 4 Q uesti o n naire  ............................................. 9 3 
Gl o bal Versi o n I D: C CI
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E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
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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 
6/ 1 1 6  
 
 
 
A p pe n di x 1 2: Pers o nal Diar y ........................................................... 1 0 2  
 
A p pe n di x 1 3: Statistics Ass u m pti o ns  ............................................... 1 0 5 
 
A p pe n di x 1 4: Si g nat ure Pa ges a n d Res p o nsi ble Pers o ns f or t he Trial 1 0 7  
 
A p pe n di x 1 5:  Hi g hl y Effecti ve Birt h C o ntr ol Met h o ds .................. 1 1 1  
 
A p pe n di x 1 6: Pr ot oc ol A me n d me nts a n d List of C ha n ges .............. 1 1 2  
 
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Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7/ 1 1 6  
 
 
T a ble of I n- Te xt T a bles  
Ta ble 1: D ose of M a ve ncla d ®  per treat me nt w ee k b y s u bject wei g ht i n eac h treat me nt 
year  ..................................................................................................... 2 6 
Ta ble 2: Ma ve n cla d ®  1 0 m g ta blets per wee k da y ............................................................ 2 6 
Ta ble 3:  L ocal La b orat or y Assess me nts  ............................................................................ 5 0 
T a ble of  I n-Te xt  Fi g ures  
Fi g ure 1: Sc he matic of t h e Trial Desi g n  ............................................................................ 1 9 
 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8/ 1 1 6  
 
 
List of A b bre vi ati o ns  
 
A E  
A d verse E v e nt  
A L T  
Ala ni ne a mi n otra nsf eras e - 
A R R  
A n n ualize d Rela pse Rate  
B V M T -R  
Brief Vis u os patial Me m or y T est  - Re vise d  
C M O  
C o ntract Ma n ufact uri n g Or ga nizati o n  
C R F  
Case Re p ort F or m  
C R O  
C o ntract  Resear c h Or ga nizati o n  
C U L  
C o m bi ne d U ni q ue Lesi o ns  
C V L T -II 
Calif or nia Ver b al Lear ni n g Test  –  Sec o n d e diti o n  
D M D  
Disease M o dif yi n g Dr u g  
e C R F 
Electr o nic Case Re p ort F or m  
E Q -5 D  
E ur o pea n Q u alit y of Life Fi ve Di me nsi o ns Q uesti o n naire  
F A S  
F ull A nal ysis Set  
F S  
F u ncti o nal s yste m  
G C P  
G o o d Cli nical Practice  
G d  
Ga d oli ni u m  
HI V  
H u ma n I m m u n o deficie n c y Vir us  
H R Q o L  
Healt h Relate d Q u alit y of Life  
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C ou ncil  o n Har m o ni sati o n 
I C H G C P 
I nter nati o nal C o u n cil o n Har m o ni sati o n f or G o o d Cli nical Practice 
I E C 
I n d e pe n de nt Et hics C o m mittee  
I M P 
I n v esti gati o nal Me dici nal Pr o d uct 
I P M P 
I nte grate d Pr oject Ma na ge me nt Pla n 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
I nteracti ve Res p o nse Tec h n ol o g y 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9/ 1 1 6  
 
 
I T T 
I nte nt-T o -Tr eat  
M CI D  
Mi ni mall y Cli nicall y I m p orta nt Differe nce  
M RI  
Ma g n etic Res o na nce I ma gi n g  
M S  
M ulti ple Scler 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  
P M L  
Pr o gr essi ve M ultif ocal Le u k oe nce p hal o pat h y 
P R O  
Patie nt Re p orte d O utc o m es  
P Y  
Patie nt Years  
Q o L  
Q ualit y of Lif e  
R C T  
Ra n d o mize d C o ntr ol Trial  
R M S  
Rela psi n g M ulti ple Scler osis  
S A E  
Seri o us A d verse E v e nt  
S C  
Steeri n g C o m mittee  
S D M T  
S y m b ol Di git M o dalities Test  
S F -3 6  
3 6 -It e m S h ort F or m H ealt h S ur ve y  
S m P C  
S u m mar y of Pr o d u ct C haracteristics  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T B  
T u berc ul osis  
T S Q M  v 1. 4  
Treat me nt Satisfacti o n Q uesti o n naire Me dicati o n  versi o n 1. 4  
V Z V  
Varicella Z oster V ir us 
W O C B P  
W o me n of C hil d Beari n g  P ote ntial  
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
1  
S y n o psis  
Cli nic al Tri al Pr ot oc ol N u m ber  
M S 7 0 0 5 6 8 _ 0 0 2 1  
Title  
A 
2- year 
pr os pecti ve
 st u d y
 t o
 assess
 
h ealt h-rel ate 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 treate d 
wit h Ma ve ncla d
®  
Tri al P h ase  
I V 
I N D N u m ber 
N ot a p plica ble  
F D A c o vere d tri al  
N ot a p plica ble 
E u dr a C T N u m ber  
2 0 1 7 -0 0 2 6 3 2 -1 7  
C o or di n ati n g I n vesti g at or  
 
S p o ns or  
Merc k K G a A, Fra n kf urter Str. 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y  
S p o ns or Le g al Re prese nt ati ve i n t he 
E ur o pe a n U ni o n  
Merc k K G a A, Fra n kf urter Str. 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y   
Tri al ce ntr es/c o u ntries 
E ur o pe (i ncl u di n g, b ut n ot li mite d t o):   A ustria, 
Bel gi u m, Czec h  Re p u blic , De n mar k,   Fi nla n d, 
Fra n ce,  Greece,  H u n gar y, 
Ital y,  Lit h ua nia, 
Net herla n ds,  N or wa y,  P ola n d,  P ort u gal,  S pai n,  
Sl o va kia, S we de n, U K , A ustralia  
Pl a n ne d tri al peri o d  
(first s u bject i n-l ast s u bject o ut) 
First S u bject  First Visit: Q 2/ 2 0 1 8 
Last S u bject  Last Visit: Q 4/ 2 0 2 1  
Tri al Re gistr y  
E U Cli nical Trials Re gist er  
Cli nical Trials. g o v  
O bjecti ves:  
Pri m ar y:  
• 
T o assess t he healt h -relate d q ualit y of life ( H R Q o L) t hr o u g h t he M S Q o L- 5 4 scale i n 
hi g hl y- acti ve r ela psi n g m ulti ple scler osis ( R M S) s u bjects treate d wit h Ma ve ncla d
® f or 
2 years  ( 2 4 m o nt hs) 
Sec o n d ar y:  
• 
T o assess treat me nt satisf acti o n t hr o u g h t he T S Q M v 1. 4 q uesti o n naire i n hi g hl y acti ve 
R M S  s u bjects at 6 m o nt hs  of treat me nt  wit h Ma ve ncla d ®  
Gl o bal Versi o n I D: 
P P D
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
Met h o d ol o g y: T his will be a n o pe n  la bel, si n gle ar m, e x pl orat or y, m ultice ntre, 2- year  P hase 
I V st u d y. 
S u bject s will atte n d visits f or assess me nts at Baseli ne a n d at M o nt hs 6, 1 2, 1 8, a n d 2 4. 
S u bject s will atte n d visits f or l y m p h o c yt e c o u nt as per ma n d at or y m o nit ori n g at Scree ni n g, 
Baseli ne a n d at M o nt hs 2, 6, 1 2, 1 4 , 1 8 a n d 2 4. 
Pl a n ne d n u m ber of s u bjects: 4 4 5  
Pri m ar y e n d p oi nt:  
•  C ha n ges i n M S Q o L- 5 4 at 2 4 m o nt hs c o m pare d t o B aseli ne, i.e., t h e c h a n ges i n t he p h ysical 
a n d me ntal healt h c o m p osite sc ores  
Sec o n d ar y e n d p oi nts:  
•  Treat me nt gl o bal satisfacti o n assesse d b y T S Q M v 1. 4 at 6 m o nt hs 
Gl o bal Versi o n I D: C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
P h ar m a c o ki netics: N ot  a p plica ble  
S af et y assess me nts  
Safet y assess me nts will i ncl u de p h ysical e x a mi nati o n, i ncl u di n g vital si g ns, r o uti ne la b orat or y 
tests, a n d re p orti n g of a d verse e v e nts ( A Es) a n d S A Es . 
Di a g n osis a n d ke y i ncl usi o n a n d e xcl usi o n criteri a:  
Key i ncl usi o n criteri a  
•  Male or fe m ale s u bjects ≥ 1 8 years ol d  
•  H i g hl y acti ve R M S as defi ne d b y:  
o  O ne  rela ps e i n t he pre vi o us year a n d at least 1 T 1 Ga d oli ni u m ( G d ) + lesi o n or 9 or m ore 
T 2  lesi o ns, w hile o n t her a p y wit h ot her disease m o dif yi n g dr u gs (D M Ds ) 
o  T w o or m ore r ela pses i n t he pre vi o us year, w het h er o n D M D treat me nt or n ot 
•  E D S S sc ore ≤ 5. 0 
Ke y e xcl usi o n criteri a:  
•  P ositi ve test f or he patitis C or p ositi ve tests f or he patitis B i nfecti o n: eit her he patitis B 
s urface a nti ge n ( H Bs A g) p ositi ve, or p ositi ve he patitis B c ore a nti b o d y (t otal a nti-H Bc A b) 
c o nfir me d b y a p ositi ve viral p ol y merase c hai n reacti o n ( P C R) 
•  C urre nt or pre vi o us hist or y of i m m u ne deficie n c y dis or d ers i ncl u di n g a p ositi ve h u ma n 
i m m u n o deficie nc y vir us ( HI V) res ult 
•  C urre ntl y r ecei vi n g i m m u n os u p pressi ve  or  myel os u p pressi ve t hera p y  (e. g., m o n ocl o n al  
a nti b o dies, met h otre x ate, c ycl o p h os p ha mi de, c ycl os p ori ne , mit o x a ntr o ne or azat hi o pri ne ), 
or c hr o nic use of c ortic oster oi ds 
•  Hist or y of t u b erc ul osis, prese nce of acti ve t u berc ul osis, or late nt t u berc ul osis 
•  Prese nce of si g ns of pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  (P M L ) detecte d b y M RI, 
cli nical a n d/ or bi o mar ker e val uati o ns   or ot her (t ha n M S) maj or Ce ntral Ner v o us S yste m 
disease cli nicall y dia g n os e d or e vi de n ce d i n scree ni n g M RI Acti ve mali g na n c y   
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
I n vesti g ati o n al Me dici n al Pr o d uct: d ose/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule: 
Ma ve ncla d
® ,  3. 5  m g/ k g  di vi de d  i n  2  yearl y treat me nt  c o urses.  Eac h  c o urse  of  treat me nt  
c o nsists of 2 tr eat me nt w ee ks, o n e at t he b e gi n ni n g of t he first m o nt h a n d o ne at t h e be gi n ni n g 
of t he sec o n d m o nt h of t he res p ecti ve treat me nt year. E ac h treat me nt w ee k c o nsists o f 4 or 5 
da ys o n w hi c h a s u bject recei v es 1 0 m g or 2 0 m g ( o ne or t w o ta blets) as a si n gle dail y d os e, 
de pe n di n g o n b o d y wei g ht.  
Ref ere nce t her a p y: d os e/ m o de of a d mi nistr ati o n/ d osi n g sc he d ule: N ot a p plica ble . 
Pl a n ne d tri al a n d tre at me nt d ur ati o n per s u bje ct: T w o  years treat me nt per s u bject . 
St atistic al met h o ds:  
Differ e nces i n M S Q o L - 5 4 p h ysi cal healt h a n d me ntal healt h c o m p osite sc ores bet wee n t he 
Baseli ne  assess me nt a n d t he 2 4 -m o nt h assess me nt will be e val uate d wit h mi x e d -effects li near 
re gressi o n,  acc o u nti n g  f or  wit hi n-s u bject  c orrel ati o n  a n d  wit hi n-ce ntr e/re gi o n c orrelati o n 
t hr o u g h a hierar c hical m o del. T he m o del will i ncl u de all a v aila ble ass ess me nt data u p t o a n d 
i ncl u di n g t he 2 4-m o nt h assess me nt a n d c o nsi d er ti me as a cate g orical c o variate. T h e F ull 
A nal ysis Set ( F A S) will be t he pri mar y p o p ulati o n. Sec o n dar y a n d tertiar y e n d p oi nts will be 
assesse d usi n g si milar m et h o ds. T reat me nt satisfacti o n assesse d b y T S Q M v 1. 4 at 6 m o nt hs  
will be e val uate d d uri n g a n i nteri m a nal ysis t hat will be perf or me d as s o o n as all e nr olle d 
s u bjects reac h 6 m o nt hs after treat me nt i nitiati o n. T he a n al ysis at 6 m o nt hs will be c o nsi dere d 
as s u p p orti ve of t he 2 4 m o nt hs a nal ysis ( m ai n a nal ysis).  
S afety a n alysis:  
All safet y assess me nts will be descri pti vel y s u m m arize d .  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
2  
S p o ns or, I n vesti g at ors a n d Tri al A d mi nistr ati ve Str uct ure  
T he S p o ns or of t his cli nical trial wit h Ma ve ncla d
®  is Merc k K G a A, Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 
Dar msta dt,  Ger ma n y.  
T he trial will be c o n d uct e d at a p pr o xi matel y 1 2 0 sites acr oss E ur o pe i ncl u di n g A ustria, Bel gi u m, 
Czec h Re p u blic, De n mar k, Fi nla n d F ra n ce, Greece, H u n gar y, It al y, Lit h u a nia, Net herla n ds, N or wa y, 
P ola n d, P ort u gal, S pai n, Sl o va kia, S we de n, U K, as we ll as i n A ustralia. T he st u d y is o pe n t o ot her 
c o u ntries if t her e a p pears a nee d t o i ncr eas e t he recr uit me nt.  
T he  C o or di nati n g  I n v esti gat or,  
 re prese nts  all  
I n v esti gat ors f or d ecisi o ns a n d disc ussi o ns re gar di n g this trial, c o nsiste nt wit h t he I nter nati o nal 
C o u ncil f or Har m o nisati o n (I C H) T o pic E 6 G o o d Cli nical Practice (I C H 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 relati n g t o trial d esi g n a n d e x ec uti o n a n d 
is res p o nsi ble f or t he r e vie w a n d si g n off of t he cli nical trial re p ort. 
Si g nat ure p a ges f or t h e Pr ot oc ol Lea d a n d t he C o or di nati n g I n v esti gat or as well as a list of S p o ns or 
res p o nsi ble pers o ns are i n Secti o n  1 2. 1 4 . 
T he trial will a p pear i n t he f oll o wi n g cli nical trial re gistries:  Cli nical Trials. g o v , E U Cli nical Tri als 
Re gister a n d nati o nal r e gistries as per l ocal re g ulati o ns. 
A c o ntract researc h or ga ni zati o n ( C R O),
will u n derta ke t he o p erati o nal 
aspects  of  t his  trial  wit h  o versi g ht  b y  t he  S p o ns or.  Details  of  s uc h  str uct ures  a n d  ass oci ate d  
pr oce d ur es will be defi n e d i n a se par ate I nte grate d Pr oject Ma na ge m e nt Pla n (I P M P).  
T he  I P M P will be pre pare d b y t he C R O . Cli nical q ualit y ass ura nce will be perf or m e d u n der t he 
res p o nsi bilit y of t he D e v el o p me nt Q ualit y Ass ura nce de p art me nt at Merc k K Ga A D ar msta dt. 
T he  i n vesti gati o nal  me dici nal  pr o d ucts  (I M P)  will  be  s u p plie d  b y  t he  Cli nical  Trial  S u p pl y 
De part me nt of t h e S p o ns or a n d pac k a ge d a n d la bele d b y 
 
Details of str uct ures a n d ass ociate d pr o ce d ures will be defi ne d i n a se parat e Ma n ual of O perati o ns, 
w hic h will be pre pare d u n der t he s u per visi o n of t he Cli nical Trial Lea d er. 
3  
B ac k gr o u n d I nf or m ati o n  
 
M ulti ple Scler osis  
M ulti ple scler osis ( M S) is a c hr o nic, i nfla m mat or y, pr o gressi ve, de m yeli nati n g disease of t he ce ntral 
ner 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 ne ur ol o gi cal disa bilit y i n y o u n g a d ults 
( Prz y be k et al., 2 0 1 5). T he disease c o urse 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 ul ar m e dical  m o nit ori n g b y n u mer o us  met h o ds s uc h as f or e x a m ple, 
ma g n etic  res o na n ce  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 s u bjects wit h M S ( Oreja- G u e vara e Para di g, 2 0 1 5). 
S o me s u bject s e x perie nce a hi gh l y acti ve disease c o urse wit h ra pi d a n d earl y disa bilit y ofte n h eral de d 
b y hi g h rel a pse rates a n d earl y m ot or, cere bellar a n d/ or c o g niti ve d ysf u n cti o n ( Hirst C L et al, 2 0 0 8). 
Gl o bal Versi o n I D: 
P P D
C CI
P P D
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
Earl y i nitia ti 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 s u bjects 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 be y D et al, 
2 0 1 6). 
 
Cl a dri bi ne  T a blets ( M a ve ncl a d
® ) 3. 5/ k g  
D es pite  t he  r ece nt  a p pr o vals  of  se veral  ne wer  t hera pies ,  t he  treat me nt  b ur de n  of  M S  re mai ns  
si g nifica nt. T he e vi de n ce f or t he effects of ne w t hera pies are wea k a n d oft e n of a s h ort -ter m nat ure 
wit h little f oll o w u p of ori gi nal trial partici p a nts  (Tra macare  et al., 2 0 1 5). 
It h as bee n de 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 s u bjects acr oss 
t he s pectr u m of R ela psi n g Re mitti n g M ulti ple Scler osis  ( R R M S) (earl y to l ate  sta ges, treat me nt n aï v e 
or e x perie nce d s u bjects) ( Gi o va n n o ni et al., 2 0 1 0; Leist et al., 2 0 1 4). I n p artic ular, it was f o u n d t hat 
treat me nt  wit h  oral  Cla dri bi ne  Ta blets  res ulte d  i n  si g nifica nt  i m pr o v e me nts  i n  cli nical  a n d  
ra di ol o gical effi cac y o ut c o mes, wit h si g nifica ntl y m ore s u bjects re mai ni n g free fr o m rela pse, free 
fr o m 3-m o nt h s ustai ne d E x pa n de d Disa bili t y Stat us Scale (E D S S ) pr o gressi o n a n d free fr o m M RI 
lesi o n acti vit y o ver 9 6 w ee ks c o m pare d t o place b o ( Gi o va n n o ni et al., 2 0 1 0). 
Efficac y  dat a  fr o m  t he  C L A RI T Y  trial s ho we d  statisticall y  si g nifica nt  i m pr o ve me nts  i n  t he  
a n n ualiz e d rela ps e rat e  ( A R R), pr o p orti o n of s u bjects rela ps e-free o ver 9 6 wee ks, pr o p orti o n of 
s u bjects free of s ustai n e d disa bilit y o ver 9 6 wee ks a n d ti me t o 3-m o nt h E D S S pr o gressi o n i n s u bject 
recei vi n g  cla dri bi ne  3. 5  m g/ k g  c o m pare d  t o  s u bjects o n  place b o.  I n  a d diti o n,  cla dri bi ne  w as 
statisticall y si g nifica ntl y s u peri or t o place b o wit h re gar d t o n u m ber a n d relati ve re d ucti o n of T 1 
Ga d oli ni u m ( G d )+ lesi o ns, acti ve T 2 lesi o ns , a n d c o m bi ne d u ni q ue lesi o ns ( C U L) as de m o nstrate d 
i n brai n M RI o v er t he e ntire 9 6 wee ks of t he trial. 
Ma ve ncla d
® is a p pr o v e d  ( E ur o pea n  Me di ci nes  A ge nc y  a p pr o v al  o n  2 5  A u g ust  2 0 1 7) f or  t he  
treat me nt of a d ult s u bjects wit h hi g hl y acti ve rela psi n g M S as defi ne d b y cli nical or i ma gi n g feat ures:  
•  s u bjects wit h 1 rela ps e i n t he pre vi o us year a n d at least 1 T 1 G d +  lesi o n or 9 or m ore T 2 
lesi o ns, w hile o n t hera p y wit h ot her disease m o dif yi n g dr u gs (D M Ds ), 
•  s u bjects wit h 2 or m ore r ela pses i n t he pre vi o us year, w h et her o n D M D treat me nt or n ot 
 
S afet y a n d T oler a bilit y of M a ve ncl a d
®  
T he saf et y pr ofile of M a ve ncla d
®  h as b ee n assesse d i n de pt h base d o n data fr o m all st u dies of 
cla dri bi ne i n M S, i ncl u di n g t h e l o n g -ter m safet y f oll o w-u p re gistr y, a n d p ost -mar keti n g d ata s o urces. 
Ma ve ncla d
® , w h e n a d mi nistere d as m o n ot hera p y at a c u m ulati ve d ose of 3. 5 m g/ k g o ver 2 years, 
was well t olerat e d a n d de m o nstrate d a ma na gea ble safet y pr ofile.  
T he c o m pre h e nsi ve assess me nt of t he safet y d ata h as acc u m ulate d m ore t ha n 8 5 0 0  patie nt  years ( P Y)  
of Ma ve n cla d
®  e x p os ure wit h u p t o 8  years of f oll o w -u p i n Ma v e ncla d
® -treate d s u bjects a n d t h us 
pr o vi des a d diti o nal c o nfi de nce of t h e safet y pr ofil e of Ma ve n cla d
® . 
T he  i m p orta nt  i de ntifie d  ris ks  ass ociate d  wit h  Ma ve ncla d
® are  se vere  l y m p h o p e nia,  w hic h  is  
ass ociate d wit h t he mec h a nis m of acti o n of t he dr u g, her p es z oster , a n d t u berc ul osis. Base d pri maril y 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
o n t he mec ha nis m of acti o n of Ma ve ncla d
®  5 i m p orta nt p ote ntial ris ks ha ve bee n i de ntifie d: se vere 
i nfecti o ns, pr o gressi ve m ultif ocal le u k oe nce p h al o pat h y ( P M L) , o p p ort u nistic i nfecti o ns ( ot her t ha n 
t u berc ul osis a n d P M L) , mali g na n cies, a n d terat o ge nicit y/a d v erse pre g na nc y o utc o mes. T he S p o ns or 
will  f oll o w  t he  pr o p ose d  ris k  mi ni mizati o n  meas ures  s p ecifie d  i n  t he  s u m mar y  of  pr o d uct  
c haracteristics ( S m P C) of Ma ve ncl a d ® . 
 
Be nefit - Ris k Assess me nt  
T he st u dies hi g hli g hte d i n S ecti o n 3. 2  ha ve pr o vi de d i nf or mati o n o n t h e efficac y a n d s afet y of 
Ma ve ncla d
® . As r eflecte d i n t he Ma ve ncla d
® S m P C, a p pr o priate ris k miti gati o n meas ures will be 
f oll o we d f or i de ntifie d a n d p ote ntial ris ks Ma ve n cla d
® i n t he partici pati n g s u bjects. 
T he be n efit -ris k relati o ns hi p was caref ull y c o nsi dere d i n t he pla n ni n g of t he trial. Bas e d o n t he 
cli nical a n d safet y data a vaila ble, t he S p o ns or c o nsi ders t hat Ma ve ncla d ® has a p ositi ve be nefit -ris k 
pr ofile t hat s u p p orts its use i n t his s u bject gr o u p as s pecifie d i n t his cli nical trial pr ot oc ol. T he trial 
will be disc o nti n ue d i n t he e ve nt of a n y n e w fi n di n gs t hat i n dicate  a rele va nt deteri orati o n of t h e 
ris k- be nefit r elati o ns hi p a n d w o ul d re n d er c o nti n uati o n of t he trial u net hical. 
Base d o n t he a vaila ble n o ncli nical a n d cli nical data t o date, t he c o n d uct of t he trial s pecifie d i n t his 
pr ot oc ol is c o nsi dere d j ustifia ble. 
 
Sc ie ntific R ati o n ale f or Tri al  Desi g n  
3. 5. 1  
Q u alit y of life a n d Tre at me nt S atisf acti o n  
T he rel a psi n g f or m of M S is c haracterize d b y e pis o des of n e ur ol o gical d eteri orati o n ( V oll mer, 2 0 0 7; 
Tra p p e Na v e, 2 0 0 8)  re q uiri n g i ncr ease d me dical care a n d s o meti mes h os pitalizati o n ( M orr o w, 2 0 0 7; 
Olee n - B ur ke y et al., 2 0 1 2; Ma urer et al., 2 0 1 6). St u dies ha ve li n ke d t he n u m ber of rec urri n g r ela pses 
wit h disa bilit y pr o gressi o n ( O'c o n n or et al., 2 0 1 1) a n d i m pacti n g s yst e ms s uc h as m ot or f u ncti o n a n d 
c o g niti o n ( Arr o y o G o nzalez et al., 2 0 1 6). T he acc u m ulati o n a n d w orse ni n g of disa bilities o ver ti me 
disr u pts s u bjects’ fa mil y, s ocial, a n d w or ki n g life, u n der mi ni n g t h eir ca pacit y t o f u ncti o n i n s ociet y 
a n d ta n gi bl y di mi nis hi n g t heir H R Q o L (J o nes  et al., 2 0 1 6). 
T he  q ualit y of  life  ( Q o L)  of s u bjects wit h  M S  is  l o wer  t ha n  s u bjects  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 heart diseas e, t y p e -2 dia b etes, a n d Cr o h n’s disease ( Or me et al., 
2 0 0 7) . T his is f urt her e x acer bat e d b y i ncreas e d rela pse fre q ue n c y a n d pr o gressi o n of diseas e ( Par ki n 
et al., 2 0 0 0; Ba u mstar c k et al., 2 0 1 5). 
H R Q o L  ca n  b e  i m pacte d  i n  ma n y differe nt  wa ys.  T he  b ur de n  of  disa bilit y a n d  c o m or bi dities  
e x perie nce d b y s u bjects wit h M S has a detri me nt al effect o n Q o L ( Gr ytte n et al., 2 0 1 2, A y meric h  et 
al., 2 0 0 9, Or me  et al., 2 0 0 7). B ot h pr o gressi o n of disa bilit y a n d fre q u e nc y of rela pse c o ntri b ute t o 
w orse ni n g of Q o L ( Par ki n et al., 2 0 0 0; Ba u mstarc k et al., 2 0 1 5). T h e prese nce of a rela pse ca n b e 
ass ociate d wit h re d uce d Q o L i n e m oti o nal, me ntal healt h, a n d s ocial f u ncti o n d o mai ns c o m pare d 
wit h s u bject w h o h a d n ot e x perie nce d a rela pse ( Par ki n et al., 2 0 0 0). Rela pses ha ve bee n f o u n d t o 
w orse n f ati g u e ( Ma urer et al., 2 0 1 6) w hic h is a pre d o mi na nt s y m pt o m f or M S s u bjects. Hi g h er le v els 
of fati g u e ar e  n ot o nl y  c o nc o mita nt wit h greater i m pair me nts i n f u ncti o nal m o bilit y a n d p h ysical 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
H R Q o L, b ut als o ha ve a m ut uall y i ntert wi ne d rel ati o ns hi p wit h c o g niti o n, de pressi o n, a n d me ntal 
healt h ( Gar g et al., 2 0 1 6). 
M a ve ncla d ®  is a dr u g gi v e n orall y wit h a u ni q ue p os ol o g y of ma xi m u m 2 0 da ys of treat me nt i n t w o 
years. T h e saf et y m o nit ori n g is n ot fre q ue nt, d u e t o t he hi g hl y sele cti ve m ec ha nis m of acti o n t hat  
tar gets s pecificall y t he mat ure i m m u ne s yste m. I n s uc h a c o nte xt, M S Q ol -5 4 is pr o ba bl y a n i deal 
q uesti o n naire. It ca n a d dr ess t he i m pact of s u c h a l o w b ur de n treat me nt i n o verall q ualit y of life, i n 
a st u d y w h ere f u ncti o nal scales ar e als o use d f or fati g ue, de pressi o n a n d a n x iet y a n d M ulti ple 
Scler osis F u ncti o nal C o m p osite ( M S F C) assess me nts li ke 
 ar e i ncl u de d.  
T S Q M  v 1. 4  q uesti o n naire  is  a  si m ple,  n o n -M S  s pecific,  b ut  t he  m ost  wi del y  use d  treat me nt  
satisfacti o n q uesti o n naire i n M S. It has n ot bee n us e d i n pi v otal Cla dri bi ne Ta blets trials. 
W hilst t he Ma ve ncla d
®  r a n d o mize d c o ntr ol trials (R C Ts ) 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, eff ects f or H R Q o L, c o g niti o n, treat me nt satisfacti o n , a nd e m pl o y m e nt stat us 
nee d  t o  be  f urt her  e x pl ore d.  I n  C L A RI T Y  trial M S Q o L -5 4  a n d  E Q -5 D  scales  were  use d  a n d  
o utc o mes were a nal yze d , b ut n o clear differe nces i n ter ms of res p o nsi ve ness bet wee n t he ra n d o mize d 
s u bject gr o u ps (t h os e treate d wit h Ma ve ncla d
®  a n d th ose treate d wit h place b o) w ere e vi d e nce d. A 
p ossi ble e x pla nati o n f or t his c o ul d be t h e fact t hat s u bjects e nteri n g t he tri al ha d alrea d y hi g h H R Q o L 
le vels. H o w e ver, s u bjects e nr olle d i n t he C L A RI T Y trial were n ot dia g n ose d wit h hi g h disease 
acti vit y R M S, as defi ne d i n t he i ncl usi o n criteria of t he prese nt tri al. 
3. 5. 2  
C o g niti o n a n d C orrel ati o n wit h Br ai n A tr o p h y 
T he effect of M S u p o n c o g niti o n is als o si g nifi ca nt. C o g niti ve i m pair me nt ca n affect s u bjects at all 
sta ges, b ut it is c halle n gi n g t o cli nicall y assess t his i m pact ( La n g d o n et al., 2 0 1 2). T he y ca n i ncl u d e 
l oss of me m or y f u ncti o ns a n d pr ocessi n g s pee d or i m pact e x ec uti ve f u ncti o ns ma ki n g dail y life a 
c halle n ge ( M u c ksc hel  et al., 2 0 1 6). Su bject s ha v e re p ort e d t hat c o g niti ve i m pair me nts ca n ha v e a 
gr eater ne gati ve i m pact o n t heir H R Q o L t ha n t heir p h ysical s y m pt o ms ( Pe n ner, 2 0 1 6). C o g niti o n 
t heref or e carries a si g nifica nt disease b ur de n. 
Brai n atr o p h y h as bee n li n ke d t o c o g niti ve i m pair me nt i n pre vi o us st u dies   (A mat o et al., 2 0 1 3 , 
Mi nee v et al., 2 0 0 9, a n d H o utc he ns et al., 2 0 0 7 ). T he S y m b ol Di git M o dalities Test ( S D M T ) (a Brief 
I nter nati o nal  C o g niti ve  Assess me nt  f or  M ulti ple  Scler osis  [BI C A M S ] c o m p o ne nt)  has  bee n  
c orrel ate d t o Dee p G ra y Matter v ol u me ( Batista et al ., 2 0 1 1).  
T his  st u d y  is  a n  o p p ort u nit y  t o  c ollect  lar ge  scale  dat a  o n  b ot h  BI C A M S,  a  M S  s pecific  
ne ur o ps yc h ol o gic test a n d M RI lesi o ns bef ore a n d after Ma v e ncla d ®  a d mi nistrati o n . 
3. 5. 3  
Ot her F u ncti o n al S c ales 
A part fr o m c o g niti ve pr o ble ms s uc h as i n me m or y a n d atte nti o n, ot her fact ors c o ntri b uti n g t o Q o L 
w orse ni n g are de pressi o n a n d fati g ue ( Fle ns ner et al., 2 0 1 3). A p pr o xi matel y 6 0  t o 8 0 % of s u bjects 
wit h M S e x perie nce fati g ue, w hi c h has bee n descri be d as disti nct fr o m a n y pri or e x perie nce of 
feeli n g tire d ( Fle ns n er et al., 2 0 1 3). Fati g u e was f o u n d t o si g nifica ntl y w orse n Q o L a n d ca p acit y t o 
w or k ( Fl e ns ner et al., 2 0 1 3). 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
A lar ge n u m ber of s u bjects wit h M S ( 5 5 - 5 8 %) are u na ble t o retai n e m pl o y m e nt f oll o wi n g dia g n osis 
(J ulia n et al., 2 0 0 8; B øe L u n de et al., 2 0 1 4). 
L o w er pr o d ucti vit y e n ge n ders a re d uce d se nse of a ut o n o m y a n d fi na ncial press ures d ue t o re d uce d 
i nc o me w hic h ne gati vel y i m pacts t he s u bject a n d t he wi der ec o n o m y (J o nes et al., 2 0 1 6). 
4  
Tri al O bjecti ves  
 
Pri m ar y  O bjecti ve 
T o assess t he H R Q o L t hr o u g h t he M S Q o L- 5 4 s cale i n hi g hl y acti ve R M S  s u bjects treate d wit h 
Ma ve ncla d
® f or 2 years  ( 2 4 m o nt hs). 
4. 1. 1  
Pri m ar y E n d p oi nt  
•  C ha n ges i n M S Q o L -5 4 at 2 4 m o nt hs c o m pare d t o Baseli ne , i.e., t he c h a n ges i n t he p h ysical 
a n d me ntal healt h c o m p osite sc ores  
 
Sec o n d ar y  O bjecti ve  
 
T o assess treat me nt satisf acti o n t hr o u g h t h e T S Q M  v 1. 4 q uesti o n naire i n hi g hl y acti ve R M S s u bjects 
at 6 m o nt hs of treat me nt wit h Ma ve ncla d ®  
4. 2. 1  
Sec o n d ar y E n d p oi nt  
•  Treat me nt gl o bal satisfacti o n assesse d b y T S Q M v 1. 4 at 6 m o nt hs 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
5  
I n vesti g ati o n al Pl a n 
 
O ver all Tri al Desi g n a n d Pl a n  
A sc he matic of t h e trial d esi g n is pr ese nte d i n Fi g ure 1. 
Fi g ure 2: Sc he m atic of t he Tri al Desi g n  
 
 
† Sec o n d treat me nt c o urse ma y be dela ye d f or s o me s u bj ects  (see Secti o n  5. 5. 1 ). § 0– 3 m o nt h wi n d o w f or 
t hese trial visits.  
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
 
Disc us si o n of Tri al Desi g n 
T his will be a s i n gle ar m, o pe n la bel,  m ultice ntre, 2 4 -m o nt h P hase I V trial. S u bjects wit h R M S will 
recei v e Ma ve ncl a d
® 3. 5 m g/ k g b o d y w ei g ht o ver t w o years, a d mi nistere d as 1 treat me nt c o urse of 
1. 7 5 m g/ k g per year. Eac h treat me nt c o urse will c o nsist of 2 treat me nt wee ks, o ne at t he be gi n ni n g 
of t he first m o nt h a n d o n e at t he be gi n ni n g of t he sec o n d m o nt h of t he res p ecti ve year.  T here will be 
a 3- m o nt h wi n d o w all o w a nce f or s u bjects f or w h o m t he sec o n d year c o urs e dela ys (5. 4. 1  a n d 5. 5. 1 ) 
At scree ni n g, all s u bjects will ha ve a pre-Baseli ne  M RI sca n  as w ell as t u berc ul osis (T B ; acti ve a n d 
late nt) a n d ser ol o g y tests wit hi n t he m o nt h lea di n g u p t o t he Baseli ne visit  i n or der t o s u p p ort t he 
dia g n osis of hi g hl y acti v e R M S a n d e ns ure c o m plia nce wit h i ncl usi o n a n d e x cl usi o n criteria. 
Re -scree ni n g will be all o we d o nce f or t h ose s u bjects w h o d o n ot meet t he i n cl usi o n/e x cl usi o n criteria 
wit hi n t he a b o ve s pecifie d ti me li mits. T he Me dical M o nit or m ust pr o m ptl y i nf or m t he S p o ns or a b o ut 
re q uests a n d r eas o ns f or r e-scr ee ni n g. 
Baseli ne is defi n e d as t he d a y o n w hic h t he first d ose of Ma ve ncl a d
®  is a d mi nistere d. All Baseli n e  
assess me nt s h o ul d ta ke place bef ore M a ve ncl a d
® a d mi nistrati o n. 
S u bject s will atte n d visits  f or assess me nts at Baseli ne, M o nt h 6, 1 2, 1 4, 1 8 , a n d 2 4. A ti me wi n d o w 
of u p t o 3 m o nt hs will be all o we d f or t he visits f oll o wi n g t he sec o n d c o urs e (see als o S ecti o n 7). 
S u bject s will atte n d visits f or l y m p h o c yte c o u nt as per ma n dat or y m o nit ori n g  at Scree ni n g, Baseli ne 
a n d at M o nt hs 2, 6, 1 2, 1 4, 1 8 a n d 2 4. 
S u bject s w h o disc o nti n ue Ma ve ncla d
® at a n y ti me d uri n g t he trial will c o nti n ue t o partici pate i n t he 
sc he d ule d  visit  f or  safet y assess ments a n d  ma n dat or y  m o nit ori n g .  I n  t he  e ve nt  of  earl y  
disc o nti n uati o n fr o m t he trial, t he s u bject s h o ul d ret ur n f or t he Earl y Ter mi nati o n visit f or fi nal 
assess me nt.  
Visit  sc he d ules  f or  effi cac y  a n d  safet y  assess me nts  are  d etaile d  i n  A p pe n di x  1 :  Sc he d ule  of  
Assess me nts . 
5. 2. 1  
I ncl usi o n of S peci al P o p ul ati o ns 
N ot a p plica ble.  
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
5. 2. 2  
Steeri n g C o m mittee  
A Steeri n g C o m mittee ( S C) has bee n esta blis he d; t he Steeri n g C o m mittee C harter will be i n place 
t hat descri bes t he S C res po nsi bilities.  
T he S C is a m ulti disci pli nar y gr o u p of lea d trial  I n vesti gat ors, m e 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 s cie ntific, me dical, a n d cli nical trial ma na ge me nt e x perie nce 
t o desi g n, c o n d u ct a n d e v al uate t he trial. 
T h e 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 h e desi g n, t he c o n d uct, a n d t he 
e val uati o n of t he trial. 
T he S C is res p o nsi ble f or saf e g uar di n g t h e i nterests of partici pati n g s u bjects a n d f or t he c o n d uct of 
t he trial. 
 
Selecti o n of Tri al P o p ul ati o n  
O nl y  p ers o ns meeti n g all i ncl usi o n criteria a n d n o e x cl usi o n criteria ma y b e e nr olle d  i nt o t he tri al as 
s u bjects. Pri or t o perf or mi n g a n y trial assess me nts n ot part of t he s u bject’s r o uti ne me dical care, t h e 
I n v esti gat or will e ns ure t hat t he s u bject or t he s u bject’s le gal re prese nt ati ve has pr o vi de d writte n 
i nf or me d c o nse nt f oll o wi n g t he pr oce d ure des cri b e d i n Secti o n 9. 2 . 
5. 3. 1  
I ncl usi o n Criteri a 
T o be eli gi ble f or i ncl usi o n i nt o t his st u d y, t he s u bjects m ust f ulfill all of t he f oll o wi n g criteria:  
1.  S u bjects   m ust v ol u ntaril y  gi ve  writte n  i nf or me d  c o nse nt.  S u bjects  m ust  rea d  a n d  f ull y  
u n dersta n d t he I nf or me d C o nse nt F or m (I C F) a n d t he re q uire me nts of t he trial a n d m ust be 
willi n g t o c o m pl y wit h all trial visits a n d assess me nts  
2.  Male or fe m ale s u bjects  ≥ 1 8 years ol d  
3.  Hi g hl y acti ve rela psi n g M S as defi ne d b y:  
- 
O ne rela ps e i n t he pre vi o us year a n d at least 1 T 1 G d + lesi o n or 9 or m ore T 2 lesi o ns, 
w hile o n t hera p y wit h ot her D M Ds 
- 
T w o or m ore r ela pses i n t he pre vi o us year, w het h er o n D M D treat me nt or n ot 
4.  E D S S sc ore ≤5. 0  
5.  Fe male s u bj ects of c hil d -beari n g  p ote ntial m ust use hi g hl y effecti ve met h o ds of c o ntrace pti o n 
t o pre ve nt pr e g na nc y f or 4 wee ks bef ore i nitiati o n of Ma ve ncl a d
®  a n d m ust a gree t o c o nti n ue 
t o practice a de q uat e c o ntrace pti o n f or at least 6 m o nt hs after t he last d ose ( See A p p e n d i x 1 5 
f or t he list of Hi g hl y Eff ecti ve Birt h C o ntr ol Met h o d. A w o ma n is c o nsi dere d of c hil d -beari n g  
p ot e ntial ( W O C B P), i.e. fertile, f oll o wi n g me n arc he a n d u ntil bec o mi n g p ost - me n o pa usal 
u nless per ma n e ntl y  st er ile. W o me n  usi n g  s yste micall y  acti n g  h or m o nal  c o ntrace pti ves 
s h o ul d a d d a barrier met h o d d uri n g Ma ve ncl a d
®  treat me nt a n d f or at least 4 wee ks after t he 
last d ose i n eac h treat me nt year. W O C B P  m ust n ot be pre g na nt   n or lactati n g, or breast -
fee di n g at Scr ee ni n g t hr o u g h at least 1 wee k after t he last d ose 
6.  Male s u bjects m ust be willi n g t o use a c o n d o m i n a d diti o n t o ha vi n g t heir fe male part ner us e 
a n ot her f or m of c o ntrace pti o n (s uc h as a n i ntra -uteri ne de vice [I U D], barrier met h o d wit h 
s per mici de, or h or m o nal c o ntrace pti ve [e. g., i m pla nt, i njecta ble, patc h or oral]) fr o m Baseli ne 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
u ntil  6  m o nt hs  after  t he  last  d ose  of  Ma ve ncla d
® ,  u nless  t heir  part ners  are  i nfertile  or  
s ur gicall y sterile 
7.  S u bject s w h o test   p ositi ve f or V ari cella Z oster vir us ( V Z V) will be i ncl u de d. I n case of  
ne gati ve  ser ol o g y,  t he  s u bject ma y  be  i nc l u de d  after  4  t o  6  wee ks  of  recei vi n g  V Z V  
vacci nati o n  
5. 3. 2  
E xcl usi o n Criteri a  
T o be eli gi ble f or i ncl usi o n i n t his st u d y t he s u bjects m ust n ot meet a n y of t he f oll o wi n g criteria:  
1.  H y p erse nsiti vit y t o Ma v e ncla d
®  or t o a n y of t he e x ci pie nts liste d i n t he S m P C  
2.  L y m p h oc yte c o u nt n ot wit hi n n or mal li mits of t he l ocal, h os pital la b orat or y bef ore i nitiati o n 
of first treat me nt c o urse  
3.  Prese nce of si g ns of P M L d etecte d b y M RI, cli nical a n d/ or bi o mar ker e v al uati o ns  or ot her 
(t ha n  M S)  maj or  Ce ntral  Ner v o us  S yste m  disease  cli nicall y di a g n ose d  or  e vi de nce d  i n  
scree ni n g M RI 
4.  P ositi ve f or H u ma n I m m u n o deficie nc y Vir us ( HI V ),  
5.  P ositi ve he patitis C or p ositi ve tests f or he patitis B i nfecti o n: eit her he patitis B s urface a nti ge n 
( H Bs A g) p ositi ve, or p ositi ve he patitis B c ore a nti b o d y (t otal a nti H Bc A b) c o nfir me d b y a 
p ositi ve viral p ol y m er ase c hai n reacti o n ( P C R). A n i n di vi d ual be nefit -ris k e val uati o n s h o ul d 
be perf or me d bef ore i nitiati n g Ma v e ncla d ®  i n n o n-i m m u ne s u bjects f or He patitis B a n d t he 
i n di vi d ual le vel of ris k f or H B V i nfecti o n s h o ul d b e assesse d b y t he I n vesti gat or 
6.  Hist or y of acti ve t u berc ul osis ( T B), c urre nt dia g n osis of acti ve t u ber c ul osis,  u n der g oi n g 
c urre nt treat me nt f or late nt T B i nfecti o n ( L T BI), L T BI  as detecte d b y l ocal sta n dar d of 
practise li ke i ma gi n g (e. g., c h est X-ra y, c hest c o m p uterize d t o m o gra p h y [ C T]  sca n, M RI) 
a n d/ or p ositi ve Q ua nti F E R O N- T B G ol d test a n d/ or s k i n test a n d/ or cli nical e x a mi nati o n  
7.  I m m u n oc o m pr o mise d s u bjects, i ncl u di n g s u bjects c urre ntl y recei vi n g i m m u n os u p pressi ve  or 
m yel os u p pr essi ve
 t her a p y  
wit h,
 e. g.,
 m o n ocl o nal
 a nti b o dies,
 met h otre x ate,
 
c ycl o p h os p ha mi de,  c ycl os p ori ne,  mit o x a ntr o ne  or  azat hi o pri ne,  or  c hr o nic  use  of  
c ortic oster oi ds  
8.  Acti ve  mali g n a nc y.  A n  i n di vi d ual  be nefit -risk  e val uati o n  s h o ul d  be  perf or me d  bef ore  
i nitiati n g Ma ve ncla d
®  i n s u bjects wit h pri or mali g na nc y.  S u bject s treate d wit h Ma ve ncla d
®  
s h o ul d be a d vise d t o f oll o w sta n dar d ca ncer scree ni n g g ui deli nes 
9.  S u bjects wit h here ditar y pr o ble ms of fr u ct ose i nt olera nce 
1 0.  S u bjects  ha vi n g  r ecei v e d  a  li ve  vacci ne  wit hi n  4  t o  6  wee ks  pri or  t o  Ma ve ncla d
®  
a d mi nistrati o n or i nte n ds t o recei ve a li ve v acci n at i o n d uri n g t he tri al. Aft er t he l ast d ose of 
Ma ve ncla d
® , t he s u bject s h o ul d a v oi d li ve vacci n e as l o n g as t he s u bj ect's w hite bl o o d cell 
c o u nts are n ot wit hi n n or mal li mits  
1 1.  Aller g y or h y perse nsiti vit y t o G d  a n d/ or a n y ot her c o ntrai n dicati o n t o perf or m a n M RI 
1 2.  M o derate or s e ver e r e nal i m pair me nt c o nfir me d as per t he sta n dar ds of l ocal cli nical practice  
(f or e x a m ple, cr eati ni ne clear a nce < 6 0  m L/ mi n)  
1 3.  M o derate or s e ver e he p atic i m pair me nt c o nfir m e d as per t he sta n d ar ds  of l ocal cli nical 
practice (f or e x a m ple, C hil d - P u g h sc ore > 6) 
1 4.  S u bject 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 trial 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
 
Criteri a f or  I niti ati o n of Tri al Tre at me nt 
5. 4. 1  
Criteri a f or I niti ati n g a n d C o nti n ui n g T her a p y  
L y m p h oc yte c o u nts m ust be: 
•  N or mal bef or e i nitiati n g Ma ve ncla d
®  i n year 1, 
•  A t least 8 0 0 cells/ m m³ bef ore i nitiati n g Ma ve n cla d
®  i n year 2. 
 
Criteri a f or S u bject Wit h dr a w al  
S u bjects  will be i nf or me d t hat t he y h a ve t he ri g ht t o wit h dra w fr o m t he trial at a n y ti me, wit h o ut 
prej u dice t o t heir me dical care, a n d t hat t he y are n ot o bli ge d t o state t heir reas o ns. A n y wit h dra w al 
m ust be f ull y d oc u me nt e d i n t he electr o ni c cas e re p ort f or m ( e C R F) a n d s o urce d oc u m e nts, a n d 
s h o ul d be f oll o we d u p b y t he I n v esti gat or. 
5. 5. 1  
Wit h dr a w al fr o m Tri al T her a p y  
Wit h dr a w al m a y  be c o nsi dere d  i n t he f oll o wi n g c ases: 
•  A n y s u bject t hat d oes n ot f ulfill t he a b o ve me nti o ne d criteri a (Secti o n  5. 4) f or t he first 
a n d/ or t he sec o n d c o urse of treat me nt 
•  
Occ urre nce of i nf ecti o n s uc h as h er p es z oster, late nt he patitis or late nt t u berc ul osis. I n t his 
case a d e q uate a nti -i nfecti o n treat me nt s h o ul d be i nitiate d a n d wit h dra wal fr o m or dela y of 
sec o n d c o urs e of Ma v e ncla d
®  s h o ul d be c o nsi dere d 
S u bjects  wit h l y m p h o pe nia l o wer t hat t he a b o ve -m e nti o ne d li mit a n d/ or occ urre nce of t he a b o ve 
me nti o ne d i nfecti o ns, res ulti n g i n dela y  of sc he d ule d sec o n d year treat me nt c o urse be y o n d 3 
m o nt hs will be e x cl u de d fr o m , tertiar y or e x pl orat or y e n d p oi nt a n al ysis. H o we ver, t hese s u bj ects 
will recei v e t he s ec o n d treat me nt c o urse o n ce t he l y m p h o c yt e c o u nt is a p pr o pri ate a n d / or 
i nfecti o n is r es ol ve d. Dat a fr o m t hese s u bjects will be re p orte d as a n a d de n d u m t o t he fi n al trial 
re p ort. If r ec o v er y fr o m l y m p h o pe nia a n d/ or i nfecti o us disease ta kes m ore t ha n 6 m o nt hs, t he 
s u bject s h o ul d n ot recei v e t he sec o n d treat me nt c o urse of Ma v e ncla d® . 
Wit h dr a w al is m a n d at ory  i n t he f oll o wi n g c ases: 
•  Wit h dra wal of c o nse nt 
•  Pr ot oc ol vi olati o n, i ncl u di n g n o n-c o m plia nce t hat i n t he o pi ni o n of t he I n v esti gat or or 
S p o ns or necessitates t he s u bject bei n g re m o ve d. T he decisi o n t o wit h dra w t he s u bject 
s h o ul d be ta ke n i n c o ns ultati o n wit h t he Me dical M o nit or 
•  Pre g n a nc y  
•  I nitiati o n of treat me nt wit h a n e x peri me ntal dr u g 
•  I nitiati o n of treat me nt wit h a n ot her disease m o dif yi n g t hera p y f or M S  
•  Occ urre nce of acti ve mali g na n cies  
•  E vi de nce or s us p ect  of P M L  
•  Occ urre nce of a n e x cl usi o n criteri o n t hat is cli nicall y rele v a nt a n d affects t he s u bject ’s 
safet y, if disc o nti n uati o n is c o nsi dere d necessar y b y t he I n v esti gat or a n d/ or S p o ns or 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
•  L y m p h oc yte c o u nt less t ha n 8 0 0 cells/ m m³ f or m ore t ha n 6 m o nt hs bef ore i nitiati o n of 
sec o n d treat me nt c o urse 
•  Li ve or li ve atte n uate d v acci ne at a n y ti me d uri n g t he trial d urati o n  
•  A n y e ve nts t hat u nacce pt a bl y e n da n ger t he safet y of t he s u bject  
If a s u bject is l ost t o f oll o w-u p, e ver y p ossi ble eff ort m ust be ma de b y trial ce ntre pers o n nel t o c o ntact 
t he s u bject a n d deter mi n e t he r eas o n f or disc o nti n uati o n. T he meas ures t a ke n t o f oll o w -u p m ust b e 
d oc u me nte d.  If  a  s u bject disc o nti n ues  bef ore  c o m pleti o n  of  trial  pr oce d ures,  t he  reas o n  f or  
disc o nti n uati o n m ust be d oc u me nte d i n t he case re p ort f or m ( C R F ) a n d s o urce d oc u m e nts. 
S u bjects  w h o disc o nti n ue Ma ve ncla d
®  at a n y ti me d uri n g t he trial will c o nti n ue t o partici pate i n t he 
sc he d ule d  visits  f or  ass ess me nts  u ntil  his/ her  pla n ne d  trial c o m pleti o n.  I n  t he  e ve nt  of  earl y  
disc o nti n uati o n fr o m t he trial, t he s u bject s h o ul d ret ur n f or t he Earl y Ter mi nati o n visit f or fi nal 
assess me nt.  
Wit h dra w n s u bjects will n ot be re place d. 
5. 5. 2  
Wit h dr a w al fr o m t he Tri al  
 
S u bjects  ma y wit h dra w fr o m t he trial at a n y ti me wit h o ut gi vi n g a reas o n. Wit h dra wal of c o nse nt 
will be c o nsi dere d wit h dra wal fr o m t he trial. T h e I n v esti gat or s h o ul d ma ke e ver y atte m pt t o clarif y 
t he le vel of wit h dr a wal: e. g., w het her or n ot dat a c ollecte d ca n b e e v al uate d, ba n ke d sa m ples ca n still 
be ret ai ne d a n d e val u ate d, if t he s u bject ca n still be c o ntacte d b y p h o n e f or c hec ki n g his/ her stat us 
(e. g., ali ve or n ot), or t o ret ur n f or sc h e d ule d visits. I n cas e of wit h dra w al fr o m t he trial f or reas o ns 
ot her t ha n c o nse nt wit h dra wal, t he assess me nts sc he d ule d f or t he E arl y T er mi nati o n visit s h o ul d be 
perf or me d i m me diatel y. I n a n y case, t he a p pr o pri ate eC R F secti o n m ust be c o m plete d. S u bject  will 
be as ke d t o c o nfir m t hat a n y s a m ples c ollect e d b ut n ot yet a n al yze d ca n be utilize d.  
S u bjects  wit h dra w n fr o m trial me dicati o n will c o nti n ue t he sc h e d ule d assess me nts u ntil his/ her 
pla n ne d trial c o m pleti o n.  T hese  s u bjects will  be  ma na ge d  bas e d  o n  t he  I n v esti gat or’s  cli nical  
j u d g me nt a n d per l ocal g ui deli nes, a n d a n y ne w me dicati o n prescri be d i n s uc h a peri o d will be 
rec or d e d. I n a n y cas e, t he a p pr o priate eC R F secti o n m ust be c o m plete d.  
T he I n v esti gat or ma y wit h dra w a s u bject at a n y ti me if t his is c o nsi dere d t o be i n t he s u bject’s best 
i nterest. 
 
Pre m at ure Ter mi n ati o n of t he Tri al  
T he  cli nical trial ma y be t er mi nate d pre mat urel y or s us pe n de d at t he re q uest of Healt h A ut h orities or  
if ne w s afet y or effi cac y i nf or mati o n lea ds t o a n u nfa v ora bl e ris k  b e nefit j u d g me nt f or t h e I M P. Th e 
S p o ns or ma y disc o nti n ue t he trial if it bec o mes  u nj ustifia ble f or me dical or et hical reas o ns , f or po or 
e nr oll me nt, or beca us e of  disc o nti n uati o n of cli nical de vel o p me nt of t he I M P or w it h dra wal of t he 
I M P or c o m parat or fr o m t he mar ket f or s afet y reas o ns. 
Healt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees (I E Cs)/I nstit uti o nal Re vie w B o ar ds (I R Bs)  
will be i nf or me d  a b o ut t h e disc o nti n uati o n of t he trial i n acc or da nce wit h a p plica ble re g ulati o ns. 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
 
Defi niti o n of E n d of Tri al  
T he e n d of t he tri al is defi ne d as t he last s u bject ’s E n d of T rial visit. 
 
Pl a n ne d E xte nsi o n S t u dies 
U p o n c o m pleti o n of trial, s u bjects will be offere d t he o p p ort u nit y of e nr olli n g i nt o a n E xte nsi o n trial 
t hat ma y be pla n ne d b y t he S p o ns or, f or a f urt h er 2 years (u ntil 4 years pl us t he all o wa n ce wi n d o ws 
fr o m first treat me nt year c o urse). A se p arate pr ot o c ol will be f oll o we d f or t he E xte nsi o n trial. F or all 
s u bjects w h o f or a n y reas o n d o n ot e nter t he E xte nsi o n trial, all t heir data will be use d f or t he a nal ysis 
i n t he E xte nsi o n trial, gi ve n t hat c o nse nt is o btai ne d f or t hese s u bjects. 
6  
I n vesti g ati o n al Me dici n al Pr o d uct a n d Ot her Dr u gs Use d i n t he 
Tri al  
T he ter m “I n vesti gati o nal Me dici nal Pr o d uct” refers t o t he acti ve s u bsta nce cla dri bi ne bei n g teste d 
i n t his trial. 
I M P pr o visi o n t o t he site is a ut o mate d a n d is tri g gere d b y t he Site Acti vati o n i n i nteracti ve res p o ns e 
tec h n ol o g y (I R T). F oll o wi n g res u p plies are c o ntr olle d b y I R T al g orit h ms a n d are als o a ut o mate d. 
I M P dis pe nsati o n t o t he patie nts is d o ne t hr o u g h I R T w e b i nterface w he n Baseli ne a n d M o nt h 1 2 
visits are re gister e d i n t he s yste m.  
 
Descri pti o n of t he I n vesti g ati o n al Me dici n al Pr o d uct 
T he I M P is oral cla dri bi n e (I N N n a me) / Ma v e ncl a d ® 1 0 m g ta blets (tra de n a me).  
Ma ve ncla d
®  1 0 m g ta bl ets are w hite, r o u n d, bi c o n ve x ta blets of 8. 5 m m dia meter, e n gra v e d wit h ' C' 
o n o ne si de a n d ' 1 0' o n t h e ot her si de. 
T he  ta blets  c o ntai n  t he  f oll o wi n g  e x ci pie nts:  
 
 
D os a ge a n d A d mi nistr ati o n  
6. 2. 1  
P os ol o g y  
T he  r ec o m me n de d  c u m ulati ve  d ose  of  Ma v e n cla d
®  is  3. 5 m g/ k g  b o d y  w ei g ht  o ver  2  years, 
a d mi nistere d  as  1  treat me nt  c o urse  of  1. 7 5 m g/ k g  per  year.  Eac h  treat me nt  c o urse  c o nsists  of  
2 treat me nt wee ks, o ne at t he be gi n ni n g of t he first m o nt h a n d o ne at t he be gi n ni n g of t he sec o n d 
m o nt h of t he r es pecti ve treat me nt year. Eac h treat me nt wee k c o nsists of 4 or 5  d a ys o n w hic h a 
s u bject recei ves 1 0 m g or 2 0  m g ( o ne or t w o ta blets) as a si n gle dail y d ose, de pe n di n g o n b o d y 
wei g ht.  F oll o wi n g  c o m pleti o n  of  t he  2  treat me nt  c o urses,  n o  f urt h er  Ma ve ncla d
®  treat me nt  is  
re q uire d i n years 3 a n d 4. 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
6. 2. 2  
Distri b uti o n of D ose  
T he distri b uti o n of t he t otal d ose o ver t he 2  year s of treat me nt is pr o vi de d i n Ta ble 1 .  For s o me 
wei g ht ra n ges t he n u m b er of ta blets ma y var y fr o m o ne treat me nt wee k t o t he ne xt. Use of oral 
Ma ve ncla d
®  i n s u bjects wei g hi n g less t ha n 4 0 k g has n ot bee n i n vesti gate d. 
T a ble 1: D ose of M a ve ncl a d ®  per tre at me nt w ee k b y s u bject w ei g ht i n e ac h tre at me nt y e ar  
Wei g ht ra n ge  
D ose i n m g ( n u m ber of 1 0 m g ta blets) per treat me nt wee k  
k g 
Treat me nt wee k  1 
T reat me nt wee k 2  
4 0 t o < 5 0 
4 0 m g ( 4  ta blets) 
4 0 m g ( 4  ta blets) 
5 0 t o < 6 0 
5 0 m g ( 5  ta blets) 
5 0 m g ( 5  ta blets) 
6 0 t o < 7 0 
6 0 m g ( 6  ta blets) 
6 0 m g ( 6  ta blets) 
7 0 t o < 8 0 
7 0 m g ( 7  ta blets) 
7 0 m g ( 7  ta blets) 
8 0 t o < 9 0  
8 0  m g ( 8  ta blets) 
7 0  m g ( 7  ta blets) 
9 0 t o < 1 0 0 
9 0 m g ( 9  ta blets) 
8 0 m g ( 8  ta blets) 
1 0 0 t o < 1 1 0  
1 0 0 m g ( 1 0  ta blets) 
9 0 m g ( 9  ta blets) 
1 1 0 a n d a b o ve  
1 0 0 m g ( 1 0  ta blets) 
1 0 0 m g ( 1 0  ta blets) 
 
Ta ble 2  s h o ws h o w t he t otal n u m ber of ta blets per treat me nt wee k is distri b ute d o ver t he i n di vi d ual 
da ys. It is rec o m me n de d t hat t he dail y Ma v e ncla d
®  d oses i n eac h treat me nt w ee k be ta ke n at i nter val s 
of 2 4  h o urs at a p pr o xi matel y t h e sa me ti me eac h da y. If a dail y d ose c o nsists of t w o ta blets, b ot h 
ta blets are ta k e n t o get her as a si n gl e d ose. 
 
T a ble 2 : M a ve ncl a d ® 1 0 m g t a blets per w ee k d a y  
T otal n u m ber of ta blets  
per wee k  
Da y 1 
Da y 2  
Da y 3  
Da y 4  
Da y 5  
4  
1  
1  
1  
1  
0  
5  
1  
1  
1  
1  
1  
6  
2  
1  
1  
1  
1  
7  
2  
2  
1  
1  
1  
8  
2  
2  
2  
1  
1  
9  
2  
2  
2  
2  
1  
1 0  
2  
2  
2  
2  
2  
A misse d d ose m ust be ta ke n as s o o n as re me m bere d o n t he sa me da y acc or di n g t o t he treat me nt 
sc he d ule. 
A misse d d ose m ust n ot be ta ke n t o get her wit h t h e ne xt sc he d ule d d ose o n t he f oll o wi n g d a y. I n t he 
case of a misse d d ose, t he s u bject m ust ta ke t he misse d d ose o n t he f oll o wi n g d a y, a n d e xte n d t he 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
n u m ber of d a ys i n t hat tr eat me nt wee k. If t w o c o nsec uti ve d oses are misse d, t he s a me r ule a p plies, 
a n d t he n u m ber of d a ys i n t he treat me nt wee k is e xte n de d b y t w o da ys.  
 
 
Assi g n me nt t o Tre at me nt Gr o u ps  
N ot a p plica ble.  
 
N o n -in vesti g ati o n al Me dici n al Pr o d ucts t o be Use d  
N ot a p plica ble. 
 
C o nc o mit a nt Me dic ati o ns a n d T her a pies  
All c o nc o mita nt me dicati o ns ta ke n b y t he s u bject d uri n g t he trial, fr o m t he date of si g nat ure of 
i nf or me d c o nse nt are t o be rec or d e d i n t he a p pr o priate secti o n of t he C R F, n oti n g t he na me, d ose, 
d urati o n a n d i n dicati o n of eac h dr u g. N o n dr u g i nter ve nti o ns a n d a n y c h a n ges t o a c o nc o mita nt 
me dicati o n or ot her i nter ve nti o n s h o ul d als o be rec or d e d i n t he C R F.  A n y me di cati o ns t hat are 
c o nsi dere d necessar y t o pr otect s u bject welfare a n d will n ot i nterfere wit h t he trial me dicati o n ma y 
be gi v e n at t he I n v esti gat or’s discreti o n. 
T h e treati n g p h ysicia n m ust c o nsi der t he f oll o wi n g c o n diti o ns wit h partic ular atte nti o n, s pecificall y 
c hec ki n g t he reas o ns f or t he a d mi nistrati o n of a c o nc o mita nt me dicati o n f or t he cases t h at f oll o w 
(see Secti o n 6. 5. 1 ). 
6. 5. 1  
Per mitte d Me dici nes  
6. 5. 1. 1  
Dise ase Rel ate d  
All c o nc o mita nt me dicati o n s 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, fati g ue 
or wea k n ess, i nc o or di nati o n, bla d der d ysf u ncti o n, s pasticit y, etc.).  
6. 5. 1. 2  
Me dic al Hist or y Rel ate d  
All c o nc o mita nt me dicati o n use d f or a me dical c o n diti o n alrea d y re p orte d i n t he s u bject's me dical 
hist or y (f or e x a m ple, a n y f or m of pai n, es peci all y l o w bac k pai n a n d h ea dac he, de pressi o n, etc.) or 
fa mil y hist or y ( pri mar y h ea dac he, i ns o m nia, etc.). 
6. 5. 1. 3  
Self -me dic ati o n  
As t his is a n o ut patie nt trial, s pecial care will be ta ke n t o q uesti o n s u bjects o n a n y self-me dicati o n 
a n d will be as ke d t o r es 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 h e c o n c o mita n t 
me dicati o ns i n a diar y. T he use of a n y her b al or nat ural pr o d uct, or ot her " h o me re me dies" is all o we d. 
H o we ver, t he use of t hes e pr o d ucts, a n d t he use of vita mi ns, n utriti o nal s u p ple me nts a n d all ot her 
c o nc o mita nt me dici nal pr o d ucts s h o ul d be als o n ote d i n a diar y. 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
6. 5. 1. 4  
Rel a pse m a n a ge me nt  
I n case of ne ur ol o gical e ve nts relate d t o M S , wit h rela pse criteria (Secti o n  7. 3. 3 ), treat me nt wit h 
eit her ac ute s h ort -ter m s yste mic c ortic oster oi ds or adre n o c ortic otr o pic h or m o ne ( A C T H ) or plas ma 
e x c ha n ge ca n b e a d mi nistere d 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 m e dical 
practice a n d i nter nati o nal g ui deli nes.  
T he i nitiati o n of Ma ve ncla d
®  f oll o wi n g ac ute ma na ge me nt of rela ps e will be at t he I n vesti gat or’s 
discreti o n. T he i nitiati o n of t he sec o n d treat me nt c o urse ca n start as s o o n as t he rela ps e treat me nt is 
fi nis he d or ca n b e p ost p o ne d at t he In vesti gat or’s discreti o n. 
6. 5. 2  
Pr o hi bite d  Me dici nes  
T he f oll o wi n g tr eat me nts are pr o hi bite d: 
•  Im m u n os u p pr essi ve
 or
 m yel os u p pressi ve
 t hera p y
 wit h,
 e. g.,
 met h otre x ate,
 
c ycl o p h os p ha mi de,  c ycl os p ori ne,  mit o x a ntr o ne  or  azat hi o pri ne,  or  c hr o nic  use  of  
c ortic oster oi ds beca use of a ris k of a d diti ve effects o n t he i m m u ne s yste m  
•  Ot her disease - m o dif yi n g me dici nal pr o d ucts 
•  S u bsta nces t hat aff ect t he hae mat ol o gical pr ofile (e. g. car b a maze pi ne)  
•  V acci n ati o n  wit h  li ve  or  atte n uate d  li ve  vacci n es  s h o ul d  be  a v oi d e d  d uri n g  a n d  after  
Ma ve ncla d
®  tr eat me nt as l o n g as t he s u bject's w hite bl o o d cell c o u nts are n ot wit hi n n or mal 
li mits 
F oll o w as per M a ve n cla d
®  S m P C . 
6. 5. 3  
Ot her I nter ve nti o ns 
N ot a p plica ble. 
6. 5. 4  
S peci al Prec a uti o ns  
As per S m P C, s pecial c o nsi derati o ns s h o ul d be ta ke n a hea d of t he use of p artic ular s u bsta n ces . 
6. 5. 4. 1  
S witc hi n g fr o m Ot her D M Ds 
F or t he s u bjects  s witc hi n g fr o m a n ot her D M D, t he m o de of acti o n a n d d urati o n of effect of t he 
c urre nt, or pre vi o us  D M D s h o ul d be c o nsi dere d pri or t o i nitiati o n of M a ve ncla d ® . I n s uc h cases, it 
is at t he In v esti gat or's dis creti o n t o d efi ne t he re q uire d ti me i nter val b et wee n c o m pleti n g t he pre vi o us 
treat me nt a n d i nitiati n g Ma ve ncla d®  treat me nt. T his decisi o n m ust be base d u p o n t he res pecti ve 
treat me nts’ E ur o pea n  Me dici nes  A ge nc y  S m P C *,  i n de pe n de ntl y  p u blis he d  g ui deli nes  (i.e.  
K o m pete nz netz M ulti ple S kler ose [K K N M S ]) a n d sta n dar ds of care 
* T he was h o ut peri o d/ ti me t o wait bef ore s witc hi n g fr o m o ne  D M D t o a n ot her, ca n be descri be d i n t he pr o d uct 
c haracteristics of t he res pecti ve dr u g .” 
 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
6. 5. 5  
M a n a ge me nt  of  S pecific  A d verse  E ve nts  or  A d verse  Dr u g  
Re acti o ns  
A nti - her pes pr o p h yl a xis will be pr o vi de d t o s u bjects wit h gra d e 4 l y m p h o pe nia. Sta n dar d a nti -
i nfecti o us treat me nt is all o we d i n case of t he occ urre nce of i nfecti o n. 
 
P ac k a gi n g  a n d  L a beli n g  of  t he  I n vesti g ati o n al  Me dici n al  
Pr o d uct  
Ma ve ncla d
®  will be s u p plie d i n 
 p ac k a ges, c o ntai ni n g o n e, f o ur a n d si x ta blets (t o be c o nfir me d 
b y si m ulati o n a n d will f or eit her 
 
All I M Ps will be pac ka ge d a n d la bele d i n acc or d a n ce wit h all a p plica ble re g ulat or y re q uire m e nts a n d 
G o o d Ma n ufact uri n g Practice G ui deli nes. 
 
Pre p ar ati o n,  H a n dli n g , a n d  St or a ge  of  t he  I n vesti g ati o n al  
Me dici n al Pr o d uct  
As t he ta bl ets ar e u n c oate d, t he y m ust be s wall o we d i m me diatel y o n ce re m o ve d fr o m t he 
 a n d 
n ot be left e x p ose d o n s urfaces or ha n dl e d f or a n y p eri o d of ti me greater t ha n t hat re q uire d f or d osi n g. 
If a ta blet is left o n a s urface or if brea ks a n d fra g me nts fall fr o m t he blister, t he area m ust be 
t h or o u g hl y was h e d. Ha n ds m ust be dr y w he n ha n dli n g t he ta blets a n d was h e d t h or o u g hl y after war ds.  
St ore i n t he ori gi nal p ac k a ge i n or der t o pr otect fr o m m oist ure. 
O n site, all I M P s h o ul d be st ore d i n a sec ure l o cati o n, i n a te m perat ure -c o ntr olle d e n vir o n me nt, 
prefera bl y wit h a te m per at ure l o g mai ntai ne d dail y, a n d ma y be dis pe nse d o nl y b y t he I n vesti gat or 
or b y a me m ber of staff s p ecificall y a ut h orize d b y t he I n v esti gat or, or b y a p har macist, as a p pr o priate. 
A n y de viati o ns fr o m t he rec o m me n de d st ora ge c o n diti o ns s h o ul d be i m me diatel y re p orte d t o t he 
S p o ns or a n d us e of t he I M P i nterr u pte d u ntil t he S p o ns or has gi ve n a ut h orizati o n f or its c o nti n ue d 
use.  
 
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y 
T he  I n vesti gat or  ( or  desi g nee)  is  res p o nsi ble  f or  e ns uri n g  I M P  acc o u nta bilit y,  i ncl u di n g 
rec o nciliati o n of dr u gs a n d mai nte na nce of rec or ds. 
•  U p o n recei pt of I M P, t he res p o nsi ble pers o n will c hec k f or acc urate deli ver y a n d ac k n o wl e d ge 
recei pt b y si g ni n g or i nitiali n g a n d dati n g t he a p pr o priate d oc u me ntati o n a n d ret ur ni n g it t o t he 
l ocati o n s pecifie d. A c o p y will be arc hi ve d f or t he I n v esti gat or Site File.  
•  I M P dis pe nsi n g will be rec or de d o n t he a p pr o priate dr u g acc o u nta bilit y f or ms s o t hat acc urate 
rec or ds will be a vaila ble f or verifi cati o n at eac h m o nit ori n g visit. 
•  Trial site I M P acc o u nta bilit y rec or ds will i ncl u de t he f oll o wi n g:  
o  C o nfir mati o n of I M P r ecei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge. 
o  T he i n ve nt or y of I M P pr o vi de d f or t he cli nical trial a n d pre p are d at t he site.  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
o  T he use of eac h d os e b y eac h s u bject.  
o  T he dis p ositi o n (i ncl u di n g r et ur n, if a p plica ble) of a n y u n us e d I M P. 
o  Dates, q u a ntities, batc h n u m bers, b o x n u m bers, e x pir y dat es, a n d t he i n di vi d ual s u bject trial 
n u m bers. 
T he  I n v esti gat or  site  s h o ul d  mai ntai n  rec or ds,  w hic h  a de q uatel y  d oc u me nt  t hat  s u bjects  were  
pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all I M Ps pr o vi de d were f ull y rec o ncile d. 
U n use d I M P m ust n ot b e discar de d or us e d f or a n y p ur p ose ot h er t h a n t he prese nt trial. N o I M P t h at 
is dis pe nse d t o a s u bject ma y b e re dis pe ns e d t o a differe nt s u bject.  
A Trial M o nit or will peri o dicall y c ollect t he I M P acc o u nta bilit y f or ms a n d will c hec k all ret ur ns 
( b ot h u n use d a n d use d c o ntai ners) bef ore arra n gi n g f or t heir ret ur n t o t he S p o ns or or desi g nee or 
a ut h orizi n g t heir destr u cti o n b y t he tri al site.  I n t he e ve nt t he site is u n a ble t o destr o y u n use d a n d 
use d c o ntai ners, it is rec o m me n de d l ocal or re gi o nal destr ucti o n is or ga nize d b y t he C R O. U n use d 
a n d use d c o nt ai ners m ust o nl y be ret ur ne d t o t he s p o ns or C o ntract M a n ufact uri n g Or ga nizati o n 
(C M O ) de p ot, if re quire d b y t he l ocal la w. 
 
Assess me nt of I n vesti g ati o n al Me dici n al Pr o d uct C o m pli a nce  
S u bjects s h o ul d be i nstr ucte d t o bri n g wit h t he m t o eac h visit; b ot h o p e ne d a n d u n o p e ne d I M P 
pac ka ges, i n or der t o all o w t he assess me nt of c o m plia nce wit h trial treat me nt. IM P a d mi nistrati o n 
m ust be rec or d e d i n t he e C R F. 
S u bjects  will  be  pr o vi d e d  wit h  s u bject  diar y  f or ms  t o  rec or d  t h e  d os e  a n d  ti me  of  treat me nt  
a d mi nistrati o n.  S u bject  diar y  e ntries  s h o ul d  be  c ollecte d  at  eac h  trial visit  a n d  c hec ke d  f or  
c o m plete ness a n d acc ur ac y. S u bjects s h o ul d be as ke d t o e x plai n/c orrect a n y discre p a ncies i n t heir 
diar y f or ms (see A p pe n di x 1 2: Pers o nal Diar y ) 
 
Bli n di n g  
N ot a p plica ble.  
 
E mer ge nc y U n bli n di n g  
N ot a p plica ble.  
 
Tre at me nt of O ver d ose  
A n o ver d ose is defi n e d as a n y d os e greater t ha n t he hi g h est dail y d ose i ncl u de d i n a cli nical trial 
pr ot oc ol or pl a n ne d f or a n i n di vi d ual s u bject e nr olle d i n t he tri al. T he deter mi nati o n of a n o v er d os e 
will be left t o t he dis creti o n of t he I n v esti gat or, ba se d o n t he q ua ntit y of o v er d ose, e mer ge nce of a n y 
cli nical si g ns a n d s y m pt o ms s u g gesti ve of a t o xic a d mi nistrati o n, as w ell as his/ her o w n cli nical 
j u d g me nt as it a p plies t o eac h i n di vi d ual cas e. 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
T here is n o k n o w n s pecific a nti d ote t o a n o ver d ose of t he I M P. Treat me nt c o nsists of caref ul  
o bser vati o n a n d i nitiati o n of a p pr o priate s u p p orti ve meas ures. Disc o nti n uati o n of t he I M P ma y n ee d 
t o  be  c o nsi dere d.  Beca use  of  t he  ra pi d  a n d  e xte nsi ve  i ntracell ular  a n d  tiss ue  distri b uti o n,  
he m o dial ysis is u nli kel y t o eli mi nate t he I M P t o a si g nifica nt e xte nt.  
E ve n if it d oes n ot meet ot her criteria f or a n S A E, a n y o ver d ose m ust b e rec or de d i n t h e I M P s ecti o n 
of t he e C R F a n d re p orte d t o Dr u g Safet y i n a n e x pe dite d ma n ner b y c o m pleti n g t he e C R F S A E pa ge , 
a n d f oll o wi n g t he pr oce d ure i n Secti o n  7. 4 . 
 
Me dic al C are of S u bjects after E n d of Tri al  
T he S p o ns or will n ot pr o vi de a n y a d diti o nal care t o s u bjects after t he y lea ve t he trial beca use s uc h 
care s h o ul d n ot diff er fr o m w hat is n or mall y e x pecte d f or s u bjects wit h R M S. 
7  
Tri al Pr oce d ures a n d Assess me nts  
A sc he d ule of t he tests a n d e val uati o ns t o be c o n d ucte d d uri n g t he c o urse of t his trial is l ocate d i n 
A p pe n di x 1 : Sc he d ule of Assess me nts . 
Patie nt  re p orte d o utc o me ( P R O) q uesti o n naires m ust be perf or me d pri or t o cli nical assess me nts at 
all visits a n d pri or t o  Ma ve ncla d
® a d mi nistrati o n f or b ot h  treat me nt  c o urses . T he  or der of  t h e 
assess me nts is as bel o w :  
1.  M S Q o L - 5 4  
2.  T S Q M v 1. 4  
P R Os will be c o m plete d o n a ha n d hel d ta bl et de vice, o n site at t he cli nic. P R Os will be mi grate d t o 
a n a p p base d s ol uti o n w hic h all o ws te xt a n d scale q uesti o ns t o be c o nfi g ure d t o mai ntai n t he val i dit y 
of t he assess me nt. T he ta blet de vice use d i n t his trial will be t he A p ple i P A D Air 2 . Partici pa nts ca n 
as k f or assista nce i n o perati n g t he de vice a n d accessi n g t he q u esti o n naires. Data c ollecte d t hr o u g h 
t he e P R O q uesti o n naires will be st ore d i n t he trial electr o nic d ata ca pt ure ( E D C ). 
Res p o nsi ble  s ite staff will be trai ne d o n M S Q o L-5 4,  
, T S Q M   v 1. 4, 
 
 bef ore first test i m ple me ntati o n t o s u bjects. 
Trai ni n g m o d ules w o ul d be usef ul f or t he sites a b o ut t hese a n d ot her q u esti o n naires f or sa ke of l o w 
i nterrater v aria bilit y. W h e ne ver p ossi ble, t he sa me assess or s h o ul d ma na ge t he sa me patie nt f or t hese 
scales. 
I n t his pr ot oc ol, s y m pt o ms a n d si g ns of rel a pse or w ors e ni n g of M S si n ce t he pre vi o us visit will 
us uall y b e c a pt ure d i n t h e c o nte xt of t he efficac y assess me nt, a n d rec or de 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 b l y relate d t o t he I M P 
(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). 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
 
Sc he d ule of Assess me nts  
7. 1. 1  
Scree n i n g (M o nt h - 1 t o B aseli ne) 
A c o m plete Scree ni n g  E val uati o n is t o be perf or me d u p t o -1 m o nt h  bef ore  Baseli ne . Scree ni n g  will 
i ncl u de t he f oll o wi n g ass ess me nts: 
•  Si g ni n g I C F  
•  De m o gra p hic d ata, i ncl u di n g date of birt h, ge n der a n d race 
•  Me dical hist or y, i n cl u di n g c o n c o mita nt me dicati o ns a n d c o nc o mita nt pr oce d ures 
•  Disease hist or y, i n cl u di n g classificati o n of diseas e, n u m ber of rel a pses wit hi n t he past 1 2  m o nt hs, 
treat me nt hist or y, di a g n osis date 
•  Bl o o d sa m ples f or s er ol o g y a n d s afet y a nal ysis at l ocal la b orat or y (see Secti o n  7. 4. 3 ) * 
•  A l y m p h oc yte c o u nt * * * at l ocal la b orat or y facilities  
•  P h ysical e x a mi nati o n, i ncl u di n g vital si g ns ( bl o o d press ure, h eart rate, te m perat ure) 
•  M RI ass ess me nt (see Secti o n  7. 3. 5 ) 
•  
 
•  T he c o ntr ace pti ve met h o d use d will be rec or de d, or, alter nati vel y, if a p plica ble, t he a ge at  
me n o pa use will be ca pt ure d  
•  Uri ne  or ser u m p re g n a nc y test (f or W O C B P  o nl y) at l ocal la b orat or y* * 
•  Re vie w of i ncl usi o n/e x cl usi o n criteria  
* If t he l oc al l a b or at or y bl o o d test f or ser ol o g y a n d s afet y a n al ysis me nti o ne d at Scree ni n g visit 
is c o n d ucte d wit hi n 1 0 d a ys of t he visit, n o bl o o d s a m ples nee d t o be re pe ate d at Scree ni n g visit . 
* * A d diti o n al ser u m or uri ne pre g n a nc y tests will be per mitte d t hr o u g h o ut t he tri al peri o d as 
re q uire d b y c o u ntr y s pecific re g ul ati o ns.  
* * * L y m p h oc yte c o u nt m ust be n or m al bef ore i niti ati n g M a ve ncl a d i n Ye ar 1. 
Assi g n me nt of S u bject I D N u m ber: 
O nce t he s u bject has pr o vi de d i nf or me d c o nse nt, t he I R T S yste m will be n otifie d w hic h will ge n erat e 
a S u bject I D N u m ber i n t he f oll o wi n g f or mat: 
( 1 0 Di git St u d y N u m ber) ( 3 Di git Site N u m ber) ( 4 Di git S u bject C o u nt at Site starti n g fr o m 0 0 0 1). 
F or e x a m ple, a t site 1 0 1, t he 5t h patie nt scree ne d  i n st u d y 7 0 0 5 6 8 0 0 2 1. 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
St u d y N o.  
Site N o.  
S u bject N o.  
7 0 0 5 6 8 0 0 2 1  
1 0 1  
7 0 0 5 6 8 0 0 2 1 1 0 1 0 0 0 5  
O nce all pr o ce d ur es a n d assess me nts f or t his visit are c o m plete d, a n a p p oi nt me nt f or t he Baseli ne  
visit ( wit hi n 1 m o nt h fr o m Scree ni n g) will be ma de a n d t he s u bject will be disc har ge d.  
I n cert ai n cases, pr ol o n gati o n of scree ni n g peri o d is all o we d. E x a m ples of s uc h cases are b el o w:  
•  Re q uire me nt of a ti me i nter val bet w ee n c o m pleti n g t he pre vi o us treat me nt a n d i nitiati n g 
Ma ve ncla d
®  treat me nt. (s ee Secti o n  6. 5. 4. 1) 
•  Re q uire me nt of a 4 t o 6 wee k pa us e aft er t he vari cella vacci nati o n  
Eac h case of s cree ni n g peri o d e xte nsi o n m ust recei ve i n a d v a nce, a writte n a p pr o val fr o m t he 
Me dical M o nit or.  
 
7. 1. 2  
Rescree ni n g  
S u bjects w h o d o n ot m eet t he i n cl usi o n/e x cl usi o n criteri a wit hi n t he s p ecifie d ti me li mits (i.e., 
1 m o nt h ) a n d scree n f ail ma y u n der g o re-scree ni n g o nce if a p pr o ve d b y t he Me dical M o nit or. If t he 
s u bject is r e-scr ee n e d, t h e s u bject will recei ve a n e w s u bject i de ntificati o n n u m ber a n d will be as ke d 
t o si g n a ne w I C F. 
S u bjects  wit h test res ults t hat d o n ot meet t he i ncl usi o n/ e x cl usi o n criteria ma y ha ve testi n g re p eate d 
o nce o nl y if t he res ults are t h o u g ht t o re pres e nt a la b orat or y err or or a re versi ble or cli nicall y 
i nsi g nifica nt i nter mitte nt c o n diti o n. If t esti n g is re peate d f or s uc h s u bjects, all scree ni n g tests will 
nee d t o  be re p eate d e x ce pt f or t he T B test, h u m a n i m m u n o deficie nc y vir us, a n d he p atitis testi n g, 
w hic h ma y b e r e peate d s e parat el y fr o m t he ot her t ests as necess ar y. T h e M e dical M o nit or m a y als o 
gi ve per missi o n f or tests t o be re peate d se parate fr o m ot her tests as  necessar y. If i ncl usi o n/e x cl usi o n 
criteria are n ot met base d o n t he res ults of t he re peate d tests, t he s u bject s h o ul d be c o nsi dere d a 
scree n fail ure a n d n ot be e nr olle d i n t he trial. Re p eat tests s h o ul d be c o n d ucte d a n d res ults a v aila ble 
pri or t o Bas eli ne . 
7. 1. 3  
Tre at me nt Peri o d  
T he treat me nt peri o d be gi ns wit h t he c o m pleti o n of all Baseli ne  assess me nts  a n d t he i nitiati o n of 
trial dr u g tr eat me nt o n Trial  Da y 1 a n d c o nti n ues t hr o u g h t o t he c o m pleti o n of t he treat me nt peri o d 
at t he M o nt h 2 4 Visit. 
7. 1. 4  
B aseli ne Visit ( Visit  1)  
 
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d at t his visit: 
•  Re vie w  of i ncl usi o n/e x cl usi o n criteria  
•  
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
•  
 
•  Uri ne or Ser u m pr e g na n c y test (f or fe m ale s u bjects of c hil d - beari n g p ot e ntial o nl y) 
•  Assess me nt of c o nc o mita nt me dicati o ns a n d c o nc o mita nt diseases  
•  A l y m p h oc yte c o u nt * * , at l ocal la b orat or y facilities 
•  H R Q o L  
o  M S Q o L - 5 4 
o  
 
o  
 
•  
 
•  
 
•  Wei g ht meas ur e me nt a n d assi g n me nt of I M P via I R T  
•  A d mi nistrati o n of trial me dicati o n  a n d pr o visi o n of trial me dicati o n i nta ke f or M o nt h 2 
* If t he ne ur ol o gic al e x a mi n ati o n is c o n d ucte d wit hi n 1 0 d a ys of B aseli ne  a n d t he s u bject 
re p orts n o c h a n ge i n st at us, n o ne ur ol o gic al e x a mi n ati o n nee d s t o be re pe ate d o n B aseli ne 
( Visit 1). 
* *If t he l y m p h oc yte c o u nt h as bee n  perf or me d wit hi n o ne m o nt h of B a seli ne, n o l y m p h oc yte 
c o u nt nee ds t o be re pe ate d o n B aseli ne.  
Eac h s u bject will b e gi ve n a di ar y f or m t o rec or d t he d ose, d ate a n d ti me of eac h a d mi nistrati o n of 
I M P, A Es, c o nc o mita nt me dicati o ns a n d pr o ce d ures (see A p p e n di x 1 2 : Pers o nal Diar y ). T he s u bject 
diar y e ntries m ust be re vie we d b y t he trial c o or di nat or(s)/ n urse(s) wit h t he s u bject t o clarif y a n y 
discre pa n cies a n d e ns ure pr o per 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 r ec or de d i n t he s u bject’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  s u bject  r ec or ds  o n  his/ her  s u bject  f or m  a n d  a n y  i nf or m ati 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 s u bjects. 
Si nce acc ur ate dr u g d osi n g is base d o n wei g ht, pri or t o dis pe nsi n g t h e treat me nt me dicati o n at D a y  1 
f or treat me nt c o urse Y ear 1 a n d Year 2, t he s u bject’s wei g ht s h o ul d be acc uratel y assess e d. 
O nce all pr oce d ures a n d assess me nts f or t his visit are c o m plete d, a n a p p oi nt me nt f or t he ne xt visit 
will be ma de a n d t he s u bject will be disc har ge d.  
7. 1. 5  
M o nt h 2 Visit 2 ( ± 7  d a ys)  
S u bject s will un der g o: 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
•  A l y m p h oc yte c o u nt as p er ma n dat or y m o nit ori n g at l ocal la b orat or y facilities * 
•  Re vie w of s u bject diar y 
•  Assess me nt of A Es, c o n c o mita nt me dicati o ns a n d c o nc o mita nt pr oce d ures 
* L y m p h oc yte c o u nt will be c hec k e d l ocall y aft er 2 m o nt hs of starti n g treat me nt. If t he l y m p h oc yt e 
c o u nt is bel o w 5 0 0 cells/ m m³, it s h o ul d be acti vel y m o nit ore d u ntil val ues i ncreas e a gai n . 
O nce all pr oce d ures a n d assess me nts f or t his visit are c o m plete d, a n a p p oi nt me nt f or t he ne xt visit 
will be ma de a n d t he s u bject will b e disc har ge d.  
7. 1. 6  
M o nt h 6 Visit 3 ( ± 7 d a ys)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d at t he M o nt h 6 visit  ( Visit 3): 
•  A l y m p h oc yte c o u nt as p er ma n dat or y m o nit ori n g at l ocal la b orat or y facilities *  
•  Re vie w of s u bject diar y 
•  Treat me nt Satisfacti o n ( T S Q M v 1. 4) 
•  
 
•  Assess me nt of A Es, c o n c o mita nt me dicati o ns a n d c o nc o mita nt pr oce d ures 
* L y m p h oc yte c o u nt will be c hec k e d l ocall y aft er 6 m o nt hs of starti n g treat me nt. If t he l y m p h oc yt e 
c o u nt is bel o w 5 0 0 cells/ m m³, it s h o ul d be acti vel y m o nit ore d u ntil val ues i ncreas e a gai n . 
O nce all pr oce d ures a n d assess me nts f or t his visit are c o m plete d, a n a p p oi nt me nt f or t he ne xt visit 
will be ma de a n d t he s u bject will be disc har ge d.  
7. 1. 7  
M o nt h 1 2 Vi sit 4 ( ± 7 d a ys) 
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d at t he M o nt h 1 2 visit  ( Visit 4) * * *: 
•  Bl o o d sa m ples f or s er ol o g y a n d s afet y a nal ysis at l ocal la b orat or y (see Secti o n  7. 4. 3 ) 
•  A l y m p h oc yte c o u nt at l o cal la b orat or y facilities * 
•  Re vie w of s u bject diar y 
•  Assess me nt of A Es, c o n c o mita nt me dicati o ns a n d c o nc o mita nt pr oce d ures 
•  P h ysical e x a mi nati o n i ncl u di n g vital si g ns ( bl o o d press ure, h eart rate, te m p erat ure) 
•  
 
•  
 
•  H R Q o L  
o  M S Q o L - 5 4 
o  
 
o  
 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
•  Treat me nt Satisfacti o n ( T S Q M  v 1. 4) 
•  
 
•  Uri ne or Ser u m P re g n a nc y test (f or fe m ale s u bjects of c hil d- beari n g p ot e ntial o nl y) 
•  Wei g ht meas ur e me nt a n d assi g n me nt of I M P via I R T 
•  A d mi nistrati o n of trial me dicati o n a n d pr o visi o n of trial me dicati o n i nta ke f or M o nt h 1 3 
* L y m p h oc yte c o u nt s h o ul d be at least 8 0 0 cells/ m m³ bef ore i nitiati n g Ma ve ncla d
®  i n Year 2. If 
necessar y, t he treat me nt c o urse i n Year 2 ca n be d ela ye d f or u p t o 6 m o nt hs t o all o w f or rec o ver y of 
l y m p h oc ytes. If t his rec o ver y t a kes m ore t ha n 6 m o nt hs, t he s u bject s h o ul d n ot recei ve Ma ve n cla d
®  
a n y m or e.  
F or p atie nts wit h l y m p h oc yt e c o u nt bel o w 8 0 0  cells/ m m³, l y m p h o c yt es s h o ul d be m o nit ore d a n d 
d oc u me nte d u n der u ns c h e d ule d visits u ntil t he c o u nt is a b o ve 8 0 0  cells/ m m³. M o nt h  1 2 visit is s plit 
i n t his case i nt o t w o parts ( M o nt h 1 2 wit h l y m p h o c yt e c o u nt, all efficac y p ara meters pl us vital si g ns 
a n d p h ysi cal  e x a mi nati o n.  M o nt h  1 2B - after  rec o ver y  of  l y m p h oc ytes  - i ncl u des  t he  safet y  
para meters ser ol o g y, T B C testi n g a n d pre g na nc y test pl us wei g ht a n d d o c u me ntati o n of treat me nt 
a d mi nistrati o n). F or pati e nts wit h l y m p h o c yte c o u nt a b o ve 8 0 0 cells/ m m³ date of M o nt h 1 2 a n d 
M o nt h 1 2 B is i de ntical. 
O nce all pr oce d ures a n d assess me nts f or t his visit are c o m plete d, a n a p p oi nt me nt f or t he ne xt visit 
will be ma de a n d t he s u bject will be disc har ge d.  
* * A ll assess me nts of Visit 4 will ta ke place bef ore t he I M P a d mi nistrati o n 
* * * A n all o wa nce wi n d o w of 0 -3 m o nt hs will ta k e place i n case of del a y i n l y m p h oc yte rec o ver y t o 
t he le vels me nti o ne d i n Secti o n  5. 4. 1  
7. 1. 8  
M o nt h 1 4 Visit 5 ( ± 7 d a ys)  
S u bject s will u n der g o * *: 
•  A l y m p h oc yte c o u nt as p er ma n dat or y m o nit ori n g, at l ocal la b orat or y facilities  * 
•  Re vie w of s u bject diar y 
•  A ssess me nt of A Es, c o n c o mita nt me dicati o ns a n d c o nc o mita nt pr oce d ures 
* L y m p h oc yte c o u nt will be c hec k e d l ocall y after 2 m o nt hs of starti n g t he 2n d c o urse treat me nt. If t he 
l y m p h oc yte c o u nt is bel o w 5 0 0 cells/ m m³, it s h o ul d be acti vel y m o nit ore d u ntil val ues i ncrease a gai n . 
* * A n all o wa n ce wi n d o w of 0 -3 m o nt hs will ta ke place i n cas e of dela y i n l y m p h oc yte rec o ver y t o 
t he le vels me nti o ne d i n Secti o n  5. 4. 1. 
7. 1. 9  
M o nt h 1 8 Visit 6 ( ± 7 d a ys)  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d at t he M o nt h 1 8 visit ( V isit 6) * *: 
•  A l y m p h oc yte c o u nt as p er ma n dat or y m o nit ori n g, at l ocal la b orat or y facilities  * 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
•  Re vie w of s u bject diar y 
•  
 
•  Assess me nt of A Es, c o n c o mita nt me dicati o ns a n d c o nc o mita nt pr oce d ures 
* L y m p h oc yte c o u nt will be c hec k e d l ocall y after 6 m o nt hs of starti n g t he 2n d c o urse treat me nt. If 
t he l y m p h o c yte c o u nt is bel o w 5 0 0 cells/ m m³, it s h o ul d be acti vel y m o nit ore d u ntil val ues i ncrease 
a gai n. 
* * A n all o wa nce wi n d o w of 0 -3 m o nt hs will ta ke place i n case of d ela y i n l y m p h oc yte rec o v er y t o 
t he le vels me nti o ne d i n Secti o n  5. 4. 1. 
7. 1. 1 0  
Fi n al Visit/ E arl y T er mi n ati o n/ M o nt h 2 4 Visit 7  (± 7 d a ys)  
T o c o m plete t he trial, t he s u bject s h o ul d ret ur n f or a fi nal e val uati o n at t he e n d of M o nt h 2 4* * . I n 
t he  e ve nt  of  earl y  disc o nti n uati o n  fr o m  t he  trial,  t he  s u bject  s h o ul d  ret ur n  f or  t he  M o nt h 2 4 
pr oce d ur es o utli ne d bel o w. T he reas o n f or earl y disc o nti n uati o n s h o ul d be acc uratel y assess e d a n d 
e ntere d i nt o t he e C R F.  
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d at t he e n d of M o nt h 2 4 visit: 
•  L y m p h oc yte c o u nt, at l ocal la b orat or y facilities  * 
•  Re vie w of s u bject diar y 
•  P h ysical e x a mi nati o n i ncl u di n g vital si g ns (i ncl u di n g bl o o d press ure, heart rate,  te m perat ure) 
•  M RI  sca n (see Secti o n  7. 3. 5) 
•  
 
•  
 
•  H R Q o L  
o  M S Q o L - 5 4 
o  
 
o  
 
•  Treat me nt Satisfacti o n ( T S Q M  v 1. 4) 
•  
 
•  
 
•  Assess me nt of A Es, c o n c o mita nt me dicati o ns a n d c o nc o mita nt pr oce d ures 
* L y m p h oc yte  c o u nt  s h o ul d  be  at  least  8 0 0  cells/ m m³.  If  t he  l y m p h oc yt e  c o u nt  is  bel o w  
5 0 0 cells/ m m³, it s h o ul d be acti vel y m o nit ore d u ntil val ues i ncrease a gai n. 
* * A n all o wa n ce wi n d o w of 0 -3 m o nt hs will ta ke place i n cas e of dela y i n l y m p h oc yte rec o ver y t o 
t he le vels me nti o ne d i n Secti o n  5. 4. 1. 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
7. 1. 1 1  
U nsc he d ule d Visits  
A s u bject ma y ret ur n f or a n u ns c he d ule d visit at t he discreti o n of t he I n vesti gat or t o u n d er g o 
a d diti o nal  safet y  e val uati o ns  (i.e.  la b orat or y  retesti n g,  A E  assess me nts),  or  f or ne ur ol o gical 
e val uati o ns f oll o wi n g a r ela pse. T he d ata fr o m u nsc he d ule d visits will be c ollecte d i n t he e C R F.  
 
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics  
At pre -Baseli ne  visit , t he f oll o wi n g de m o gra p hic data will be c ollecte d: date of birt h, se x ( ge n der), 
race, a n d et h nicit y.  F ull  details  of  t he  v ari o us  assess me nts  are  d etaile d  i n  t he S c he d ul e  of  
A ssess me nts i n Secti o n  7. 1 . 
 
Effic ac y Assess me nts  
Ne ur ol o gical  ass ess me nts  
 a n d   
 s h o ul d  be  d o ne  b y  t h e 
I n v esti gat or. It is n ot nee de d t o ha ve se p arat e rater f or ne ur ol o gical assess m e nts. 
Res p o nsi ble  Site  staff  will  be  trai ne d  o n  M S Q o L -5 4,   
,  T S Q M  v 1. 4,  
 
 bef ore first test i m ple me ntati o n t o s u bject.  
7. 3. 1  
H R Q o L 
7. 3. 1. 1  
M S Q o L -5 4  
T he M S Q o L -5 4 q uesti o n naire s h o ul d be c o m plete d at Baseli ne  a n d t he n at M o nt hs 1 2 , a n d 2 4. T he 
pri mar y e n d p oi nt will be deter mi ne d at M o nt h 2 4 of t his trial. 
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 n eric 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  was  d e vel o pe d  t o  meas ure  H R Q o L  i n  s u bjects  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. M S Q o L -5 4 q uesti o n naire (s ee  A p pe n di x 2: M S Q o L -
5 4 S C A L E ).  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
7. 3. 2  
Tre at me nt S atisf acti o n  
7. 3. 2. 1  
T S Q M v 1. 4  
T S Q M  v 1. 4 q uesti o n nair e (see A p p e n di x 8: T S Q M v 1. 4 Q uesti o n naire ) s h o ul d be c o m plet e d at 6, 
1 2 a n d 2 4 m o nt hs t o deter mi ne treat me nt satisfacti o n, w hic h is a sec o n dar y e n d p oi nt i n t his trial. T he 
T S Q M  v 1. 4 q uesti o n naire is a ge neric q uesti o n naire t o test tr eat me nt satisfacti o n wit h d o mai ns i n 
Effecti ve n ess, Si de  Effects, C o n ve nie nce a n d Gl o bal Satisfacti o n a n d has pre vi o usl y bee n use d i n 
M S s u bjects ( Ver mers c h et al., 2 0 1 4). 
T his q uesti o n naire will be i m ple me nte d i n all c o u ntries w here a l ocal la n g ua ge tra nslati o n fr o m t he 
a ut h or is a vaila ble, a n d t h e n i ncl u de d i n st u d y a n al ysis w here t he q u esti o n naire la n g ua ge is vali date d . 
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
7. 3. 5  
M RI  
All sca ns will be perf or me d acc or di n g t o a sta n dar d pr ot oc ol detaile d i n a s e parat e M RI sca n us er’s 
ma n ual.  
7. 3. 5. 1  
Sc he d ule  
T he M RI s ca ns will be assesse d at t he Pre -Baseli ne  Scree ni n g, a n d at M o nt h 2 4. 
7. 3. 5. 2  
M RI Sc a n ni n g Pr oce d ure  
T he M RI m eas ur es of w hite matter lesi o nal acti vit y (i.e. n e w/e nlar gi n g T 2 lesi o ns or G d -e n h a nci n g 
T 1 lesi o ns) a n d t h ose of 
) ha ve s h o w n t o be 
vali d s urr o gate e n d p oi nts f or cli nical o utc o mes. 
T he f oll o wi n g M RI p ara meters will be meas ure d f or all s u bjects f or eac h sca n o btai ne d d uri n g t he 
trial: 
•  Acti ve lesi o ns defi ne d as ne w T 1 ga d oli ni u m -e n ha nci n g, or ne w T 2 or e nlar gi n g T 2 lesi o ns 
( desi g n ate d “C U L M RI l esi o ns”) 
•  T 2 lesi o n v ol u me 
•  
 
All sca ns will be perf or me d acc or di n g t o a sta n dar d pr ot oc ol detaile d i n a se parate I ma ge Ac q uisiti o n 
G ui deli nes (I A G)   d o c u me nt. I n v esti gat or is res p o nsi ble t o e ns ure l ocal ra di ol o gic a nal ysis of t he 
Scree ni n g M RI as p er l o cal sta n dar ds of care t o assess patie nt eli gi bilit y as well as t o ma ke f urt her 
me dical decisi o ns rel ate d t o t his patie nt  (see als o Secti o n  7. 3. 5. 3. 1 ). Ce ntral i ma gi n g c ore la b will 
i n de pe n de ntl y p erf or m  t he  a nal ysis  of  all  M RI  sca ns  t o  meet  st u d y  e n d p oi nts  (see  als o  
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
Secti o n  7. 3. 5. 3. 2 ). As wit h ot her la b orat or y tests a n d cli nical meas ures, strict a d here n ce t o t he M RI 
sca n ni n g pr ot oc ol, a n d pr o m pt ha n dli n g of t he sca ns is esse ntial i n o btai ni n g a m ea ni n gf ul res ult. 
I n v esti gat or s h o ul d als o e ns ure t hat t he M RI sca n is l ocall y e val u ate d f or safet y t o r ule o ut P M L 
a n d/or a n y seri o us ce ntr al ner v o us s yste m diseas e (e. g., t u m or, str o ke etc). F or p atie nts s witc hi n g 
fro m diseas e m o dif yi n g treat me nts  t hat h a ve bee n pre vi o usl y li n ke d t o P M L, t h e safet y/eli gi bilit y 
assess me nt  will  be  a d diti o nall y  assess e d  b y  ce ntral  i ma gi n g  c ore  la b  re vie w  (see  als o  
Secti o n  7. 3. 5. 3. 3 ). 
Pri or t o s u bject assess me nt, eac h trial site will be as ke d t o se n d a ‘test’ or ‘ d u m m y-r u n’ sca n t o assess 
i ma ge q u alit y a n d s hi p m e nt pr oce d ures, t o e val u ate t he accessi bilit y of t he electr o nic d ata carrier, 
a n d t o assess t he a bilit y t o c orr ectl y re p ositi o n  s u bjects s o as t o get c o m p ara ble brai n i ma ges. O nl y 
u p o n fi nal a p pr o val of t his test sca n, sites will be all o we d t o be gi n assessi n g s u bjects. 
Eac h s u bject s h o ul d be sca n ne d usi n g t he sa me mac hi ne t hr o u g h o ut t he trial. I n case of mac hi n e 
c ha n ge, or h ar d w are/s oft ware u p gr a de t he n ecessit y t o c o m plet e a n ot her test sca n usi n g t he ne w 
e q ui p me nt s h o ul d be a gr ee d wit h t he ce ntral i ma gi n g c ore la b. 
 
7. 3. 5. 2. 1  
D at a H a n dli n g  
D uri n g t h e trial, t he q u alit y of eac h sca n p erf or me d will be assesse d b y t h e ce ntral i ma gi n g c ore la b. 
As s o o n as t h e sca n is r ecei ve d b y t he ce ntral i ma gi n g c ore la b, it will be e v al uate d f or q u alit y, 
c o m plete ness a n d a d here nce t o t he pr ot oc ol. A case acce pta nce n otificati o n or q uer y will be se nt t o 
t he c o ntri b uti n g site a n d t he m o nit or. If sca ns are i n c om plete or i nc orrectl y p erf or me d, t h e trial ce ntre 
will be as ke d t o re p eat it as s o o n as p ossi ble. 
After t he q ualit y c hec k, all sca ns will be e val uate d b y t h e ce ntral i ma gi n g c ore la b t h at will a nal yz e 
t he varia bles. T he electr o nic i ma ge data of t he M RI sca ns will be st ore d at t he ce ntral i ma gi n g c ore 
la b, a n d at t he r es pecti ve trial sites. 
7. 3. 5. 3  
E v al u ati o n of M RI Sc a ns  
7. 3. 5. 3. 1  
Dise ase D i a g n osis 
All M RI s ca ns will be l ocall y o btai ne d a n d assess e d  b y t he l ocal ne ur ora di ol o gist a n d or ra di ol o gist, 
f oll o wi n g Sta n dar d of Care. 
7. 3. 5. 3. 2  
M RI Effic ac y E n d p oi nts  
All c ollecte d M RI varia bles , f or b ot h Scree ni n g a n d Fi nal visit M RI will be e val uate d b y t he ce ntral 
rea der. Res ults will n ot be s hare d wit h i n vesti gati o nal sites . 
F or eac h sca n, t he M RI I n v esti gat or at eac h ce nt re m ust se n d t he electr o nic data f or t he i ma ges 
ac q uire d wit h o ut t he c orr es p o n di n g plates t o t he ce ntral i ma gi n g c ore la b.  
 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
7. 3. 5. 3. 3  
E v al u ati o n of Scree ni n g M RI Sc a ns f or E li gi bilit y 
I n v esti gat or s hall e ns ur e safet y e v al uati o n of all M RIs b y l ocal ra di ol o gist/ ne ur ora di ol o gist 
F or s u bjects s witc hi n g t o Ma ve ncla d®  fr o m a n y D M D p ote ntiall y li n ke d t o P M L as a n a d verse e ve nt 
s h o ul d ha ve t heir scree ni n g M RI se nt t o t he ce ntral rea der f or verificati o n of a bse nce of P M L. A 
n o n-e x ha usti ve list of s uc h D M Ds i ncl u des:  
•  Nataliz u ma b ( T ys a bri ® )  
•  Fi n g oli m o d ( Gile n ya ® )  
•  D M F ( T ecfi dera ® )  
•  Ale mt uz u ma b ( Le mtr a da ® ) 
•  Ocreliz u ma b ( Ocre v us ® )  
•  Mit o x a ntr o ne ( N o va ntr o ne
® )  
•  Rit u xi ma b ( off la bel pre p arati o ns) D M Ds, pre vi o usl y 
Scree ni n g M RI sca ns, acc o m pa nie d b y rele va nt cli nical data  a vaila ble i n E D C at t he ti me of e val uati o n , 
fr o m t he a b o ve- me nti o ne d s u bjects will be prese nte d t o t he i n de pe n de nt ce ntral rea der , w h o will 
e val uate t he M RI f or si g ns of P M L a n d pr o vi de t he res ults of t his e val uati o n t o all rele va nt parties, as 
s pecifie d i n t he site o perati o ns ma n ual a n d i n de pe n de nt re vie w c o m mittee  d oc u me nts. 
Gl o bal Versi o n I D: C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
 
Assess me nt of S afet y  
T he saf et y pr ofile of t h e I M P 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 n al ysis of 
Baseli ne  m e dical c o n diti o ns, A Es, p h ysical e x a mi nati o n fi n di n gs i ncl u di n g vital si g ns a n d la b orat or y 
tests. 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
T he i nci de nce of T E A Es will be s u m marize d b y treat me nt gr o u p a n d o verall, b y se v erit y, a n d b y 
relati o ns hi p t o treat me nt. T he s u m mar y t a bles will i ncl u de i nci de nce rat es of T E A Es f or o v erall 
s yste m or ga n classes a n d b y pr eferre d t er m wit hi n eac h s yste m or ga n class.  
C o m pre he nsi ve assess m e nt of a n y a p p are nt t o xicit y e x perie n ce d b y eac h s u bject will be perf or me d 
fr o m t he ti me of gi vi n g i nf or me d c o ns e nt a n d t hr o u g h o ut t he trial. T he I n vesti gat or will re p ort a n y 
A Es, w het her o bs er ve d b y t he I n v esti gat or or re p orte d b y t h e s u bject (s ee S ecti o n  7. 4. 1. 2). 
7. 4. 1  
A d verse E ve nts  
7. 4. 1. 1  
A d verse E ve nt Defi niti o ns  
A d verse E ve nt  
A n A E is a n y u nt o w ar d me dical occ urre n ce i n a s u bject or cli nical i n vesti gati o n s u bject a d mi nistere d 
a p har m ace utical pr o d uct, re gar dless of ca us al rel ati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore 
be a n y u nf a v or a ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or m al la b orat or y fi n di n g), s y m pt o m, or 
disease te m p orall y ass oci ate d wit h t he use of a me dici nal pr o d uct, w het her or n ot c o nsi dere d relate d 
t o t he me dici nal pr o d uct. 
F or s ur gical or dia g n ostic pr oce d ur es, t he 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 h er t ha n t he pr oce d ur e itself.  
T he I n v esti gat or is r e q uire d t o gra d e t he se v erit y or t o xicit y of eac h A E.  I n vesti gat ors m ust ass ess 
t he se verit y of A Es acc or di n g t o t he Q ualitati ve T o xicit y Scale, as f oll o ws: 
•  Mil d:  T he s u bject is a ware of t he e ve nt or s y m pt o m, b ut t he e ve nt or s y m pt o m is easil y 
t olerate d. 
•  M o derate: T h e s u bject e x perie nces s uffici e nt disc o mf ort t o i nterfere wit h or re d uce his or her 
us ual le vel of acti vit y.  
•  Se vere: Si g nifica nt i m pair me nt of f u ncti o ni n g: t he s u bject is u na ble t o carr y o ut his or her 
us ual acti vities.  
I n v esti gat ors m ust als o s yste maticall y assess t he ca usal relati o ns hi p of A Es t o I M Ps (i n cl u di n g a n y 
ot her n o n -I M Ps, ra diati o n t hera p y, etc.) usi n g t he f oll o wi n g defi niti o ns. Decisi ve fact ors f or t h e 
assess me nt of ca us al rel ati o ns hi p of a n A E t o t he I M Ps i ncl u de, b ut m a y n ot be li mite d t o, te m p oral 
relati o ns hi p bet wee n t he A E a n d t he I M Ps, k n o w n si de effects of I M Ps, me dical hist or y, c o n c o mita nt 
me dicati o n, c o urse of t he u n derl yi n g disease, trial pr oce d ures. 
U nrel ate d:  N ot
 reas o n a bl y
 relate d
 t o
 t he
 I M P.
 A E
 c o ul d
 n ot
 me d icall y 
( p har mac ol o gi call y/ cli nicall y) be attri b ute d t o t he I M P u n d er trial i n t his cli nical trial 
pr ot oc ol. A reas o na ble alter nati ve e x pla nati o n m ust be a vaila ble. 
Rel ate d:  
Reas o na bl y r elate d t o t he I M P. A E c o ul d m e dicall y ( p har mac ol o gicall y/cli nicall y) be  
attri b ute d t o t he I M P u n d er trial i n t his cli nical trial pr ot oc ol. 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs 
A b n or mal  la b orat or y fi n di n gs  a n d ot her a b n or m al  i n vesti gati o nal  fi n di n gs (f or e x a m ple, o n a n  
electr ocar di o gr a m [ E C G ] trace) s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical 
si g ns  a n d  s y m pt o ms,  lea d  t o  treat me nt  disc o nti n uati o n  or  are  c o nsi dere d  ot her wise  me dicall y  
i m p orta nt b y t he I n vesti gat or. If a la b or at or y a b n or malit y f ulfills t hese criteria, t he i de ntifie d me dical 
c o n diti o n (f or e x a m ple, a ne mia, i ncr ease d a la ni ne ami n otra nsferase  [ A L T]) m ust be re p orte d as t he 
A E rat her t h a n t he a b n or mal val ue itself.  
Seri o us A d verse E ve nts  
A n S A E is a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose:  
•  Res ults i n  deat h.  
•  Is lif e-t hreate ni n g. ( N ote: T he ter m “life-t hreate ni n g” refers t o a n e v e nt i n w hic h t he s u bject is at 
ris k of deat h at t he ti me of t he e v e nt, n ot a n e ve nt t hat h y p ot h eticall y mi g ht ha ve ca use d d eat h if 
it was m ore se vere.) 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gs a n e xisti n g h os pitalizati o n. 
•  Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y.  
•  Is a c o n ge nital a n o mal y or birt h defect. 
•  Is ot h er wise c o nsi der e d t o be me dicall y i m p orta nt. ( N ote: I m p orta nt m e dical e ve nts t hat ma y n ot 
res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d as S A Es w h e n, 
base d u p o n a p pr o priat e m e dical j u d g me nt, t he y m a y je o p ar dize t he s u bject or ma y re q uire m e dical 
or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. E x a m ples of s uc h e ve nts 
i ncl u de aller gic br o nc h os pas m re q uiri n g 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, 
bl o o d d yscr asias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt 
of dr u g de pe n d e nc y or dr u g a b us e.) 
F or t he p ur p oses of re p orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a n I M P is als o 
c o nsi dere d a n S A E, as descri be d i n Secti o n  7. 4. 1. 4. 
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E  
Electi ve  h os pitalizati o ns t o a d mi nister, or t o si m plif y trial treat me nt or trial pr oce d ures (f or e x a m ple, 
a n o ver ni g ht st a y t o f acilitate t hera p y) are n ot c o nsi dere d S A Es. H o we v er, 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 el ecti ve h os pitalizati o n (f or e x a m ple, 
u n desira ble effects of a n y a d mi nister e d treat me nt) m ust be d oc u me nte d a n d re p orte d as S A Es. 
E ve nts N ot t o Be C o nsi dere d as A Es/ S A Es  
Me dical c o n diti o ns prese nt at t he i nitial trial visit t hat d o n ot w orse n i n se verit y or  fre q u e nc y d uri n g 
t he trial are d efi ne d as Baseli ne me dical c o n diti o ns, a n d are n ot t o be c o nsi dere d A Es. 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
M S 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 ors e ni n g of M S will us uall y b e 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 rela 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 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 relate d t o t he I M P (i.e. w orse ni n g is n ot 
c o nsiste n t wit h t he a ntici pate d nat ural pr o gressi o n of t he disease). 
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 gr essi o n of t he diseas e/ dis or der bei n g st u die 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) s h o ul d n ot be re p orte d as a n ( S) A E, u nless t he s u bjects’s ge n eral c o n diti o n is m ore 
se vere t ha n e x pecte d f or t he partici pa nt’s 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 n e d i n Secti o n  7. 4. 1.3 ). 
A d verse E ve nt of S peci al I nterest  
N ot a p plica ble.  
7. 4. 1. 2  
Met h o ds of Rec or di n g a n d Assessi n g A d verse E ve nts  
At eac h trial visit, t he s u bject will be q uerie d o n c h a n ges i n his or her c o n diti o n. D uri n g t he re p orti n g 
peri o d, a n y u nfa v ora ble c ha n ges i n t he s u bject’s c o n diti o n will be rec or de d as A Es, w het h er re p orte d 
b y t he s u bject or o bser v e d b y t he I n vesti gat or. 
C o m plete, acc urate a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urat i o n of t he re p orti n g 
peri o d ( defi n e d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he C R F. 
All S A Es m ust be a d diti o nall y d oc u me nte d a n d re p orte d i n t he S A E e C R F pa ge as descri be d i n 
S ecti o n 7. 4. 1. 4. 
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri 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 he rec or d e d treat me nt 
a d mi nistrati o n ti me), its se verit y, its ca usal relati o ns hi p wit h t he trial treat me nt, a n y ot her p ote ntial 
ca usal  f act ors,  a n y  tr eat me nt  gi v e n  or  ot her  acti o n  ta ke n,  i ncl u di n g  d os e  m o dificati o n  or  
disc o nti n uati o n of t he I M P, 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 priate s eri o us ness criteria d oc u me nte d. 
S pecific g ui da nce ca n be f o u n 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. 
7. 4. 1. 3  
Defi niti o n of t he A d verse E ve nt Re p orti n g Peri o d  
T he A E r e p orti n g peri o d f or safet y s ur veilla n c e b e gi ns w h e n t he s u bject is i nitiall y i n cl u de d i n t h e 
trial ( date of first si g n at ure of i nf or me d c o nse nt/ d ate of first si g nat ure of first i nf or me d c o nse nt) a n d 
c o nti n ues u ntil at e n d of m o nt h 2 4 as per t he Fi n al Visit g ui deli nes. 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
A n y S A E assesse d as r elat e d t o Ma ve ncla d
®  m ust be re p orte d w he n e ver it occ urs, irres p ecti ve of t he 
ti me ela pse d si nce t he last a d mi nistrati o n of Ma ve ncla d
® . 
7. 4. 1. 4  
Pr oce d ure f or Re p orti n g Seri o us A d verse E ve nts  
Seri o us A d verse E ve nts  
I n  t he  e v e nt  of  a n y  ne w  S A E  occ urri n g  d uri n g  t he  re p orti n g  peri o d,  t he  I n vesti gat or  m ust  
i m me diatel y ( wit hi n a ma xi m u m of 2 4 H O U R S after bec o mi n g a ware of t he e ve nt) i nf or m t h e 
S p o ns or or its desi g nee i n t he e C R F S A E p a ge, w hic h m ust be c o m plete d b y t he I n vesti gat or 
f oll o wi n g s pecific c o m pl eti o n i nstr ucti o ns. 
I n case t he e C R F is n ot a vaila ble, t he S A Es m ust be re p orte d via e mail usi n g t he pa per S A E Re p ort 
F or m f oll o wi n g s pecif ic c o m pleti o n i nstr ucti o ns. Als o  in e x ce pti o nal circ u msta nces, a n S A E ( or 
f oll o w- u p i nf or mati o n) ma y be re p ort e d b y t ele p h o ne; i n t hese cases t he C R F m ust be c o m plete d as 
s o o n as it bec o mes a vaila ble. 
Rele va nt pa ges fr o m t he C R F ma y be pr o vi de d i n parallel (f or e x a m ple, me dical hist or y, c o nc o mita nt 
dr u gs).  A d diti o nal  d oc u me nts  ma y be  pr o vi de d  b y t h e  I n v esti gat or,  if  a vaila ble  (f or  e x a m ple,  
la b orat or y res ults, h os pital re p ort, a ut o ps y re p ort). I n all cases, t h e i nf or mati o n pr o vi de d o n t he S A E 
Re p ort F or m m ust be c o nsiste nt wit h t he data a b o ut t he e ve nt rec or de d i n t h e C R F. 
T he I n v esti gat or m ust res p o n d t o a n y re q uest f or f oll o w - u p i nf or mati o n (f or e x a m ple, a d diti o nal 
i nf or mati o n,  o utc o me,  fi nal  e val uati o n,  ot her  rec or ds  w h ere  nee d e d)  or  t o  a n y  q uesti o n  t he  
S p o ns or/ desi g nee ma y h a ve o n t h e A E wit hi n t he sa me ti meli nes as t h os e n ote d a b o ve f or i nitial 
re p orts. T his is necessar y t o e ns ure pr o m pt assess me nt of t he e v e nt b y t he S p o ns or or desi g nee a n d 
(as a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociate d wit h e x pe dite d 
safet y re p orti n g o bli gati o ns. 
Re q uests f or f oll o w -u p will us uall y be ma de via t he res p o nsi ble M o nit or, alt h o u g h i n e x ce pti o nal 
circ u msta nces t he Gl o bal Dr u g Safet y d e part me nt ma y c o nt act 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. 
7. 4. 1. 5  
S afet y  Re p orti n g  t o  He alt h  A ut h orities,  I n de pe n de nt  Et hics  
C o m mittees/ I nstit uti o n al Re vie w B o ar ds a n d I n vesti g at ors  
T he S p o ns or will se n d a p pr o priate safet y n otificati o ns t o Healt h A ut h orities i n acc or da nce wit h 
a p plica ble la ws a n d re g ulati o ns. T he I n v esti gat or m ust c o m pl y wit h a n y a p plica ble site -s pecific 
re q uire me nts relate d t o t he re p orti n g of S A Es ( p artic ularl y d eat hs) i n v ol vi n g trial s u bjects t o t he 
I E C/I R B t hat a p pr o v e d t he trial. 
I n acc or da n ce wit h I C H G C P, t he S p o ns or/ desi g nee will i nf or m t he I n vesti gat or of “fi n di n gs t hat 
c o ul d a d versel y aff ect t h e saf et y of s u bjects, i m pact  t he c o n d uct of t he trial or alter t he I E C’s/I R B’s 
a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t h e trial.” I n partic ular a n d i n li ne wit h res pecti ve re g ulati o ns, 
t he S p o ns or/ desi g nee will i nf or m t he I n vesti gat or of A Es t hat are b ot h seri o us a n d u ne x pecte d a n d 
are c o nsi dere d t o be rel ate d t o t he a d mi nistere d pr o d uct (“s us pect e d u n e x pecte d seri o us a d vers e 
reacti o ns” or s us pecte d u ne x pecte d seri o us a d verse reacti o n [ S U S A Rs]). T he I n v esti gat or s h o ul d 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
place c o pies of Saf et y Re p orts i n t he I n vesti gat or Site File. Nati o nal re g ulati o ns wit h re gar d t o Safet y 
Re p ort n otificati o ns t o I n vesti gat ors will be ta ke n i nt o acc o u nt. 
W he n  s pecificall y  re q uire d  b y  re g ul ati o ns  a n d  g ui deli nes,  t he  S p o ns or/ desi g n ee  will  pr o vi de  
a p pr o priate Safet y R e p orts directl y t o t he c o ncer ne d lea d I E C/I R B a n d will mai ntai n rec or ds of t hese 
n otificati o ns. W he n direct re p orti n g is n ot clearl y d efi ne d b y nati o nal or site -s pecific re g ulati o ns, t he 
I n v esti gat or will be res p o nsi ble f or pr o m ptl y n otif yi n g t he c o ncer ne d I E C/I R B of a n y Safet y R e p orts 
pr o vi de d b y  t he  S p o ns or/ desi g n ee  a n d  of  fili n g  c o pies  of  all  relate d  c orres p o n d e nce  i n  t he  
I n v esti gat or Site File. 
F or trials c o vere d b y t he E ur o pea n Dir ecti ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities re gar di n g 
t he re p orti n g of S A Es/ S U S A Rs/ Safet y Iss u es will be carrie d o ut i n acc or d a nce wit h t hat Directi ve 
a n d wit h t he relate d Detaile d G ui da nce d o c u me nts.  
7. 4. 1. 6  
M o nit ori n g of S u bjects wit h A d verse E ve nts  
A Es are r ec or d e d a n d ass esse d c o nti n u o usl y t hr o u g h o ut t he trial a n d are assesse d f or  fi nal o utc o m e 
at t he E n d of T rial visit. All S A Es o n g oi n g at t he E n d of Trial visit m ust be m o nit ore d a n d f oll o we d 
u p  b y t h e  I n vesti gat or  u ntil  sta bilizati o n  or  u ntil  t he  o utc o me  is  k n o w n,  u nless  t he  s u bject  is  
d oc u me nte d as “l ost t o f oll o w -u p”. Reas o na bl e att e m pts t o o btai n t his i nf or mati o n m ust be ma de a n d 
d oc u me nte d. It is als o t he res p o nsi bilit y of t he I n vesti gat or t o e ns ure t hat a n y n ecess ar y a d diti o nal 
t hera pe utic meas ures a n d f oll o w- u p pr oce d ures are perf or me d. 
M o nit ori n g of S pecific A d verse E ve nts  
N ot a p plica ble.  
7. 4. 2  
Pre g n a nc y a n d I n Uter o Dr u g E x p os ure  
O nl y pre g n a ncies  c o nsi dere d  b y t h e  I n vesti gat or  t o  be  relate d  t o  trial  treat me nt  (f or  e x a m ple,  
res ulti n g  fr o m  a  dr u g  i nteracti o n  wit h  a  c o ntrace pti ve  me dicati o n)  are  c o nsi dere d  t o  b e  A Es.  
H o we ver,  all  pre g n a nci es  wit h  a n  esti mate d  c o nce pti o n  date  d uri n g  t he  peri o d  defi ne d  i n  
Secti o n  7. 4. 1. 3 m ust be r ec or de d b y c o n ve nti o n i n t he A E p a ge/secti o n of t he C R F. T h e sa me r ule 
a p plies t o pre g na nci es i n fe male s u bjects a n d t o pre g n a ncies i n fe male part ners of male s u bjects. T he 
I n v esti gat or m ust n otif y t he S po ns or/ desi g n ee i n a n e x pe dite d ma n n er of a n y pre g na nc y usi n g t he 
Pre g n a nc y R e p ort F or m, w hic h m ust b e tra ns mitte d via a n e mail i m me diatel y ( wit hi n a m a xi m u m 
of 2 4 h o urs after bec o mi n g a war e of t he e ve nt), f oll o wi n g s pecifi c c o m pleti o n i nstr ucti o ns. 
I n v estigat ors m ust acti vel y f oll o w u p, d o c u me nt a n d re p ort o n t he o utc o me of all t hese pre g n a ncies, 
e ve n if t he s u bjects are wit h dra w n fr o m t he trial.  
T he I n v esti gat or m ust n otif y t he S p o ns or/ desi g n ee of t hese o utc o mes usi n g t he Pre g na n c y R e p ort 
F or m. If a n a b n or m al o utc o me occ urs, t he S A E Re p ort F or m will be use d if t he s u bject s ustai ns a n 
e ve nt a n d t he Par e nt - C hil d/ Fet us A E Re p ort F or m if t he c hil d/fet us s ustai ns a n e ve nt. 
A n y a b n or mal o ut c o me m ust be re p ort e d i n a n e x pe dite d ma n ner as d escri be d i n Secti o n  7. 4. 1. 4 , 
w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da ys after deli ver y. 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
I n t he e v e nt of a pre g na n c y i n a s u bject occ urri n g d uri n g t he c o urs e of t he trial, t he s u bject m ust be 
disc o nti n ue d fr o m trial me dicati o n i m me diatel y. T he S p o ns or/ desi g n ee m ust be n otifie d wit h o ut 
dela y a n d t he s u bject m ust be f oll o we d as me nti o ne d a b o ve. 
7. 4. 3  
Cli nic al L a b or at or y Assess me nts  
L ocal cli nical la b orat or y sa m ples will  be c ollecte d f or scree ni n g, p ost-treat me nt effect ( Mo nt hs 2, 6, 
1 4, 1 8)  a n d e m er ge n c y s afet y e v al uati o ns b ut are n ot re q uire d t o b e c ollect e d/rec or de d i n t he C R Fs  
(see Ta bl e 3 ). 
T a ble 3:  L oc al l a b or at or y a ssess me nts 
Scree ni n g  
 
He mat ol o g y  
L y m p h oc yte c o u nt  
Ser ol o g y  
He patitis B, He p atitis C, HI V , 
V Z V * *  
T B scree ni n g as p er l ocal 
sta n dar d of care*  
T B (acti ve a n d/ or l ate nt)  
M RI  
F oll o wi n g esta blis he d pr ot oc ol 
of M RI s e q ue nces, descri be d i n 
I A G 
Uri ne a n d/ or s er u m tests  
Pre g n a nc y  
Baseli ne  
He mat ol o g y  
L y m p h oc yte c o u nt t o be 
re peat e d if i nter val is m ore t ha n 
4 wee ks fr o m scree ni n g sa m ple  
Uri ne a n d/ or s er u m tests  
Pre g n a nc y  
P ost -treat me nt ( Year 1 a n d 2) 
He mat ol o g y  
L y m p h oc yte c o u nt at 2, 6, 1 2, 
1 4, 1 8, 2 4 m o nt hs  
Bef ore Y ear 2 d osi n g  
He mat ol o g y  
L y m p h oc yte c o u nt  
Uri ne a n d/ or s er u m tests  
Pre g n a nc y  
Ser ol o g y  
He patitis B, He p atitis C, HI V  
T B scree ni n g as p er l ocal 
sta n dar d of care *  
T B (acti ve a n d/ or l ate nt)  
A b bre viati o ns: C T =c o m p uterise d t o m o gra p h y; HI V = h u ma n i m m u n o deficie nc y vir us; I A G = i ma ge ac q uisiti o n 
ma n ual; M RI = ma g netic res o na nce i ma gi n g; M S = m ulti ple s cler osis;  P M L = pr o gressi ve m ultif ocal 
le u k oe nce p hal o pat h y; T B = T u berc ul osis; V Z V = varicella z oster vir us . 
* I ma gi n g (e. g., c hest X -ra y, c hest C T sca n, M RI) a n d/ or p ositi ve Q ua nti F E R O N-T B G ol d test a n d/ or s ki n test a n d/ or 
cli nical e xa mi nati o n  
* * O nl y if t he patie nt has n o  hist or y of varicella  i nfecti o n or i m m u nit y 
7. 4. 4  
Vit al Si g ns, P h ysic al E x a mi n ati o ns, a n d Ot her Assess me nts  
Vital si g ns i ncl u di n g b o d y te m per at ure, res pirat or y rate, a n d heart rate (after 5 -mi n ute rest)  a n d 
arterial  bl o o d press ur e (after 5 -mi n ute rest) will  be meas ure d o nce at Scree ni n g a n d at visits 4 ( m o nt h 
1 2) a n d 7 ( m o nt h 2 4). 
A c o m plete p h ysical e x a mi nati o n (i ncl u di n g, e. g., ge n eral a p peara n ce, s ki n, hea d/ nec k, p ul m o nar y, 
car di o vas c ular,  gastr oi ntesti nal,  e xter nal  ge nit o uri nar y,  l y m p hatic,  m usc ul os keletal  s yste m,  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
e xtre mities,  e yes  [i ns pecti o n  a n d  visi o n  c o ntr ol],  n ose,  t hr oat,  a n d  ne ur ol o gic  stat us)  will  be  
perf or me d at scr ee ni n g a n d at s u bse q ue nt visits as d oc u me nte d i n t he Sc he d ule of Assess me nts 
(A p pe n di x  1 : Sc he d ule of Assess me nts ) a n d t he a b n or mal res ults d oc u me nte d i n t he C R F. All 
cli nicall y  si g nifica nt  a b n or malities  occ urri n g  b ef ore  si g n at ure  of  i nf or me d  c o nse nt  s h o ul d  b e  
rec or d e d i n t he Me dical  Hist or y secti o n a n d/ or Disease Hist or y; all a b n or malities occ urri n g or  
w orse ni n g after si g n at ur e of i nf or me d c o nse nt s h o ul d be rec or d e d i n t h e A Es secti o n. A b n or mal 
fi n di n gs are t o be r eassesse d at s u bse q ue nt visits. 
B o d y wei g ht will be rec or de d at Baseli ne  a n d at m o nt h 1 2, bef or e t he treat me nt a d mi nistrati o n,  as 
i n dicate d i n t he Sc he d ule of Assess me nts ( A p pe n di x 1 : Sc he d ule of Assess me nts ) a n d d oc u me nte d 
i n t he C R F. All ne wl y di a g n ose d c o n diti o ns, si g ns, a n d s y m pt o ms o bser v e d fr o m scree ni n g, w het her 
relate d t o trial me dicati o n or n ot, are t o be re p ort e d as A Es. T he rela ps e will n ot be re p orte d as a n 
A E a n d will be ca pt ure d i n a de dicate d e C R F pa ge f or efficac y a n al ysis.  
 
P h ar m ac o ki netics  
N ot a p plica ble.  
 
Bi o m ar kers  
N ot a p plica ble.  
 
Ot her Assess me nts  
N ot a p plica ble 
8  
St atistics  
Gl o bal Versi o n I D: 
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
 
R a n d o miz ati o n  
N ot a p plica ble 
 
E n d p oi nts  
8. 3. 1  
Pri m ar y E n d p oi nt (s) 
•  C ha n ges i n M S Q o L -5 4 at 2 4 m o nt hs c o m pare d t o Bas eli ne , i.e. t he c ha n ges i n t he p h ysical a n d 
me ntal healt h c o m p osite sc ores  
8. 3. 2  
Sec o n d ar y E n d p oi nt  
•  Treat me nt gl o bal satisfacti o n assesse d b y T S Q M v 1. 4 at 6 m o nt hs 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
 
A n al ysis Sets  
E nr olle d Set: All s u bjects e nr olle d . 
I nte nt-t o-treat Set (I T T): All s u bjects classifie d as eli gi ble. 
F ull A nal ysis Set  ( F A S): All s u bjects fr o m t he I T T treate d wit h at least o ne d ose of trial treat me nt. 
Treat me nt C o m pleter Set – Year 1: All s u bjects fr o m t he F A S w h o c o m plete d t he f ull treat me nt 
c o urse of t he first year.  
Treat me nt C o m pleter Set – Year 2: All s u bjects fr o m t he F A S w h o c o m plete d t he f ull treat me nt 
c o urse of t he first a n d t he sec o n d year. 
Safet y Set: All s u bject s tr eate d wit h at least o n e d ose of trial treat me nt. 
T he pri mar y a n al yses a n d all efficac y a nal yses will be perf or me d o n t h e F A S. T he pri mar y a n d 
sec o n dar y a nal yses will be re peate d f or t he Treat me nt C o m pleter Sets a n d t he pri mar y f or t he I T T, 
if differ e nt. All safet y a n al yses will be perf or me d o n t he Safet y Set. 
S u bject s w h o ha v e wit h dra w n c o nse nt f or t he trial will be i ncl u de d i n t he a n al ysis u nless it was 
s pecifie d b y t he m t hat t heir data n ot be use d, after clarificati o n of t he l e vel of wit h dra w al b y t he  
I n v esti gat or. 
 
Descri pti o n of St atistic al A n al yses  
T he statistical a nal yses d escri 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 S A P, 
w hic h will be fi nalize d pri or t o data base l oc k a n d will be i ncl u de d i n t he cli nical trial re p ort f or t his 
pr ot oc ol. T he fi nal S A P will ta ke i nt o acc o u nt a n y a m e n d me nt t o t he pr ot oc ol 
8. 5. 1  
Ge ner al C o nsi der ati o ns  
T he st u d y is e x pl orat or y i n nat ure. A c o ntr ol of t he p ote ntial t y pe -I-err or i nfl ati 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 i m ple me nte d . 
F or a nal ysis of all e n d p oi nts, differe n ces wit h a p -val ue of 0. 0 5 or less will be c o nsi dere d  n o mi nall y 
statisticall y  si g nifica nt.  Para meter  esti mates  wit h  ass ociate d  9 5 %  c o nfi de nce  i nter v als  will  be  
re p orte d i n eac h a nal ysis. 
S u bject s’ de m o gra p hi c f act ors a n d Baseli ne  cli nical c h aracteristics will b e s u m marize d wit h t he 
f oll o wi n g meas ur es: mea n wit h sta n dar d de viati o n, mi ni m u m a n d ma xi m u m f or n or mall y distri b ute d 
c o nti n u o us varia bles, me dia n wit h i nter q uartile ra n ge, mi ni m u m a n d ma xi m u m f or ot her c o nti n u o us 
varia bles a n d c o u nts wit h perce nt a ges f or cat e g ori cal varia bl es.  
As t he a nal ysis set c o ncer ns re peat e d meas ure me nts f or o utc o mes f or eac h i n di vi d ual, it is li kel y t hat 
o bser vati o ns pertai ni n g t o eac h i n di vi d ual will be c orrelat e d. F urt her m ore, as t his i s a m ulti-ce ntre 
trial, it is li kel y t hat cl usteri n g of i n di vi d uals wit hi n trial sites will pr o d uce a n a d diti o nal s o urce of 
c orrel ati o n.  Mi x e d -effects  re gr essi o n,  w here b y a t hree -le v el  hierarc hi cal  m o del  is  s pecifie d  f or  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
o bser vati o ns wit hi n s u bjects wit hi n trial sites, will be use d t o acc o u nt f or wit hi n-s u bject a n d wit hi n-
ce ntre c orr elati o n ( Gi b b o ns et al., 2 0 1 0). 
Assess me nt sc he d ules  
It is li kel y t hat t he 2n d year treat me nt ma y b e dela ye d s u bsta ntiall y f or a s mall n u m ber of s u bjects f or 
w h o m t he sec o n d d ose is n ot re q uire d i m me diatel y. D u e t o t he nee d f or a fi nite f oll o w - up peri o d, a 
b uffer of 3 m o nt hs is gi ve n f or s u bjects w h o d o n ot recei ve t he sec o n d treat me nt at t he s pecifie d 
ti me. S u bject s f or w h o m treat me nt is dela ye d b y o ver 3 m o nt hs ma y n ot ha ve all assess me nt data 
ca pt ure d a n d as s uc h, t hese o bser vati o ns will be treate d as missi n g. 
I n each a n al ysis, s h o ul d assess me nt be dela ye d, s u bjects’ assess 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 a n d i nfere n ces will be c o n d ucte d acc or di n gl y. 
Missi n g d at a 
S h o ul d missi n g data be prese nt i n Baseli ne  c o variates i ncl u de d i n t he a nal ysis m o dels, mea n or 
me dia n i m p utati o n a n d use of a missi n g i n dicat or will be us e d f or c o nti n u o us a n d cate g orical  
c o variates, res pecti vel y.  
T he trial datas et c o m pris es of m ulti ple o utc o me assess me nts ma de f or eac h s u bject o ver a 2 4 - m o nt h 
peri o d. T her ef or e, d ue t o t he l o n git u di nal nat ure of t he data a n d t he le n gt h y f oll o w -u p p eri o d, it is 
li kel y t h at missi n g o utc o me data will be prese nt d ue t o l oss t o f oll o w-u p. Patter ns a n d de grees of 
missi n g ness will be s u m marize d a n d will i nf or m t he a p pr oac h ta ke n t o d eali n g wit h missi n g data.  
8. 5. 2  
A n al ysis of Pri m ar y E n d p oi nts  
T he pri mar y e n d p oi nt s f or t he trial are t he c ha n ges i n H R Q o L assesse d b y M S Q o L - 5 4 p h ysical healt h 
a n d me ntal healt h at 2 4 m o nt hs p ost -Baseli ne  assess me nt. Differe n ces i n M S Q o L -5 4 sc ores b et wee n 
meas ure me nts at 2 4 m o nt hs a n d Bas eli ne  will b e assess e d usi n g mi x e d -effects li near re gressi o n , 
acc o u nti n g f or wit hi n -s u bject c orr elati o n a n d wit hi n-ce ntre/re gi o n c orrelati o n  (see Secti o n  8. 5. 1 f or 
details ). T he a nal ysis will als o a dj ust f or fact ors dee me d t o be pr o g n ostic f or t he pri mar y e n d p oi nt, 
as j u d ge d b y cli nical e x perts.  
Li near  r e gressi o n  m o delli n g  ass u mes  t hat  o utc o mes  are  n or m all y  distri b ute d.  A p pr o priate  
tra nsf or mati o ns (s uc h as s q uare r o ot or l o g tra nsf or m) ma y be use d t o ac hie ve n or malit y. 
A n esti mate f or t he mea n differ e nce i n M S Q ol -2 4 sc ores b et wee n Baseli ne  a n d 2 4 m o nt hs will be 
re p orte d, wit h a 9 5 % c o nfi de nce i nter val a n d t w o-si de d p-val u e . T he i nte ri m a nal ysis at 6 m o nt hs 
will be c o nsi der e d as s u p p orti ve of t he 2 4 -m o nt hs a nal ysis ( mai n a n al ysis), a n d t h us, d oes n ot re q uire 
a dj ust me nt f or m ulti plicit y.  
8. 5. 3  
A n al ysis of Sec o n d ar y a n d 
 
A nal ysis  c o m pari n g  c o nti n u o us sec o n dar y a n d  
 (i ncl u di n g  sc ores) meas ure d 
re peat e dl y at s pecifi c ti me p oi nts will be u n derta k e n usi n g si milar tec h ni q ues t o t h ose o utli ne d f or 
t he  pri mar y  a nal ysis.  M o dels  will  be  a dj uste d  t o  i ncl u de  Baseli ne  as  a v aila ble.  If  o nl y  o ne  
Gl o bal Versi o n I D: C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
meas ure me nt is a v aila ble (e. g., f or 6 m o nt hs) t he m o dels will be si m plifie d as t he wit hi n-s u bject 
c orrel ati o n ca n n ot be esti mate d . 
O t her o utc o mes ( e. g., s u bsc ores a n d s cales) will be s u m marize d descri pti vel y . 
T o assess c orr elati o n bet wee n t h e H R Q o L assesse d b y M S Q o L -5 4 a n d 
 
, a p pr o pri ate statistics s uc h as t he 
Pears o n pr o d u ct -m o me nt c orr elati o n c oefficie nt a n d R 2 statistic will be pr o d uce d al o n gsi de vis u al 
s u m maries. 
I nf or mati o n o n  T E A Es  a n d S A Es  t hes e e ve nts will  be c ollecte d  a n d  s u m marize d  acc or di n gl y,  
pr o vi di n g detail of t h e fr e q ue nc y, t y pe, s e verit y a n d o utc o me of t he e v e nts. 
 
I nteri m a n d A d diti o n al Pl a n ne d A n al yses  
A n i nteri m  a nal ysis will be u n derta ke n aft er all s u bjects ha ve c o m plete d t he 6 -m o nt h assess me nt. 
T his will i ncl u de a nal ysis of t he o utc o me T S Q M   v 1. 4, i ncl u di n g all assess me nt data u p t o a n d 
i ncl u di n g  t he  6-m o nt h  assess me nt.  A  descri pti ve  a nal ysis  will  als o  be  u n derta k e n,  i ncl u di n g  
s u m maries of Bas eli ne  c h aract eristics, o utc o me meas ures a n d a d v erse e ve nts . F or efficac y e n d p oi nts, 
t he a nal ysis at 6 m o nt hs will be c o nsi dere d as s u p p orti ve of t he 2 4-m o nt h a nal ysis ( mai n a n al ysis).  
9  
Et hic al a n d Re g ul at or y As pects  
 
Res p o nsi bilities of t he I n vesti g at or  
T he I n v esti gat or is r es p o nsi ble f or t he c o n d u ct of t he trial at  t he site a n d will e ns ure t hat t he trial is 
perf or me d i n acc or da n ce wit h t h is pr ot oc ol, t he et hical pri nci ples o utli ne d i n t he Declarati o n of 
Helsi n ki, I C H G C P  a n d a n y ot her a p plica ble re g ulati o ns. T he I n vesti gat or m ust e ns ure t h at o nl y 
s u bjects w h o ha ve gi ve n i nf or me d c o nse nt are i ncl u de d i n t he trial. 
 
S u bject I nf or m ati o n a n d I nf or me d C o nse nt  
A n u nc o n diti o nal prere q uisite f or  eac h s u bject pri or t o  partici pati o n i n t he trial is writte n i nf or m e d 
c o nse nt , w hic h m ust be gi ve n bef ore a n y trial-relat e d acti vities are carri e d o ut. A de q uate i nf or mati o n 
m ust t heref ore be gi ve n t o t he s u bject b y t he I n vesti gat or  or a n a p pr o priate desi g nee (if l ocal  
re g ulati o ns per mit) bef or e i nf or me d c o ns e nt is o btai ne d. 
A s u bject i nf or mati o n s heet  m ust be pre pare d  i n t he l ocal la n g u a ge i n acc or da nce wit h I C H G C P  a n d 
will be pr o vi de d b y t h e S p o ns or f or t he p ur p os e of o btai ni n g i nf or me d c o nse nt. I n a d diti o n t o 
pr o vi di n g t his w ritte n i nf or mati o n t o a p ote ntial s u bject, t he I n v esti gat or or a desi g n ee will i nf or m 
t he s u bject ver ball y of all perti ne nt as pects of t h e trial, usi n g la n g ua ge c h ose n s o t hat t he i nf or mati o n 
ca n be f ull y a n d r ea dil y u n derst o o d b y la y pers o ns. T he s u bject w ill be gi v e n s ufficie nt ti me t o rea d 
Gl o bal Versi o n I D: C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
t he i nf or mati o n a n d t he o p p ort u nit y t o as k q u esti o ns a n d t o re q uest a d diti o nal i nf or mati o n a n d 
clarificati o n.  
If per mitte d b y nati o nal r e g ul ati o ns, a p ers o n ot her t ha n t he I n vesti gat or m a y i nf or m t he s u bject a b o ut 
t he trial a n d si g n t h e IC F , as a b o ve. 
After t he i nf or mati o n is pr o vi de d b y t he I n vesti gat or, t he I C F  m ust be si g n e d a n d dat e d b y t he s u bject 
a n d t he I n vesti gat or. 
T he si g n e d a n d date d declarati o n of i nf or me d c o ns e nt will re mai n at t he I n v esti gat or’s site, a n d m ust 
be saf el y arc hi ve d s o t h at t he f or ms ca n b e retrie 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. T he pr ocess of I nf or me d C o nse nt c ollecti o n m ust b e cl earl y d o c u me nte d i n t h e 
s o urce n otes. A c o p y of t he si g n e d a n d date d i nf or mati o n a n d IC F  s h o ul d b e pr o vi de d t o t he s u bject 
pri or t o partici pati o n. 
W he ne ver i m p orta nt ne w i nf or mati o n bec o mes a v aila ble t hat m a y be rele v a nt t o i nf or me d c o ns e nt,  
t he S p o ns or will re vise t h e s u bject i nf or m ati o n s heet a n d a n y ot h er writte n i nf or mati o n t o be pr o vi de d 
t o t he s u bjects a n d I n vesti gat or will s u b mit t he m t o t he I R B/I E C f or re vie w a n d o pi ni o n. Usi n g t he 
a p pr o ve d r e vise d s u bject i nf or mati o n s heet a n d ot her writte n i nf or mati o n, the I n vesti gat or will  
e x plai n t he c ha n ges t o t he pre vi o us versi o n t o eac h trial s u bject a n d o btai n ne w writte n c o nse nt f or 
c o nti n ue d partici p ati o n i n t he trial. T h e s u bject will be gi ve n s ufficie nt ti me t o rea d t h e i nf or m ati o n 
a n d t he o p p ort u nit y t o as k q uesti o ns a n d t o re q uest a d diti o nal i nf or mati o n a n d clarifi cati o n a b o ut t he 
c ha n ges.  
 
S u bject I de ntific ati o n a n d Pri v ac y  
A u ni q ue n u m ber will be assi g n e d t o eac h s u bject, i m me diatel y aft er i nf or me d c o nse nt has bee n 
o btai ne d. T his n u m ber w ill ser ve as t h e s u bject’s i de ntifier i n t he tri al as w ell as i n t he cli nical trial 
data base. All s u bject d ata c ollect e d i n t he trial will be st ore d u n d er t h e a p pr o priate s u bject n u m ber. 
O nl y t h e I n v esti gat or will be a ble t o li n k trial d ata t o a n i n di vi d ual s u bject via a n i de ntificati o n list 
ke pt at t he site. F or eac h s u bject, ori gi n al me dical data will be accessi ble f or t he p ur p oses of s o urce 
data verificati o n b y t he M o nit or, a u dits a n d re g ulat or y i ns pecti o ns, b ut s u bject c o nfi de ntialit y will 
be strictl y m ai ntai ne d.  
Data pr ot ecti o n a n d pri v ac y r e g ulati o ns will be o bser ve d i n ca pt uri n g, f or war di n g, pr o cessi n g, a n d 
st ori n g s u bject d ata. S u bjects will be i nf or me d acc or di n gl y, a n d will be re q ueste d t o gi v e t heir 
c o nse nt o n data ha n dli n g pr oce d ur es i n acc or da n ce wit h nati o nal re g ulati o ns.  
 
E mer ge nc y Me dic al S u p p ort a n d S u bject C ar d  
S u bjects will be pr o vi de d wit h E mer ge nc y M e dical S u p p ort car ds  s u p plie d b y t he S p o ns or f or use 
d uri n g  tri al  partici p ati o n  i n  or der  t o  pr o vi de  cli nical  trial  s u bjects  wit h  a  w a y  of  i d e ntif yi n g 
t he msel ves  as  partici p ati n g  i n  a  cli nical  trial  a n d  t o  gi ve  h ealt h  care  pr o vi ders  access  t o  a n y 
i nf or mati o n a b o ut t his partici pati o n t hat ma y be nee de d t o deter mi ne t he c o urse of me di cal treat me nt 
f or t he s u bject. 
T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical trial I n v esti gat or cari n g f or t he 
affecte d s u bject. T he I n v esti gat or a gr ees t o pr o vi d e his or h er e mer ge nc y c o ntact i nf or mati o n o n t h e 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
car d f or t his p ur p ose. If t he I n v esti gat or is a vaila ble w he n a n e ve nt occ urs,  t he y will a ns wer a n y 
q uesti o ns. A n y s u bse q u e nt acti o n will f oll o w t he sta n dar d pr ocess esta blis he d f or I n v esti gat ors. 
 
Cli nic al Tri al I ns ur a nce a n d C o m pe ns ati o n t o S u bjects  
I ns ura nce c o vera ge wi ll be pr o vi de d f or eac h c o u ntr y partici pati n g t o t he trial. I ns ura nce c o nditi o ns 
s hall meet g o o d l ocal sta n dar ds, as a p plica ble. 
 
I n de pe n de nt Et hics C o m mittee or I nstit uti o n al Re vie w B o ar d 
Pri or t o c o m me nce me nt of t he trial at a gi ve n site, t h is cli nical trial pr ot oc ol will be s u b mitte d 
t o get her wit h its ass ociate d d oc u me nts t o t he res p o nsi ble I E C or I R B f or its fa v ora ble o pi ni o n or 
a p pr o val , w hic h will be file d i n t he I n v esti gat or Site File . A c o p y will be file d i n t he  S p o ns or Trial 
Master File . 
T he I E C  or I R B will be as ke d t o d oc u me nt t he date of t he meeti n g at w hic h t he fa v ora bl e o pi ni o n or 
a p pr o val w as gi v e n a n d t he me m bers a n d v oti n g me m bers pres e nt. Writte n e vi de nce of fa v ora ble 
o pi ni o n or a p pr o v al t hat clearl y i de ntifi es t he trial, t he cli nical tri al pr ot oc ol versi o n a n d t h e S u bject 
I nf or mati o n a n d IC F  v ersi o n re vie w e d s h o ul d b e pr o vi de d. W here p ossi ble, c o pies of t he m eeti n g 
mi n utes s h o ul d be o btai ne d. 
A me n d me nts t o t h is cli nical trial pr ot o c ol will als o be s u b mitte d t o t he c o n cer ne d I E C  or I R B, b ef ore 
i m ple me ntati o n of s u bsta ntial  c ha n ges  (see  Secti o n  1 0. 5 ).  Rele va nt  safet y  i nf or mati o n  will  be  
s u b mitte d t o t he I E C or I R B d uri n g t he c o urse of t he trial i n acc or d a nce wit h nati o nal re g ulati o ns 
a n d re q uir e me nts. 
 
He alt h A ut h orities  
T he cli nical trial pr ot oc ol a n d a n y a p plica ble d o c u me ntati o n (f or e x a m ple, I n vesti gati o nal Me dici n al 
Pr o d uct D ossier, S u bject I nf or mati o n a n d I C F ) 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. 
1 0  
Tri al M a n a ge me nt  
 
C ase Re p ort F or m H a n dli n g  
Refer t o t he  e C R F C o m pleti o n I nstr ucti o ns. 
T he mai n p ur p ose of t he e C R F is t o o btai n data re q uire d b y t he cli nical trial pr ot oc ol i n a c o m plete, 
acc ur ate, le gi ble a n d ti mel y. T he d ata i n t he e C R F s h o ul d be c o nsiste nt wit h t he rele va nt s o urce 
d oc u me nts. 
T he I n v esti gat or or desi g nee is res p o nsi ble f or e ns uri n g t h at t he d ata c ollecte d i n t he c o urs e of t his 
trial is acc urat e a n d d oc u me nte d  a p pr o priat el y o n all a p plica ble f or ms. T he y will t he n be pr ocesse d, 
e val uate d, a n d st or e d i n a n o n y m o us f or m i n acc or da nce wit h a p plica bl e dat a pr otecti o n re g ulati o ns. 
T he I n vesti gat or m ust e ns ure t hat t he e C R Fs a n d a n y ot her ass ociat e d d oc u me nts f or war de d t o 
S p o ns or or its desi g nate d or ga nizati o n c o ntai n n o me nti o n of a n y s u bj ect n a mes. 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
F or patie nt -re p ort e d o utc o me data s uc h as Q o L, e P R O will be use d. 
T he data will be e ntere d i nt o a vali date d data base. T he S p o ns or or its desi g nee will be res p o nsi ble 
f or data pr ocessi n g, i n acc or da nce wit h t he Sp o ns or’s data ma n a ge me nt pr oce d ures. Data b ase l oc k 
will occ ur o nce q ualit y c o ntr ol a n d q u alit y ass ura nce pr oce d ures h a ve bee n c o m plete d. P D F files of 
t he e C R Fs will be pr o vi d e d t o t he I n vesti gat ors at t he c o m pleti o n of t he trial. 
 
S o urce D at a a n d S u bject Fi les 
T he I n v esti gat or m ust k ee p a file ( me dical file, ori gi nal me di cal rec or ds) o n pa per or electr o nicall y 
f or e v er y s u bject i n t he trial. It m ust b e p ossi ble t o i de ntif y eac h s u bject b y usi n g t his s u bject file. 
T his file will c o ntai n t he de m o gr a p hic a n d me dical i nf or mati o n f or t he s u bject  liste d bel o w a n d 
s h o ul d be as c o m plete as p ossi ble. 
•  S u bject’s f ull na me,  date of birt h, se x, hei g ht, 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 ges d uri n g t h e trial) 
•  Tria l i de ntificati o n, t hat is, t he S p o ns or trial n u m ber f or t his cli nical trial, a n d s u bject n u m ber 
•  Date s f or e ntr y i nt o t he trial (i nf or me d c o ns e nt) a n d visits t o t he site 
•  A n y me di cal 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 his  cli nical trial pr ot ocol 
•  All A E s 
•  Date t hat t he s u bject left t he trial 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 trial or I M P 
(if a p plica ble). 
A ll d oc u me nts c o nt ai ni n g s o urce data m ust be file d, i n clu di n g , b ut n ot li mite d t o C T or MRI sca n 
i ma ges, a n d la b orat or y r es ults. S uc h d oc u me nts m ust bear t he s u bject n u m ber a n d t he date of t he 
pr oce d ur e. I f p ossi ble,  t his  inf or mati o n s h o ul d be pri nte d b y t he i nstr u me nt use d t o perf or m t h e 
assess me nt or meas ur e m e nt. As n ecess ar y, m edical e val u ati o n of s u c h rec or ds s h o ul d be perf or me d; 
all e val uati o ns s h o ul d be d oc u me nte d, si g n e d, a n d date d b y t he I n vesti gat or. 
Electr o nic s u bject files will be pri nte d w he ne ver t he Cli nical researc h ass oci ate perf or ms s o urce data 
verificati o n. Pri nt o uts m ust be si g ne d a n d dat e d b y t he I n v esti gat or, c o u ntersi g ne d b y t he C R A  a n d 
ke pt i n a safe pl ace at t he site.  
 
I n vesti g at or Site File a n d Arc hi vi n g 
U p o n i nitiati o n of t he trial, t he I n vesti gat or will be pr o vi de d wit h a n I n vesti gat or Site File c o ntai ni n g 
all necessar y trial d oc u m e nts , w hic h will be c o m plete d t hr o u g h o ut t he trial  a n d u p date d as necessar y. 
T he file  m ust be a vaila ble f or re vie w b y t he M o nit or , d uri n g S p o ns or a u dit s a n d f or i ns pecti o n b y 
Healt h A ut h orities d uri n g a n d after t he trial, a n d m ust be safel y arc hi ve d f or at least 1 5 years ( or  
l o n ger, p er l ocal re q uire me nts or as ot her wise n otifie d b y t he S p o ns or) after t he e n d of t he trial. T he 
d oc u me nts t o be arc hi ve d i ncl u de t he S u bject I d e ntificati o n List a n d t he si g ne d s u bj ect I C Fs . If 
arc hi vi n g of t he I n v esti gat or Site File is n o l o n ger p o ssi ble at t he site, t he I n v esti gat or m ust n otif y 
t he S p o ns or/ desi g nee. 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
All ori gi nal s u bject files ( me dical rec or ds) m ust be st ore d at t he site ( h os pital, researc h i nstit ute, or 
practice) 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 h e v er is l o n ger. I n a n y case, t he I n vesti gat or s h o ul d e ns ure t hat n o destr u cti o n 
of me dical r ec or ds is perf or me d wit h o ut t he writte n a p pr o val of t he S p o ns or. 
 
M o nit ori n g,  Q u alit y  Ass ur a nce  a n d  I ns pecti o n  b y   He alt h 
A ut h orities  
T his trial will be m o nit ore d i n acc or da n ce wit h t he I C H G C P,  a n d a n y ot h er a p plica ble re g ul ati o ns . 
T he site M o nit or will perf or m visits t o t he trial site at re g ular i nter vals.  
T he cli nical trial pr ot oc ol, eac h ste p of t he data ca pt ure p r o ce d ure, a n d t he ha n dli n g of t he d ata, 
i ncl u di n g t he fi nal cli nical trial re p ort, will be s u bject t o i n de pe n de nt Q ualit y Ass ura nce acti vities. 
A u dits ma y be c o n d ucte d at a n y ti me d uri n g or after t he trial t o e ns ure t h e vali dit y a n d i nte grit y of 
t he trial data. Re pr ese nt ati ves of t he Q ualit y Ass ura nce u nit  fr o m t h e S p o ns or or a desi g nat e d 
or ga nizati o n, as w ell as Healt h A ut h orities, m ust be per mitte d t o access all trial d oc u me nts a n d ot her 
materials at t he site, i ncl u di n g t he I n vesti gat or Site File, t h e c o m plet e d C R Fs, all I M P a n d  I M P 
acc o u nta bilit y rec or ds,  a n d t he ori gi nal me di cal rec or ds or files f or eac h s u bject. 
 
C h a n ges t o t he Cli nic al Tri al Pr ot oc ol  
C ha n ges t o t he cli nical trial pr ot oc ol will be d oc u me nte d i n writi n g. S u bsta nti ve a me n d me nts will 
us uall y re q uire s u b missi o n t o t he H ealt h A ut h orities a n d t o t he rel e va nt I E C/ I R B f or a p pr o v al or 
fa v ora bl e  o pi ni o n.  I n  s uc h  cas es,  t he  a m e n d me nt  will  be  i m ple me nte d  o nl y  after  a p pr o v al  or  
fa v ora bl e o pi ni o n has bee n o btai ne d. 
Mi n or ( n o n -s u bsta ntial) pr ot oc ol a me nd me nts, i ncl u di n g a d mi nistrati ve c ha n ges, will be file d b y t h e 
S p o ns or a n d at t he site. T he y will be s u b mitte d t o t he rel e va nt I E C/I R B or t o Healt h A ut h orities o nl y 
w here r e q ueste d b y p erti ne nt re g ul ati o ns. A n y a m e n d me nt t hat c o ul d affect t he s u bject’s a gr ee me nt 
t o partici pate i n t he trial r e q uires a d diti o nal i nf or m e d c o nse nt pri or t o i m ple me ntati o n f oll o wi n g t he 
pr ocess as d escri be d i n S ecti o n  9. 2 . 
 
Cli nic al Tri al Re p ort a n d P u blic ati o n P olic y  
1 0. 6. 1  
Cli nic al Tri al Re p ort  
After c o m pleti o n of t he trial, a cli nical trial re p ort will be writte n b y t he S p o ns or 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 f oll o wi n g t h e g ui da n ce i n I C H T o pic E 3. 
1 0. 6. 2  
P u blic ati o n  
T he first p u blicati o n will i ncl u de t he res ults of t he a nal ysis of t h e pri mar y e n d p oi nts a n d will i ncl u de 
data fr o m all trial sites . T he I n vesti gat or will i nf or m t he S p o ns or i n a d v a nce a b o ut a n y pl a ns t o 
p u blis h or pres e nt data fr o m t he trial. A n y p u blicati o ns a n d pres e ntati o ns of t he res ults (a bstracts i n 
j o ur nals or n e ws pa p ers, oral pr ese ntati o ns, etc.), eit her i n w h ole or i n p art, b y I n v esti gat ors or t heir 
re pres e ntati ves will r e q uire r e vie w b y t h e S p o ns or bef ore s u b missi o n . T he S p o ns or will n ot s u p press 
p u blicati o n, b ut mai ntai ns t he ri g ht t o dela y p u blicati o n i n or der t o pr otect i ntellect ual pr o pert y ri g hts.  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
P osti n g of data o n t he E ur o pea n Cli nical Trials Re gister a n d Cli nical Trials. g o v is pla n ne d a n d will 
occ ur 1 2 m o nt hs after t he last cli nic visit of t he fi nal trial s u bject or a n ot her a p pr o priate dat e t o meet 
a p plica ble r e q uire me nts.  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
1 1  
Refere nces Cite d  i n t he Te xt 
A M A T O M . P.  et al. C o g niti ve reser ve a n d c ortical atr o p h y i n m ulti ple scler osis: a l o n git u di nal 
st u d y. J Ne ur ol. v. 8 0, n. 1 9, p. 1 7 2 8- 3 3, 2 0 1 3.I S S N 1 5 2 6- 6 3 2 X.  
A R R O Y O G O N Z A L E Z, R. et al. Ale mt uz u ma b i m pr o ves q ualit y - of-life o utc o mes c o m pare d wit h 
s u bc uta ne o us i nterfer o n beta-1a i n patie nts wit h acti ve rela psi n g -re mitti n g m ulti ple scler osis. M ult 
Scler, p. 1 3 5 2 4 5 8 5 1 6 6 7 7 5 8 9, N o v 0 1 2 0 1 6. I S S N 1 3 5 2- 4 5 8 5. 
A Y M E RI C H, M.; G UI L L A M Ó N, I.; J O V E L L, A. J. Healt h -relate d q ualit y of life assess me nt i n 
pe o ple wit h m ulti ple scler osis a n d t heir fa mil y care gi vers. A m ultice nter st u d y i n Catal o nia ( S o ut her n 
E ur o pe). Patie nt Pref er A d here n ce, v. 3, p. 3 1 1 -2 1, N o v 2 0 0 9. I S S N 1 1 7 7 -8 8 9 X. Dis p o ní vel e m: < 
htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 1 9 9 3 6 1 7 4 >. 
B A TI S T A . S., et al. Bas al ga n glia, t hal a m us a n d ne oc ortical atr o p h y pre dicti n g sl o we d c o g niti ve 
pr ocessi n g i n m ulti ple scler osis . J Ne ur ol, v. 2 5 9, p. 1 3 9-1 4 6, J a n 2 0 1 2. 1 4 3 2- 1 4 5 9. I S S N 1 4 3 2- 1 4 5 9. 
B A U M S T A R C K, K. et al. Pre dict ors of q ualit y of life i n p atie nts wit h rela psi n g -re mitti n g m ulti ple 
scler osis: a 2-year l o n git u di nal st u d y. Re v Ne ur ol ( Paris), v. 1 7 1, n. 2, p. 1 7 3 -8 0, Fe b 2 0 1 5. I S S N 
0 0 3 5- 3 7 8 7. Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 5 5 5 8 7 9 8 >. 
B Ø E L U N D E, H. M. et al. E m pl o y m e nt a m o n g p atie nts wit h m ulti ple scler osis -a p o p ulati o n st u d y. 
P L o S  O ne,  v.  9,  n.  7,  p.  e 1 0 3 3 1 7,  2 0 1 4.  I S S N  1 9 3 2 -6 2 0 3.  Dis p o ní vel  e m:  <  
htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 5 0 5 4 9 7 2 >.  
F L E N S N E R, G. et al. W or k ca pacit y a n d h ealt h -relate d q ualit y of life a m o n g i n di vi d uals wit h 
m ulti ple scler osis re d uce d b y fati g ue: a cr oss -secti o nal st u d y. B M C P u blic Healt h, v. 1 3, p. 2 2 4, Mar 
2 0 1 3. I S S N 1 4 7 1- 2 4 5 8. Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 3 4 9 7 2 8 1 >. 
G A R G, H.; B U S H, S.; G A P P M AI E R, E. Ass ociati o ns Bet wee n Fati g ue a n d Disa bilit y, F u ncti o nal 
M o bilit y, D e pressi o n, a n d Q ualit y of Lif e i n Pe o ple wit h M ulti ple Scler osis. I nt J M S Care, v. 1 8, n. 
2, p. 7 1- 7, Mar- A pr 2 0 1 6. I S S N 1 5 3 7- 2 0 7 3 ( Pri nt). 1 5 3 7- 2 0 7 3. 
GI B B O N S, R. D.; H E D E K E R, D.; D U T OI T, S. A d va nces i n a nal ysis of l o n git u di nal data. A n n u 
Re v  Cli n  Ps yc h ol,  v.  6,  p.  7 9 -1 0 7,  2 0 1 0.  I S S N  1 5 4 8 -5 9 5 1  ( Electr o nic)  1 5 4 8 -5 9 4 3  ( Li n ki n g).  
Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 0 1 9 2 7 9 6 >. 
GI O V A N N O NI, G. et al. A place b o -c o ntr olle d trial of oral cla dri bi ne f or rel a psi n g m ulti ple scler osis. 
N E n gl J Me d, v. 3 6 2, n. 5, p. 4 1 6 -2 6, Fe b 0 4 2 0 1 0. I S S N 1 5 3 3 -4 4 0 6 ( Electr o nic)   0 0 2 8- 4 7 9 3 
( Li n ki n g). Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 0 0 8 9 9 6 0 >. 
G R Y T T E N, N. et al. Healt h -relate d q ualit y of life a n d disease-m o dif yi n g treat me nt be ha vi o ur i n 
rela psi n g-r e mitti n g m ulti ple scler osis--a m ultice ntre c o h ort st u d y. A cta N e ur ol Sca n d S u p pl, n. 1 9 5, 
p. 5 1 -7, 2 0 1 2. I S S N 1 6 0 0 -5 4 4 9. Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 3 2 7 8 6 5 7 
>.  
H O U T C H E N S M . K. et al. T hala mic atr o p h y a n d c o g niti o n i n m ulti ple scler osis. J Ne ur ol. v. 6 9, n. 
1 2, p. 1 2 1 3- 2 3, Se p 2 0 0 7. I S S N 1 5 2 6- 6 3 2 X.  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
J O N E S, E. et al. Q ua ntif yi n g t he r elati o ns hi p bet wee n i n crease d dis a bilit y a n d h ealt h care res o urce 
utilizati o n, q ualit y of life, w or k pr o d ucti vit y, healt h care c osts i n patie nts wit h m ulti ple scler osis i n 
t he U S. B M C Healt h Ser vices Researc h, v. 1 6, p. 2 9 4, J ul 2 2 2 0 1 6. I S S N 1 4 7 2- 6 9 6 3. 
J U LI A N, L. J. et al. E m pl o y me nt i n m ulti ple scler osis. E xiti n g a n d re -e nteri n g t h e w or k f orce. J 
Ne ur ol,  v.  2 5 5,  n.  9,  p.  1 3 5 4 -6 0,  Se p  2 0 0 8.  I S S N  0 3 4 0 -5 3 5 4.  Dis p o ní vel  e m:  <  
htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 1 8 6 7 7 6 3 9 >. 
 
L EI S T, T. P. et al. Eff ect of oral cla dri bi ne o n ti me t o c o n versi o n t o cli nicall y d efi nite m ulti ple 
scler osis i n patie nts wit h a first de m yeli nati n g e v e nt ( O R A C L E M S): a p hase 3 ra n d o mise d trial. 
La n cet N e ur ol o g y, v. 1 3, n. 3, p. 2 5 7 -2 6 7, Mar 2 0 1 4. I S S N 1 4 7 4 -4 4 6 5 ( Electr o nic) .  1 4 7 4- 4 4 2 2 
( Li n ki n g). Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 4 5 0 2 8 3 0 >. 
M A U R E R, M. et al. M ulti ple scler osis rela pses are ass oci ate d wit h i ncrease d fati g ue a n d re d uce d 
healt h -rel ate d q ualit y of life - A p ost h oc a nal ysis of t he T E M S O a n d T O W E R st u dies. M ult Scler 
Relat Dis or d, v. 7, p. 3 3- 4 0, Ma y 2 0 1 6. I S S N 2 2 1 1- 0 3 4 8. 
MI N E E V K . K. et al. C haracteristics of ne ur ol o gical a n d c o g niti ve stat us i n patie nts wit h m ulti ple 
scler osis i n relati o n t o t he l ocati o n a n d v ol u mes of de m yeli nati o n f oci a n d t he se verit y of brai n 
atr o p h y. Ne ur os ci Be ha v P h ysi ol, v. 3 9, n. 1, p. 3 5- 8, 2 0 0 9. I S S N 1 5 7 3- 8 9 9 X. 
M O R R O W,  T.  J.  T he  c osts  a n d  c o nse q ue n ces  of  m ulti ple  scler osis  rela pses:  a  ma na ge d  care  
pers pecti ve. J Ne ur ol Sci, v. 2 5 6 S u p pl 1, p. S 3 9 -4 4, Ma y 1 5 2 0 0 7. I S S N 0 0 2 2 -5 1 0 X ( Pri nt) . 0 0 2 2-
5 1 0 X ( Li n ki n g). Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 1 7 3 6 2 9 9 5 >. 
M U C K S C H E L, M.; B E S T E, C.; ZI E M S S E N, T. I m m u n o m o d ulat or y treat me nts a n d c o g niti o n i n 
M S. Acta Ne ur ol Sca n d, v. 1 3 4 S u p pl 2 0 0, p. 5 5- 9, Se p 2 0 1 6. I S S N 0 0 0 1- 6 3 1 4. 
O' C O N N O R, P. et al. R a n d o mize d trial of oral terifl u n o mi de f or rela psi n g m ulti ple scler osis. Ne w 
E n gla n d  J o ur nal  of  Me dici ne,  v.  3 6 5,  n.  1 4,  p.  1 2 9 3 -1 3 0 3,  O ct  0 6  2 0 1 1.  I S S N  1 5 3 3 - 4 4 0 6 
( Electr o nic).  
0 0 2 8-4 7 9 3
 ( Li n ki n g).
 Dis p o ní vel
 e m:
 <
 
htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 1 9 9 1 9 5 1 >. 
O L E E N -B U R K E Y, M. et al. B ur de n of a m ulti ple scler osis rela pse: t h e pati e nt's pers p ecti ve. Patie nt, 
v.  5,  n.  1,  p.  5 7 -6 9,  2 0 1 2.  I S S N  1 1 7 8 -1 6 5 3  ( Pri nt) .  1 1 7 8-1 6 5 3  ( Li n ki n g).  Dis p o ní vel  e m:  <  
htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 2 2 1 7 2 6 3 >. 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
O R M E, M. et al. T h e eff ect of diseas e, f u n cti o nal stat us, a n d rela ps es o n t he utilit y of pe o pl e wit h 
m ulti ple scler osis i n t he U K. Val ue Healt h, v. 1 0, n. 1, p. 5 4 -6 0, 2 0 0 7 J a n -Fe b 2 0 0 7. I S S N 1 0 9 8 -
3 0 1 5. Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 1 7 2 6 1 1 1 6 >. 
P A R KI N,  D.  et  al.  Treat me nt  of  m ulti ple  scler osis  wit h  i nterfer o n  bet a:  a n  a p prais al  of  c ost -
effecti ve ness a n d q ualit y of life. J Ne ur ol Ne ur os ur g Ps yc hiatr y, v. 6 8, n. 2, p. 1 4 4 -9, Fe b 2 0 0 0. I S S N 
0 0 2 2- 3 0 5 0. Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 1 0 6 4 4 7 7 7 >. 
P E N N E R, I. K. E v al uati o n of c o g niti o n a n d fati g ue i n m ulti ple scler osis: dail y practice a n d f ut ure 
directi o ns. Act a N e ur ol S ca n d, v. 1 3 4 S u p pl 2 0 0, p. 1 9 -2 3, Se p 2 0 1 6. I S S N 1 6 0 0 -0 4 0 4 ( Electr o nic) . 
0 0 0 1- 6 3 1 4 ( Li n ki n g). Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 7 5 8 0 9 0 2 >. 
P R Z Y B E K, J. et al. E v ol uti o n of dia g n ostic criteri a f or m ulti ple scler osis. Ne ur ol N e ur oc hir P ol, v. 
4 9,  n.  5,  p.  3 1 3 -2 1,  2 0 1 5.  I S S N  0 0 2 8 -3 8 4 3  ( Pri nt) .  0 0 2 8-3 8 4 3  ( Li n ki n g).  Dis p o ní vel  e m:  <  
htt ps:// w w w . nc bi. nl m. ni h. g o v/ p u b me d/ 2 6 3 7 7 9 8 3 >. 
S T R A N D, V et al. I m pr o ve d healt h -r elate d q ualit y of life a n d p h ysical f u ncti o n i n patie nts wit h 
refr act or y c hr o nic g o ut f oll o wi n g treat me nt wit h pe gl oticase: e vi de nce fr o m p hase III ra n d o mize d 
c o ntr olle d trials. J R he u mat ol, v. 3 9, n. 7, p. 1 4 5 0- 7, J ul 2 0 1 2. I S S N 0 3 1 5- 1 6 2 X ( Pri nt). 0 3 1 5- 1 6 2 X 
( Li n ki n g). Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 2 6 6 0 8 0 5 >. 
T R A M A C E R E,  I.  et  al.  I m m u n o m o d ulat ors  a n d  i m m u n os u p pressa nts  f or  rela psi n g -re mitti n g 
m ulti ple scler osis: a net w or k meta -a nal ysis. C oc hra ne D ata bas e S yst R e v, n. 9, p. C D 0 1 1 3 8 1, Se p 
1 8
 2 0 1 5.
 I S S N   1 4 6 9-4 9 3 X
 ( Electr o nic) . 
1 3 6 1- 6 1 3 7
 ( Li n ki n g).
 Dis p o ní vel
 e m:
 <
 
htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 6 3 8 4 0 3 5 >. 
T R A P P, B. D.; N A V E, K. A. M ulti ple scler osis: a n i m m u ne or ne ur o de ge nerati ve dis or d er? A n n ual 
Re vie w of Ne ur oscie nce, v. 3 1, p. 2 4 7 -2 6 9, 2 0 0 8. I S S N 0 1 4 7 -0 0 6 X ( Pri nt) . 0 1 4 7-0 0 6 X ( Li n ki n g). 
Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 1 8 5 5 8 8 5 5 >. 
V E R M E R S C H, P. et al. Terifl u n o mi de vers us s u bc uta ne o us i nterfer o n beta -1a i n patie nts wit h 
rela psi n g m ulti ple scler osis: a ra n d o mise d, c o ntr olle d p hase 3 trial. M ult Scler, v. 2 0, n. 6, p. 7 0 5 -
1 6, Ma y 2 0 1 4. I S S N 1 4 7 7 -0 9 7 0. Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 4 1 2 6 0 6 4 
>.  
VI C K R E Y, B. G. 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 u alit y-of -life 
meas ures f or m ult i 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. 
Dis p o ní vel e m: < 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 >. 
A healt h -relat e d q ualit y of life meas ure f or m ulti ple scler osis. Q ual Life Res, v. 4, n. 3, p. 1 8 7- 2 0 6, 
J u n 1 9 9 5. I S S N 0 9 6 2- 9 3 4 3. Dis p o ní vel e m: < htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 7 6 1 3 5 3 0 >. 
V O L L M E R, T. T he nat ural hist or y of rela pses i n m ulti ple scler osis. J Ne ur ol Sci, v. 2 5 6 S u p pl 1, p. 
S 5 -1 3,  Ma y  1 5  2 0 0 7.  I S S N  0 0 2 2 -5 1 0 X  ( Pri nt) .  0 0 2 2-5 1 0 X  ( Li n ki n g).  Dis p o ní vel  e m:  <  
htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 1 7 3 4 6 7 4 7 >. 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
1 2  
A p pe n dices  
 
A p pe n di x 1: S c he d ule  of Assess me nts  
 
Visit  
 
1 
2 
3 
4 
5 
6 
7 
Ti me
 of
 
Assess me nt
s* 
Scree ni n g * * 
B aseli n
e 
M o nt h 2  
( ± 7 d a ys) 
M o nt h 6  
( ± 7 d a ys) 
M o nt h 1 2  
( ± 7 d a ys)a 
M o nt h 1 4  
( ± 7 d a ys)a 
M o nt h 1 8  
( ± 7 d a ys)a 
M o nt h 2 4  
( ± 7 d a ys)a 
I nf or me d 
C o nse nt b 
X 
 
 
 
 
 
 
 
I R Tc 
 
X 
 
 
X 
 
 
 
Wei g ht  
 
X 
 
 
X 
 
 
 
Vital Si g ns  
X 
 
 
 
X 
 
 
X 
P h ysical 
E xa mi nati o n  
X 
 
 
 
X 
 
 
X 
Me dical 
H ist or y 
X 
 
 
 
 
 
 
 
Disease 
Hist or y  
X 
 
 
 
 
 
 
 
L y m p h oc yte 
C o u nt e 
X 
X 
X 
X 
X 
X 
X 
X 
H R Q o L 
( M S Q o L-
5 4)  
 
X 
 
 
X 
 
 
X 
Treat me nt 
S atisfacti o n 
( T S Q M 
v 1. 4 ) 
 
 
 
X 
X 
 
 
X 
M RI 
X 
 
 
 
 
 
 
X 
Ser ol o g y 
( HI V,  H B V,  
H C V, V Z V)  
X h 
 
 
 
X f 
 
 
 
T B 
Scree ni n g  
X 
 
 
 
X 
 
 
 
 C CI
C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
Pre g na nc y 
testg 
X 
X 
 
 
X 
 
 
 
S u bject 
Diar y  
 
X 
X 
X 
X 
X 
X 
X 
A Es  
 
X 
X 
X 
X 
X 
X 
X 
a An all o wa nce wi n d o w of 0 -3 m o nt hs will ta ke place i n case of d ela y i n l y m p h o c yte rec o v er y t o t h e le vels me nti o n e d i n Secti o n  5. 4. 1 . 
b T he I C F s h o ul d b e si g n e d b y t h e s u bject b ef ore a n y c h a n ges i n t h e c o n c o mita nt me dicati o ns are ma d e . 
c I nteracti ve Res p o nse Tec h n ol o g y  f or assi g n me nt of s u bject I D n u m b er a n d I M P acc o u nta bilit y.  
d Trial visits f or s u bjects w h o are rela psi n g will b e re q uire d t o p erf or m t h e o utc o me e val u ati o n at t h e res ol uti o n of t h e rela pse, w he n 
it is a p pr o priate f or t h e s u bject t o c o m plete trial visit assess me nts. 
e L y m p h oc yte c o u nt s h o ul d b e (i) n or mal b ef ore i nitiati n g cla dri bi n e i n year 1, (ii) at least 8 0 0 cells/ m m³ b ef ore i nitiati n g i n year 2 
(iii) c hec ke d at 2 a n d 6 m o nt hs after start of treat me nt i n eac h treat me nt ye ar. If n ecessar y, t h e tr eat me nt c o urse i n year 2 ca n be 
dela ye d f or u p t o 6 m o nt hs t o all o w f or rec o ver y of l y m p h o c ytes. If t his rec o ver y ta kes m ore t h a n 6 m o nt hs, cla dri bi n e treat m e nt 
s h o ul d be ter mi nate d . 
f O nl y f or HI V, H B V a n d H C V.  
g Uri ne or ser u m test will b e d o n e acc or di n g t o l o cal re g ulati o ns.  
h: If t he l ocal la b orat or y bl o o d test f or ser ol o g y a n d safet y a n al ysis is c o n d u cte d wit hi n 1 0 d a ys of t h e Scree ni n g visit, n o bl o o d sa m ples 
nee d to be re peate d .   
* T he or der of assess me nts will b e M S Q o L -5 4, T S Q M v 1. 4, 
 
* * I n certai n cases, scree ni n g p eri o d ma y b e l o n ger t h a n 4 wee ks (s ee Secti o n  7. 1. 1 ) 
* * * If t he ne ur ol o gical e xa mi n ati o n at t h e Scree ni n g visit is c o n d u cte d wit hi n 1 0 d a ys of Bas eli n e a n d t h e s u bject re p orts n o c ha n ge i n 
stat us, n o ne ur ol o gical e xa mi n ati o n n ee ds t o b e re p eate d o n Baseli n e ( Visit 1). 
 
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
 
A p pe n di x 2 : M S Q o L-5 4 S C A L E  
 
M ulti ple  Scler osis Q u alit y of Life ( M S Q o L) -5 4 I nstr u me nt  
I N S T R U C TI O N S: 
T hi s s ur v e y a s k s a b o ut y o ur h e alt h a n d d ail y a cti viti e s. A n s w er e v er y q u e sti o n  b y s el e cti n g  t h e 
a p pr o pri at e n u m b er ( 1, 2, 3...) . 
If y o u ar e u n s ur e a b o ut h o w t o a n s w er a q u e sti o n, pl e a s e gi v e t h e b e st a n s w er y o u c a n. 
Pl e a s e f e el fr e e t o a s k s o m e o n e t o a s si st y o u if y o u n e e d h el p r e a di n g or m ar ki n g t h e f or m.  
1. I n g e n er al, w o ul d y o u s a y y o ur h e alt h i s:  
  
(s el e ct  o n e n u m b er)  
 
E x c ell e nt … … … … … … … … … … … ….. 1 
 
V er y g o o d … … … … … … … … … … … … 2  
 
G o o d … … … … … … … … … … … … … …. 3 
 
F air … … … … … … … … … … … … … … … 4 
 
P o or … … … … … … … … … … … … … ….. 5 
 
2. C o m p ar e d t o o n e y e ar a g o , h o w w o ul d y o u r at e y o ur h e alt h i n g e n er al n o w ? 
 
  
  
  
  
  
  
  
(s el e ct  o n e n u m b er)  
 
M u c h b ett er n o w t h a n o n e y e ar a g o … … … … … … … … … … … … ….. 1 
 
S o m e w h at b ett er n o w t h a n o n e y e ar a g o … … … … … … … … … … …. 2  
 
A b o ut t h e s a m e a s o n e y e ar a g o … … … … … … … … … … … … … … … 3  
 
S o m e w h at w or s e n o w t h a n o n e y e ar a g o … … … … … … … … … … …. 4  
 
M u c h w or s e n o w t h a n o n e y e ar a g o … … … … … … … … … … … … …... 5  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
3- 1 2.  T h e f oll o wi n g q u e sti o n s ar e  a b o ut a cti viti e s y o u mi g ht d o d uri n g a t y pi c al d a y. D o e s y o ur 
h e alt h  n o w li mit y o u i n t h e s e a cti viti e s ? If s o, h o w m u c h ?  
(S el e ct  1, 2, or 3 o n e a c h li n e)  
 
Y e s,  
li mit e d 
a l ot  
Y e s,  
li mit e d 
a littl e  
N o, n ot  
li mit e d 
at all  
3. Vi g or o u s a cti viti e s , s u c h a s 
r u n ni n g, lifti n g h e a v y o bj e ct s, 
p arti ci p ati n g i n str e n u o u s s p ort s  
1 
2 
3 
4. M o d er at e a cti viti e s , s u c h a s 
m o vi n g a t a bl e, p u s hi n g  
a v a c u u m cl e a n er, b o wli n g, or 
pl a yi n g g olf  
1 
2 
3 
5. Lifti n g or c arr yi n g gr o c eri e s  
1 
2 
3 
6. Cli m bi n g s e v er al  fli g ht s of 
st air s 
1 
2 
3 
7. Cli m bi n g o n e  fli g ht of st air s 
1 
2 
3 
8. B e n di n g, k n e eli n g, or  
st o o pi n g  
1 
2 
3 
9. W al ki n g m or e t h a n a mil e  
1 
2 
3 
1 0. W al ki n g s e v er al h u n dr e d y ar d s  
1 
2 
3 
1 1. W al ki n g o n e h u n dr e d y ar d s  
1 
2 
3 
1 2. B at hi n g a n d dr e s si n g  
y o ur s elf  
1 
2 
3 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
1 3 -1 6.   
 
D uri n g t h e p a st 4 w e e k s  h a v e y o u h a d a n y of t h e f oll o wi n g pr o bl e m s wit h  
  
 
y o ur w or k or ot h er r e g ul ar d ail y a cti viti e s a s a r e s ult of y o ur p h y si c al     
 
h e alt h ? 
  
  
(S el e ct  o n e n u m b er o n e a c h li n e)  
 
Y E S  
N O  
1 3. C ut d o w n o n t h e a m o u nt of ti m e  y o u s p e nt o n 
w or k or ot h er a cti viti e s  
1 
2 
1 4. A c c o m pli s h e d l e s s  t h a n y o u w o ul d li k e 
1 
2 
1 5. W er e li mit e d i n t h e ki n d  of w or k or ot h er 
a cti viti e s  
1 
2 
1 6. H a d diffi c ult y  p erf or mi n g t h e w or k or ot h er 
a cti viti e s (f or e x a m pl e, it t o o k e xtr a eff ort)  
1 
2 
 
1 7 -1 9.   
 
D uri n g t h e p a st 4 w e e k s , h a v e y o u h a d a n y of t h e f oll o wi n g pr o bl e m s wit h  
  
 
y o ur w or k or ot h er r e g ul ar d ail y a cti viti e s a s a r e s ult of a n y e m oti o n al    
 
pr o bl e m s  ( s u c h a s f e eli n g d e pr e s s e d or a n xi o u s) ? 
  
  
(S el e ct  o n e n u m b er o n e a c h li n e)  
 
Y E S  
N O  
1 7. C ut d o w n o n t h e a m o u nt of ti m e  y o u s p e nt o n 
w or k or ot h er a cti viti e s  
1 
2 
1 8. A c c o m pli s h e d l e s s  t h a n y o u w o ul d li k e 
1 
2 
1 9. Di d w or k or ot h er a cti viti e s l e s s c ar ef ull y  t h a n 
u s u al  
1 
2 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
2 0.  D uri n g  t h e  p a st  4  w e e k s ,  t o  w h at  e xt e nt  h a s  y o ur  p h y si c al  h e alt h  or  e m oti o n al  
 
pr o bl e m s i nt erf er e d wit h y o ur n or m al s o ci al a cti viti e s wit h f a mil y, fri e n d s,  
 
n ei g h b o ur s, or gr o u p s ?  
  
  
  
  
  
  
(s el e ct  o n e n u m b er)  
 
  
 
N ot at all … … … … … … … … … … … ….. 1  
 
  
  
Sli g htl y … … … … … … … … … … … … …. 2 
 
  
 
M o d er at el y … … … … … … … … … … ….. 3 
 
  
 
Q uit e a bit … … … … … … … … … … … … 4  
 
  
  
E xtr e m el y … … … … … … … … … … … … 5 
 
P ai n  
 
2 1.  H o w m u c h b o dil y  p ai n h a v e y o u h a d d uri n g t h e p a st 4 w e e k s ? 
 
  
  
  
  
  
  
(s el e ct  o n e n u m b er)  
  
  
N o n e … … … … … … … … … … … … … … 1 
 
  
 
V er y mil d … … … … … … … … … … … … 2  
 
  
 
Mil d … … … … … … … … … … … … … …. 3  
 
  
 
M o d er at e … … … … … … … … … … … … 4  
 
  
  
S e v er e … … … … … … … … … … … … …. 5 
 
  
 
V er y s e v er e … … … … … … … … … … … 6  
 
2 2.  D uri n g  t h e  p a st  4  w e e k s ,  h o w  m u c h  di d  p ai n  i nt erf er e  wit h  y o ur  n or m al  w or k  
 
(i n cl u di n g b ot h w or k o ut si d e t h e h o m e a n d h o u s e w or k) ? 
 
  
  
  
  
  
  
(s el e ct  o n e n u m b er)  
  
 
N ot at all … … … … … … … … … … … ….. 1 
 
  
 
A littl e bit … … … … … … … … … … … ….. 2  
 
  
  
M o d er at el y … … … … … … … … … … ….. 3 
 
  
 
Q uit e a bit … … … … … … … … … … … … 4  
 
  
  
E xtr e m el y … … … … … … … … … … … …. 5 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 1 /1 1 6  
 
 
2 3 -3 2.  
T h e s e q u e sti o n s ar e a b o ut h o w y o u f e el a n d h o w t hi n g s h a v e b e e n f or y o u d uri n g  
 
t h e  p a st  4  w e e k s.  F or  e a c h  q u e sti o n,  pl e a s e  gi v e  t h e  o n e  a n s w er  t h at  c o m e s  
 
cl o s e st t o t h e w a y y o u h a v e b e e n f e eli n g.  
 
H o w m u c h of t h e ti m e d uri n g t h e p a st 4 w e e k s ... 
 
(S el e ct  o n e n u m b er o n e a c h li n e)  
 
All of 
t h e ti m e 
M o st of 
t h e ti m e 
A g o o d  
bit of  
t h e 
ti m e 
S o m e of 
t h e ti m e 
A littl e of 
t h e ti m e 
N o n e  of 
t h e ti m e 
2 3. Di d y o u f e el f ull of lif e ?  
1 
2 
3 
4 
5 
6 
2 4. H a v e y o u b e e n v er y 
 
n er v o u s ?  
1 
2 
3 
4 
5 
6 
2 5. H a v e y o u f elt s o d o w n i n t h e  
 
d u m p s t h at n ot hi n g c o ul d  
 
c h e er y o u u p ?  
1 
2 
3 
4 
5 
6 
2 6. H a v e y o u f elt c al m a n d  
 
p e a c ef ul ?  
1 
2 
3 
4 
5 
6 
2 7. Di d y o u h a v e a l ot of  
 
e n er g y ?  
1 
2 
3 
4 
5 
6 
2 8. H a v e y o u f elt d o w n h e art e d  
 
a n d l o w ?  
1 
2 
3 
4 
5 
6 
2 9. Di d y o u f e el w or n o ut ?  
1 
2 
3 
4 
5 
6 
3 0. H a v e y o u b e e n h a p p y ?  
1 
2 
3 
4 
5 
6 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 2 /1 1 6  
 
 
3 1. Di d y o u f e el tir e d ?  
1 
2 
3 
4 
5 
6 
3 2. Di d y o u f e el r e st e d o n  
w a ki n g i n t h e m or ni n g ?  
1 
2 
3 
4 
5 
6 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 3 /1 1 6  
 
 
3 3.  D uri n g t h e p a st 4 w e e k s , h o w m u c h of t h e ti m e h a s y o ur p h y si c al h e alt h or  
e m oti o n al 
pr o bl e m s  i nt erf er e d wit h y o ur s o ci al a cti viti e s (li k e vi siti n g wit h fri e n d s, r el ati v e s, et c.) ? 
  
  
  
  
  
  
(s el e ct  o n e n u m b er)  
 
  
  
 
All of t h e ti m e … … … … … … … …. 1  
 
  
  
 
M o st of t h e ti m e … … … … … … …. 2  
 
  
  
 
S o m e of t h e ti m e … … … … … … … 3  
 
  
  
 
A littl e of t h e ti m e … … … … … … … 4  
 
  
  
 
N o n e of t h e ti m e … … … … … … …. 5  
 
H e alt h i n G e n er al  
 
3 4 -3 7.  
H o w T R U E or F A L S E i s e a c h  of t h e f oll o wi n g st at e m e nt s f or y o u ?  
(S el e ct  o n e n u m b er o n e a c h li n e)  
 
D efi nit el y  
tr u e 
M o stl y  
tr u e 
D o n't  
k n o w  
M o stl y  
f al s e 
D efi nit el y  
f al s e 
 
3 4. I s e e m t o g et ill 
 
m or e e a sil y t h a n 
 
ot h er p e o pl e  
1 
2 
3 
4 
5 
 
3 5. I a m a s h e alt h y a s  
 
a n y b o d y I k n o w  
1 
2 
3 
4 
5 
 
3 6. I e x p e ct m y h e alt h 
 
t o g et w or s e 
1 
2 
3 
4 
5 
 
3 7. M y h e alt h i s  
 
e x c ell e nt  
1 
2 
3 
4 
5 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 4 /1 1 6  
 
 
H e alt h Di str e s s  
 
H o w m u c h of t h e ti m e d uri n g t h e p a st 4 w e e k s...  
 
(S el e ct  o n e n u m b er o n e a c h li n e)  
 
All  
of t h e  
ti m e 
M o st  
of t h e  
ti m e 
A g o o d  
bit of  
t h e 
ti m e 
S o m e  
of t h e  
ti m e 
A littl e  
of t h e  
ti m e 
N o n e  
of t h e  
ti m e 
3 8. W er e y o u di s c o ur a g e d b y  
 
y o ur h e alt h pr o bl e m s ?  
1 
2 
3 
4 
5 
6 
3 9. W er e y o u fr u str at e d a b o ut  
 
y o ur h e alt h ?  
1 
2 
3 
4 
5 
6 
4 0. W a s y o ur h e alt h a w orr y  
 
i n y o ur lif e ? 
1 
2 
3 
4 
5 
6 
4 1. Di d y o u f e el w ei g h e d  
 
d o w n b y y o ur h e alt h  
 
pr o bl e m s ?  
1 
2 
3 
4 
5 
6 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 5 /1 1 6  
 
 
C o g niti v e F u n cti o n  
 
H o w m u c h of t h e ti m e d uri n g t h e p a st 4 w e e k s...  
 
(S el e ct  o n e n u m b er o n e a c h li n e)  
 
All  
of t h e  
ti m e 
M o st  
of t h e  
ti m e 
A g o o d  
bit of  
t h e 
ti m e 
S o m e  
of t h e  
ti m e 
A littl e  
of t h e  
ti m e 
N o n e  
of t h e  
ti m e 
4 2. H a v e y o u h a d diffi c ult y  
 
c o n c e ntr ati n g a n d  
 
t hi n ki n g ? 
1 
2 
3 
4 
5 
6 
4 3. Di d y o u h a v e tr o u bl e  
 
k e e pi n g y o ur att e nti o n  
 
o n a n a cti vit y f or l o n g ?  
1 
2 
3 
4 
5 
6 
4 4. H a v e y o u h a d tr o u bl e  
 
wit h y o ur m e m or y ?  
1 
2 
3 
4 
5 
6 
4 5. H a v e ot h er s, s u c h a s  
 
f a mil y m e m b er s or  
 
fri e n d s, n oti c e d t h at  
 
y o u h a v e tr o u bl e wit h  
 
y o ur m e m or y or pr o bl e m s  
 
wit h y o ur c o n c e ntr ati o n ?  
1 
2 
3 
4 
5 
6 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
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 /1 1 6  
 
 
S e x u al F u n cti o n  
 
4 6 -5 0. T h e n e xt s et of q u e sti o n s ar e a b o ut y o ur s e x u al f u n cti o n a n d y o ur s ati sf a cti o n wit h 
y o ur s e x u al f u n cti o n. Pl e a s e a n s w er a s a c c ur at el y a s p o s si bl e a b o ut y o ur f u n cti o n d uri n g 
t h e p a st 4 w e e k s o nl y. 
 
H o w m u c h of a pr o bl e m w a s e a c h of t h e f oll o wi n g f or y o u d uri n g t h e p a st 4 w e e k s ?  
 
 
  
(S el e ct  o n e n u m b er o n e a c h li n e)  
M E N  
N ot a 
pr o bl e m  
A littl e of 
a pr o bl e m  
S o m e w h at 
of a 
pr o bl e m  
V er y 
m u c h a 
pr o bl e m  
N ot 
a p pli c a bl e  
4 6. L a c k of s e x u al  
 
i nt er e st 
 
1 
 
2 
 
3 
 
4 
 
5 
4 7. Diffi c ult y g etti n g  
 
or k e e pi n g a n 
 
er e cti o n  
 
1 
 
2 
 
3 
 
4 
 
5 
4 8. Diffi c ult y h a vi n g a n  
 
or g a s m  
 
1 
 
2 
 
3 
 
4 
 
5 
4 9. A bilit y t o s ati sf y  
 
s e x u al p art n er  
 
1 
 
2 
 
3 
 
4 
 
5 
 
 
  
(S el e ct  o n e n u m b er o n e a c h li n e)  
W O M E N  
N ot a 
pr o bl e m  
A littl e of 
a pr o bl e m  
S o m e w h at 
of a 
pr o bl e m  
V er y 
m u c h a 
pr o bl e m  
N ot 
a p pli c a bl e  
4 6. L a c k of s e x u al  
 
i nt er e st 
 
1 
 
2 
 
3 
 
4 
 
5 
4 7. I n a d e q u at e  
 
l u bri c ati o n 
 
1 
 
2 
 
3 
 
4 
 
5  
4 8. Diffi c ult y h a vi n g a n  
 
or g a s m  
 
1 
 
2 
 
3 
 
4 
 
5  
4 9. A bilit y t o s ati sf y  
 
s e x u al  p art n er  
 
1 
 
2 
 
3 
 
4 
 
5  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 7 /1 1 6  
 
 
5 0.  O v er all, h o w s ati sfi e d w er e y o u wit h y o ur s e x u al f u n cti o n d uri n g t h e p a st 4 w e e k s ? 
 
  
  
  
  
  
  
  
(s el e ct  o n e n u m b er)  
 
  
  
 
V er y s ati sfi e d … … … … … … … … … … ….. 1  
 
  
  
 
S o m e w h at s ati sfi e d … … … … … … … … … 2  
 
  
  
 
N eit h er s ati sfi e d n or  
  
  
  
di s s ati sfi e d … … … … … … … … … … … … … 3 
 
  
  
 
S o m e w h at di s s ati sfi e d … … … … … … … … 4  
 
  
  
 
V er y di s s ati sfi e d … … … … … … … … … …... 5  
 
 
5 1.  D uri n g  t h e  p a st  4  w e e k s ,  t o  w h at  e xt e nt  h a v e  pr o bl e m s  wit h  y o ur  b o w el  or  bl a d d er  
 
f u n cti o n  i nt erf er e d  wit h  y o ur  n or m al  s o ci al  a cti viti e s  wit h  f a mil y,  fri e n d s,  n ei g h b o ur s,  
 
or gr o u p s ?  
  
  
  
  
  
  
  
(s el e ct  o n e n u m b er)  
 
  
  
 
N ot at all … … … … … … … … … … … … … … 1  
 
  
  
  
Sli g htl y … … … … … … … … … … … … … … … 2 
 
  
  
  
M o d er at el y … … … … … … … … … … … … …. 3 
 
  
  
 
Q uit e a bit … … … … … … … … … … … … …... 4  
 
  
  
  
E xtr e m el y … … … … … … … … … … … … … … 5 
 
5 2.  D uri n g t h e p a st 4 w e e k s , h o w m u c h di d p ai n  i nt erf er e wit h y o ur e nj o y m e nt of lif e ? 
 
  
  
  
  
  
  
  
(s el e ct  o n e n u m b er)  
 
  
  
 
N ot at all … … … … … … … … … … … … … ….. 1  
 
  
  
  
Sli g htl y … … … … … … … … … … … … … … …. 2 
 
  
  
  
M o d er at el y … … … … … … … … … … … … ….. 3 
 
  
  
 
Q uit e a bit … … … … … … … … … … … … … … 4  
 
  
  
 
E xtr e m el y … … … … … … … … … … … … … … 5  
 
5 4. O v er all, h o w w o ul d y o u r at e y o ur o w n q u alit y of lif e ?  
 
 
 
S el e ct  o n e n u m b er o n t h e s c al e b el o w:  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 8 /1 1 6  
 
 
 
 
 
 
Best p ossi ble  
q u alit y of life  
 
W orst p ossi ble 
q u alit y of life  
 
 
As  b a d as or 
w orse t h a n  
bei n g de a d  
 
 
 
5 4.  W hi c h b e st d e s cri b e s h o w y o u f e el a b o ut y o ur lif e a s a w h ol e ?  
 
  
  
  
  
  
  
  
(s el e ct  o n e n u m b er)  
 
  
  
  
  
T erri bl e … … … … … … … … … ….. 1 
 
  
  
  
  
U n h a p p y … … … … … … … … … … 2 
 
  
  
  
 
M o stl y di s s ati sfi e d … … … … … … 3  
 
  
  
  
 
Mi x e d - a b o ut e q u all y  
  
  
  
 
s ati sfi e d a n d di s s ati sfi e d … … …. 4  
 
  
  
  
 
M o stl y s ati sfi e d … … … … … … …. 5  
 
  
  
  
  
Pl e a s e d … … … … … … … … … ….. 6 
 
  
  
  
  
D eli g ht e d … … … … … … … … … … 7 
 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 9 /1 1 6  
 
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 0 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 1 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 2 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 3 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 4 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 5 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 6 /1 1 6  
 
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 7 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 8 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 9 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 0 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 1 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 2 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 3 /1 1 6  
 
 
 
A p pe n di x 8 : T S Q M v 1. 4  Questi o n n aire  
 
 
I nstr ucti o ns: Ple as e t a ke s o me ti me t o t hi n k a b o ut y o ur le vel of s atisf acti o n or diss atisf acti o n 
wit h t he me dic ati o n y o u are t a ki n g i n t his cli nic al tri al. We are i ntereste d i n y o ur e v al u ati o n 
of t he eff ecti ve ness, si de eff ects, a n d c o n ve nie nce of t he me di c ati o n o ver t he l ast t w o t o t hree 
wee ks, or si nce y o u l ast use d it . F or e ac h q uesti o n, ple ase pl ace a si n gle c hec k m a r k ne xt t o t he 
res p o nse t h at m ost cl os el y c orres p o n ds t o y o ur o w n e x perie nces.  
1.  H o w satisfie d or dissatisfie d are y o u wit h t he a bilit y of t h e me di cati o n t o pre ve nt or treat 
y o ur c o n diti o n?  
□
 E xtre m el y Dissatisfie d  
□
 Ver y Dissatisfie d  
□
 Dissatisfie d  
□
 S o me w ha t Satisfie d 
□
 Satisfie d  
□
 Ver y S atisfie d 
□
 E xtre m el y Satisfie d  
2.  H o w satisfie d or dissatisfie d are y o u wit h t he w a y t he me dicati o n relie v es y o ur s y m pt o ms? 
□
 E xtre m el y Dissatisfie d  
□
 Ver y Dissatisfie d  
□
 Dissatisfie d  
□
 S o me w ha t Satisfie d 
□
 Satisfie d  
□
 Ver y S atisfie d 
□
 E xtre m el y Satisfie d  
3.  H o w satisfie d or dissatisfie d are y o u wit h t he a m o u nt of ti me it ta kes t he me dicati o n t o 
start w or ki n g? 
□
 E xtre m el y Dissatisfie d  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 4 /1 1 6  
 
 
□
 Ver y Dissatisfie d  
□
 Dissatisfie d  
□
 S o me w ha t Satisfie d 
□
 Satisfie d  
□
 Ver y S atisfie d 
□
 E xtre m el y Satisfie d  
4.  As a res ult of ta ki n g t his me dicati o n, d o y o u e x perie nce a n y si de effects at  all?  
□
 Yes  
□
 N o (if N o , t he n please s kip t o Q uest i on 9) 
5. H o w b ot hers o me are t he si de eff ects of t he m e dicati o n y o u ta k e t o treat y o ur c o n diti o n? 
□
 E xtre m el y B ot hers o me 
□
 Ver y B o t hers ome 
□
 S o m e w hat B ot hers o m e 
□
 A Littl e B ot hers o me 
□
 N ot at All B ot hers o me 
6.  T o w hat e xte nt d o t he si de eff ects i nterfere wit h y o ur p h ysical healt h a n d a bilit y t o f u n cti o n 
(i.e., stre n gt h, e ner g y le v els, etc.)?  
□
 A Grea t Deal  
□
 Q uite a  Bit  
□
 S o me w hat  
□
 Mi ni mall y  
□
 N ot at All 
7.  T o w hat e xte nt d o t he si de eff ects i nterfere wit h y o ur me ntal f u ncti o n (i.e., a bilit y t o 
t hi n k clearl y, sta y a w a ke, etc.)?  
□
 A Grea t Deal  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 5 /1 1 6  
 
 
□
 Q uite a  Bit  
□
 S o me w hat  
□
 Mi ni mall y  
□
 N ot at All 
8.  T o w hat de gr ee ha v e me dicati o n si de effects affecte d y o ur o verall satisfacti o n wit h 
t he me dicati o n? 
□
 A Grea t Deal  
□
 Q uite a  Bit  
□
 S o me w hat  
□
 Mi ni mall y  
□
 N ot at All 
9.  H o w eas y or diffic ult is it t o use t he me dicati o n i n its c urre nt  f or m? 
□
 E xtre m el y Diffic ult  
□
 Ver y Diffic ult  
□
 Diffic ult  
□
 S o me w ha t Eas y 
□
 Eas y  
□
 Ver y Ea s y 
□
 E xtre m el y E as y  
1 0. H o w eas y or diffic ult is it t o pla n w he n y o u will use t he me dicati o n eac h ti me? 
□
 E xtre m el y Diffic ult  
□
 Ver y Diffic ult  
□
 Diffic ult  
□
 S o me w ha t Eas y 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 6 /1 1 6  
 
 
□
 Eas y  
□
 Ver y Ea s y 
□
 E xtre m el y E as y  
1 1.  H o w c o n ve nie nt or i nc o n ve nie nt is it t o ta ke t he me dicati o n as i nstr uct e d? 
□
 E xtre m el y I nc o n v e nie nt 
□
 Ver y I nc o n ve nie nt 
□
 I nc o n v e nie nt 
□
 S o me w hat C o n ve nie nt 
□
 C o n ve nie nt 
□
 Ver y C o n v e nie nt 
□
 E xtre m el y C o n venie nt  
1 2.  O verall, h o w c o nfi de nt are y o u t hat ta ki n g t his me dicati o n is a g o o d t hi n g f or y o u? 
□
 N ot at All C o nfi de nt 
□
 A Little  C o nfi de nt 
□
 S o me w ha t C o nfi de nt 
□
 Ver y C o nfi de nt 
□
 E xtre m el y C o nfi de nt 
1 3.  H o w certai n ar e y o u t hat t he g o o d t hi n gs a b o ut y o ur me dicati o n o ut wei g h t he ba d t hi n gs? 
□
 N ot at All Certai n 
□
 A Little  Certai n  
□
 S o me w ha t Certai n 
□
 Ver y C ertai n  
□
 E xtre m el y Certai n  
1 4.  Ta ki n g all t hi n gs i nt o acc o u nt, h o w satisfie d or dissatisfie d are y o u wit h t his me dicati o n?  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 7 /1 1 6  
 
 
□
 E xtre m el y Dissatisfie d  
□
 Ver y Dissatisfie d  
□
 Dissatisfie d  
□
 S o me w ha t Satisfie d 
□
 Satisfie d  
□
 Ver y S atisfie d 
□
 E xtre m el y Satisfie d  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y- acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 8 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 9 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 0 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 1 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 2 /1 1 6  
 
 
 
A p pe n di x 1 2 : Pers o n al  Di ar y 
T his is a n E x a m ple  of Pers o nal Diar y : 
 
 
 
 
 
 
S u bject I niti als: 
 
 
  
S u bject  N u m ber:  
Dear S u bject, 
 
Ple ase c o m plete t his di ar y c ar d ( wit h a pe n) f or e ac h d ail y t a blet 
i nt a ke of M a ve ncl a d
®  a n d al w a ys t a ke it wit h y o u t o t he h os pit al 
w he n y o u visit.  
Please als o re me m ber t o b ri n g y o ur use d a n d u n use d tri al dr u g wit h 
y o u i n t heir ori gi n al c o ntai ner s. 
T his diar y has als o bee n desi g ne d t o hel p us f oll o w y o ur ge neral healt h 
a n d a n y pr o ble m or disc o mf ort y o u ma y e x peri e nce w hile y o u are at 
h o me a n d t o rec or d all me dicati o n y o u ta ke a d diti o nall y t o t he trial dr u g.  
If y o u ha ve a n y pr o ble ms please call y o ur d oct or or n urse: 
Y o ur c o ntact pers o n is: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 
S u bject Di ar y C ar d: Wee k _ _ _ _ _ t o _ _ _ _ _  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 3 /1 1 6  
 
 
S u bject Tri al  Me dic ati o n Rec or d  
 
Wee k  
D ate  
Ti me 
(select a m or 
p m)  
N u m ber of 
T a blets 
T a ke n  
B atc h # or 
Kit #  
C o m me nts  
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 4 /1 1 6  
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
 
 
a m 
p m  
 
 
 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 5 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 /1 1 6  
 
 
Gl o bal Versi o n I D: C CI
C CI


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


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


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 9 /1 1 6  
 
 
Si g n at ure P a ge – Pri nci p al I n vesti g at or  
Tri al Title  
A 2 -year Pr os pecti ve St u d y t o Assess Healt h -rel ate d 
Q ualit y  of  Life  i n  S u bjects  wit h  Hi g hl y -A cti ve 
Rela psi n g
 M ulti ple
 Scler osis
 Treate d
 wit h
 
Ma ve ncla d
®  
E u dr a C T N u m ber  
2 0 1 7 -0 0 2 6 3 2 -1 7  
Cli nic al Tri al Pr ot oc ol D ate / 
Versi o n  
1 4 Dece m b er  2 0 1 8/ Versi o n 2. 0 
Ce nt re N u m ber  
 
Pri nci p al I n vesti g at or  
 
I,  t he  u n dersi g ne d,  a m  res p o nsi ble  f or  t he  c o n d uct  of  t he  trial  at  t his site  a n d  affir m  t hat  I 
u n dersta n d a n d will c o n d uct t he trial acc or di n g t o t he cli nical trial pr ot oc ol, a n y a p pr o ve d pr ot o c ol 
a me n d me nts, I nter nati o n al C o nfere nce o n Har m o nisati o n G o o d Cli nical Practice ( T o pic E 6) a n d 
all a p plica ble Healt h A ut h orit y r e q uire me nts a n d nati o nal la ws.  
I als o affir m t hat I u n dersta n d t hat Healt h A ut h orities ma y re q uire t he S p o ns ors of cli nical trials t o 
o btai n a n d s u p pl y det ails a b o ut o w ners hi p i nterests i n  t he S p o ns or or I n v esti gati o nal Me dici nal 
Pr o d uct a n d a n y ot h er fi na ncial ties wit h t he S p o ns or. T he 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 t he p ur p ose of c o m pl yi n g wit h t he re g ul at or y re q uire me nts. I t heref ore a gree t o s u p pl y 
t he  S p o ns or  wit h  a n y  n ecessar y  i nf or mati o n  re gar di n g  o w ners 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 d e nt c hil dre n, a n d t o pr o vi de u p dat es as necessar y t o meet 
Healt h A ut h orit y re q uir e me nts. 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Si g nat ure 
Date of Si g nat ure  
Na me, aca de mic d e gree:   
F u ncti o n / Title:  
 
I nstit uti o n: 
 
A d dress:  
 
Tele p h o ne n u m ber:  
 
Fa x n u m ber:  
 
E -mail a d dress:  
 
 
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 0 /1 1 6  
 
 
S p o ns or Res p o nsi ble Pers o ns  n ot N a me d o n t he C o ver P a ge  
Na me:  
 
F u ncti o n / Title:  
Bi ostatisticia n  
I nstit uti o n: 
Merc k K G a A  
A d dress:  
Fra n kf urter Str. 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y  
Tele p h o ne n u m ber:  
 
E -mail a d dress:  
 
 
Na me:  
 
F u ncti o n / Title:  
 
I nstit uti o n: 
Merc k Ser o n o G m b H   
A d dress:  
Alsfel der Stra ß e 1 7, 6 4 2 8 9 Dar msta dt  
Tele p h o ne n u m ber:  
 
E -mail a d dress:  
 
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 1 /1 1 6  
 
 
 
A p pe n di x 1 5:  Hi g hl y Effecti ve Birt h C o ntr ol Met h o ds  
Acc or di n g t o t he H M A Cli nical Trial Facili tati o n Gr o u p *, birt h c o ntr ol m et h o ds t hat ca n ac hie v e 
a fail ure r ate of less t ha n 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y  are c o nsi dere d as hi g hl y 
effecti ve. S uc h hi g hl y eff ecti ve birt h c o ntr ol met h o ds i ncl u de: 
•  C o m bi ne d  (estr o ge n  a n d  pr o gest o ge n  c o ntai ni n g)  h or m o nal  c o ntrace pti o n  ass ociate d  wit h  
i n hi biti o n of o v ulati o n: 
o  Oral  
o  I ntr a va gi nal 
o  Tra ns der m al  
•  Pr o gest o ge n - o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n1: 
o  Oral  
o  I njecta ble 
o  I m pla nta bl e2 
•  I ntr a- uteri ne de vice2 
•  I ntr a- uteri ne h or m o ne-rel easi n g s yst e m2 
•  Bilater al t u bal occl usi o n 2 
•  Vasect o mise d part ner 2, 3 
•  Se x ual a bsti ne nce 4 
1H or m o nal c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he I M P, w hic h ma y re d uce t he efficac y of t he 
c o ntrace pti o n met h o d.  
2C o ntrace pti o n met h o ds t hat i n t he c o nte xt of t his g ui da nce are c o nsi dere d t o ha ve l o w us er de pe n de nc y.  
3Vasect o mise d part ner is a hi g hl y effecti ve birt h c o ntr ol met h o d pr o vi de d t hat part ner is t he s ole se x ual part ner of t he 
w o me n of c hil d -beari n g  p ote ntial ( W O C B P )* *  trial partici pa nt a n d t hat t he vasect o mise d part ner has recei ve d me dical 
assess me nt of t he s ur gical s uc cess.  
4I n t he c o nte xt of t his g ui da nc e sex ual a bsti ne nce is c o nsi der e d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g 
fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nts. T he relia bilit y of 
se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n t o t he d urati o n of t he cli nical trial a n d t he preferre d a n d us ual 
lifest yle of t he s u bj ect. 
* Cli nical Trial Facilitati o n Gr o u p Fi nal Rec o m me n dati o ns r elate d t o c o ntrace pti o n a n d pre g na nc y testi n g i n cli nical 
trials. Fi nal Versi o n 1 5 Se pte m ber 2 0 1 4. 
* * A w o ma n is c o nsi dere d of c hil d -beari n g p ote ntial ( W O C B P), i.e. fertile, f oll o wi n g me narc he a n d u ntil bec o mi n g 
p ost -me n o pa usal  u nless  per ma ne ntl y  sterile.  P er ma ne nt  sterilisati o n  met h o ds  i ncl u de  h ysterect o m y,  bilateral  
sal pi n gect o m y, a n d bilateral o o p h orect o m y. A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut 
a n alter nati ve me dical ca use.  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 2 /1 1 6  
 
 
 
A p pe n di x 1 6 : Pr ot oc ol A me n d me nts a n d List of C h a n ges  
Pr ot oc ol A me n d me nt S u m mar y of C ha n ges a n d O verall Rati o nale f or A me n d me nt  
C ha n ges w ere ma de acr oss vari o us secti o ns of t he pr ot oc ol f or clarificati o n of st u d y c o n d uct. T he 
c ha n ges ma d e ar e descri be d i n detail i n t he ta ble bel o w.  
Gl o bal Versi o n I D: C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 3 /1 1 6  
 
 
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  
1 S y n o p si s  
2 S p o n s or, 
I n v e sti g at or s a n d 
Tri al 
A d mi ni str ati v e 
Str u ct ur e 
R e vi s e d tri al c o u ntr y  li st. I sr a el, 
S wit z erl a n d a n d Ir el a n d w er e 
r e m o v e d fr o m t h e tri al c e ntr es li st a n d 
Sl o v a ki a w a s a d d e d . 
T h e st u d y i s n o l o n g er c o n d u ct e d i n t h e s e sit e s a s 
a r e s ult of st u d y f e a si bilit y a s s e s s m e nt s a n d 
h e n c e  t h ey ar e r e m o v e d fr o m t h e li st.  
1 S y n o p si s  
C h a n g e i n t h e pl a n n e d tri al p eri o d. 
Fir st s u bj e ct fir st vi sit d at e w a s 
c h a n g e d fr o m Q 1 2 0 1 8 t o Q 2 2 0 1 8 
a n d l a st s u bj e ct l a st vi sit d at e w a s 
c h a n g e d t o Q 4 2 0 2 1 . 
B a s e d o n t h e pr o gr e s s of t h e st u d y t h e s e 
mil e st o n e s f or  F S F V a n d L S L V w er e u p d at e d.  
1 S y n o p si s  
S e c o n d ar y o bj e cti v e w a s r e vi s e d t o 
i n cl u d e t er m “ hi g hl y a cti v e”.  
T o cl e arl y i n di c at e t h e t y p e of r el a p si n g m ulti pl e 
s cl er o si s p er t h e st u d y d e si g n a n d t o b e 
c o n si st e nt wit h t h e ot h er s e cti o n s.  
1 S y n o p si s  
M et h o d ol o g y s e cti o n w a s r e vi s e d t o 
i n cl u d e t h e t er m “ e x pl or at or y”. 
T er m ‘e x pl or at or y ' i n t h e s e cti o n w a s a d d e d t o 
cl arif y t h at t h e st u d y i s e x pl or at or y i n n at ur e . 
1 S y n o p si s  
4. 1. 1 Pri m ar y 
e n d p oi nt  
4. 2. 1 S e c o n d ar y 
e n d p oi nt  
8. 0 St ati sti c s  
S e cti o n r e vi s e d t o cl e arl y d efi n e 
e n d p oi nt s. 
 r e vi s e d 
t o i n cl u d e “tr e at m e nt eff e cti v e n e s s, 
si d e eff e ct s, a n d c o n v e ni e n c e 
a s s e s s e d b y T S Q M at 6,  1 2 a n d 2 4 
m o nt h s ”. I n a d diti o n, M S Q o L -5 4 
a s s e s s m e nt s c h e d ul e w a s u p d at e d t o 
i n cl u d e 2 4 m o nt h s . 
T h e r ati o n al e w a s t o cl arif y t h e s c or e s t h at will b e 
u s e d f or a n al y si s a s t hi s w a s n ot s p e cifi e d b ef or e . 
1 S y n o p si s  
5. 3. 2 E x cl u si o n 
crit eri a  
R e vi s e d k e y e x cl u si o n crit eri a 
r e g ar di n g i m m u n o s u p pr e s si v e 
t h er a p y t o i n cl u d e mit o x a ntr o n e.  
I n a d diti o n, s e nt e n c e s r e g ar di n g 
h e p atiti s i nf e cti o n a n d P M L w er e r e -
w or d e d f or cl arit y.  
P er t h e S m P C, i niti ati o n of M a v e n cl a d ®  i s 
c o ntr ai n di c at e d i n p ati e nt s c urr e ntl y r e c ei vi n g 
i m m u n o s u p pr e s si v e t h er a p y. 
1 S y n o p si s  
8. 0 St ati sti c s  
S e cti o n r e vi s e d t o cl e arl y d efi n e e n d 
p oi nt s, a n al y si s s et s a n d m et h o d s.  
T o cl arif y t h e s c or e s t h at will b e u s e d f or a n al y si s 
a s t hi s w a s  n ot s p e cifi e d b ef or e. I n a d diti o n, 
a n al y si s s et s w er e a d d e d a n d d efi n e d i n d et ail.  
3. 5 S ci e ntifi c 
r ati o n al e f or tri al 
d e si g n  
S u b s e cti o n h e a di n g s a n d f urt h er 
e x pl a n ati o n s  o n st u d y dr u g, 
a s s e s s m e nt s a n d br ai n atr o p h y  w er e 
a d d e d.   
S e cti o n w a s r e str u ct ur e d  t o cl arif y tri al d e si g n. 
5. 1 O v er all Tri al 
d e si g n  
Fi g ur e 1 u p d at e d t o r e m o v e T S Q M 
a s s e s s m e nt fr o m B a s eli n e . 
T hi s c h a n g e w a s m a d e t o b e c o n si st e nt wit h t h e 
tri al pr o c e d ur e. 
5. 3. 1 I n cl u si o n 
crit eri a  
I n cl u si o n crit eri o n n u m b er 5 w a s 
r e vi s e d t o i ntr o d u c e A p p e n di x 1 5 
w hi c h pr o vi d e s a li st of hi g hl y 
eff e cti v e birt h c o ntr ol m et h o d s . I n 
a d diti o n, d efi niti o n s of W O C B P a n d 
p o st m e n o p a u s al w o m e n h a v e b e e n 
i n cl u d e d a n d crit eri o n 6 w a s 
c o m bi n e d wit h crit eri o n 5.   
I n or d er t o a v oi d p o s si bl e h u m a n t er at o g e ni cit y 
wit h t h e u s e of M a v e n cl a d ® , a li st of hi g hl y 
eff e cti v e birt h c o ntr ol m et h o d s w a s pr o vi d e d t o 
e d u c at e s u bj e ct s p arti ci p ati n g i n t h e st u d y . 
Gl o bal Versi o n I D: C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 4 /1 1 6  
 
 
5. 3. 1 I n cl u si o n 
crit eri a  
7. 4. 3 T a bl e 3 
L o c al l a b or at or y 
a s s e s s m e nt s  
1 2. 1 A p p e n di x 1  
S c h e d ul e of 
A s s e s s m e nt s  
 
S er ol o g y a s s e s s m e nt f or v ari c ell a 
a d d e d.  
I n cl u si o n crit eri o n 7 w a s a d d e d t o i n cl u d e s u bj e ct s 
wit h pr e vi o u s e x p o s ur e a n d i m m u nit y t o v ari c ell a 
vir u s.  
5. 3. 2 E x cl u si o n 
crit eri a  
Crit eri a 3 : T h e p hr a s e  ‘Pr e s e n c e or  
s u s p e ct  of P M L ’ w a s r e pl a c e d wit h 
‘Pr e s e n c e of si g n s of P M L d et e ct e d 
b y M RI, cli ni c al a n d/ or bi o m ar k er 
e v al u ati o n s ’.   
Crit eri a 7 : Mit o x a ntr o n e w a s a d d e d t o 
li st of dr u g s  
A d diti o n of n e w e x cl u si o n crit eri a 1 3  
R e vi s e d t h e e x cl u si o n crit eri a 3 t o i n cl u d e pr ot o c ol 
a p pr o v e d pr o c e d ur e s t o e v al u at e t h e pr e s e n c e of 
P M L  
Crit eri a 7: P er t h e S m P C, i niti ati o n of M a v e n cl a d ®  
i s c o ntr ai n di c at e d i n p ati e nt s c urr e ntl y r e c ei vi n g 
i m m u n o s u p pr e s si v e t h er a p y. 
Crit eri a 1 3 w a s a d d e d t o e x cl u d e s u bj e ct s wit h 
m o d er at e or s e v er e h e p ati c i m p air m e nt b a s e d o n 
t h e s af et y pr ofil e of M a v e n cl a d® . 
5. 5. 1 Wit h dr a w al 
fr o m tri al t h er a p y 
R e m o v al of w or di n g r e g ar di n g ‘ a nti -
h er p e s pr o p h yl a xi s’.  
R e m o v e d d u e t o i n c orr e ct pl a c e m e nt of t h e t e xt . 
6 I n v e sti g ati o n al 
M e di ci n al Pr o d u ct 
a n d Ot h er Dr u g s 
U s e d i n t h e tri al  
G e n er al pr o c e s s of I M P pr o vi si o n a n d 
I R T c o nt a ct w a s a d d e d. 
I n or d er t o cl arif y t h e pr o c e s s b y w hi c h t h e 
s hi p m e nt i s tri g g er e d aft er I R T c o nt a ct.  
6. 5. 4 S p e ci al 
pr e c a uti o n s   
A d diti o n of s u b s e cti o n 6. 5. 4. 1 .  
T o cl arif y t h e pr o c e s s of s wit c hi n g fr o m ot h er 
D M D s t o i niti ati o n of M a v e n cl a d ® . 
6. 1 2 Tr e at m e nt of 
o v er d o s e  
S A E r e p ort f or m r e pl a c e d wit h e C R F 
r e p ort p a g e w h er e v er a p pli c a bl e. 
I n or d er t o e n s ur e pr o p er d o c u m e nt ati o n of t h e 
e v e nt s e C R F p a g e will b e u s e d i n t h e st u d y . 
7. 1. 1 S cr e e ni n g  
1 2. 1 A p p e n di x 1  
S c h e d ul e of 
A s s e s s m e nt s  
R e vi s e d s e cti o n t o i n cl u d e m et h o d of 
s u bj e ct I D a s si g n m e nt  a n d s cr e e ni n g 
p eri o d e xt e n si o n  
D et ail e d i nf or m ati o n i n t h e s e cti o n w a s a d d e d t o 
h el p cl arif y s u bj e ct a s si g n m e nt a n d c o n diti o n s f or 
s cr e e ni n g p eri o d e xt e n si o n i n t h e st u d y. 
7. 1. 4 B a s eli n e vi sit  
7. 3. 2. 1 T S Q M v 1. 4  
1 2. 1 A p p e n di x 1  
S c h e d ul e of 
A s s e s s m e nt s  
Tr e at m e nt s ati sf a cti o n s c ori n g 
( T S Q M v 1. 4) d el et e d fr o m B a s eli n e  
vi sit . 
T S Q M i s n ot t o b e a d mi ni st er e d t o t h e s u bj e ct s at 
B a s eli n e  vi sit, a s s u bj e ct s h a v e n ot y et b e e n 
di s p e n s e d n or a d mi ni st er e d wit h a n y tri al 
m e di c ati o n.  
7. 1. 7 M o nt h 1 2 
Vi sit 4 ( ± 7 d a y s)  
S er ol o g y a n d s af et y a n al y si s a d d e d 
f or m o nt h 1 2 
T e xt r e g ar di n g s plit of M o nt h  1 2 
a s s e s s m e nt a d d e d . 
Mi s s e d st at e m e nt w a s a d d e d p er t h e S c h e d ul e of 
A s s e s s m e nt s  
T o d efi n e M o nt h  1 2 a n d M o nt h 1 2 B a s s e s s m e nt i n 
d et ail.  
Gl o bal Versi o n I D: C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 5 /1 1 6  
 
 
7. 3. 5. 2 S c a n ni n g: 
M RI s c a n ni n g 
pr o c e d ur e  
N a m e of t h e M RI s c a n u s er’ s m a n u al 
w a s u p d at e d.  
G e n er al w or di n g o n s c a n ni n g 
m a c hi n e  a d d e d.  
S af et y a s s e s s m e nt pr o c e d ur e a d d e d . 
I m a g e A c q ui siti o n G ui d eli n e s (I A G) i s t h e n a m e of 
t h e m a n u al. 
T o cl arif y u s a g e of n e w e q ui p m e nt a n d  
T o cl arif y t h e r e s p o n si bilit y of c e ntr al r e a d er a n d 
i n v e sti g at or.   
7. 3. 5. 3 E v al u ati o n 
of M RI S c a n s  
A d diti o n of n e w s u b s e cti o n s a s b el o w  
7. 3. 5. 3. 1 Di s e a s e di a g n o si s  
7. 3. 5. 3. 2 M RI effi c a c y e n d p oi nt s  
7. 3. 5. 3. 3  E v al u ati o n of S cr e e ni n g 
M RI s c a n s f or eli gi bilit y . 
T o i n cl u d e d et ail e d e x pl a n ati o n o n t h e e v al u ati o n 
of M RI s c a n s a n d t o cl arif y t h e r e s p o n si bilit y of 
sit e a n d i n v e sti g at or.  
7. 4. 1. 2, M et h o d s 
of R e c or di n g a n d 
A s s e s si n g 
A d v er s e E v e nt s  
7. 4. 1. 4 Pr o c e d ur e 
f or R e p orti n g 
S eri o u s A d v er s e 
E v e nt s, A d v er s e 
E v e nt s of S p e ci al 
I nt er e st a n d D o s e 
Li miti n g T o xi citi e s  
R e vi s e d s e cti o n t o s p e cif y S A E  
r e p orti n g 
H e a di n g c h a n g e d fr o m “ Pr o c e d ur e f or 
R e p orti n g S eri o u s A d v er s e E v e nt s, 
A d v er s e E v e nt s of S p e ci al I nt er e s t 
a n d D o s e Li miti n g T o xi citi e s” t o 
“Pr o c e d ur e f or R e p orti n g S eri o u s 
A d v er s e E v e nt s”.  
S A E s m u st b e r e p ort e d b y c o m pl eti n g t h e e C R F 
S A E p a g e a n d t h e R e p ort F or m i s t o b e u s e d o nl y 
if t h e e C R F i s n ot a v ail a bl e. 
A d v er s e e v e nt s of s p e ci al i nt er e st a n d d o s e 
li miti n g t o xi citi e s ar e n ot a p pli c a bl e f or t hi s st u d y  
7. 4. 2 Pr e g n a n c y 
a n d I n Ut er o Dr u g 
E x p o s ur e  
R e vi s e d s e cti o n t o i n cl u d e 
a p pr o pri at e r e p orti n g m et h o d a s 
pr e g n a n ci e s ar e still r e p ort e d u si n g a 
p a p er f or m.  
T h e pr o c e s s f or S A E r e p orti n g i s vi a e C R F 
w h er e a s pr e g n a n c y i s r e p ort e d u si n g a p a p er 
f or m. 
7. 4. 3 T a bl e 3 
L o c al l a b or at or y 
a s s e s s m e nt s  
R e vi si o n of t e xt f or M RI a s s e s s m e nt.  
T o cl arif y M RI s cr e e ni n g pr o c e d ur e.  
1 2. 1  A p p e n di x 1  
S c h e d ul e of 
A s s e s s m e nt s  
A d d e d l e g e n d f or l y m p h o c yt e c o u nt  
Vi sit wi n d o w ali g n e d wit h s e cti o n 
7. 1. 5  
L e g e n d t h at st at e s  H R Q o L /  
 
 ar e “ o pti o n al 
a s s e s s m e nt s, t o b e a p pli e d i n 
s u b gr o u p s, i n c e nt r es f a mili ari z e d i n 
t h e r e s p e cti v e s c al e s” i s d el et e d  
I R T a s s e s s m e nt a d d e d 
R e m o v e d t h e w or d ‘ Uri n e ’ fr o m 
pr e g n a n c y t e st a n d a l e g e n d a d d e d t o 
i n cl u d e uri n e/ s er u m f or e x pl a n ati o n.  
I n c orr e ctl y a d d e d t e xt w a s r e m o v e d a n d all 
s e cti o n s w er e ali g n e d f or c o n si st e n c y.  
1 2. 2 A p p e n di x 2 
M S Q o L -5 4 s c al e 
t o 1 2. 1 2 A p p e n di x 
1 2  P er s o n al di ar y  
R e pl a c e d t h e w or d ‘ cir cl e’ wit h ‘ s el e ct’  
Si n c e t h e q u e sti o n n air e s will b e c o m pl et e d 
el e ctr o ni c all y, ‘ cir cl e’ w a s r e pl a c e d wit h ‘ s el e ct’  
S e cti o n 1 2. 1 5  
A p p e n di x 1 5 
Hi g hl y eff e cti v e 
birt h c o ntr ol  
m et h o d s  
T h e A p p e n di x w a s pr o vi d e d t o li st 
hi g hl y eff e cti v e birt h c o ntr ol m et h o d s . 
I n or d er t o a v oi d p o s si bl e h u m a n t er at o g e ni cit y 
wit h t h e u s e of M a v e n cl a d ® , a li st of hi g hl y 
eff e cti v e birt h c o ntr ol m et h o d s w a s pr o vi d e d t o 
e d u c at e s u bj e ct s p arti ci p ati n g i n t h e st u d y.  
 
S o m e mi n or t y p o s  a n d  
i n c o n si st e n ci e s w er e c orr e ct e d i n t h e 
pr ot o c ol  
 
Gl o bal Versi o n I D: C CI
C CI
C CI


Cl a dri bi ne  
E v al u ati o n of  Q o L i n Hi g hl y Acti ve Rel a psi n g M S  
M S 7 0 0 5 6 8 _ 0 0 2 1 
 
 
 
 
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 /1 1 6  
 
 
T his a me n d me nt is s u bsta ntial base d o n t he criteria i n Articl e 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of 
t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n. 
Pr ot oc ol Hist or 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  S e pt e m b er 2 0 1 7  
2. 0  
A m e n d m e nt 1  
1 4  D e c e m b er  2 0 1 8  
Pr ot oc ol Versi o n ( 2. 0) ( 1 4  Dece m ber  2 0 1 8)  
Gl o bal Versi o n I D: C CI

SAP_001.pdf: 
M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
I nte gr ate d A n al ysis Pl a n 
Cli nic al Tri al Pr ot oc ol 
I de ntific ati o n N o. 
M S 7 0 0 5 6 8 _ 0 0 2 1  
Title  
A 2 -year Pr os pecti ve St u d y t o Assess H ealt h-relat e d Q ualit y of 
Life  i n S u bjects wit h Hi g hl y-acti ve Rel a psi n g M ulti ple Scler osis 
Treate d wit h Ma ve ncla d ®  
Tri al P h ase  
I V 
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)  
Ma ve ncla d
®  
Cli nic al Tri al Pr ot oc ol 
Versi o n  
1 4 Dece m b er 2 0 1 8 / 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  
 
Bi o st ati sti c s, 
 
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
Bi o st ati sti c s, 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n  
2 1  Se pte m ber  2 0 2 1 / Versi o n 5 . 0, Fi nal  
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  
L e a d Bi o st ati sti ci a n  
 
M e di c al R e s p o n si bl e  
 
M e di c al R e s p o n si bl e ( b a c k -u p)  
 
 
C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa 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 part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p yri g ht © 2 0 2 1  b y Merc k K G a A, D ar mst a dt, Ger m a n y or its affili ate. All ri g hts reser ve d.  
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Si g n at ure P a ge  
 
I nte gr ate d A n al ysis Pl a n: M S 7 0 0 5 6 8 _ 0 0 2 1  
 
A 2 -year Pr os pecti ve St u d y t o Assess Healt h -relat e 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 o sis Treate d wit h Ma ve ncla d ®  
 
A p pr o val of t he I A P b y all Merc k Data A nal ysis Res p o nsi ble is d oc u me nte d wit hi n E L D O R A D O. 
Wit h t he a p pr o val wit hi n El d ora d o, t he M erc k res p o nsi ble f or eac h of t he a nal ysis als o t a 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.  
 
Merc k res p o nsi ble  
D ate  
Si g n at ure  
 Lea d Bi ostatisticia n  
Via Vee v a Va ult  a p pr o val pr ocess  
 
 
 
 
 
Gl o bal Versi o n I D: 
P P D
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
1  
T a ble of C o nte nts  
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  
4  
P ur p ose of t he I nte grate d A nal ysis Pla n  .............................................1 2  
5  
O bjecti ves a n d E n d p oi nts  ...................................................................1 3  
6  
O ver vie w of Pla n ne d A nal yses  ...........................................................1 4  
6. 1  
I nteri m A nal ysis ..................................................................................1 4  
6. 1. 1  
6 -m o nt h I nteri m A nal ysis  ...................................................................1 4  
6. 1. 2  
1 -year I nteri m A nal ysis  ......................................................................1 6  
6. 2  
Fi nal A nal ysis  .....................................................................................1 8  
7  
C ha n ges t o t he Pla n ne d A nal yses i n t he Cli nical Trial Pr ot oc ol  ........2 0  
8  
Pr ot oc ol De viati o ns a n d A nal ysis Sets  ...............................................2 1  
8. 1  
Defi niti o n of Pr ot oc ol De viati o ns  .......................................................2 1  
8. 2  
Defi niti o n of A nal ysis Sets a n d S u b gr o u ps  ........................................2 1  
9  
Ge neral S pecificati o ns f or Data A n al yses  ..........................................2 3  
1 0  
Trial Partici pa nts  .................................................................................2 8  
1 0. 1  
Dis p osi ti o n of Partici pa nts a n d Disc o nti n uati o ns ...............................2 8  
1 0. 2  
Pr ot oc ol De viati o ns  ............................................................................2 8  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De viati o ns ............................................................2 8  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................2 9  
1 1. 1  
De m o gra p hics  .....................................................................................2 9  
1 1. 2  
Me dical Hist or y  ..................................................................................3 0  
1 1. 3  
Ot her Baseli ne C haracteristics  ............................................................3 0  
1 2  
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures  .............................3 3  
1 3  
Treat me nt C o m plia nce a n d E x p os ure  .................................................3 4  
1 4  
Efficac y A nal yses  ...............................................................................3 7  
1 4. 1  
Pri mar y E n d p oi nts: C ha n ges 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 fr o m Baseli ne t o  M o nt h 2 4 Visit  .................3 7  
1 4. 1. 1  
Pri mar y O bjecti ve: A nal ysis of t he pri mar y e n d p oi nts  ......................3 9  
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1 4. 2  
Sec o n dar y E n d p oi nt: Treat me nt gl o bal satisfacti o n assesse d b y 
T S Q M v 1. 4 at M o nt h 6 Visit (I nteri m A nal ysis)  ...............................4 4  
1 4. 3. 1  
C ha n ges i n M S Q o L -5 4  O verall q ualit y of life  ...................................4 5  
1 4. 3. 2  
Treat me nt gl o bal satisfacti o n, Effecti ve ness, Si de effects, a n d 
C o n ve nie nce ass ess me nt b y T S Q M v 1 . 4 ............................................4 5  
1 5  
Safet y A nal yses  ..................................................................................6 2  
1 5. 1  
A d verse E v e nts  ...................................................................................6 2  
1 5. 1. 1  
All A d verse E v e nts  .............................................................................6 2  
1 5. 1. 2  
A d verse E v e nts Lea di n g t o Treat me nt Disc o nti n uati o n  .....................6 3  
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 4  
1 5. 2. 1  
Deat hs  .................................................................................................6 4  
1 5. 2. 2  
Seri o us A d verse E v e nts  ......................................................................6 4  
1 5. 2. 3  
Ot her Si g nifica nt A d verse E ve nt  ........................................................6 4  
1 5. 3  
Cli nical La b orat or y E val uati o n  ...........................................................6 5  
1 5. 4  
Vital Si g ns  ..........................................................................................6 5  
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns  ............................................6 6  
1 6  
A nal yses of Ot her E n d p oi nts  ..............................................................6 7  
1 7  
Refere n ces  ...........................................................................................6 8  
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1 8  
A p pe n dices  .........................................................................................6 9  
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2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms 
 
A Da M  
A nal ysis Data M o del  
A E  
A d verse E v e nt  
A R R  
A n n ualize d Rela ps e Rate  
A T C  
A nat o mical T hera pe utic C he mical classificati o n  
B V M T -R  
Brief Vis u os patial Me m or y Test –  Re vise d  
C DI S C  
Cli nical Data I nterc ha n g e Sta n dar ds C o ns orti u m  
C D P  
C o nfir me d Disa bilit y Pr o gressi o n  
CI  
C o nfi de nce I nter val  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C R F  
Case Re p ort F or m  
C S R  
Cli nical St u d y Re p ort  
C V L T -II 
Calif or nia Ver bal Lear ni n g Test –  Sec o n d e diti o n  
D M D  
Disease M o dif yi n g Dr u g  
E AI R  
E x p os ure a dj uste d i nci de nce rat es 
E T  
Earl y Ter mi nati o n  
F A S  
F ull A nal ysis Set  
H R Q O L  
Healt h Relate d Q u alit y of Life  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n  
I A 
I nteri m A nal ysis 
I A P 
I nte grate d A nal ysis Pla n 
i R T 
I nteracti ve Res p o nse Tec h n ol o g y 
I T T 
I nte nti o n t o Treat 
L S  
Least S q uare  
M CI D  
Mi ni mall y Cli nicall y I m p orta nt Differe nce  
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Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
M RI  
Ma g netic Res o na nce I ma gi n g  
N A  
N ot A p plica ble  
N CI -C T C A E  
Nati o nal Ca ncer I nstit ute –  C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts  
M RI  
Ma g netic Res o na nce I ma gi n g  
M S  
M ulti ple Scler osis  
M S Q o L -5 4  
M ulti ple Scler osis Q ualit y of Life -5 4 Q uesti o n naire  
e C R F 
electr o nic Cas e Re p ort F or m  
eP R O  
electr o nic Patie nt Re p ort e d O utc o mes  
P B V C  
Perce nta g e brai n v ol u me c ha n ge  
P D  
Pr ot oc ol De viati o n  
P D G M V C  
Perce nta g e dee p gre y matter v ol u me c ha n ge  
P G M V C  
Perce nta g e gre y m atter v ol u me c ha n ge  
P M L  
Pr o gressi ve M ultif ocal L e u k oe nce p hal o pat h y  
P T  
Preferre d Ter m  
P W M V C  
Perce nta g e w hite matter v ol u me c ha n ge  
S A E  
Seri o us A d verse E v e nt  
S A F  
Safet y A nal ysis Set  
S D  
Sta n dar d De viati o n  
S D M T  
S y m b ol Di git M o dalities Test  
S D T M  
St u d y Data Ta b ulati o n M o del  
S F -3 6  
3 6 -Ite m S h ort F or m Healt h S ur ve y 
S O C  
S yste m Or ga n Class  
T C S -1  
Treat me nt C o m pleter Set –  Year 1  
T C S -2  
Treat me nt C o m pleter Set –  Year 2  
T E A E  
Treat me nt E mer ge nt A d v erse E ve nt  
T L F  
Ta bles, Listi n gs, a n d Fi g ures  
T S Q M v 1. 4  
Treat me nt Satisfacti o n Q uesti o n naire Me dicati o n versi o n 1. 4  
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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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I N F O R M A T I O N 
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M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 0  
 
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I N F O R M A T I O N 
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M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 0  
 
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M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 0  
 
 
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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 i nteri m a n d fi nal  a nal ys es of data c ollect e d f or pr ot oc ol M S 7 0 0 5 6 8 _ 0 0 2 1. 
Res ults of t he a nal yses descri be d i n t his I A P will b e i ncl u de d i n t he Cli nical St u d y  Re p ort ( C S R).  
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 yse s 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 S ecti o n 8 ( Statistics) 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 pare d i n c o m plia nce wit h I C H E 9. It descri b es a nal yses pla n ne d i n t he pr ot oc ol a n d pr ot o c ol 
a me n d me nts . T he I A P s pecifies als o a 1 -year i nteri m a nal ysis, w hic h  is n ot pla n ne d  i n t he pr ot oc ol, 
a n d a n y a d diti o nal a nal ysis t o descri be t he p ote ntial i m pact of t he C O VI D -1 9 pa n de mic. Als o, a n 
a d diti o nal Baseli ne  a n al ysis  was perf or me d , w hic h is n ot me nti o ne d i n t he  pr ot oc ol , a n d will be 
descri be d a n d re p orte d se paratel y.  
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5  
O bjecti ves a n d E n d p oi nts  
 
O bj e cti v e  
E n d p oi nt  
I A P 
s e cti o n  
Pri m ar y  
O bj e cti v e  
T o a s s e s s t h e h e alt h -r el at e d q u alit y of lif e 
( H R Q o L) t hr o u g h t h e 
M S Q o L-5 4 s c al e i n 
hi g hl y -a cti v e r el a p si n g m ulti pl e s cl er o si s ( R M S) 
s u bj e ct s tr e at e d wit h M a v e n cl a d ® f or 2 y e ar s 
( 2 4 m o nt h s). 
Pri m ar y E n d p oi nt  
•  
C h a n g e s i n 
M S Q o L -5 4 
at 
2 4 
m o nt h s c o m p ar e d t o B a s eli n e , i. e. 
t h e c h a n g e s i n t h e p h y si c al a n d 
m e nt al h e alt h c o m p o sit e s c or e s . 
1 4. 1  
S e c o n d ar y 
O bj e cti v e  
T o a s s e s s tr e at m e nt s ati sf a cti o n t hr o u g h t h e 
Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e 
M e di c ati o n (T S Q M ) v 1. 4 q u e sti o n n air e i n 
hi g hl y a cti v e R M S s u bj e ct s at 6 m o nt h s of 
tr e at m e nt wit h M a v e n cl a d® . 
S e c o n d ar y E n d p oi nt  
•  
Tr e at m e nt gl o b al s ati sf a cti o n 
a s s e s s e d b y T S Q M v 1. 4 at 6 
m o nt h s . 
0  
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6  
O ver vie w of Pl a n ne d A n al yses  
T he f oll o wi n g a nal yses are pla n ne d f or t he st u d y:  
•  I nteri m anal ysis (I A) aft er all s u bjects ha ve c o m plete d t he 6-m o nt h assess me nt , 
•  I A after all s u bjects ha v e c o m plete d t he 1 -year ( M o nt h 1 2a  Visit ) assess me nts,  
•  Fi nal anal ysis at t he e n d of t he st u d y . 
T he 1 -year I A is n ot s pecifie d i n t he pr ot o c ol. T he a p pr o val t o perf or m t he u n pla n ne d I A was gi ve n 
3 0 J ul y 2 0 2 0.  
I n a d diti o n, a Baseli ne  a n al ysis was  perf or me d. T his Baseli ne  a nal ysis is n ot s pecifie d i n t he st u d y 
pr ot oc ol a n d is descri b e d i n a se parate A nal ysis P la n. 
6. 1  
I nteri m A n al ysis 
6. 1. 1  
6 -m o nt h I nteri m A n al ysis  
A n i nteri m a nal ysis will be u n derta ke n after all s u bjects ha ve c o m plete d t he 6 -m o nt h assess me nt. 
As t he pri mar y e n d p oi nt is n ot a vaila ble at t his ti me, t he i nteri m a nal ysis will f oc us o n t he 
sec o n dar y e n d p oi nt w hic h is t he treat me nt gl o bal satisfacti o n assesse d b y T S Q M v 1. 4 at M o nt h 6 
Visit  w hic h will be a n al yze d wit h a mi xe d li near regressi o n m o del  o verall a n d b y t he s u b gr o u p, 
“Pre vi o us treat me nt wit h Disease M o dif yi n g  Dr u gs ( D M D s)”, s ee Secti o n 0  f or details.  
T he i nteri m a n al ysis will be c o nsi dere d as s u p p orti ve of t he 2 4 -m o nt h a nal ysis ( fi nal a nal ysis). 
D ue t o t h e e x pl or at or y n at ure of t he st u d y, n o al p ha s pe n di n g was pl a n ne d t o c o n tr ol f or o verall 
t y pe-I-err or i nfl ati o n.  
I n a d diti o n,  t he I nteri m A nal ysis will descri be t he f oll o wi n g c haracteristics of t he st u d y p o p ulati o n : 
•  Dis p ositi o n  (S ecti o n 1 0. 1 ) i ncl u di n g a n d u p t o t he c ut-off p oi nt , 
•  Baseli ne  C haracteristics i ncl u di n g M S Disease C haract eristics  (S ecti o n  1 1 ), 
•  R ele va nt Pre vi o us Me dic ati o ns  (S ecti o n 1 2 ), 
a n d will i ncl u de t he f oll o wi n g e n d p oi nts : 
•  Trea t me nt Effecti ve n ess, Si de effects, a n d C o n ve nie nce assess e d b y T S Q M v 1. 4 at t he 
M o nt h 6 Visit ( S ecti o n 0 ), 
•  C ha n ges i n le vel of disa bilit y as mea s ure d b y 
 at t he M o nt h 6 V isit 
c o m pare d t o Baseli ne  (S ecti o n 1 4. 3 ), 
•  R ela pse re p orts i ncl u di n g a n d u p t o t he c ut-off p oi nt  ( N u m ber a n d Perce nta ge of S u bjects 
wit h (q ualif yi n g ) rela ps es), 
•  Occ urre nces of T E A Es a n d S A Es as well as L y m p h oc yte c o u nts i ncl u di n g a nd u p t o t h e 
c ut-off p oi nt  (S ecti o n 1 5 ). 
T he c haracteristics  will be s u m marize d descri pti v el y  u p t o M o nt h 6 Visit  i n t he sa me wa y as f or 
t he fi nal a nal ysis.   
Ta ble 1  lists all assess me nts w hic h will be i ncl u de d i n t he i nteri m a nal ysis. 
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T a ble 1 : List of assess me nts i ncl u de d i n t he i nteri m a n al ysis 
Assess m e nts  
Scree ni n g  
B aseli ne  
M o nt h 2  
M o nt h 6  
I nf or me d C o nse nt 
X  
 
 
 
De m o gra p hic  
X  
 
 
 
iR T  
 
X  
 
 
Disease Hist or y  
X  
 
 
 
L y m p h oc yte C o u nt  
X  
X  
X  
X  
Treat me nt Satisfacti o n ( T S Q M v 1. 4)  
 
 
 
X  
Treat me nt A d mi nistrati o n  
 
X  
 
 
Rela pse Re p ort  
 
 
X  
X  
A Es  
 
X  
X  
X  
Treat me nt a n d St u d y Ter mi nati o n  
 
X  
X  
X  
Rele va nt P re vi o us Me dic ati o n  
X  
 
 
 
C ut -off d ate  
O nl y  data  u p t o t he M o nt h 6 Visit  of eac h s u bj ect will be a n al yze d  i n t he i nteri m a nal ysis. 
T heref ore , t h e c ut-off d ate is defi ne d as t he ma xi m u m M o nt h 6 Visit  date (i.e. d ate of t he last 
assess me nt f or t he M o nt h 6 Visit ). F or s u bjects wit h a missi n g M o nt h 6 Visit  t he c ut-off dat e will 
be  1 8 0  da ys after start of st u d y medicati o n . T his i ncl u des s u bjects w h o dis c o nti n ue d bef ore Da y 
1 8 0.  
•  C ut -off date ( M o nt h 6 Visit d o ne) = M a xi m u m M o nt h 6 V isit date 
•  C ut -off date ( M o nt h 6 Visit n ot d o ne) = S tart of st u d y me dicati o n + 1 8 0 da ys   
All e ve nts of deat h will be i ncl u de d i n t he i nteri m a nal ysis re g ar dless of t he ti me p oi nt (i.e. a n y 
deat h t hat is i ncl u de d i n t he data bas e at t he ti me of t he s na ps h ot will be re p orte d i n t he i nteri m 
a nal ysis ). 
All data i n cl u de d i n t he I A will u n der g o a data  cl ea ni n g pr ocess, h o we ver, as t he k e y d ata p oi nt is 
a n e P R O a n d n o decisi o ns o n f urt her st u d y c o n d uct are base d o n t his I A, it is n ot re q uire d t o ha ve 
all data 1 0 0 % cle a ne d. T he q ualit y of t he data will be re vie we d d uri n g t he Data Re vie w M eeti n g.  
D at a h a n dli n g after c ut -off d ate  
Data aft er c ut -off d o n ot u n der g o t he clea ni n g pr o cess.  
Gl o bal Versi o n I D: C CI
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Data ot her t h a n t he date of deat h o btai ne d after t he c ut -off will n ot be dis pla ye d i n a n y listi n gs or 
use d f or s u m mar y statistics.  
If t he st o p date f or a n A E s is after t he d at e of c ut -off , t he A E s will be c o nsi d ere d as  o n g oi n g d uri n g 
t he I nt eri m A nal ysis. 
6. 1. 2  
1 -y e ar I nteri m A n al ysis 
A  sec o n d u n pla n n e d I A will be u n derta k e n after all s u bjects ha ve c o m plete d t he i nitial 1 2 -m o nt h 
assess me nt.  
T he i nteri m a nal ysis will f oc us o n t he ne w defi ne d tertiar y e n d p oi nt, t he c ha n ge i n  M ulti ple 
Scler osis Q ualit y of Lif e -5 4 ( M S Q o L 5 4 ) p h ysical a n d me ntal h ealt h c o m p osite sc ores at t he 
M o nt h 1 2 Visit c o m pare d t o Baseli ne , w hic h will be a nal yze d a p pl yi n g the sa me met h o d ol o g y as 
s pecifie d f or t he pri mar y e n d p oi nt t he M S Q o L 5 4 at M o nt h 2 4 (see secti o n 1 4. 1  f or det ails) e xce pt 
f or t he re p eate d visit effect as t here is o nly o ne p ost -baseli ne assess me nt i n t his a nal ysis . As 
a se nsiti vit y a nal ysis, t he a n al ysis will be re peate d b y t he s u b gr o u p  “ Pre vi o us treat me nt wit h 
D M Ds” ( Secti o n 8. 2 ). I n or der t o e val uat e a p ote ntial i m pact of t he C or o na vir us disease 2 0 1 9  
(C O VI D -1 9 ) pa n de mic o n t he Q o L of patie nts, t he a nal ysis will als o be re peate d b y a s u b gr o u p of 
patie nts t hat ha d t heir M o nt h  1 2  M S Q o L assess me nt after t he start of t h e C O VI D -1 9 pa n d e mic 
vers us patie nts t hat ha d t heir res ults alrea d y re p orte d bef ore t his date. 
 
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  
As t his I A is u n pla n ne d , n o al p ha s p e n di n g was pl a n ne d t o c o ntr ol f or o v erall t y pe-I-err or i nflati o n  
a n d n o st o p pi n g r ules or a n y ot her m o dificati o ns t o t he st u d y are defi ne d wit h t his I A.  
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I n a d diti o n, t he I nteri m A nal ysis will descri be t he f oll o wi n g c haracteristics of t he st u d y p o p ulati o n: 
•  Dis p ositi o n ( S ecti o n 1 0. 1 ) i ncl u di n g a n d u p t o t he c ut-off p oi nt , 
•  S u m mar y of visits  / M S Q o L assess me nt s perf or me d bef ore a n d after start of C O VI D-1 9 
pa n de mic ,   
•  Baseli ne C haracteristics i ncl u di n g M S Disease C haract eristics a n d res ults fr o m t he ce ntral 
M RI re vie w f or t he scree ni n g M RI (S ecti o n 1 1 ), 
•  Rele va nt Pre vi o u s Me dicati o n (S ecti o n 1 2 ), 
a n d will i ncl u de t he f oll o wi n g e n d p oi nts:  
•  C ha n ge i n M S Q o L O verall q ualit y of life at t he M o nt h 1 2 Visit c o m pare d t o Baseli ne 
(Secti o n 1 4. 3. 1 ) 
•  Gl o bal satisfacti o n, Treat me nt effecti ve ness, Si de effects, a n d C o n ve nie nce assesse d b y 
T S Q M v 1. 4 at t he M o nt h 6 a n d M o nt h 1 2 Visit ( S ecti o n1 4. 3. 2 ), 
•  C ha n ges i n le vel of disa bilit y as meas ure d b y E D S S, at t he M o nt h 6 a n d M o nt h 1 2 Visit 
c o m pare d t o Baseli ne ( S ecti o n 1 4. 3 ), 
•  Rela pse re p orts i ncl u di n g a n d u p t o t he c ut -off p oi nt ( n u m ber a n d p erce nt a ge of su bjects 
wit h ( q ualif yi n g) rela ps es),  
•  Occ urre nces of T E A Es a n d S A Es as well as L y m p h o c yte c o u nts i ncl u di n g a n d u p t o t h e 
c ut-off p oi nt ( S ecti o n 1 5 ). 
T hese c haracteristics will be s u m mari ze d d escri pti vel y u p t o M o nt h 1 2 a Visit i n t he  sa me wa y as 
f or t he fi nal a nal ysis. I n a d diti o n, all T S Q M sc ores will be a nal yze d a p pl yi n g t he re peate d mi xe d-
effects li near re gressi o n as s pecifi e d i n Secti o n 1 4. 3. 2  (a part fr o m t he i ncl usi o n of t he Visit effect 
f or 
M o nt h 2 4). M S Q o L  a n d selecte d dis p ositi o n a n d Baseli ne a nal yses will be re peate d b y 
s u b gr o u p “ M o nt h 1 2  M S Q o L assess me nt aft er start of C O VI D -1 9 p a n de mi c ”.  
Ta ble 2  lists all assess me nts w hic h will be i ncl u de d i n t he 1 -year i nteri m a n al ysis. 
T a ble 2 : List of assess me nts i ncl u de d i n t he 1 -ye ar  i nteri m a n al ysis 
Assess m e nts  
Scree ni n g  
B aseli ne  
M o nt h 2  
M o nt h 6  
M o nt h 1 2 a  
I nf or me d C o nse nt 
X  
 
 
 
 
De m o gra p hic  
X  
 
 
 
 
i R T 
 
X  
 
 
 
Disease Hist or y  
X  
 
 
 
 
M S Q o L -5 4  
 
X  
 
X  
M RI  
X  
 
 
 
 
L y m p h oc yte C o u nt  
X  
X  
X  
X  
X  
Treat me nt Satisfacti o n 
( T S Q M v 1. 4) 
 
 
 
X  
X  
Gl o bal Versi o n I D: C CI
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Assess m e nts  
Scree ni n g  
B aseli ne  
M o nt h 2  
M o nt h 6  
M o nt h 1 2 a  
Treat me nt A d mi nistrati o n  
 
X  
 
 
 
A Es  
 
X  
X  
X  
X  
Treat me nt a n d St u d y 
Ter mi nati o n  
 
X  
X  
X  
X  
Rele va nt Pre vi o us 
Me dicati o n  
X  
X  
 
 
 
C ut -off d ate  
O nl y data u p t o  a n d i ncl u di n g  t he M o nt h 1 2 a Visit of eac h s u bject will be a nal yze d i n t he I A. 
T heref ore, t he c ut -off date is defi ne d as t he ma xi m u m M o nt h 1 2 a Visit date (i.e. date of t he last 
assess me nt f or t he M o nt h 1 2a  Visit). F or s u bjects wit h a missi n g M o nt h 1 2 a Visit t he c ut -off date 
will be 3 6 0  da ys after st art of st u d y me dicati o n. T his i ncl u des s u bjects w h o disc o nti n ue d bef ore 
Da y 3 6 0 .  
•  C ut -off date ( M o nt h 1 2a  Visit d o ne) = M o nt h 1 2 a Visit E n d Date (i.e. M a xi m u m M o nt h 
1 2a  Visit date ) 
•  C ut -off date ( M o nt h 1 2a  Visit n ot d o ne) = Start of st u d y me dicati o n + 3 6 0  da ys -1  
A n y assess me nts  fr o m t he M o nt h 1 2 b  or later Visit s will n ot be i ncl u de d i n t he I A , h o we ver, a n y 
e ve nts  or c o nc o mita nt me dicati o ns  re p orte d d uri n g t hese visits t hat ha ve a n o nset /start date bef ore 
or at t he c ut-off date  will be i ncl u de d.   
All e ve nts of deat h will be i ncl u de d i n t he i nteri m a nal ysis re g ar dless of t he ti me p oi nt (i.e. a n y 
deat h t hat is i ncl u de d i n t he data bas e at t he ti me of t he s na ps h ot will be re p orte d i n t he i nteri m 
a nal ysis). 
All data i n cl u de d i n t he I A will u n der g o a data cl ea ni n g pr ocess, h o we ver, as t he k e y d ata p oi nt is 
a n e P R O a n d n o decisi o ns o n f urt her st u d y c o n d uct are base d o n t his I A, it is n ot re q uire d t o ha ve 
all data 1 0 0 % cle a ne d. T he q ualit y of t he data will be re vie we d d uri n g t he Data Re vie w M eeti n g.  
D at a h a n dli n g after c ut -off d ate  
Data n ot i ncl u de d i n t he 1 2 m o nt h I A d o n ot u n der g o t he clea ni n g pr ocess.  
Data ot her t h a n t he date of deat h o btai ne d after t he c ut -off will n ot be dis pla ye d i n a n y listi n gs or 
use d f or s u m mar y statistics.  
If the st o p date f or a n A Es  is after t he d ate of c ut -off, t he A Es will be c o nsi d ere d as o n g oi n g d uri n g 
t he I nt eri m A nal ysis. 
6. 2  
Fi n al A n al ysis  
T he fi nal a nal ysis will i ncl u de all des cri be d a nal ys e s of t his I A P e xce pt f or t he m o del of  t he T S Q M 
v 1. 4 at M o nt h 6 Visi t (S ecti o n 0 ), w hic h will o nl y be d o ne f or t he i nteri m a nal ysis. T he T S Q M 
v 1. 4 at M o nt h 6 Visit will be i ncl u de d i n a re p eat e d m o del at t he fi nal a n al ysis ( S ecti o n 1 4. 3. 2 ). 
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I N F O R M A T I O N 
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T he fi nal a nal ysis  will be base d o n all data a vaila bl e i n t he d ata bas e at t he ti me of t he fi nal d ata bas e 
l oc k. 
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I N F O R M A T I O N 
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7  
C h a n ges t o t he Pl a n ne d A n a l yses i n t he Cli nic al Tri al 
Pr ot oc ol  
Ha n dli n g of data of s u bjects wit h a dela ye d 2 n d treat me nt c o urse: 
T he st u d y pr ot oc ol pr o vi des t he f oll o wi n g g ui da nce h o w data of s u bjects wit h a dela ye d 
2 n d treat me nt c o urse b e y o n d 3 m o nt hs s h o ul d be ha n dle d i n t he statistical a nal yses.  
Secti o n 5. 5. 1: “ S u bjects wit h l y m p h o pe nia l o wer t hat t he a b o ve -me nti o ne d li mit a n d/ or 
occ urre nce of t he a b o ve -me nti o ne d  i nfecti o ns, res ulti n g i n dela y of sc h e d ule d sec o n d y ear 
treat me nt c o urse b e y o n d 3 m o nt hs will be e xcl u de d fr o m, tertiar y or e x pl or at or y e n d p oi nt 
a nal ysis. ”  
Secti o n 8. 5. 1: “ S u bjects f or w h o m treat me nt is dela ye d b y o ver 3 m o nt hs ma y n ot ha ve all 
assess me nt data ca pt ure d a n d as s uc h, t hes e o bser vati o ns will be treate d as missi n g.” 
As t he data of t he 1 st treat me nt c o urse are e x pect e d t o pr o vi de vali d efficac y i nf or mati o n  
an d  t he treat me nt d ela y of t he 2n d year d oes n ot affect t he 1 st year c o urse , it is deci de d t hat 
all data fr o m t h e 1 st treat me nt c o urse s h o ul d b e i n cl u de d i n all efficac y a nal yses  w hile d ata 
fr o m t he 2n d treat me nt c o urse will be e xcl u de d fr o m all efficac y a n al yses f or s u bjects wit h 
a dela ye d 2 n d treat me nt c o urse be y o n d t hr ee m o nt hs. 
F or safet y  a nal ys es, all data fr o m b ot h Treat me nt C o urses will be use d  i n de pe n de ntl y fr o m 
t he dela ye d start of Treat me nt C o urse 2. Secti o n 9  defi nes t he details of t he data ha n dli n g 
of s u bjects wit h a Dela y e d Treat me nt C o urse 2 . 
1 -year i nteri m a nal ysis:  
A 1 -year I A w as a d d e d d uri n g t he c o urse of t he st u d y  wit h o ut a c orres p o n di n g pr ot oc ol 
a me n d me nt . 
C O VI D -1 9 pa n d e mic:  
A d diti o nal a nal yses t o des cri be t he p ote ntial i m pact of t he C O VI D -1 9 pa n d e mic a d de d.  
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8  
Pr ot oc ol De vi ati o ns  a n d A n al ysis Sets  
8. 1  
Defi niti o n of Pr ot oc ol De vi ati o ns  
Maj or  pr ot oc ol d e viati o ns are pr ot oc ol de vi ati o ns  ( P D) t hat mi g ht si g nifica ntl y affect t h e 
c o m plete ness, acc urac y, a n d/ or rel ia bilit y of t he st u d y data or t hat mi g ht si g nifica ntl y affect a 
s u bject's ri g hts, safet y, or well-bei n g.  
Maj or p r ot oc ol d e viati o ns a n d a n y acti o n t o be ta ke n re g ar di n g t h e e x cl usi o n of s u bjects or affecte d 
data fr o m s pecific a n al yses are d efi ne d i n t he pr o ject-s pecific Pr ot oc ol De viati o n S pecificati o n. 
All pr ot oc ol de viati o ns are d oc u me nte d i n St u d y Data Ta b ulati o n M o del  (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. Ta bles a n d listi n gs of  P D s are 
defi ne d i n S ecti o n 1 0. 2 . 
8. 2  
Defi niti o n of A n al ysis Sets a n d S u b gr o u ps  
E nr olle d  Set ( E S ) 
All  s u bjects e nr olle d i n t he st u d y, i.e. all s u bjects wit h a si g ne d i nf or me d c o nse nt.  
I nte nt-t o-tre at Set (I T T) 
All s u bjects classifie d as eli gi ble  (i.e. me dicati o n assi g ne d b y i R T at t he Baseli ne  V isit). 
F ull A n al ysis Set ( F A S)  
All s u bjects fr o m t he I T T treate d wit h at least o ne d ose of st u d y me dicati o n . 
Tre at me nt C o m pleter Set –  Ye a r  1 ( T C S -1)  
All s u bjects fr o m t he F A S w h o c o m plete d t he full T reat me nt C o urse of t he first year  ( Treat me nt 
C o urse 1) . S u bjects will be classifie d  as T reat m e nt C o m pleter  f or t he first year, if t h e y ha v e a 
c o m plia nce greater  t h a n or  e q ual t o 1 0 0 %  f or Treat me nt C o urse 1. 
Tre at me nt C o m pleter Set –  Ye a r 2 ( T C S -2)  
All s u bjects fr o m t he F A S w h o c o m plete d t he f ull T reat me nt C o ur se of t h e first a n d t he sec o n d 
year . S u bjects will be classifie d as T reat me nt C o m pleter f or t he sec o n d year, if t he y ha ve  a 
c o m plia nce great er  t ha n or e q ual  t o 1 0 0 % f or Treat me nt C o urse 1 a n d Treat me nt C o urse 2  a n d 
recei v e d t he treat me nt wit ho ut dela y (see Secti o n 9 f or defi niti o n).  
S afet y A n al ysis Set ( S A F)  
All s u bjects treate d wit h at least o ne d ose of st u d y me dicati o n . 
U nless  ot her wise s pecifi e d, all effic ac y a nal yses will be p erf or me d  o n t he F A S.  T he pri mar y 
a nal ys is will be re peate d o n  t he Treat me nt C o m pleter Sets a n d o n  t he I T T, if differe nt, t o e val uate 
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t he se nsiti vit y of t he pri mar y res ults t o de viati o ns of t he pla n ne d treat me nt re gi me n. F urt her details 
are gi ve n i n t he res pecti ve secti o ns.  All safet y a nal yses wi ll be perf or me d o n t he S A F. 
A d diti o n al S u b gr o u p A n al ysis Sets  
S u b gr o u p a nal yses will be perf or me d o n s u b gr o u ps as defi ne d b el o w.  
Pre vi o us treat me nt wit h Disease M o dif yi n g  Dr u gs ( D M D s): 
•  D M D pre -treate d: S u bje cts will be cate g orize d as D M D pre -treate d if t h e y ha ve ta ke n 
D M Ds a n y ti me bef ore start of st u d y me dicati o n.  Details of t he  defi niti o n of  D M D s are 
s pecifie d i n A p pe n di x 1 (Secti o n 1 8. 1 ). 
•  P re-treat me nt n aï ve: all s u bjects n ot classifie d as D M D pre-tr eate d. 
U nless ot her wise i n dicat e d , all descri pti ve statistical a nal yses will be prese nte d se paratel y f or 
pre -treat me nt naï ve a n d D M D pre-tr eate d s u bj ects. 
M o nt h 1 2  M S Q o L assess me nt  after start of C O VI D -1 9 pa n de mic:  
•  Yes:  Date of M o nt h 1 2 M S Q o L assess me nt  (if missi n g, M o nt h 1 2a Visit E n d Date ) after 
start of C O VI D -1 9 p a n de mic (see Secti o n 9 f or defi n iti o n).  
•  N o: Ot her wise . 
T his s u b gr o u p i s use d i n 1-year I A a n d a n y e P R O a nal yses de dicate d t o 1 -y ear dat a as s pecifie d i n 
t he res pecti ve secti o ns. 
S pecific a nal ys es as s pecifie d i n t he res pecti ve secti o ns will be re peate d f or t h ese s u b gr o u ps.  
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9  
Ge ner al S pecific ati o ns f or D at a A n al yses  
Tre at me nt gr o u ps  
T he treat me nt gr o u p will be la bele d as Ma ve n cla d
® . 
Si g nific a nce le vel  
All statistical tests me nti o ne d i n t his I A P are t o be re gar de d as e x pl orat or y. All statistical tests will 
be perf or me d 2 -si de d. If c o nfi de nce i nter vals are t o be calc ulate d, t h ese will be 2 -si de d wit h a 
c o nfi de nce pr o ba bilit y of 9 5 %, u nless ot her wise s pecifie d i n t his I A P. 
Prese nt ati o n of c o nti n u o us a n d q u alit ati ve v ari a bles  
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.  n u m ber of s u bjects, 
n u m ber of s u bjects wit h missi n g a n d  n o n -missi n g val ues , mea n, sta n dar d d e 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 will be s u m marize d b y c o u nts  a n d perce nta ges . 
U nless ot her wis e state d , t he cal c ulati o n of pr o p orti o ns will be b ase d o n t he n u m ber of s u bjects of  
t he a nal ysis set of i nterest. T heref ore, c o u nts of missi n g o bser vati o ns will be i ncl u de d i n t he 
de n o mi nat or a n d prese nt e d as a se p arat e cat e g or y.  
I n cas e t he a n al ysis refers o nl y t o certai n Visit s p erce nta ges will be b ase d o n t he n u m ber of s u bjects 
still prese nt i n t he st u d y at t hat Visit , u nless ot her wise s pecifie d. 
Defi niti o n of B aseli ne  
T he last  n o n -missi n g  meas ure me nt pri or t o start of st u d y me dicati o n will ser ve as t he Baseli ne  
meas ure me nt. M eas ure m e nts perf or me d o n t he da y of first i nta k e of st u d y me dicati o n are ass u me d 
t o be “ pri or t o start of st u d y me dicati o n” as l o n g as it has n ot bee n c o nfir me d t hat t he pr oce d ure 
was perf or me d after war ds. T his ass u m pti o n is j ustifie d as f oll o wi n g t he s e q ue nce of pr oce d ures as 
s pecifie d i n t he st u d y pr ot oc ol. T he i nta ke of st u d y me dicati o n s h o ul d be t he last pr oce d ure o n t he 
visit da y.  
Defi niti o n of c h a n ge fr o m B aseli ne  
C ha n ge fr o m Baseli ne  = Visit  val ue –  Baseli ne  val ue  
Perce nt C ha n ge fr o m Baseli ne  = 1 0 0 * ( Visit  val u e –  Baseli ne  val ue) / Baseli ne  val ue  
Defi niti o n of visit d ate s 
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 visit.  
T he visit e n d date is t he date of t he last as s ess me nt w hic h bel o n gs t o t he c orres p o n di n g visit .  
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Defi niti o n of d ur ati o n  
D urati o n will be calc ulate d b y t he differe nce of start a n d st o p date + 1  i n da ys (if n ot ot her wise 
s pecifie d). 
Tre at me nt P eri o d  
T he treat me nt p eri o d be gi ns wit h t he start of st u d y me dicati o n  o n S t u d y Da y 1 a n d c o nti n ues 
t hr o u g h t o t he c o m pleti o n of t he treat me nt peri o d at t he M o nt h 2 4 Visit  (see pr ot oc ol 
S ecti o n 7. 1. 3).  Start of st u d y me dicati o n is t he d ate of first i nta k e of st u d y me dicati o n. Start of 
st u d y me dicati o n i n Y ear 2 is t he date of first i nta ke of st u d y me dicati o n at or after t he M o nt h 1 2 
Visit . 
Treat me nt Peri o d:  
•  Start = Start of st u d y me dicati o n , 
•  E n d = Visit e n d date of M o nt h 2 4 Visit  or Earl y Ter mi nati o n  ( E T) Visit i n case of earl y 
disc o nti n uati o n , or t he st u d y disc o nti n uati o n date, if t he E T Visit was n ot perf or me d. 
C o urse 1 Treat me nt P eri o d:  
•  Start = Start of st u d y me dicati o n , 
•  E n d = Start of st u d y me dicati o n at or after t he M o nt h 1 2 Visi t -1 da y  or if t he s u bject di d 
n ot recei ve Treat me nt C o urse 2: Start of st u d y me dicati o n of Treat me nt C o urse 1 + 4 5 7 
da ys ( w hic h is o btai ne d b y 3 6 0 ( 1 2 m o nt hs) + 9 0 ( 3 m o nt hs) + 7 ( visit wi n d o w)), or dat e 
of t he st u d y disc o nti n uati o n, if earlier . 
C o urse 2 Treat me nt P eri o d:  
•  Start = St art of st u d y me dicati o n at or after t he M o nt h 1 2 Visit , 
•  E n d = E n d of Treat me nt Peri o d . 
Defi niti o n of Del a ye d Tre at me nt C o urse 2  
•  T he Treat me nt C o urse 2 will be defi ne d as dela ye d, if t he start of st u d y me dicati o n is 
dela ye d b y m ore t h a n 3 m o nt hs ( = 9 0 da ys) or di d n ot start at all i.e.: 
o  Start of St u d y Me dicati o n of Treat me nt C o urse 2  > Start of St u d y Me dicati o n of 
Treat me nt C o urse 1 + 4 5 7 da ys  ( w hic h is o btai ne d b y 3 6 0 ( 1 2 m o nt hs) + 9 0 ( 3 
m o nt hs) + 7 ( visit wi n d o w)) , or 
o  Treat me nt C o urs e 2 ne v er starte d (i.e. n o st u d y me dicati o n ta ke n at or after t he 
M o nt h 1 2 Visit).  
D at a h a n dli n g i n c ase of a Del a ye d Tre at me nt C o urse 2  
F or s u bjects wi t h a Dela y e d Treat me nt C o urse 2, o nl y data o bser ve d d uri n g t he C o urse 1 Treat me nt 
Peri o d  will be a nal yze d  i n all efficac y a n al yses. Efficac y data after t he C o urse 1 Treat me nt Peri o d 
will be c o u nte d as missi n g i n t he statistical a nal yses a n d mar k e d i n t he l isti n gs. I n all effi cac y 
a nal yses d efi ne d b y Peri o d, t he s u bject s will be cl assifie d as if t he y  disc o nti n ue d at t he e n d of t h e 
C o urse 1 Treat me nt Peri o d. F or s u bjects wit h o ut a dela y t he w h ole Treat me nt Peri o d will be 
a nal yze d. 
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F or all ot her a nal yses (e x ce pt efficac y) t he dat a is n ot li mite d t o t he C o urse 1 Treat me nt Peri o d f or 
s u bjects wit h a Dela y e d Treat me nt C o urse 2. 
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 ntr e 
f or 
Disease 
Pre v e nti o n 
a n d 
C o ntr ol 
o n 
2 6t 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-data 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 H O d eclare d C O VI D -1 9 pa n d e mic).  
Visit ti mi n g wit h res pect t o C O VI D -1 9 p a n de mic  
A visit if defi ne d t o be perf or me d after t he start of C O VI D -1 9 pa n d e mic if t he visit 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 .  
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 Visit 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.  
Ti m e wi n d o w  
•  Da y 1 is t he da y of start of st u d y me dicati o n, t he da y bef ore is Da y -1 ( n o Da y 0 is defi ne d).  
•  St u d y  da y / Treat me nt da y is defi ne d relati ve t o Da y 1.  
T he visit sc he d ule 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 h e start d ate of t he Bas e li ne Visit f or Treat me nt C o urse 1 a n d relati ve t o t he start date 
of t he  M o nt h 1 2 b Visit  as defi ne d i n t he e C R F (see als o Secti o n 1 5. 3) f or Treat me nt C o urse 2 . 
I n eac h a n al ysis, s h o ul d assess me nt be dela ye d, s u bjects’ assess me nt d ata 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. o ut of visit wi n d o ws will be n ot e xcl u de d or a dj uste d 
f or a n y a n al yses) a n d i nf ere nces 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 Visit s will be i ncl u de d o nl y i n t he a nal yses of Visit  i n de pe n de nt 
s u m maries (e. g. c o u nts of e v e nts, pr o gressi o ns or w orst val ue d uri n g T reat me nt P eri o d) u nless f or 
t he last assess me nt a vaila ble. I n t his cas e t he missi n g 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 , the assess me nts of t he E T visit will be ma p pe d t o t he nearest ne xt  
pla n ne d p ost -baseli ne visit 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 des cri pti ve s u m maries . As n ot all assess me nts of t he E T 
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are perf or me d  at eac h visit , t he differe nt assess me nts of t he E T ca n be assi g ne d t o differe nt visits. 
If t he d urati o n (i n da ys) bet wee n t he E T visits a n d t w o missi n g pla n ne d visits are e q ual, t he n t he 
assess me nt will be assi g ne d t o t he later visit.  
H a n dli n g of missi n g d at a  
U nless ot her wise s pecifie d i n res pecti ve secti o ns, missi n g data will n ot be re place d.  
T he h a n dli n g of missi n g c o variate a n d stratificati o n fact or i nf or mati o n is descri be d bel o w . 
T he ha n dli n g of missi n g D M D e n d date  is des cri b e d i n Secti o n 1 2 . 
I n c o m plete or missi n g o nset dates  of  rela pses fr o m “ M S Rela pse Re p ort” 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 or 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 u al t o t he start of st u d y me dicati o n t he n t he o nset date will be 
re place d b y t he start dat e of st u d y me dicati o n. 
•  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 all s u bject data listi n g s, i m p ute d val ues will be prese nt e d. I n all listi n gs 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 ul ate d, s h o ul d be pres e nte d as “ n d ”.  F or e xa m ple, 
if n = 1, t he meas ur e of varia bilit y (e. g. S D) ca n n ot be c o m p ute d a n d s h o ul d be prese nt e d as “ n d ”.  
W here ta bles are prese nt e d o ver ti me, t he t otal of 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 p o p ulati o n still i n t he st u d y at t hat ti me. T his d oes n ot a p pl y w he n 
i m p utati o ns are ma de be y o n d st u d y wit h dra wal.  
D at a H a n dli n g i n c ase of m aj or P Ds  
E lectr o nic Patie nt Re p orte d O utc o mes (e P R O) assess me nts perf or me d c o m pletel y i n n o n-nati ve 
la n g ua ge will n ot be use d f or t he statistical s u m maries or a nal yses as pla n ne d i n t his I A P a n d will 
be fla g ge d acc or di n gl y i n a n y listi n gs . 
A n y ot her P D will n ot be c o nsi dere d  i n t he pla n ne d statistical a nal yses. 
C o v ari ates a n d str atific ati o n f act ors  
•  A ge  
A ge ( years) at ti me of I nf or me d C o nse nt (l oa de d fr o m iR T). Missi n g a ge will be re place d as 
f oll o ws if use d as a c o variate: 
1.  A ge will be esti mate d fr o m t he year of b irt h ( year of I C –  year of birt h) , as rec or de d i n t he 
electr o nic Cas e Re p ort F or m  (e C R F) 
2.  If year of birt h is missi n g, a ge  will be i m p ute d b y t he mea n a g e of t he F A S.  
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•  P o ole d  ce nters  
S o me ce nters  will ha ve fe w eli gi ble s u bjects o nl y . T heref ore, t he ce nters  will be p o ole d t o get h er 
i n ge o gra p hical gr o u ps  b y c o u ntr y  a n d the Sca n di na via n c o u ntries  will be f urt her p o ole d t o get her  
t o o ne Sca n di na via n p o ol. 
S oft w are(s)  
All a nal yses will be perf or me d usi n g S A S ®  S oft ware versi o n 9. 3  or hi g her . 
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1 0  
Tri al P artici p a nts  
T he s u bsecti o ns i n t his secti o n i ncl u de s pecifi cati o ns f or re p orti n g s u bject dis p ositi o n a n d 
treat me nt/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 de d.  
1 0. 1  
Dis p ositi o n of P artici p a nts  a n d Disc o nti n u ati o ns  
S u bject  dis p ositi o n will be prese nt e d f or t he E S:  
•  T otal n u m ber of s u bjects e nr olle d (i.e. s u bjects w h o ga ve i nf or me d c o nse nt), 
•  N u m ber of s u bjects w h o disc o nti n ue d fr o m t he st u d y pri or t o treat me nt o verall a n d gr o u pe d b y 
t he mai n reas o n (i.e. t he Reas o n w h y t he s u bject di d n ot c o nti n ue be y o n d scree ni n g as rec or de d 
i n t he C R F. If t he S u bject di d n ot meet all Eli gi bilit y Criteria t he faile d s pecific i ncl usi o n or 
e xcl usi o n criteria  will be pr o vi de d i n a d diti o n ). S u bject s n ot classifie d as scree n e d fail ure b ut 
wit h o ut treat me nt assi g n me nt b y t he i R T will be liste d as “ n o treat me nt assi g ne d” , 
•  N u m ber of eli gi ble s u bjects (i.e. s u bjects wit h treat me nt assi g n me nt b y t he i R T s yste m), 
•  o verall  a n d b y Treat me nt C o urse , w h o recei ve d at least o ne d ose of st u d y m e dicati o n ,  
•  w h o disc o nti n ue d t he  st u d y me dicati o n, gr o u pe d b y mai n reas o n (reas o n fr o m last 
treat me nt st o p pe d), 
•  w h o disc o nti n ue d /c o m plete d t he st u d y (acc or di n g t o t he i nf or mati o n o n t he St u d y 
Ter mi nati o n C R F pa ge) . 
•  N u m ber of visits perf or me d bef ore a n d after Start of C O VI D -1 9 p a n de mic  
•  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  
Perce nta g es will be pres e nte d wit h res pect t o t he n u m ber of eli gi ble s u bjects. 
T he  n u m ber of s u bjects i n eac h a n al ysis set will b e 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 s u bject data listi n g s wi ll be pr o vi de d: 
•  Listi n g of disc o nti n ue d s u bjects  f or t he I T T, 
•  Listi n g of s u bjects e xcl 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  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De vi ati o ns 
T he f oll o wi n g s u m mar y ta bles a n d listi n gs of maj or pr ot oc ol de viati o ns (see Secti o n 8. 1  f or 
details) will be pr o vi de d b y I n cl usi o n/ E xcl usi o n a n d ot her de viati o ns  f or t h e I T T: 
•  Fre q u e nc ies per reas o n of maj or  pr ot oc ol de viati o ns  (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 d e mic) , 
•  Listi n g of maj or  pr ot oc ol de viati o ns  (i ncl u di n g i nf or mati o n re g ar di n g rel ati o ns hi p t o 
C O VI D -1 9 pa n d e mic) . 
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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, s u m maries will be prese nt e d o n t he F A S . 
1 1. 1  
De m o gr a p hics  
De m o gra p hic c haracteristics will be s u m marize d usi n g t he f oll o wi n g i nf or mat i o n fr o m t he 
Scree ni n g/ Baseli ne  Visit C R F pa ges.  
De m o gra p hic c haracteristics  
•  Ge n der:  
•  M ale, 
•  F e male, 
•  M issi n g. 
•  Race :  
•  W hite , 
•  B lac k or Afri ca n A merica n , 
•  A sia n, 
•  A merica n I n dia n or Alas ka Nati ve , 
•  Nati ve Ha w aiia n or O t her Pacific Isla n d er, 
•  O t her, 
•  N ot c ollecte d at t his site , 
•  M issi n g. 
•  Et h nicit y:  
•  His pa nic or Lati n o , 
•  Yes , 
•  N o,  
•  Missi n g . 
•  Ja pa nese, 
•  Yes,  
•  N o,  
•  Missi n g.  
•  A ge ( years)  
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•  A ge cat e g ories:  
•  ≤ 4 0 years,  
•  > 4 0  years, < 6 5 years , 
•  ≥6 5 years , 
•  Missi n g . 
•  Re gi o n:  
•  Easter n  & Ce ntral  E ur o p e:  
•  (A ustria, H u n gar y, Lit h ua nia, P ola n d, Sl o va kia, Czec h Re p u blic)  
•  S ca n di na via: 
•  ( De n mar k, Fi nla n d, N or wa y, S we de n) 
•  S o ut her n E ur o pe:  
•  ( Greece, It al y, P ort u gal, S pai n) 
•  Wester n E ur o pe:  
•  ( Bel gi u m, Fra nce, Net h erla n ds, U nite d Ki n g d o m) 
•  A ustralia  
•  P o ole d Ce nter   
•  Defi ne d p o ole d ce nter . 
•  C o u ntr y  
•  C o u ntr y 1  
•  …  
T he f oll o wi n g s u bject data listi n g will be pr o vi de d:  
•  De m o gra p hic Data ( C o u ntr y, Se x,  Race, A ge, E D S S at Baseli ne , N u m ber of rela pses 
d uri n g last year ). 
1 1. 2  
Me dic al Hist or y  
T he me dical hist or y will be c o de d usi n g t he 
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) i n t he latest a vaila ble versi o n. S u m mar y ta ble will be prese nt e d b y pri mar y s yste m 
or ga n class ( S O C) a n d preferre d ter m ( P T).  
1 1. 3  
Ot her B aseli ne  C h ar acteristics  
M S Dise ase C h ar acteristics  
T he d urati o n si nce o ns et  a n d dia g n osis of M S at Baseli ne  i n m o nt hs, t he n u m ber of pre vi o us D M Ds 
as well as t he E D S S at Baseli ne  will be prese nt e d . I n a d diti o n, t he n u m ber of s u bjects gr o u pe d b y 
t he maj or s yste m affecte d (at o nset of M S ) will be prese nt e d.   
•  Ti me si nce  o nset of M S ( m o nt hs) =  (visit start date of Baseli ne  Visit - date of first 
s y m pt o m +  1 ) / 3 0. 4 3 7 5, 
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•  Ti me si nce Dia g n osis  ( m o nt hs) =  (visit start date of Baseli ne  Visit - date of dia g n osis 
+  1 ) / 3 0. 4 3 7 5, 
•  Ti me si nce first rela pse ( m o nt hs) =  (visit start date of Baseli ne  Visit - date of first 
rela pse +  1) / 3 0. 4 3 7 5 , 
•  N u m ber of pre vi o us D M Ds  (i.e. n u m b er of differe nt P Ts of D M Ds as  e ntere d i nt o t he 
“ Rele va nt Pre vi o us Me di cati o n F or m ” ( A p pe n di x 1)):  
•  0  
•  1 , 
•  2 , 
•  > 2,  
M RI  Dise ase C h ar a cteristics  
T he f oll o wi n g Scree ni n g M RI res ults will be prese nte d:  
•  N u m ber of T 1 -G d +  e n h a nci n g lesi o ns ,  
•  N u m ber of T 1 -G d + e n h a nci n g lesi o ns:  
•  0,  
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•  > 0,  
•  N o n -e val ua bl e  
•  Missi n g  
•  T otal n u m ber of T 2 lesi o ns ,  
•  T otal n u m ber of T 2 lesi o ns :  
•  0,  
•  1 - 8,  
•  ≥ 9  
•  N o n -e val ua bl e  
•  Missi n g  
•  T otal T 2 lesi o n v ol u me  (c m3), 
•  Brai n v ol u me  (c m3), 
•  Gre y m atter v ol u me  (c m3), 
•  W hite m atter v ol u me  (c m3), 
•  Dee p g re y m atter v ol u me  (c m3). 
Vit al Si g ns  
T he f oll o wi n g Baseli ne  c haract eristics will be pr o vi de d i n s u m mar y ta bles:  
•  Hei g ht, wei g ht, b o d y s urface area, b o d y mass i n d e x , 
•  B o d y te m perat ure, h eart rate, S yst olic Bl o o d Press ure, Diast olic Bl o o d Press ure . 
 
T he b o d y s urface area ( B S A) a n d b o d y mass i n de x ( B MI) will be calc ul ate d wit h t he f oll o wi n g 
e q uati o ns:  
•  B S A( m²) = ([ hei g ht(c m) * wei g ht( k g)] / 3 6 0 0) ^ 0. 5  
•  B MI ( k g/ m²) = [wei g ht ( k g) / hei g ht (c m) ²] * 1 0 0 00  
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1 2  
P re vi o us  or C o nc o mit a nt Me dic ati o ns/ P r oce d ures  
C o nc o mit a nt me 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 ta ke n b y 
s u bjects d uri n g t he st u d y. 
C o nc o mita nt me dicati o ns  will be s u m marize d fr o m t he “ Co nc o mita nt me dicati o n” e C R F  p a ge . 
A T C -1 st le vel a n d preferre d ter m will be ta b ulat e d as gi ve n fr o m t he W H O-D D  dicti o nar y c urre nt 
versi o n . I n case m ulti ple A T C’s are assi g ne d t o a dr u g, all A T C-1 st le vel will be use d f or re p orti n g. 
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 g e  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 dat es.  I n a d diti o n, all c o nc o mita nt  
me dicati o ns  as well as  c o nc o mita nt  me dicati o ns  gi ve n f or d isease relat e d co n diti o n s will be 
prese nte d b y P T  a n d b y d ecreasi n g fre q ue nc y . 
Rele v a nt p re vi o us me 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 st o p pe d  
bef ore  e nr ol me nt (i. e. d ate of i nf or me d c o ns e nt  [I C]). D M Ds  (see Secti o n 8. 2) a d mi nistere d 
bet wee n I C a n d start of st u d y me dicati o n are maj or P Ds t hat will be re p orte d as rele va nt pre vi o us 
me dicati o ns as well.  
Rele va nt p re vi o us me di cati o ns  will be s u m marize d fr o m t he “ Rele va nt pre vi o us me dicati o n  
detai ls” e C R F pa g e. A T C -1 st le vel an d preferre d ter m will be ta b ulate d as gi ve n fr o m t he W H O -
D D  dicti o nar y c urre nt versi o n . I n case m ulti ple A T C’s are assi g ne d t o a dr u g, all A T C-1 st le vel 
will be use d f or re p orti n g . All me dicati o ns e ntere d i nt o t he “ Rele va nt pre vi o us me dicati o n  details ” 
e C R F pa ge will be ass u me d t o be “ pre vi o us” irres pecti ve of t he act ual start a n d e n d d ates. I n 
a d diti o n , all rele v a nt pre vi o us me dicati o ns  a n d r ele va nt pre vi o us me dicati o ns  gi ve n f or d ise as e 
relate d co n diti o n s will be prese nte d b y P T  a n d d ecreasi n g fre q ue n c y . 
All r ele va nt pre vi o us me dicati o ns , w hic h are classifie d  as D M Ds will be prese nte d b y P T.  D M Ds , 
w hic h a re ta k e n wit hi n 6 m o nt hs  pri or t o start of st u d y me dicati o n  (i.e. D M D e n d date ≥ start of 
st u d y me dicati o n –  1 8 2. 6 2 5 ) will be prese nte d  b y P T . T he le n gt h of t he was h o ut  peri o d  (start of 
st u d y me dicati o n - D M D e n d date + 1)  of t he last D M D wit hi n  6 m o nt hs  pri or t o start of st u d y 
m e dicati on will be s u m marize d.  T h e last D M D will be defi ne d as t he D M D wit h t he latest st o p 
date.  If t he D M D e n d date is partiall y missi n g, t he da y will be i m p ute d b y t he 1 5t h of t he m o nt h 
b ut t he date will be tr u n cate d t o I C date -1 if t he i m p utati o n res ul ts i n a later date of t he sa me 
m o nt h w he n t he I C w as pr o vi de d . If t h e m o nt h is missi n g as well or t he dat e is c o m pletel y missi n g 
t he e n d d ate will n ot be re place d a n d it will be ass u me d t hat t he D M D st o p pe d earlier t ha n 6 m o nt hs 
pri or t o start of st u d y me d icati o n.  
C o nc o mit a nt  pr oce d ures  w hic h were u n dert a ke n a n y ti me o n st u d y will be liste d b y s u bject. 
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Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
1 3  
Tre at me nt C o m pli a nce a n d E x p os ure  
T w o years of tr eat me nt are pla n n e d i n t his st u d y. S u bjects will ta ke ta blets i n wee k 1 a n d  wee k  5 
of eac h y ear . All d osi n g calc ulati o ns a n d s u m maries will be b ase d o n “ Treat me nt A d mi nistrati o n” 
a n d “ Treat me nt Ter mi nati o n ” eC R Fs pa ges . 
T he f oll o wi n g s u m mar y ta bles will be pr o vi de d  f or t he S A F: 
•  D urati o n of t her a p y  
•  C o m plia nce a n d Dr u g A cc o u nta bilit y  
T h e d urati o n will be prese nt e d f or Treat me nt C o urse  1  Treat me nt Peri o d, C o urse 2 Treat me nt 
Peri o d  a n d t he Treat me nt Peri o d i n da ys. 
•  D urati o n ( da ys)= ( date of last ta blet i n peri o d  –  date of first ta blet i n peri o d  + 1)  
C o u nts of ta blets a n d c o m plia nce will be calc ul ate d first f or eac h tr eat me nt wee k: 
•  C o m plia nce  ( %) = 1 0 0 * n u m ber of ta blets ta ke n d uri n g t he treat me nt wee k / n u m ber of 
pla n ne d ta blets  f or t he treat me nt wee k 
If a s u bject disc o nti n ue d t he treat me nt bef ore t he start o f t he res pecti ve treat me nt wee k, 
c o m plia nce will n ot be deri ve d f or t his wee k . If t he s u bject di d n ot ta ke a n y ta blet d uri n g t he 
res pecti ve treat me nt wee k, b ut ha d n ot disc o nti n ue d t he treat me nt bef ore, c o m plia nce will b e 0.  
If t he s u bject was treat e d d uri n g t he res pecti ve treat me nt wee k, b ut t h e n u m ber of ta blets is 
u n k n o w n, c o m plia nce will be missi n g.  
C o m plia nce f or eac h year (c o urs e) a n d t otal  will be calc ulate d f or all s u bjects t hat starte d t he 
res pecti ve treat me nt peri o d (i.e. ta k e n at least o ne ta blet)  as a n a vera ge of a vaila ble rec or ds  
o btai ne d f or t he c orres p o n di n g  treat me nt wee ks. T hat mea ns,  treat me nt wee ks after t he s u bject’s 
treat me nt disc o nti n uati o n are n ot i ncl u de d i n t he deri vati o n, rec or ds of 0 c o m plia nce f or t he 
c orres p o n di n g tr eat me nt wee ks are i ncl u d e d i n t h e deri vati o n as s uc h, a n d missi n g rec or ds res ult 
i n missi n g c o m plia nce f or t he res pecti ve treat me nt peri o d. 
I n a d diti o n, c o m plia nce will be cate g orize d as f oll o ws : 
•  < 6 0 %  
•  [ 6 0 %-8 0 %[  
•  [ 8 0 %-9 0 %[  
•  [ 9 0 %-1 1 0 %]  
•  > 1 1 0 %  
•  Missi n g  
T he n u m ber of pla n ne d ta blets is base d o n t he wei g ht at t he be gi n ni n g of eac h treat me nt c o urse  
(Ta ble 3 ).  
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Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 0  
 
 
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 3 : D ose of M a ve n cl a d ®  per tre at me nt wee k b y s u bject wei g ht i n e ac h tre at me nt ye ar  
Wei g ht r a n ge  
D ose i n m g ( n u m ber t a blets) per tre at me nt wee k  
k g  
Tre at me nt wee k 1  
Tre at me nt wee k 5  
4 0 t o < 5 0  
4 0 m g ( 4 ta blets)  
4 0 m g ( 4 ta blets)  
5 0 t o < 6 0  
5 0 m g ( 5 ta blets)  
5 0 m g ( 5 ta blets)  
6 0 t o < 7 0  
6 0 m g ( 6 ta blets)  
6 0 m g ( 6 ta blets)  
7 0 t o < 8 0  
7 0 m g ( 7 ta blets)  
7 0 m g ( 7 ta blets)  
8 0 t o < 9 0  
8 0 m g ( 8 ta blets) 
7 0 m g ( 7 ta blets)  
9 0 t o < 1 0 0  
9 0 m g ( 9 ta blets)  
8 0 m g ( 8 ta blets)  
1 0 0 t o < 1 1 0  
1 0 0 m g ( 1 0 ta blets)  
9 0 m g ( 9 ta blets)  
1 1 0 a n d a b o ve  
1 0 0 m g ( 1 0 ta blets)  
1 0 0 m g ( 1 0 ta blets)  
T he n u m ber of s u bjects wit h t he sa me  pla n ne d  d osi n g sc he ma i n b ot h Treat me nts C o urses a n d a 
differe nt pl a n ne d d osi n g sc he ma  (i.e. s u bjects e xc ha n ge d wei g ht ra n g e as defi ne d i n t he ta ble 
ab o ve)  i n Treat me nt C o urse 2 will be prese nte d f or all s u bjects, w h o ha v e starte d Treat me nt C o urse 
2  (i.e. ta ke n at least o ne t a blet i n Treat me nt C o urse 2) . 
T he ti me differe n ce b et w ee n t he start of t he C o urse 1 Treat me nt Peri o d a n d t he start of t he C o urse 
2 Treat me nt Peri o d will be calc ul ate d as f oll o ws:  
•  Relati ve  S tart of Treat me nt C o urse 2 ( da ys) = Start of Treat me nt C o urse 2 - Start of 
Treat me nt C o urse 1  + 1 .  
T he Relati ve Start of Treat me nt C o urse 2 will be prese nte d t o g et her wit h t he n u m ber of s u bjects 
i n t he f oll o wi n g gr o u ps f or t he S A F: 
•  Treat me nt C o urse 2 n ot s tarte d, 
•  a n d disc o nti n ue d bef ore t he M o nt h 1 2 Visit , 
•  a n d disc o nti n ue d at or after M o nt h 1 2 Visit  
•  L y m p h oc yte c o u nt < 8 0 0  cells/ m m³ at M o nt h 1 2 Visit , 
•  Treat me nt C o urse 2  starte d, 
•  a n d n ot dela ye d (s ee Secti o n 9 f or defi niti o n ), 
•  a n d dela ye d , 
•  a n d a n y L y m p h oc yte c o u nt < 8 0 0 cells/ m m³  at or after M o nt h 1 2 Visit a n d 
bef ore start of Treat me nt C o urse 2 . 
•  bef ore / after Start of C O VI D -1 9 p a n d e mic  
T he c u m ulati ve d ose is defi ne d  as t he s u m of t h e n u m ber of ta blets ta ke n  1 0 m g di vi de d b y t he 
wei g ht f or eac h  treatme nt year : 
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M a ve ncl a d
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Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
•  C u m ulati ve d ose = n u m b er of ta bl ets ta ke n i n Treat me nt C o urse 1 * 1 0 m g / wei g ht i n k g at 
Baseli ne + n u m ber of t a blets ta ke n i n Treat me nt C o urse 2 * 1 0 m g / wei g ht i n k g at M o nt h 
1 2 b  
T he c u m ulati ve d ose will be calc ul ate d o nl y  if t h e wei g ht a n d n u m b er of ta blets are a vaila bl e . 
Ot her wise it will be missi n g . If t he Treat me nt C o urse 2 was n’t starte d  (i.e. n o ta blet ta ke n i n 
Treat me nt C o urse 2) , t he c u m ulati ve d ose will be calc ulate d o nl y  f or t he Treat me nt C o urse 1. 
A s u bject data listi n g of t he treat me nt c o m plia n ce will be pr o vi de d  f or t he S A F . 
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M a ve ncl a d
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Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
1 4  
Effic ac y A n al yses  
T he f oll o wi n g secti o ns d escri be t he pl a n ne d a n al yses f or eac h efficac y e n d p oi nts. 
F or t he d etaile d defi niti o n of c o variates a n d str atificati o n fact ors t hat are use d i n t he statistical 
m o d els see Secti o n 9 . 
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 eac h visit a n d f or all efficac y e n d p oi nts  f or t h e F A S. Details a b o ut t he 
prese 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 . 
W he re 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 ve 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 . 
1 4. 1  
Pri m ar y E n d p oi nt s: C h a n ges i n M S Q o L -5 4  p h ysic al a n d 
me nt al he alt h c o m p osite sc ores fr o m B aseli ne  t o M o nt h 2 4 
Visit  
T he pri mar y e n d p oi nts are t he c ha n ges 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 M o nt hs 2 4 Visit c o m pare d t o 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 was d e vel o pe d t o meas ure H R Q o L i n s u bjects 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 p ecific 
ite ms s uc h as fati g ue a n d c o g niti ve f u ncti o n. 
T he q uest i 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,  
•  M e 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 , 
•  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, Healt 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 pri mar y a n al ysis is f oc usi n g o n t he p h ysical a n d me ntal healt h c o m p osite sc ores  w hile t he  
o verall q ualit y of life will be a nal yze d as a terti ar y e n d p oi nt. T he ot her c o m p osite sc ores a n d 
s u bscales will n ot be a nal yze d statisticall y. 
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Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
T he o bser ve d res ults a n d c ha n ge s fr o m Baseli ne  will be ta b ulate d a n d pl otte d f or P h ysical healt h 
c o m p osite, me ntal healt h c o m p osite a n d O verall q ualit y of life f or t he F A S. I n a d diti o n, t he 
esti mated  Least S q uare ( L S ) Mea n s of t he c ha n ge fr o m Baseli ne  wit h t he c orres p o n di n g sta n dar d 
err or, 9 5 % c o nfi de nce i nter val a n d t w o-si de d p -v al ue of t h e a n al ysis  m o del  (see Secti o n 1 4. 1. 1 ) 
will be s u m marize d a n d pl otte d. 
T he O v erall q u alit y of life, P h ysical a n d M e ntal healt h c o m p osite s c ores a n d t he cha n g e fr o m 
Baseli ne  of t he M S Q o L -5 4 will be liste d  b y s u bject.  
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Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
1 4. 1. 1  
Pri m ar y O bjecti ve: A n al ysis of t he pri m ar y e n d p oi nts  
T he pri mar y o bjecti ve is t o assess t he H R Q o L t hr o u g h t he M S Q o L-5 4 scale i n hi g hl y acti ve R M S s u bjects treate d wit h M a ve ncla d ®  for 
2 years ( 2 4 m o nt hs).  
T he pri mar y e n d p oi nts f or t he st u d y are t he c ha n g es i n H R Q o L assesse d b y M S Q o L -5 4 p h ysical h ealt h a n d me ntal healt h at 2 4 m o nt hs 
p ost -Baseli ne  assess me nt. Differe nces i n M S Q o L -5 4 sc ores b et wee n meas ure me nts at t he M o nt h 2 4 Visit a n d Baseli ne  will be assess e 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 nical l y rele va nt fact ors, wit hi n  s u bject c orrelati o n a n d wit hi n p o ole d 
ce nter c orrelati o n.  
As t he a nal ysis set c o ncer ns re peate d meas ure me nts f or o utc o mes f or eac h i n di vi d ual, it is li ke l y t hat o bser vati o ns pertai ni n g t o eac h 
i n di vi d ual will be c orrelate d. F urt her m ore, as t his is a m ulti-ce nter st u d y, it is li kel y t hat cl usteri n g of i n di vi d uals wit hi n st u d y sites will 
pr o d uce a n a d diti o nal s o urce of c orrelati o n. 
Mi xe d -effects re gressi o n, w here b y a t hree -le vel hierarc hical m o del is s pecifie d f or 
o bser vati o ns wit hi n s u bjects wit hi n -p o ole d ce nt ers, will be use d t o acc o u nt f or wit hi n-s u bject a n d wit hi n-p o ole d ce nter  c orrelati o n  
( Gi b b o ns et al., 2 0 1 0). 
T he a nal ysis will als o a dj ust f or fact ors dee me d t o be pr o g n ostic f or t he pri mar y e n d p oi nt, as j u d g e d b y cli nical e x p erts . T h ese fact ors 
are t he age  a n d E D S S at Baseli ne , (see Secti o n 9  f or details).  
T he pri mar y e n d p oi nts are t he c ha n g es fr o m Bas eli ne  t o M o nt h 2 4 Visit  i n P h ysical a n d M e ntal h ealt h c o m p osite of t h e M S Q o L -5 4. 
T he y will be a nal yze d wit h a re peate d mi xe d -effects li near m o del  f or c ha n ge fr o m 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 hr ee-le vel ( visits wit hi n s u bjects wit hi n ce nters) hi erarc hi cal m o del is s pecifie d f or re p eate d 
M S Q o L -5 4 P h ysical or M e ntal healt h c o m p osite sc ores . 
Y  = X β + γ + e, w here  
Y re prese nts c ha n g e fr o m baseli ne  i n M S Q o L  sc ore, 
X re prese nts val ues of fi xe d effects i ncl u di n g M S Q o L  sc ore, a ge a n d E D S S at B aseli ne, a n d Visit  (defi ne d as a class varia bl e) , 
β  re pres e nts set of re gressi o n c oefficie nts, 
γ re prese nts p o ole d ce nter ra n d o m effect, 
e re prese nts a ra n d o m err or, p ote ntiall y c orrel ate d f or differe nt visits wit hi n a s u bject ( neste d wit hi n a ce nter).  
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Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
T he L S M ea ns will be calc ulate d wit h o bser ve d mar gi n w hic h refl ects t he distri b uti o n of a ge , 
 cate g ories at Baseli ne  a n d res pecti ve 
Base li ne c o m p osite sc ore  of t he F A S . A n  u nstr uct ure d c o varia nce matri x will be ass u me d  f or t he m o del. If t he m o del d oesn’t c o n ver ge 
a varia nce c o m p o ne nts  c o varia nce str uct ure will be use d i nstea d  or t he ce nter effect will be s pecifie d as a fi xe d effect i nstea d  (sa me 
m o del as s pecifie d as a s e nsiti vit y a nal ysis bel o w) . 
T he f oll o wi n g h y p ot heses will be e val uate d e x pl orati vel y:  
H 0 1: ΔP h ysical Healt h  = 0 vs. H 1 1: ΔP h ysical Healt h  ≠ 0  
H 0 2: ΔMe ntal Heal t h = 0 vs. H 1 2: ΔMe ntal Healt h  ≠ 0 ,  
w here Δ  =  E Y  d e n otes t h e p o p ulati o n mea n c h a n g e of t he res pecti ve s c ore.    
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 h e 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.  
 
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: 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 c o m p o sit e s c or e s fr o m B a s eli n e  t o M o nt h 2 4 
Pri m ar y  
(F A S ) 
C h a n g e s  fr o m B a s eli n e  i n p h y si c al h e alt h 
c o m p o sit e ( M S Q o L -5 4) t o t h e M o nt h 1 2 
Vi sit  a n d M o nt h 2 4 Vi sit  
R e p e at e d mi x e d -eff e ct s li n e ar m o d el wit h 
t h e f oll o wi n g adj u sti n g f a ct or 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 ,  
•  
W it hi n-p o ol e d c e nt er  c orr el ati o n s,  
•  
W it 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  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.  
Mi s si n g s at B a s eli n e : 
S u bj e ct 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 r e p e at e d mi x e d-
eff e ct li n e ar m o d el  a n al y si s.  
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:  
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.  
 
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.  
Pri m ar y  
(F A S ) 
C h a n g e s  fr o m B a s eli n e  i n 
m e nt al h e alt h 
c o m p o sit e ( M S Q o L -5 4) t o t h e M o nt h 1 2 
Vi sit  a n d M o nt h 2 4 Vi sit  
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
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 uesti o n naire has bee n set -u p t o all o w o nl y s ki ppi n g of q uesti o ns 4 6  - 4 9 a b o ut t he S e x ual f u ncti o n b y selecti n g “ N ot 
a p plica ble” as a n a ns wer. If m ore t h a n o ne q u esti o n i n t his part was a ns w ere d, t he S e x ual f u ncti o n sc ore will be calc ul ate d acc or di n g t o 
t he sc ori n g ma n u al ( Vi c 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 sc ore. If o nl y o ne or n o q u esti o n was 
a ns were d, t he S e x ual f u n cti o n sc ore will be i m p ute d wit h t he a ns wer of t he S atisfacti o n w it h se x ual f u ncti o n sc ore. 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
1 4. 2  
Sec o n d ar y E n d p oi nt: Tre at me nt gl o b al s atisf acti o n assesse d b y T S Q M v 1. 4 at M o nt h 6  Visit 
(I nteri m A n al ysis) 
T he T S Q M v 1. 4 q uesti o n naire is a ge neric q u esti o n naire t o test tr eat me nt satisfacti o n wit h d o mai ns i n Effecti ve ness, Si de Eff ects, 
C o n ve nie nce a n d Gl o bal Satisfacti o n a n d has pre vi o usl y bee n use d i n M S s u bjects ( Ver mersc h et al., 2 0 1 4). T he sc ores will be deri ve d 
acc or di n g t o t he T S Q M User Ma n u al Versi o n 1. 0.  T he T S Q M v 1. 4 v sc ores ra n ge fr o m 0 % t o 1 0 0 % , wit h 1 0 0 % bei n g t he best p ossi ble 
sc ore.  
A t t he I nt eri m a nal ysis, t he Gl o bal Satisfacti o n sc ore at M o nt h 6 Visit will be a nal yze d wit h o ut ta ki n g t he later o bser vati o ns i nt o acc o u nt . 
At  t he fi nal a nal ysis, t he Mo nt h 6 V isit will be a nal yze d as tertiar y e n d p oi nt i n a re peate d m o del t hat i ncl u des t he M o nt h 1 2 a n d 2 4 Visit 
(see S ecti o n 1 4. 3. 2 ). 
Gl o bal Satisfacti o n at M o nt h 6 V isit will be a n al y ze d at t he i nteri m  a nal ysis  wit h a mi xe d li near m o del. T he m o d el will be a dj uste d f or 
a ge (i n years), E D S S at Baseli ne  (≤3,  >  3) a n d wit hi n -p o ole d ce nter  c orrelati o ns.  A n u nstr uct ure d c o varia n ce matri x will be ass u me d 
f or t he m o del. If t h e m o del d oes n’t c o n ver ge a v aria nce c o m p o n e nts  c o vari a nce str u ct ure will be use d i nstea d.  
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
All v ol u me c ha n ge s will be liste d b y s u bjects.  
Gl o bal Versi o n I D: C CI
C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CIC CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
Gl o bal Versi o n I D: C CI
C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
1 5  
S afet y A n al yses  
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or s u m marizi 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 . U nless ot her wise s pecifie d, t he safet y a n al ysis will be 
d o ne f or i nteri m a n d fi nal a nal ysis.  
1 5. 1  
A d verse E ve nts  
Tr eat me nt e mer ge nt a d v erse e ve nts  ( T E A Es) are  t h ose e ve nts wit h o ns et dates occ urri n g wit hi n 
t he T reat me nt P eri o d (see Secti o n 9  f or defi niti o n).  
All a nal yses descri be d i n Secti o n 1 5 . 1 will be base d o n T E A Es if n ot ot her wise s pecifie d. 
I n c o m plete A E-relate d d ates will be ha n dle d as f oll o ws: 
•  I n cas e t he o ns et 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 he o nset year are e q u al t o t he start of st u d y me dicati o n  t he n t he o nset date will be re place d 
b y t he start date of st u d y me dicati o n . 
•  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 he date of s u bject's deat h. I n t he latter cas e 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. 
1 5. 1. 1  
All A d verse E ve nts  
T E A Es will be s u m marize d usi n g Me d D R A (latest versi o n a vaila ble) preferre d ter m  ( P T) as e ve nt 
cate g or y a n d Me d D R A (l atest a vaila ble versi o n) pri mar y 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  o verall a n d b y s u b gr o u ps , D M D pre -tr eate d a n d pre -treat me nt naï ve. 
U nless ot her wise state d a d verse e ve 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 verit y of a n  T E A E  b y P T a n d  
s u bjects 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 o verall fre q ue nc ies of s u bjects wit h t he c orres p o n di n g T E A E  will be pre pare d . I n 
a d diti o n , t he ta bles will be pr o vi de d b y P T a n d pri mar y S O C i n al p ha betical or der: 
•  A n y A E , 
•  A n y st u d y treat me nt relat e d A Es, 
•  A n y seri o us A Es , 
•  A n y n o n -seri o us A Es 
Gl o bal Versi o n I D: C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
•  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”). 
S u m mar y ta ble f or n o n -seri o us a d verse e ve nts a p pl yi n g fre q ue nc y t hr es 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 -seri o us a d verse e ve nts a p pl yi n g fre q ue nc y t hres h ol d of 5 % 
s orte d b y decreasi n g fre q ue nc y will be pr o vi de d  b y P T . 
All A E b y  w orst se v erit y (an y se v erit y , m o derate or w orse, s e vere) will be prese nte d b y S O C a n d 
P T.  
All A Es i ncl u di n g n o n-treat me nt e mer ge nt A Es will be liste d b y s u bject  f or t he S A F. 
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 de nce rates  ( E AI R) are cal c ulate d as n u m ber of s u bjects 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 s u bjects 
i n t he safet y p o p ulati o n fr o m start of st u d y m e dicati o n t o first o nset of A E or e n d of treat me nt 
per i o d, w hic he v er occ 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): 
𝐿𝐶𝐼=
𝜒2 𝑛,𝑎
2
2
2 × 𝑡, 
𝑈𝐶𝐼=
𝜒2 (𝑛+ 1 ),1 −𝑎
2
2
2 × 𝑡
, 
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 s u bjects a n d n is t he n u m ber of s u bjects 
wit h a s pecific A E f or t he E AI R, w hic h will be t he basis f or t he n u m ber of t he de grees of free d o m 
f or t he c hi-s q u are q u a ntile f or t he u p p er tail pr o ba bilit y χ 2.  
E x p os ure a dj uste d i nci de nce rat es of T E A Es will be prese nt e d o verall , 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 Tre at me nt Disc o nti n u ati o n  
T he f oll o wi n g o v erall fre q ue nc y ta bl es will be pre pare d f or t h e a d v erse e v e nt acti o ns. T a bles will 
be pr o vi de d b y P T a n d pri mar y S O C i n al p ha betical or der:  
Gl o bal Versi o n I D: C CI


M a ve ncl a d
®  
Cl arif y -M S  
M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1  
 
 
•  A n y A E lea di n g t o te m p orar y disc o nti n uati o n of st u d y dr u g , 
•  A n y A E lea di n g t o per m a ne nt disc o nti n uati o n of st u d y dr u g . 
•  A n y A E lea di n g t o d ose re d ucti o n of st u d y treat me nt  
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 disc o nti n uati o ns d ue t o deat h (see Secti o n 1 0. 1 ) a n d a n y A E lea 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 t a ble of o bs er ve d Deat hs (fr o m “ Stu d y Ter mi nat i o n” e C R F p a ge) will be pr o vi de d 
t o get her wit h T E A Es wit h fatal o utc o me  b y P T.  
1 5. 2. 2  
Ser i o us A d verse E ve nts 
T he statistical a nal ysis a n d re p orti n g of seri o us a d verse e v e nts are defi ne d  i n S ecti o n 1 5. 1. 1. I n 
a d diti o n,  all seri o us a d verse e ve nts will be liste d.  
1 5. 2. 3  
Ot her Si g nific a nt A d verse E ve nt  
T E A Es ass oci ate d t o C O VI D-1 9  
T he fre q u e nc y of T E 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 be 
i de ntifie d base d o n t he S M Q C O VI D -1 9  ( narr o w sc o pe) a n d will be prese nte d b y S O C a n d P T . 
F ati g ue  
T he pre vale n ce of fati g u e will be prese nte d f or eac h m o nt h of t he C o urse 1 Treat me nt Peri o d a n d 
se parat el y f or eac h m o nt h of t he C o urse 2 Treat m e nt Peri o d. T h e pre vale nce at a gi ve n m o nt h is 
defi ne d as:  
(N u m ber of p atie nts wit h fati g ue d uri n g t he m o nt h / N u m ber of patie nts wit h fati g ue d uri n g t he 
m o nt h or still i n t he st u d y at t he e n d of t he m o nt h ) * 1 0 0 ,  
w here p atie nts wit h fati g ue d uri n g t he m o nt h are all patie nts w h o ha d at least o ne re p orte d T E A E 
wit h P T e q ual t o ’ F ati g ue’ t hat eit her starte d d uri n g t he m o nt h or is still o n g oi n g fr o m t he pre vi o us 
m o nt h . 
If t he e n d date of t he A E is partiall y or c o m pletel y missi n g a n d t he A E is n ot re p orte d as o n g oi n g, 
t he e n d date will be i m p ute d as f oll o ws: 
•  D a y missi n g b ut m o nt h a n d year a v aila ble: last da y of t he  m o nt h , 
•  D a y a n d m o nt h missi n g : last da y of t he year b ut n ot later t han e n d of Treat me nt Peri o d 2 , 
•  C o m pletel y missi n g: e n d of Treat me nt Peri o d 2  
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T he res ults will be prese nte d i n a ta b ular as well as gra p hical ma n ner. C o urse 1 a n d 2 Treat me nt 
Peri o ds as well as d ur ati o n of a m o nt h is defi ne d i n Secti o n  9 . 
1 5. 3  
Cli nic al L a b or at or y E v al u ati o n  
L y m p h oc yte c o u nt s fr o m l ocal la borat or y  will be use d f or s u m ma r y statistics a n d s hift ta bles. T h e y 
will be classifie d acc or di n g t o t he N CI -C T C A E  (l atest versi o n a v aila ble). T he classificati o n will 
be deri ve d o nl y fr o m t he la b orat or y res ults at a gi ve n assess me nt, t h us i g n ori n g t he u n derl yi n g 
s y n dr o me. 
T he Treat me nt C o urse 2 ca n be del a ye d beca us e of L y m p h oc yte c o u nt bel o w 8 0 0 cells/ m m³ at  t he 
M o nt h 1 2 Visit. I n t his case, t he L y m p h o c yte c o u nt ca n be meas ure d se v eral ti mes bet wee n t he 
M o nt h 1 2 Visit a n d t he start of Treat me nt C o urse 2. L y m p h oc yte  c o u nts at or after t he visit start 
date of t he M o nt h 1 2 Visit a n d bef ore or at t he start date o f t he Treat me nt C o urse 2 will be 
dis pla ye d as f oll o w s: 
•  T he earliest L y m p h oc yte c o u nt will be assi g ne d t o t he M o nt h 1 2 Visit , 
•  T he latest L y m p h oc yte will be assi g ne d t o t he M o nt h 1 2 b Visit , 
•  All ot her L y m p h oc yte c o u nt will be assi g ne d t o u nsc he d ule d visits.  
A  L y m p h oc yte c o u nt ca n be assi g ne d t o t he M o nt h 1 2 Visit a n d M o nt h 1 2 b Visit, if j ust o ne c o u nt 
is a vaila ble. If t h e Treat me nt C o urse 2 was n’t starte d, o nl y t he earliest L y m p h oc yte c o u nt will be 
assi g ne d t o t he M o nt h 1 2 Visit.  
T he w orst o n -st u d y gra de (i.e.  o n or after first st u d y treat me nt a d mi nistrati o n) will be s u m marize d 
c o nsi deri n g o nl y s u bjects wit h p ost Baseli ne  la b orat or y sa m ples: La b orat or y tests b y N CI-C T C A E  
gra de ( 0 , 1, 2, 3, 4, a n y) . 
L y m p h oc yte c o u nt s will be e xa mi ne d f or tre n ds usi n g descri pti ve statistics ( mea n, S D, me dia n , 
Q 1 , Q 3, mi ni m u m, a n d ma xi m u m) of act ual v al ues a n d c h a n ges fr o m Bas eli ne  t o eac h sc he d ul e d 
Visit  i ncl u di n g M o nt h 1 2 b Visit o ver ti me. If f or a partic ular visit a differe nt l ocal la b orat or y t ha n 
n or mal la b orat or y wa s us e d ( d ue t o C O VI D-1 9 pa n de mic), val ues c ollecte d d uri n g t hat  visit will 
n ot be i ncl u de d i n t he descri pti ve statistics . 
S hift ta bles of Baseli ne  vers us e n d p oi nt (as well as t he w orst val ue at a n y p ost -Baseli ne  Visit ) will 
be pres e nte d. A b n or malities clas sifie d acc or di n g t o N CI-C T C A E t o xicit y gra di n g (latest versi o n 
a vaila ble) will be d escri b e d usi n g t he w orst gra d e.  
All L y m p h oc yte c o u nts will be liste d b y s u bject  f or t he S A F. 
P ositi ve r es ult s of t he t u berc ul osis a n d ser ol o g y test s t hat d o n ot c o m pl y wit h t he pr ot oc ol will be 
liste d.  
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 Baseli ne  t o ma xi m u m c ha n ge after start 
of 1st treat me nt will be gr o u pe d as f oll o ws:  
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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 c r 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 s u bject t he w orst c ha n ge d uri n g t h e treat me nt peri o d  will be c o nsi dere d . Missi n g val ues 
will be prese nte d as  a se p arate 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 s u bjects wit h p ost Baseli ne  val ues:  
•  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 s u bject. 
1 5. 5  
Ot her S afet y or T oler a bilit y E v al u ati o ns  
T he res 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.  
Safet y Fi n di n gs d uri n g C e ntral Re vie w are re p ort e d bac k t o t he sites f or f urt her cli nical assess me nt 
a n d re p orti n g as A E, as o utli ne d i n t he Re vie w C harter. T h us, n o se parate sta tistical re p orti n g of 
t he Safet y M RI ce ntr al re vie w data will be d o ne.  
P ositi ve  pre g na nc y tests  or  pre g na n c y tests  n ot  d o ne  wit h o ut a reas o n will be liste d f or t he S A F.  
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I N F O R M A T I O N 
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1 6  
A n al yses of Ot her E n d p oi nts  
N ot a p plica ble.  
 
 
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1 7  
R efere nces 
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 dar di ze 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.  
V E R M E R S C H, P. et al. Terifl u n o mi de vers us s u b c uta ne o us i nterfer o n beta -1a i n patie nts wit h 
rela psi n g m ulti ple scler osis: a ra n d o mise d, c o ntr olle d p hase 3 trial. M ult Scler, v. 2 0, n. 6, p. 
7 0 5 -1 6, Ma y 2 0 1 4. I S S N 1 4 7 7 -0 9 7 0. Dis p o ní vel e m:  < 
htt ps:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 2 4 1 2 6 0 6 4 >.  
VI C K R E Y, B. G. et al. C o m paris o n of a ge n eric t o disease -tar 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. Dis p o ní vel e m: < 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 >.  
VI C K R E Y, Bar bara 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 niversity of C alif or ni a, L os A n geles , 1 9 9 5. 
Q ui ntilesI M S, User M a n ual f or t he Treat me nt Satisfacti o n Q uesti o n naire f or Me dicati o n 
( T S Q M), Versi o n 1. 0, J ul y 2 0 1 7. 
Pa r me nter, B. A., et al. T he utilit y of re gressi o n -b ase 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).  
 
 
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6 9 /7 1  
 
 
1 8  
A p pe n dices  
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I N F O R M A T I O N 
7 0 /7 1  
 
 
S u bjects w h o ha ve t a ki n g 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 pa ge will be cate g orize d as D M D pre -treate d. All ot her s u bjects will be c o nsi dere d as 
pre -treat me nt naï ve. T h e 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.  
 
 
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M S 7 0 0 5 6 8 _ 0 0 2 1  / I nte gr ate d A n al ysis Pl a n Versi o n 5. 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 1 /7 1  
 
 
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Si g nat ure Pa ge f or V V- C LI N- 2 7 9 8 5 7 v 6. 0
Si g nat ure Pa ge f or V V- C LI N- 2 7 9 8 5 7 v 6. 0
A p pr o val
2 1- Se p- 2 0 2 1 1 5: 0 7: 5 3 G M T + 0 0 0 0
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