Clinical trial NCT03364036
Conditions: Multiple Sclerosis
Keywords: Multiple sclerosis Mavenclad ® Cladribine
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-05-28; Completion date: 2022-02-21
Enrollment: 270 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of the study was to determine the onset of Mavenclad® action by frequent magnetic resonance imaging (MRI) assessment of the combined unique active (CUA) lesions in participants with highly active relapsing multiple sclerosis (MS).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Mavenclad®
Intervention descriptions: intervention 1: Participants 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.

Protocol documents:
SAP_002.pdf: 




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T a ble of C o nte nts 
1  
T a ble of C o nte nts .................................................................................. 3  
2  
List of A b bre viati o ns a n d Defi niti o n of Ter ms .................................... 6  
3  
M o difi cati o n Hist or y ............................................................................ 8  
4  
P ur p ose of t he I nte grate d A nal ysis Pl a n ............................................... 9  
5  
O bjecti ves a n d E n d p oi nts ................................................................... 1 0  
6  
O ver vi e w of Pl a n ne d A n al yses ........................................................... 1 1  
6. 1  
I nt eri m A nal ysis .................................................................................. 1 1 
6. 1. 1  
C ut- off date ......................................................................................... 1 3  
6. 1. 2  
Data ha n dli n g aft er c ut- off date .......................................................... 1 3  
6. 2  
Fi nal A nal ysis ..................................................................................... 1 3  
7  
C ha n ges t o t h e Pla n ne d A nal yses i n t he Cli ni cal Trial Pr ot o c ol ........ 1 4  
8  
Pr ot oc ol De vi ati o ns a n d A nal ysis S ets ............................................... 1 6  
8. 1  
Defi niti o n of Pr ot oc ol De viati o ns ....................................................... 1 6  
8. 2  
Defi niti o n of A nal ysis Sets a n d S u b gr o u ps ........................................ 1 6  
9  
Ge neral S pecificati o ns f or Data A n al ys es .......................................... 1 8  
1 0  
Trial Parti ci pa nts ................................................................................. 3 0  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns ............................... 3 0  
1 0. 2  
Pr ot oc ol De vi ati o ns ............................................................................ 3 0  
1 0. 2. 1  
I m p orta nt Pr ot oc ol De vi ati o ns ............................................................ 3 0 
1 1  
De m o gra p hics a n d Ot her Baseli ne C haract eristi cs ............................. 3 1  
1 1. 1  
M e di cal Hist or y .................................................................................. 3 1  
1 1. 2  
Ot her Baseli ne C haracteristics ............................................................ 3 1  
1 1. 3  
De m o gra p hics ..................................................................................... 3 1  
1 2  
Pre vi o us or C o nc o mit a nt Me dicati o ns/ Pr oce d ures ............................. 3 7  
1 3  
Treat me nt C o m plia n ce a n d E x p os ure ................................................. 3 8  
1 4  
Efficac y A nal yses ............................................................................... 4 1  
1 4. 1  
Pri m ar y E n d p oi nts: Differe nces i n t h e c o u nts of C U A M RI 
l esi o ns d uri n g t he first 6 m o nt hs c o m pare d t o Bas eli ne ..................... 4 1 
1 4. 1. 1  
Pri m ar y O bjecti ve: A nal ysis of pri m ar y e n d p oi nts ............................ 4 1  
1 4. 1. 2  
Pri m ar y O bjecti ve: S e nsiti vit y A nal ys es of t he pri m ar y 
e n d p oi nts ............................................................................................. 4 4  
1 4. 2  
Sec o n dar y E n d p oi nts: C h aracterizati o n of i m m u ne cell s u bsets 
c o u nt at t he e n d of 3, 6, 1 2, 1 5, 1 8 a n d 2 4 m o nt hs c o m p are d t o 
Baseli ne ............................................................................................... 5 0  
1 4. 3  
T erti ar y E n d p oi nts .............................................................................. 5 1  
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1 4. 3. 1  
C ha n ges i n C U A lesi o n c o u nt............................................................. 5 1  
1 4. 3. 2  
C U A lesi o n c o u nt ............................................................................... 5 6  
1 4. 3. 3  
T 1 G d + lesi o n c o u nt ........................................................................... 5 7  
1 4. 3. 4  
T 1 G d + lesi o n v ol u m e ........................................................................ 6 1  
1 4. 3. 5  
T 1 h y p oi nt e ns e lesi o n c o u nt ............................................................... 6 1  
1 4. 3. 6  
T 1 h y p oi nt e ns e lesi o n v ol u me ............................................................ 6 1  
1 4. 3. 7  
Acti ve T 2 lesi o n c o u nt ........................................................................ 6 2  
1 4. 3. 8  
Res p o n der rat e d uri n g t he differe nt Peri o ds ....................................... 6 5  
1 4. 3. 9  
T 2 lesi o n v ol u me ................................................................................ 6 6  
1 4. 3. 1 0  
M a g netizati o n Tra nsfer Rati o ( M T R) ................................................. 6 7  
1 4. 3. 1 1  
Brai n V ol u m e ...................................................................................... 6 8  
1 4. 3. 1 2  
N o E vi de nce of Dis eas e acti vit y ......................................................... 7 1  
1 4. 3. 1 3  
N o E vi de nce of Pr o gressi o n or Acti ve Dis ease .................................. 7 4  
1 4. 3. 1 4  
C ha n ges i n S D M T o utc o m e at t he e n d of 6, 1 2, 1 8 a n d 2 4 
m o nt hs c o m pare d t o Bas eli ne ............................................................. 7 6  
1 4. 3. 1 5  
C ha n ges i n le vel of disa bilit y as meas ure d b y E D S S ......................... 7 7  
1 4. 3. 1 6  
C ha n ges i n le vel of disa bilit y as meas ure d b y 9 H P T ......................... 7 8  
1 4. 3. 1 7  
C ha n ges i n le vel of disa bilit y as meas ure d b y T 2 5 F W ...................... 7 8  
1 4. 3. 1 8  
A n n ualize d Rel a ps e Rate ( A R R) bet wee n B as eli ne a n d 1 2/ 2 4 
m o nt hs................................................................................................. 7 9  
 
 
 
 
 
 
 
1 5  
Safet y A nal yses .................................................................................. 8 7  
1 5. 1  
A d vers e E v e nts ................................................................................... 8 7  
1 5. 1. 1  
All A d verse E v e nts ............................................................................. 8 7  
1 5. 1. 2  
A d vers e E v e nts Lea di n g t o Treat me nt Disc o nti n uati o n ..................... 8 9  
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 vers e E v e nts ................................................................................... 8 9  
1 5. 2. 1  
Deat hs ................................................................................................. 8 9  
1 5. 2. 2  
Seri o us A d verse E v e nts ...................................................................... 8 9  
1 5. 2. 3  
Ot her Si g nifi ca nt A d vers e E ve nt ........................................................ 8 9  
1 5. 3  
Cli nical La b orat or y E val uati o n ........................................................... 9 0  
1 5. 4  
Vit al Si g ns .......................................................................................... 9 1  
1 5. 5  
Ot her Safet y or T olera bilit y E val uati o ns ............................................ 9 1  
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A nal yses of Ot her E n d p oi nts .............................................................. 9 2  
1 7  
Refere n ces ........................................................................................... 9 3  
1 8  
A p pe n dices ......................................................................................... 9 4  
1 8. 1  
A p pe n di x 1: List of D M Ds ................................................................. 9 4  
1 8. 2  
A p pe n di x 2: S D M T Scale d S c ore ....................................................... 9 6  
 
 
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O v er vie w of Pl a n ne d A n al ys es 
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 a nal ysis aft er all s u bjects ha ve c o m plet e d t he 6- m o nt h ass ess me nt, 
 Fi nal a nal ysis at t he e n d of t he st u d y. 
I n a d diti o n, a Baseli ne a nal ysis has bee n p erf or me d. T his Baseli ne a n al ysis is n ot s pecifie d i n 
t he st u d y pr ot oc ol a n d is descri be d i n a se parat e A nal ysis Pla n. 
 
  
 
 
 
, 
 
 
 
 
 
  
  
  
  
 
6. 1  
I nteri m A n al ysis 
A n i nteri m a nal ysis f or pri mar y e n d p oi nt t hat i ncl u des all pla n ne d se nsiti vit y a nal yses will be 
u n dert a ke n after all s u bjects h a ve c o m plete d t h e 6- m o nt h ass ess m e nt. 
I n a d diti o n, t he I nteri m A nal ysis will d es cri be t he f oll o wi n g c haracteristics of t h e st u d y 
p o p ulati o n u p t o t he c ut- off: 
 Dis p ositi o n of P artici p a nts a n d Disc o nti n uati o ns ( Secti o n 1 0. 1), 
 M aj or Pr ot oc ol De viati o ns ( Secti o n 1 0. 2), 
 De m o gra p hics a n d Ot her Baseli ne C haracteristics ( Secti o n 1 1): 
o  Baseli ne C hara cteristics ( Secti o n 1 1. 2), 
o  M e dical Hist or y ( Secti o n 1 1. 1), 
o  M S Diseas e C haracteristics ( Secti o n 1 1. 2), 
o  Vital Si g ns ( Secti o n 1 1. 2). 
 Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures ( S ecti o n 1 2), 
 Treat m e nt C o m plia nce a n d E x p os ure ( Secti o n 1 3), 
a n d will e val uate t he f oll o wi n g tertiar y a n d safet y e n d p oi nts u p t o 6 m o nt hs Visit or t he c ut- off 
p oi nt: 
 N u m ber of C U A lesi o ns d uri n g t he Baseli ne a n d p ost- Baseli ne Peri o ds ( Secti o n 
1 4. 3. 2), 
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 T 1 G d + l esi o n c o u nt b y Visit a n d mea n T 1 G d + lesi o n c o u nt d uri n g t he Baseli ne a n d 
p ost- Baseli ne Peri o ds ( Secti o n 1 4. 3. 3), 
 C ha n ges i n Sta n dar di ze d t otal acti ve T 2 lesi o n c o u nt d uri n g t he p ost- Baseli ne Peri o ds 
c o m pare d t o t he Bas eli ne Peri o d ( Secti o n 1 4. 3. 7), 
 Res p o n der rat e d uri n g t he differe nt Peri o ds ( Secti o n 1 4. 3. 8), 
 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 b er a n d P erce nta g e of 
S u bjects wit h ( q ualif yi n g) rel a pses), 
 A d vers e E v e nts ( Secti o n 1 5. 1), 
 Cli nical La b orat or y E val uati o n ( Secti o n 1 5. 3), 
 Vital si g ns ( Secti o n 1 5. 4). 
T he c haract eristi cs of t he p o p ulati o n as well as rela pses will be s u m marize d descri pti vel 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 n al a nal ysis. T he t erti ar y M RI e n d p oi nts a n d 
Safet y e n d p oi nts will be a nal yze d u p t o t he M o nt h 6 Visit or c ut- off d ate i n t he s a m e wa y as 
f or t he fi n al a n al ysis, as a p plica ble.  
Ta ble 1 lists all assess me nts w hic h will be i ncl u de d i n t he i nt eri m a nal ysis. 
T a ble 1: List of ass ess me nts i ncl u de d i n t he i nteri m a n al ysis 
Assess me nts   
S cree ni n
g 
B as eli n
e 
M o nt h 1 
M o nt h 2 
M o nt h 3  
M o nt h 
6 
I nf or me d C o nse nt   
X 
 
   
   
   
 
De m o gra p hics 
X   
   
   
   
   
 
Wei g ht  
   
X   
X   
   
   
 
Vit al Si g ns 
( X)   
X   
   
   
   
 
M e di cal Hist or y 
X 
 
   
   
   
 
Disease Hist or y 
X   
   
   
   
   
 
Rela ps e Hist or y 
   
X   
   
   
   
 
M RI 
X   
X   
X   
X   
X   
X 
Disa bilit y 
( E D S S/ K F S) 
X   
X   
   
   
   
 
Rela ps e c o u nt 
   
   
X   
X   
X   
X 
L y m p h oc yt e C o u nt   
X   
    
   
X   
   
X 
Treat me nt 
A d mi nistrati o n 
   
X   
X   
   
   
 
A Es 
   
X   
X   
X   
X   
X 
C o nc o mit a nt 
m e dicati o ns a n d 
pr oce d ures 
X   
X   
X   
X   
X   
X 
Rele va nt pre vi o us 
m e dicati o ns 
X   
   
   
   
   
 
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Assess me nts   
S cree ni n
g 
B as eli n
e 
M o nt h 1 
M o nt h 2 
M o nt h 3  
M o nt h 
6 
Ser ol o g y (i ncl. 
Vari cella a n d T B) 
X   
   
   
   
   
 
Pre g na nc y test 
X   
X   
   
   
   
 
St u d y ter mi nati o n   
   
X   
X   
X   
X   
X 
Data clea ni n g will be u n derta ke n o n all data i n v ol v e d i n i nteri m re p orti n g. Details a n d le vel of 
data cle a ni n g will be d oc u me nte d i n data m a na g e me nt pla ns. 
6. 1. 1   
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 bject will b e a nal yze d i n t he i nteri m a nal ysis. 
T heref ore, t h e c ut- off date is defi ne d as t h e ma xi m u m M o nt h 6 Visit date (i.e., date of t h e last 
assess m e 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 date 
will be 1 8 0 da ys after start 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 1 8 0.  
 C ut- off dat e ( M o nt h 6 Visit d o ne) = Ma xi m u m M o nt h 6 Visit date, 
 C ut- off dat e ( M o nt h 6 Visit n ot d o ne) = Start of st u d y me dicati o n + 1 8 0 da ys - 1. 
All occ urre n ces of deat h will be i ncl u de d i n t he i nteri m a nal ysis re gar dless of t he ti me p oi nt 
(i. e., a n y d eat h t hat is i n cl u de d i n t he d at a base at t he ti me of t he s n a ps h ot will be re p orte d i n 
t he i nteri m a nal ysis). 
6. 1. 2   
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.  
Data ot her t ha n t he dat e of deat h o bt ai ne d after t h e c ut- off will n ot be dis pl a ye d i n a n y listi n gs 
or use d f or s u m mar y st atistics. 
If t he st o p date f or a n A Es is aft er t he date of c ut- off, t h e A Es will be c o nsi dere d as o n g oi n g 
d uri n g t he I nteri 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 descri b e d a nal ys es of t his I A P a part fr o m t he efficac y 
a nal yses alrea d y perf or me d f or t he pri mar y a n al ysis at t he 6 m o nt hs I nteri m A nal ysis. T he fi nal 
a nal ysis will be base d o n all data a v aila ble i n t h e data bas e at t he ti me of t he fi nal data base l oc k. 
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C h a n g es t o t he Pl a n ne d A n al ys es i n t he Cli ni c al T ri al 
Pr ot oc ol 
T he f oll o wi n g d ecisi o n was ma de pri or t o t he last e nr olle d s u bj ect starti n g st u d y treat me nt, 
wit h p ost-treat m e nt data u na vail a ble at t he ti me of t he decisi o n m a ki n g: 
Pri mar y a nal ysis will b e c o m ple me nte d b y a n o n- para metri c a n al ysis met h o ds as a dat a re vie w 
of Baseli ne data h as s h o w n t h at t he pri mar y e n d p oi nt ( Differe nces i n t he c o u nts of C U A M RI 
lesi o ns d uri n g t he first 6 m o nt hs, t hat is, d uri n g P eri o d m o nt hs 1- 6, 2- 6, 3- 6, c o m pare d t o 
Baseli ne, fr o m Scree ni n g t o e n d of Baseli ne ass ess me nt), d oes n ot f oll o w N or mal distri b uti o n.  
Ot her decisi o ns a p plie d after t he pri mar y a nal ysis was perf or me d: 
Ha n dli n g of data of s u bj ects wit h a dela ye d 2 n d treat m e 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 bje cts wit h a del a y e 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 statisti cal a nal yses.  
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 dat a ca pt ure d a n d as s u c h, t h es e o bs er v ati o ns will be treat e d as missi n g. ” 
As t h e data of t he 1 st treat me nt c o urse are e x pecte d t o pr o vi de vali d effica c y i nf or mati o n 
a n d t he treat m e nt d ela y of t he 2 n d year d oes n ot affect t he 1st year c o urse, it is deci de d 
t hat all data fr o m t he 1st treat me nt c o urse s h o ul d be i ncl u de d i n all effi cac y a nal yses 
w hile data fr o m t he 2 n d treat m e nt c o urse will be e x cl u de d fr o m all effic ac y a nal yses f or 
s u bjects wit h a dela ye d 2 n d treat me nt c o urse b e y o n d t hree m o nt hs. 
F or safet y a nal ys es, all data fr o m b ot h Treat m e nt C o urses will be us e 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 h e details of t h e data 
ha n dli n g of s u bjects wit h a Dela y e d Treat me nt C o urse 2. 
Tertiar y e n d p oi nts: 
A d diti o nal e n d p oi nts ha ve bee n a d d e d a n d e n d p oi nts w or di n g ali g ne d acc or di n g t o t he 
latest d at a tra nsfer s pe cifi cati o n, w here a p pli ca bl e. 
A nal ys es of M a g n etizati o n Tra nsfer Rati o ( M T R): 
T he Terti ar y E n d p oi nt i n t he Secti o n 4. 3. 1 of t he pr ot oc ol, “ C ha n ges i n Ma g netizati o n 
Tra nsfer Rati o ( M T R) at t he e n d of 1, 2, 3, 6, 1 2, 1 5, 1 8 a n d 2 4 m o nt hs c o m pare d t o 
Baseli ne” were list e d.  
Si n ce M T R res ults will be use d i n p arall el wit h brai n atr o p h y res ults meas ure d b y M RI, 
w hic h are c o m pari n g M o nt h 2 4 wit h Baseli ne a n d M o nt h 6 M RI sca ns, t h us c ha n ges i n 
M T R at t he e n d of 1, 2, 3, 6, 1 2, 1 5, a n d 1 8 m o nt hs c o m pare d t o Baseli ne are n ot 
pr o vi de d b y ce ntral rea di n g.    
 
C O VI D- 1 9 pa n d e mic:  
A d diti o nal a nal yses t o descri be t he p ote ntial i m pact of t h e C O VI D- 1 9 p a n de mic a d de d. 
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A nal ysis of R es p o n der rat e: 
T he st u d y pr ot oc ol lists o ne of t he Tertiar y E n d p oi nts i n S ecti o n 4. 3. 1 as f oll o ws: 
“ Res p o n der rate d uri n g t he differe nt peri o ds as d efi ne d a b o ve wit h res p o n der b ei n g 
defi ne d as s u bjects wit h a C U A lesi o n c o u nt re d u cti o n of at least 1”. 
T he defi niti o n of res p o n d ers refers t o St a n d ar di ze d C U A lesi o n c o u nt a n d will t h us be 
re p ort e d o nl y f or t h os e peri o ds f or w hi c h sta n dar dize d C U A lesi o n c o u nt is re p orte d as 
well. 
Ter mi n ol o g y: 
W or di n g of e n d p oi nts si m plifie d a n d ali g ne d t o b e c o nsist e nt wit h sta n dar ds. 
 
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Pr ot oc ol De vi ati o ns a n d A n al ysis Sets 
8. 1  
Defi niti o n of P r ot o c ol De vi ati o ns 
M aj or pr ot oc ol de viati o ns ar e pr ot oc ol de viati o ns ( P D) t h at mi g ht si g nifica ntl y affect t h e 
c o m plete ness, acc urac y, a n d/ or reli a bilit y of t he st u d y dat a, or t hat mi g ht si g nifica ntl y affect a 
s u bject's ri g hts, s afet y, or well- bei n g. 
M aj or pr ot oc ol de viati o ns a n d a n y acti o n t o be ta ke n re gar di n g t he e x cl usi o n of s u bjects, or 
affe cte d d ata fr o m s pecific a nal yses, are defi n e d i n t he pr oj ect-s pecifi c Pr ot oc ol De viati o n 
S p ecificati o n. 
All pr ot oc ol de vi ati o ns are d oc u me nt e d i n St u d y Data Ta b ulati o n M o d el ( S D T M) d atas ets 
w het her i de ntifie d t hr o u g h sit e 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 Ds are defi ne d i n Secti 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 n r oll e d S et ( 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 di cati o n assi g ne d b y i R T at t he Baseli ne Visit). 
F ull A n al ysis S et ( F A S) 
All s u bjects i n t he I T T treat e d wit h at l east o n e d ose of st u d y m e dicati o n . 
Tre at me nt C o m pleter Set – Ye ar 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 f ull Treat m e nt C o urse of t h e first year ( Treat m e nt 
C o urse 1). S u bjects will be cl assifie d as Treat me nt C o m plet er f or t he first year if t he y h a ve 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 ar 2 ( T C S- 2) 
All s u bjects fr o m t he F A S w h o c o m pl ete d t he f ull Treat m e nt C o urs e of t h e first a n d t h e sec o n d 
year. S u bjects will b e classifie d as Treat me nt C o m pleter f or t he s ec o n d y ear if t he y h a ve a 
c o m plia nce greater 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 h e treat me nt wit h o ut dela y (see Se cti o n 9 f or defi niti o n).  
S afet y A n al ysis S et ( 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 h er wise s pecifie d, all efficac y a n al ys es will be perf or me d o n t he F A S.  
 
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S o me tertiar y a nal ys es will b e re p eate d o n t he Treat m e nt C o m pl eter S ets a n d t he pri mar y 
a nal ysis, o n t h e I T T (if differe nt fr o m F A S), t o e v al uate t he r o b ust ness 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 det ails are gi ve n i n t he res pecti ve 
secti o ns. All safet y a n al yses will be perf or m e d o n t he S A F. 
A d diti o n al S u b gr o u p or S u bs et 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. 
 Hi g h-rel a ps e acti vit y ( H R A) 
o  H R A: at l east 2 rela pses i n t he pre vi o us year (i.e. t he n u m ber of hist orical 
rel a ps es wit hi n 1 2 m o nt hs pri or t o Baseli ne ≥2) re gar dl ess of pri or use of D M Ds 
o  N o n- H R A: ot her wise  
U nless ot h er wis e i n dicate d, all descri pti v e statisti cal a nal yses will be prese nte d 
se parat el y f or t he H R A s u b gr o u ps. 
 Pre vi o us treat me nt wit h Dis ease M o dif yi n g Dr u gs ( D M Ds): 
o  D M D pre-tre ate d: S u bj ects 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 di cati o n. Details of t he defi niti o n 
of D M Ds ar e s pecifie d i n A p pe n di x 1 ( Secti o n 1 8. 1). 
o  Pre-treat m e nt n aï ve: all s u bjects n ot classifie d as D M D pre-treate d. 
T he pri mar y a n al ysis a n d s electe d de m o gra p hic a n d bac k gr o u n d c haract eristics as well as 
selecte d t erti ar y a n al ys es will be re peate d f or t hes e s u b gr o u ps. 
T he f oll o wi n g s u bset(s) are defi n e d: 
 Baseli ne Peri o d C U A c o u nt > 0 (i.e. all s u bj ects wit h a C U A l esi o n c o u nt > 0 d uri n g 
t he Baseli ne P eri o d) 
As s u bjects wit h a C U A c o u nt of 0 d uri n g t h e Baseli ne Peri o d ca n n ot s h o w a n 
i m pr o ve me nt i n t he n u m ber of C U A lesi o ns d uri n g t he st u d y, s o me of t h e efficac y 
a nal yses will be re peat e d f or t his s u bset t h at has at least o ne C U A lesi o n d uri n g t h e 
Baseli ne Peri o d. 
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9  
Ge ner al S pecifi c ati o ns f o r 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 b ele d as M a ve n cla d ® . 
Si g nific a nce le vel 
T he t hree h y p ot heses of t he pri m ar y a n al ysis (see Secti o n 1 4. 1) will be teste d as o ne -si de d, o n 
a 2. 5 % si g nifica nce le v el. T he testi n g pr oce d ure will st o p as s o o n as o ne of t h e h y p ot heses 
ca n n ot be rej ect e d f oll o wi n g a pre-s p ecifie d or der. D ue t o t his se q ue nti al or der of tests a n 
a dj ust me nt f or a p ote ntial t y pe-I-err or i nflati o n d u e t o t he m ulti ple testi n g is n ot re q uire d. 
 All statistical 
tests will be perf or me d t w o-si de d. If c o nfi de nc e i nter vals are t o b e cal c ul ate d, t hese will be 
t w o-si de d wit h a c o nfi de nce pr o ba bilit y of 9 5 %, u nl ess 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 bl es 
C o nti n u o us varia bles will be s u m m arize 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 u es, mea n wit h sta n dar d d e viati o n, 
me dia n, 2 5 t h Perce ntile - 7 5t h P erce ntile ( Q 1- Q 3), mi ni m u m, a n d m a xi m u m. 
Q ualitati ve vari a bles will be s u m marize d b y c o u nts a n d perc e nta ges. 
U nless ot h er wise st ate d, t he calc ulati o n of pr o p orti o ns will be bas e d o n t he n u m ber of s u bjects 
i n t he a nal ysis s et of i nt erest. 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 h e 
de n o mi nat or a n d pres e nt e d as a se p arat e cat e g or y. 
I n case w h ere t he a nal ysis refers o nl y t o cert ai n Visits, perce nta g es will be b ase d o n t h e 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 pe cifi e d. 
Defi niti o n of B as eli ne 
T he l ast n o n- missi n g m eas ure m e nt pri or t o st art of st u d y me dicati o n will ser ve as t he B as eli ne 
meas ure me nt. M eas ure me nts perf or me d o n t he d a y of first i nta k e of st u d y me di cati 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 m e 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 se 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 di cati o n s h o ul d be t h e last 
pr oce d ure o n t he Visit d a y. 
T he M RI sca ns will b e rec o ncile d d uri n g ce ntral M RI re vi e w pr ocess. T heref ore, M RIs will be 
c o nsi d ere d as Baseli ne M RIs if assi g ne d t o t he Baseli ne Visit b y t he ce ntral i m a gi n g re vie w. 
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I N F O R M A T I O N 
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Defi niti o n of St u d y Peri o ds 
 Baseli ne Peri o d: T he Baseli n e Peri o d is defi ne d as t he P eri o d bet wee n t he Scree ni n g a n d 
t he Baseli ne M RI s ca n.  
 P ost- Baseli ne P eri o d: T he p ost- Baseli ne Peri o ds t hat are use d i n t he pri mar y a nal ysis are 
defi ne d as f oll o ws:  
 Peri o d 1 ( p 1) is defi ne d as t h e Peri o d bet wee n M o nt h 1 a n d M o nt h 6 M RI s ca ns. 
 Peri o d 2 ( p 2) is defi ne d as t h e Peri o d bet wee n M o nt h 2 a n d M o nt h 6 M RI s ca ns  
 Peri o d 3 ( p 3) is defi ne d as t h e Peri o d bet wee n M o nt h 3 a n d M o nt h 6 M RI s ca ns  
I n a d diti o n, t he f oll o wi n g p ost- Baseli ne Peri o ds are defi ne d s olel y f or tertiar y a nal yses: 
T hree m o nt hs P eri o ds 
 Peri o d 3. 1 ( p 3. 1) is defi ne d as t he P eri o d bet we e n Baseli ne a n d M o nt h 3 M RI sca ns. 
Si x m o nt hs Peri o ds 
 Peri o d 6. 1 ( p 6. 1) is defi ne d as t he P eri o d bet we e n Baseli ne a n d M o nt h 6 M RI sca ns, 
 Peri o d 6. 2 ( p 6. 2) is defi ne d as t he P eri o d bet we e n M o nt h 6 t o M o nt h 1 2 M RI s ca ns, 
 Peri o d 6. 3 ( p 6. 3) is defi ne d as t he P eri o d bet we e n M o nt h 1 2 t o M o nt h 1 8 M RI sca ns, 
 Peri o d 6. 4 ( p 6. 4) is defi ne d as t he P eri o d bet we e n M o nt h 1 8 t o M o nt h 2 4 M RI sca ns. 
Peri o ds e xcl u di n g t he Peri o d bet wee n t he B as eli ne sca n a n d t h e M o nt h 1 M RI s ca n: 
 Peri o d 1 1. 1 ( p 1 1. 1) is defi ne d as t he Peri o d bet wee n M o nt h 1 t o M o nt h 1 2 M RI s ca ns, 
 Peri o d 1 1. 2 ( p 1 1. 2) is defi ne d as t he Peri o d bet wee n M o nt h 1 t o M o nt h 2 4 M RI s ca ns. 
Yearl y P eri o ds: 
 Peri o d 1 2. 1 ( p 1 2. 1) is defi ne d as t he Peri o d bet wee n Baseli ne t o M o nt h 1 2 M RI s ca ns, 
 Peri o d 1 2. 2 ( p 1 2. 2) is defi ne d as t he Peri o d bet wee n M o nt h 1 2 t o M o nt h 2 4 M RI s ca ns. 
2 - Year Peri o d: 
 Peri o d 2 4. 1 ( p 2 4. 1) is defi ne d as t he P eri o d bet wee n Baseli n e t o M o nt h 2 4 M RI s ca ns. 
Se q ue ntial Visit P eri o ds 
 Peri o d 1 0 0. 0 ( p 1 0 0. 0) is defi ne d as t h e Peri o d bet wee n Scree ni n g a n d Baseli ne 
(e q ui vale nt t o Baseli n e P eri o d) M RI s ca ns 
 Peri o d 1 0 0. 1 ( p 1 0 0. 1) is defi ne d as t he P eri o d bet wee n Baseli ne a n d M o nt h 1 M RI sca ns, 
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 Peri o d 1 0 0. 2 ( p 1 0 0. 2) is defi ne d as t he Peri o d bet w ee n M o nt h 1 a n d M o nt h 2 M RI s ca ns, 
 Peri o d 1 0 0. 3 ( p 1 0 0. 3) is defi ne d as t he Peri o d bet w ee n M o nt h 2 a n d M o nt h 3 M RI s ca ns, 
 Peri o d 1 0 0. 6 ( p 1 0 0. 6) is defi ne d as t he Peri o d bet w ee n M o nt h 3 a n d M o nt h 6 M RI s ca ns, 
 Peri o d 1 0 0. 1 2 ( p 1 0 0. 1 2) is defi ne d as t he P eri o d bet wee n M o nt h 6 a n d M o nt h 1 2 M RI 
sca ns, 
 Peri o d 1 0 0. 1 5 ( p 1 0 0. 1 5) is d efi ne d as t he Peri o d bet wee n M o nt h 1 2 a n d M o nt h 1 5 M RI 
sca ns, 
 Peri o d 1 0 0. 1 8 ( p 1 0 0. 1 8) is d efi ne d as t he Peri o d bet wee n M o nt h 1 5 a n d M o nt h 1 8 M RI 
sca ns, 
 Peri o d 1 0 0. 2 4 ( p 1 0 0. 2 4) is d efi ne d as t he Peri o d bet wee n M o nt h 1 8 a n d M o nt h 2 4 M RI 
sca ns. 
N ote: Peri o d start a n d e n d dates are defi ne d b y t h e M RI d ates as pr o vi d e d b y ce ntral rea di n g. 
Defi niti o n of c h a n g e fr o m B aseli n e 
C ha n ge fr o m Baseli ne = Visit val ue – Baseli ne val ue. 
Perce nta ge C ha n ge fr o m Baseli n e = 1 0 0 × ( Visit val ue – Baseli ne val u e) / B as eli ne val ue. 
T he Perce nta ge C ha n g e fr o m Bas eli ne will b e set t o missi n g f or s u bje cts wit h a zer o at 
Baseli ne. 
Defi niti o n of Visit d ates 
T he Visit start d ate is t he d ate of t he first assess m e 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 h e date of t he l ast ass ess me nt w hic h bel o n gs t o t he c orres p o n di n g Visit.  
Defi niti o n of d u r ati o n 
D urati o n will be calc ul ate d b y t he differe nce of st art a n d st o p dat e + 1, i n da ys ( u nless s pecifie d 
ot her wise). 
Tre at me nt P eri o d 
T he tre at m e nt Peri o d be gi ns wit h t he start of st u d y me di cati o n o n St u d y D a 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 tr eat me nt Peri o d at t he M o nt h 2 4 Visit (see C S P, Secti o n 
7. 1. 2). St art of st u d y m e dicati o n is t he date of first i nt a ke of st u d y m e dic ati o n. Start of st u d y 
me dicati o n i n Year 2 is t he d ate of first i nta ke of st u d y m e dicati o n at or after t he M o nt h 1 2 
Visit. 
Treat m e nt Peri o d:  
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 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 E arl y Ter mi nati o n ( E T) Visit, i n case of 
earl y dis c 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 m e nt Peri 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 Visit - 1 da y, or if t he s u bject 
di d n ot recei v e Treat m e nt C o urse 2: Start of st u d y m e dicati o n of Treat me nt C o urse 1 
+ 4 5 7 da ys ( w hic h is o bt ai 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 d ate of dis c o nti n uati o n, if earlier. 
C o urse 2 Treat m e nt Peri o d: 
 Start = Start 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 m e nt C o urse 2 will be defi ne d as dela y e d, if t he st art of st u d y me dicati o n is dela ye d 
b y m ore t ha n 3 m o nt hs ( = 9 0 da ys) or di d n ot start at all i.e.: 
 Start of St u d y me dicati o n of Treat me nt C o urs e 2 > Start of St u d y Me dicati o n of 
Treat m e nt C o urse 1 + 4 5 7 da ys ( w hic h is o bt ai 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 
 Treat m e nt C o urse 2 n e ver start e d (i.e., n o st u d y m e 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 wit h a Dela ye d Treat me nt C o urse 2, o nl y data o bs er ve d d uri n g t he C o urse 1 
Treat m e nt P eri o d will b e a nal y ze d i n all efficac y a nal yses. Efficac y dat a after t he C o urs e 1 
Treat m e nt Peri o d will be c o u nt e d as missi n g i n t he statistical a n al yses a n d mar ke d i n t he 
listi n gs. I n all efficac y a n al yses defi ne d b y Peri o d, t he s u bj ect will be cl assifie d as if t h e s u bject 
disc o nti n ue d at t he e n d of t he C o urse 1 Treat m e nt P eri o d. F or s u bjects wit h o ut a dela y t he 
w h ole Tre at m e nt Peri o d will b e a n al yze d. 
F or all ot her a nal yses (e xce pt efficac y) t h e data is n ot li mite d t o t he C o urse 1 Treat m e nt P eri o d 
f or s u bj ects wit h a D el a ye d Treat m e nt C o urse 2. 
Defi niti o n of st art of C O VI D- 1 9- P a n d e mic 
T he start of C O VI D- 1 9 pa n de mic will be defi n e d b y c o u ntr y as t he earli est date of eit her t h e 
date of t he first deat h fr o m C O VI D- 1 9 occ urre d i n eac h c o u ntr y a cc or di n g t o t he p u blis he d 
data b y E ur o pea n 
C e ntre 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 p a.e u/e n/ p u bli cati o ns- data/ d o w nl oa d-t o da ys- data g e o gra p hi c-
distri b uti o n-c o vi d- 1 9-cas es- w orl d wi de) or 1 1t h 
Marc h 2 0 2 0 ( w he n t h e 
W H O decl are 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 is d efi ne d t o be perf or me d after t he start of C O VI D- 1 9 pa n de mic if t he Visit e n d date 
is greater t ha n t h e st art of C O VI D- 1 9 pa n d e mic dat e.  
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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 use 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 rel ate 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 me wi n d o w 
 Da y 1 is t he da y of start of st u d y m e 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 rel ati ve t o D a y 1. 
T he Visit s c h e d ul e 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, 
rel ati ve t o t he st art date of t he B as eli ne Visit f or Treat me nt C o urs e 1 a n d rel ati ve t o t he st art 
date of t he M o nt h 1 2 b Visit as d efi ne d i n t h e 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 nal ysis, s h o ul d assess m e nts be dela ye d, s u bj ects’ assess me nt dat a will be treat e d as 
t h o u g h it occ urre d at t he ti me p oi nt s pecifi e d (i.e., o ut of Visit wi n d o ws will be n ot e x cl u de d 
or a dj uste d f or a n y a n al ys es) a n d i nfere nc es will be c o n d ucte d acc or di n gl y. T h us, f urt her ti me 
wi n d o ws will n ot be s pecifie d.  
All o bser vati o ns fr o m u nsc he d ule d Visits will be i ncl u de d o nl y i n t h e a nal yses of Visit 
i n de pe n de nt s u m maries (e. g. c o u nts of e ve nts, pr o gressi o ns or w orst val ue d uri n g Treat m e nt 
Peri o d) u nless f or t h e u nsc he d ul e d Visits pri or t o start of st u d y me dicati o n a n d t h e last 
assess m e nt a vail a ble. I n cas e of u nsc h e d ule d Visits pri or t o start of st u d y me dicati o n, t hese 
will be c o nsi dere d t o defi n e Baseli ne. I n t he last missi n g case t he E T Visit will be i m p ute d b y 
t he u ns c he d ule d Visit. 
T he ass ess me nts of t he E T Visit will be m a p pe d t o t h e nearest pla n ne d p ost- B as eli ne Visit wit h 
a missi n g ass ess m e nt b ef ore or after t he E T Visit of t h e i n di vi d ual assess m e nt f or all statistical 
a nal yses a n d descri pti ve s u m maries. As n ot all assess me nts of t he E T are perf or me d at e ac h 
Visit, t he differe nt assess me nts of t h e E T c a n be assi g ne d t o differe nt Visits. If t he d urati o n (i n 
da ys) bet w ee n t h e E T Visits a n d t w o missi n g pla n ne d Visits are e q u al, 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 h er wise s pecifie d i n res pecti v e s ecti o ns, missi n g data will n ot be re pl ace d. 
T he ha n dli n g of missi n g c o variate a n d stratifi cati o n fact or i nf or m ati o n is descri be d b el o w. 
T he ha n dli n g of missi n g D M D e n d date is descri 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 R el a ps e Re p ort” will be i m p ut e d as 
f oll o ws: 
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Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
2 3/ 9 8  
 
 
 I n cases w here t he o nset date is partiall y missi n g b ut t he o nset m o nt h a n d year, or t h e 
o nset year are e q ual t o t he st art of st u d y me dicati o n or t he date is missi n g 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 c ases t he missi n g o nset da y or missi n g o ns et m o nt h will b e re pl ace d b y 1 
( b ut n ot bef ore start of st u d y me dicati o n). 
I n all s u bject data listi n gs, i m p ute d val ues will be pres e nte d a n d fla g ge d. 
Missi n g statistics, e. g. w he n t he y ca n n ot be cal c ulate d, s h o ul d be prese nte d as “ n d”. F or 
e xa m ple, if n = 1, t he m eas ure of v aria bilit y (e. g. S D) ca n n ot b e c o m p ute d a n d s h o ul d b e 
pres e nt e d as “ n d ”. 
W here ta bl es are pres e nte d o ver ti me, t he t otal n u m ber of s u bjects wit h missi n g a n d n o n-
missi n g o bser vati o ns at e ac h ti m e- p oi nt s h o ul d reflect t he p o p ul ati 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 m a de b e y o n d st u d y wit h dra wal. 
D at a H a n dli n g f or M RI d at a 
D at a h a n dli n g of P ri m ar y e n d p oi nt(s) a n d its c o m p o n e nts: 
T he M RI lesi o ns will b e e v al uate d b y i n de pe n d e nt ce ntral re vie w, w hic h will pr o vi de t he 
f oll o wi n g meas ure m e nts f or t he pri mar y e n d p oi nts (see I R C f or C o u nti n g Brai n M RI Lesi o ns 
[ 3]): 
 T otal n u m ber of T 1 G a d oli ni u m e n ha nci n g lesi o ns ( T 1 G d +) ( or N ot E val u a ble [ N E], 
if a p plica ble) at t he first a n d last M RI of t he res p ecti ve Peri o d, 
 T otal n u m ber of ne w T 2 lesi o ns wit h T 1 G d + ( or N E, if a p plica ble) of t he res pecti ve 
Peri o d (c o m pari n g t he last wit h t he first M RI of t he res pecti ve Peri o d), 
 T otal n u m ber of e nlar gi n g T 2 l esi o ns wit h T 1 G d + ( or N E, if a p pli ca ble) of t he 
res pecti ve P eri o d (c o m pari n g t he last wit h t he first M RI of t he res pecti ve Peri o d), 
 T otal n u m ber of ne w T 2 lesi o ns wit h o ut T 1 G d + ( or N E, if a p plica bl e) of t he 
res pecti ve P eri o d (c o m pari n g t he last wit h t he first M RI of t he res pecti ve Peri o d), 
 T otal n u m ber of e nlar gi n g T 2 l esi o ns wit h o ut T 1 G d + ( or N E, if a p plica bl e) of t he 
res pecti ve P eri o d (c o m pari n g t he last wit h t he first M RI of t he res pecti ve Peri o d). 
T he statistical 
a n al ysis 
will 
use t he res ults fr o m t he 
Gl o bal 
assess m e nt (i. e. 
Rea dt y pe = G L O B A L). 
T he assi g n me nt of M RIs t o t h e res pecti ve Visits (e. g. assi g n m e nt of E T M RIs or del a y e d M RIs 
d ue t o ster oi d treat me nt) will be e ns ure d b y t he ce ntral rea di n g pr ocess. M RIs ta k e n w hil e o n 
Ster oi d Treat me nt as i de ntifie d as a m aj or P D will be e xcl u de d fr o m t he a nal ysis. 
All deri ve d lesi o n c o u nts (e xce pt f or t he Mea n T 1 G d + lesi o n c o u nt) as s pecifi e d bel o w will 
be cl assifie d as N E if o ne of t he c o m p o ne nts re q uire d f or t h e cal c ulati o n has bee n classifi e d as 
N E b y t he ce ntral rea di n g. T he Mea n T 1 G d + lesi o n c o u nt will b e s et t o N E o nl y, if all T 1 G d + 
lesi o n c o u nts t hat c orres p o n d t o t he res pecti ve Peri o d are classifie d as N E. I n all ot her cases 
t he m ea n will be calc ulat e d bas e d o n t he a vail a ble c o u nts d uri n g t he res pecti ve P eri o d. 
T 1 G d + lesi o n c o u nt 
As wit h t his pr oce d ure a Visit is assesse d m ulti ple ti mes f or t he T 1 G d + a n d t h us T 1 G d + will 
be re p orte d m ulti pl e ti mes per Visit, t he v al ue f or a Visit of t he earliest a vaila bl e Peri o d will 
C CI


Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
2 4/ 9 8  
 
 
be select e d f or t h e st atistical a nal ysis. As t he Gl o bal Re vie w will e ns ure t hat all d u pli cates ha ve 
i de ntical lesi o n c o u nt, t his r ul e d oes n ot ha ve a n i m pact o n t he n u m b er of T 1 G d + b ut d efi nes 
f urt her attri b utes (e. g. d at e of re vie w). 
T he T 1 G d + c o u nts f or a Peri o d will be defi ne d as t he s u m of t he T 1 G d + lesi o ns fr o m all 
sc he d ul e d M RI sca ns re p orte d f or a Visit t hat is i ncl u de d i n a Peri o d di vi de d b y t he act u al 
n u m ber of M RI s ca ns wit h a re p ort e d lesi o n c o u nt (i. e. n ot N E) d uri n g a P eri o d.   
 T 1 G d + lesi o n c o u nt ( b y Visit) = T 1 G d + lesi o ns c o u nt fr o m t he M RI at t h e res p ecti ve 
Visit  
 M ea n T 1 G d + lesi o n c o u nt ( b y Peri o d) = T 1 G d + lesi o n c o u nt d uri n g t he Peri o d /  
# of sca ns bel o n gi n g t o t he res pe cti ve Peri o d wit h n o n- missi n g T 1 G d + lesi o n c o u nt. 
M RIs are assi g ne d t o a Peri o d as f oll o ws: 
 Baseli ne Peri o d:  
o  Scree ni n g Visit 
o  Baseli ne Visit 
 Peri o d 1: 
o  M o nt h 1 Visit 
o  M o nt h 2 Visit  
o  M o nt h 3 Visit 
o  M o nt h 6 Visit 
 Peri o d 2: 
o  M o nt h 2 Visit  
o  M o nt h 3 Visit 
o  M o nt h 6 Visit 
 Peri o d 3: 
o  M o nt h 3 Visit 
o  M o nt h 6 Visit 
 
Acti ve T 2 lesi o n c o u nt 
As t h e ne w or e nlar gi n g T 2 lesi o n c o u nt de pe n ds o n t he le n gt h of t he Peri o d, it will be prese nte d 
as re p orte d ( n o n-sta n d ar dize d) a n d sta n d ar dize d t o 1 m o nt hs ( 3 0. 4 3 7 5 d a ys):  
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Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
2 5/ 9 8  
 
 
 Peri o d le n gt h ( da ys) = M RI dat e at e n d of P eri o d – M RI dat e at start of Peri o d + 1, 
 Sta n dar dize d t otal T 2 lesi o n c o u nt ( b y Peri o d per 1 m o nt hs) = T ot al n u m ber of T 2 
lesi o ns per Peri o d * 3 0. 4 3 7 5 / Peri o d le n gt h. 
T he f oll o wi n g t y pes of T 2 lesi o ns are d efi ne d p er Peri o d (sta n dar di ze d a n d n o n-sta n dar diz e d): 
 T otal ne w T 2 l esi o n c o u nt =  
   
T ot al n u m b er of ne w T 2 lesi o ns wit h T 1 G d +  
   
+ T otal n u m b er of n e w T 2 lesi o ns wit h o ut T 1 G d + 
 T otal e nl ar gi n g T 2 lesi o n c o u nt =  
   
T ot al n u m b er of e nlar gi n g T 2 l esi o ns wit h T 1 G d +  
   
+ T otal n u m b er of e nlar gi n g T 2 lesi o ns wit h o ut T 1 G d +, 
 T otal acti ve T 2 lesi o n c o u nt =  
   
T ot al ne w T 2 lesi o n c o u nt  
   
+ T ot al e nl ar gi n g T 2 lesi o n c o u nt 
T he t otal acti ve T 2 L esi o n c o u nt will als o be re p ort e d f or t he Baseli n e, M o nt h 2, M o nt h 3, a n d 
M o nt h 6 Visit a n d is defi ne d as: 
 T otal acti ve T 2 Lesi o n c o u nt = T otal n u m ber of n e w or e nl ar gi n g T 2 lesi o ns si nce t he 
sca n of t he pre vi o us Visit 
a n d will be calc ul ate d as f oll o ws: 
 T otal acti ve T 2 Lesi o n c o u nt at t he Baseli ne Visit  
   
= T otal acti ve T 2 L esi o n c o u nt of t he Baseli ne Peri o d  
 T otal acti ve T 2 Lesi o n c o u nt at t he M o nt h 2 Visit 
   
= T otal acti ve T 2 L esi o n c o u nt of Peri o d 1 ( M 1- M 6) – Peri o d 2 ( M 2- M 6) 
 T otal acti ve T 2 Lesi o n c o u nt at t he M o nt h 3 Visit 
   
= T otal acti ve T 2 L esi o n c o u nt of Peri o d 2 ( M 2- M 6) – Peri o d 3 ( M 3- M 6)  
 T otal acti ve T 2 Lesi o n c o u nt at t he M o nt h 6 Visit  
   
= T otal acti ve T 2 L esi o n c o u nt of Peri o d 3  
F or t he cal c ulati o n of t he C U A lesi o n c o u nt, o nl y T 2 l esi o ns t hat di d n ot e mer ge fr o m a T 1 
G d + lesi o n will be ta ke n i nt o acc o u nt. 
 T otal acti ve T 2 lesi o n c o u nt ( wit h o ut T 1 G d +) =  
   
T ot al ne w T 2 lesi o n c o u nt wit h o ut T 1 G d + 
   
+ T ot al e nl ar gi n g T 2 lesi o n c o u nt wit h o ut T 1 G d + 
a n d will be sta n dar diz e d t o t he le n gt h of t he Peri o d. T otal acti ve T 2 lesi o n c o u nt ( wit h o ut T 1 
G d +) will o nl y be calc ulat e d if T 1 G d + c o u nts f or be gi n ni n g a n d e n d of t h e c orres p o n di n g 
Peri o d are n o n- missi n g. 
 
C U A lesi o n c o u nt 
T he n u m ber of C U A lesi o ns f or a Peri o d will be defi ne d as t he s u m of t he T 1 G d + a n d ne w or 
e nl ar gi n g T 2 c o u nts f or t he res p ecti ve Peri o d a n d will be sta n dar dize d t o o ne sca n (f or T 1) or 
o ne m o nt h (f or T 2) t o har m o nize t he u nits of t he 2 assess me nts.  
# C U A( p i)   
= Sta n dar dize d  C U A lesi o n c o u nt ( b y Peri o d i per 1 m o nt h)  
   
   
= Mea n T 1 G d + lesi o n c o u nt ( b y Peri o d i per Visit)  
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Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
2 6/ 9 8  
 
 
   
   
   
+ Sta n dar dize d t otal acti ve T 2 lesi o n c o u nt ( wit h o ut T 1 G d +)  
   
   
   
( b y Peri o d i per 1 m o nt hs)  
T he C U A lesi o n c o u nt will o nl y b e calc ul at e d if b ot h c o m p o ne nts ( T 1 a n d T 2) are n o n- missi n g. 
D at a h a n dli n g of Terti ar y e n d p oi nts: 
T he M RIs will be e v al uat e d b y i n de pe n de nt ce ntral re vie w (see I R C f or L esi o n C o u nti n g f or 
t he Tertiar y E n d p oi nt [ 6]). As t he ce ntral rea di n g pr ocess f or T erti ar y M RI E n d p oi nts is 
differe nt fr o m t he pr o cess f or Pri mar y M RI E n d p oi nts, data are pr o vi de d i n a differe nt f or m at 
(see Data Tra nsfer S p ecificati o n [ 8]). 
T he assi g n m e nt of M RIs t o t h e res p ecti v e Visits will be e ns ure d b y t he ce ntral rea di n g pr ocess 
a n d ma y differ fr o m t he i nitial M RI Visit assi g n me nts as re p orte d i n t h e e C R F. T he statistical 
a nal ysis is base d o n t he M RI assi g n m e nts as pr o vi de d b y ce ntral rea di n g. 
All deri ve d lesi o n c o u nts (e xce pt f or t he Mea n T 1 G d + lesi o n c o u nt) as s pecifi e d bel o w will 
be cl assifie d as N E if o ne of t he c o m p o ne nts re q uire d f or t h e cal c ulati o n has bee n classifi e d as 
N E b y t he ce ntral rea di n g. T he Mea n T 1 G d + lesi o n c o u nt will b e s et t o N E o nl y, if all T 1 G d + 
lesi o n c o u nts t hat c orres p o n d t o t he res pecti ve Peri o d are classifie d as N E. I n all ot her cases 
t he m ea n will be calc ulat e d bas e d o n t he a vail a ble c o u nts d uri n g t he res pecti ve P eri o d. 
 
T 1 G d + lesi o n c o u nt 
 T he T 1 G d + are d efi ne d as f oll o w: T 1 G d + lesi o n c o u nt ( b y Visit) = T 1 G d + lesi o ns 
c o u nt fr o m t he M RI at t h e res pecti ve Visit. 
 M ea n T 1 G d + lesi o n c o u nt ( b y Peri o d) = s u m of all T 1 G d + l esi o n c o u nts d uri n g t he  
Peri o d / # of s ca ns bel o n gi n g t o t he res pecti ve Peri o d wit h n o n- missi n g T 1 G d + lesi o n 
c o u nt. 
All M RI s ca ns b el o n g t o a Peri o d t hat eit h er h a ve b ee n perf or me d d uri n g t he P eri o d 
i ncl u di n g start  a n d e n d. F or p ost- Baseli ne peri o ds starti n g at B as eli ne, t he Baseli ne Visit 
will n ot be i ncl u de d. F or e xa m pl e,  Peri o d 6. 1 will i n cl u de M o nt h 1, 2, 3, 6 Visit, P eri o d 
2 4. 1 will i ncl u de all M RI sca ns e xce pt Scree ni n g a n d Baseli ne Visit). 
 Ne w T 1 G d + lesi o n c o u nt ( b y Peri o d) = n u m ber of ne w T 1 G d + lesi o n c o u nts fr o m t he 
c o m paris o n of t he t w o select e d M RI sca ns perf or me d b y ce ntral rea di n g acc or di n g t o 
t he Data Tra nsfer S pecificati o n [ 8] (e. g. f or Peri o d 6. 1 c o m paris o n of t h e M RI sca ns 
fr o m Baseli ne Visit a n d M o nt h 6 Visit will be perf or me d)  
 
Acti ve T 2 lesi o n c o u nt 
As t he acti ve (i. e t he n e w or e nl ar gi n g) T 2 lesi o n c o u nt de pe n ds o n t he le n gt h of t he Peri o d, it 
will b e prese nte d as re p ort e d ( n o n-sta n dar di ze d) a n d a n n ualize d (sta n d ar dize d t o 1 years 
( 3 6 5. 2 5 da ys)):  
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Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
2 7/ 9 8  
 
 
 Peri o d le n gt h ( da ys) = M RI dat e at e n d of P eri o d – M RI dat e at start of Peri o d + 1, 
 A n n uali ze d acti v e T 2 lesi o n c o u nt ( b y Peri o d) = T otal n u m ber of a cti ve T 2 l esi o ns 
per Peri o d * 3 6 5. 2 5/ Peri o d l e n gt h. 
T he f oll o wi n g t y pes of T 2 lesi o ns are d efi ne d p er Peri o d (sta n dar di ze d a n d n o n-sta n dar diz e d): 
 T otal ne w T 2 l esi o n c o u nt =  
   
T ot al n u m b er of ne w T 2 lesi o ns wit h T 1 G d +  
   
+ T ot al n u m ber of n e w T 2 lesi o ns wit h o ut T 1 G d + 
 T otal e nl ar gi n g T 2 lesi o n c o u nt =  
   
T ot al n u m b er of e nlar gi n g T 2 l esi o ns wit h T 1 G d +  
   
+ T ot al n u m ber of e nlar gi n g T 2 lesi o ns wit h o ut T 1 G d +, 
 T otal acti ve T 2 lesi o n c o u nt =  
   
T ot al ne w T 2 lesi o n c o u nt  
   
+ T otal e nl ar gi n g T 2 lesi o n c o u nt 
N ote: t he n u m b er of n e w or e nlar gi n g T 2 ( wit h a n d wit h o ut T 1 G d +) will be pr o vi de d b y ce ntral 
rea di n g f or eac h of t he P eri o ds i ncl u di n g t he S e q ue ntial Visit Peri o ds, e xc e pt f or Peri o d 3. 1. 
F or P eri o d 3. 1, t h e s u m of t he Se q ue nti al Visit Peri o ds 1 0 0. 1, 1 0 0. 2 a n d 1 0 0. 3 will be 
calc ulate d. 
F or t he cal c ulati o n of t he C U A lesi o n c o u nt, o nl y T 2 l esi o ns t hat di d n ot e mer ge fr o m a T 1 
G d + lesi o n will be ta ke n i nt o acc o u nt. 
 T otal acti ve T 2 lesi o n c o u nt ( wit h o ut T 1 G d +) =  
   
T ot al ne w T 2 lesi o n c o u nt wit h o ut T 1 G d + 
   
+ T otal e nl ar gi n g T 2 lesi o n c o u nt wit h o ut T 1 G d + 
a n d will be sta n dar dize d t o t he le n gt h of t h e Peri o d (i. e. a n n u alize d). T otal acti ve T 2 lesi o n 
c o u nt ( wit h o ut T 1 G d +) will o nl y be calc ul ate d if T 1 G d + c o u nts f or be gi n ni n g a n d e n d of t he 
c orres p o n di n g Peri o d are n o n- missi n g. 
C U A lesi o n c o u nt  
T he n u m ber of C U A lesi o ns f or a Peri o d will be defi ne d as t he s u m of t he T 1 G d + a n d ne w or 
e nl ar gi n g T 2 c o u nts f or t he res p ecti ve Peri o d a n d will be sta n dar dize d t o o ne sca n (f or T 1) or 
o ne year (f or T 2) t o har m o nize t he u nits of t he 2 assess me nts.  
# C U A( p p ost- B aseli ne )  
= A n n ualize d  C U A l esi o n c o u nt ( b y p ost- Baseli ne P eri o d p er 1 y ear)  
   
   
            = M ea n T 1 G d + l esi o n c o u nt ( b y Peri o d i)  
   
   
   
   + A n n ualize d t otal acti ve T 2 l esi o n c o u nt ( wit h o ut T 1 G d +)  
   
                           ( b y P eri o d i per 1 year) Differe nt fr o m t he pri mar y a nal ysis, T 2 
lesi o n c o u nt will be sta n dar dize d t o 1 year i nstea d of 1 m o nt h d ue t o l o n ger peri o ds a n d f or 
c o m paris o n wit h ot h er st u dies, 
T he C U A lesi o n c o u nt will o nl y b e calc ul at e d if b ot h c o m p o ne nts ( T 1 a n d T 2) are n o n- missi n g. 
D at a H a n dli n g i n c as e of m aj or P Ds 
P Ds will n ot be c o nsi d ere d i n t h e pl a n n e d statisti cal a nal yses (i.e., all data will be a n al yze d 
i n de pe n de nt fr o m a n y re p orte d P D) e x ce pt f or P D d ue t o M RI ta k e n d uri n g ster oi d tre at m e nt 
( M RI will be e xcl u de d fr o m t he pri m ar y a nal ysis). 
C CI


Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
2 8/ 9 8  
 
 
C o v ari ates a n d str atific ati o n f act ors 
A ge 
A ge ( years) at ti m e of I nf or me d C o nse nt (l oa de d fr o m i R T). Missi n g a ge will be re place d as 
f oll o ws if us e d as a c o variate: 
 A ge will be esti m ate d fr o m t h e year of birt h ( year of I C – year of birt h), as rec or d e d i n 
t he electr o nic Cas e Re p ort F or m (e C R F), 
 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. 
E D S S at B aseli ne  
E x pa n de d Disa bilit y Stat us S cale ( E D S S) at Baseli ne will be cat e g ori ze d b y: 
 ≤3 (refere nce), 
 > 3. 
Missi n g E D S S at B aseli ne will be i m p ut e d b y t he m e dia n Baseli ne E D S S of t he F A S if use d 
as a stratifi cati o n fact or. 
P o ole d ce nters 
S o me ce nt ers will ha ve fe w eli gi ble s u bjects o nl y. T heref ore, t he ce nt ers will be p o ole d 
t o get her b y c o u ntr y e xce pt f or  
 sites t h at ha ve m or e t ha n 1 2 s u bjects i n t he F A S (i. e. t hese sites will n ot be p o ole d wit h 
a n y ot her site). 
 f or c o u ntri es t hat h a ve 6 s u bjects or less i n t h e F A S t hat will be p o ole d as f oll o ws: 
 Sca n di na via = Fi nl a n d a n d S we de n 
 M e dit erra n n ea = Ital y a n d S pai n 
 A ustria- H u n gar y = A ustria a n d H u n gar y 
M RI s p ecific c o v ari ates 
Ti me bet wee n sc a ns: i n M o nt hs 
Ti me bet wee n s ca ns (i n M o nt hs) is calc ulate d as f oll o ws:  
 Ti me bet wee n s ca ns (i n M o nt hs) = ( M RI d ate of t he Visit - M RI of t he pre vi o us Visit 
+ 1) / 3 0. 4 3 7 5. i.e.: 
o  If ( Visit = M o nt h 1) t he n Ti me bet wee n s ca ns (i n M o nt hs) = ( M RI date at M o nt h 
1 - M RI d ate at Baseli ne + 1)/ 3 0. 4 3 7 5 
o  If ( Visit = M o nt h 2) t he n Ti me bet wee n s ca ns (i n M o nt hs) = ( M RI date at M o nt h 
2 - M RI d ate at M o nt h 1 + 1)/ 3 0. 4 3 7 5 
o  If ( Visit = M o nt h 3) t he n Ti me bet wee n s ca ns (i n M o nt hs) = ( M RI date at M o nt h 
3 - M RI d ate at M o nt h 2 + 1)/ 3 0. 4 3 7 5 
o  If ( Visit = M o nt h 6) t he n Ti me bet wee n s ca ns (i n M o nt hs) = ( M RI date at M o nt h 
6 - M RI d ate at M o nt h 3 + 1)/ 3 0. 4 3 7 5 
 
If t he c orres p o n di n g M RI is a vaila ble a n d t he ti me bet wee n s ca ns is missi n g ( d ue t o prece di n g 
M RI bei n g missi n g) it will be re plac e d b y e x pecte d ti me as f oll o ws: 
 M o nt h 1/ 2/ 3 Visit = 1 
 M o nt h 6 Visit = 3. 
C CI


Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
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Ti me bet wee n sc a ns: i n Ye ars 
Ti me bet wee n s ca ns (i n Years) is calc ulat e d as f oll o ws:  
 Ti me bet wee n sca ns (i n Years) = ( M RI date of t he Visit - M RI of t he pre vi o us Visit + 
1) / 3 6 5. 2 5, i.e.: 
 If ( Visit = M o nt h 1) t he n Ti m e bet wee n s ca ns (i n Years) = ( M RI d ate at M o nt h 
1 - M RI d ate at Baseli ne + 1)/ 3 6 5. 2 5 
 If ( Visit = M o nt h 2) t he n Ti m e bet wee n s ca ns (i n Years) = ( M RI d ate at M o nt h 
2 - M RI d ate at M o nt h 1 + 1)/ 3 6 5. 2 5 
 If ( Visit = M o nt h 3) t he n Ti m e bet wee n s ca ns (i n Years) = ( M RI d ate at M o nt h 
3 - M RI d ate at M o nt h 2 + 1)/ 3 6 5. 2 5 
 If ( Visit = M o nt h 6) t he n Ti m e bet wee n s ca ns (i n Years) = ( M RI d ate at M o nt h 
6 - M RI d ate at M o nt h 3 + 1)/ 3 6 5. 2 5 
 If ( Visit = M o nt h 1 2) t he n Ti me bet wee n sca ns (i n Years) = ( M RI date at M o nt h 
1 2 - M RI d ate at M o nt h 6 + 1)/ 3 6 5. 2 5 
 If ( Visit = M o nt h 1 5) t he n Ti me bet wee n sca ns (i n Years) = ( M RI d ate at M o nt h 
1 5 - M RI d ate at M o nt h 1 2 + 1)/ 3 6 5. 2 5 
 If ( Visit = M o nt h 1 8) t he n Ti me bet wee n sca ns (i n Years) = ( M RI d ate at M o nt h 
1 8 - M RI d ate at M o nt h 1 5 + 1)/ 3 6 5. 2 5 
 If ( Visit = M o nt h 2 4) t he n Ti me bet wee n sca ns (i n Years) = ( M RI d ate at M o nt h 
2 4 - M RI d ate at M o nt h 1 8 + 1)/ 3 6 5. 2 5 
 
If t he c orres p o n di n g M RI is a vaila ble a n d t he ti m e bet wee n s ca ns is missi n g ( d ue t o prece di n g 
M RI bei n g missi n g) it will be re plac e d b y e x pecte d ti me as f oll o ws: 
 M o nt h 1/ 2/ 3 Visit = 1 
 M o nt h 6 Visit = 3 
 M o nt h 1 2 Visit = 6 
 M o nt h 1 5 Visit = 3 
 M o nt h 1 8 Visit = 3 
 M o nt h 2 4 Visit = 6. 
 
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. 
C CI


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M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
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1 0  
Tri al P arti ci 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 bje ct dis p ositi o n a n d 
treat m e nt/st u d y disc o nti n uati o n. A d diti o nall y, pr oce d ures f or re p orti n g pr ot o c 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 Dis c o nti n u ati o ns 
S u bject dis p ositi o n will be pres e nt e d f or t he E S: 
 T otal n u m ber of s u bjects e nr oll e d (i.e., s u bje cts w h o ga ve i nf or me d c o nse nt), 
 N u m ber of s u bje cts 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 Crit eria, 
t he faile d s pecific i ncl usi o n or e xcl usi o n crit eria will b e pr o vi de d i n a d diti o n). 
S u bjects n ot classifie d as s cree ne 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 b e list e d as “ n o treat m e 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 yst e m), 
 O verall a n d b y Treat m e nt C o urse, w h o rec ei ve d at l east d ose o ne of st u d y me dicati o n,  
 W h o dis c o nti n ue d t he st u d y m e dicati o n, gr o u pe d b y mai n reas o n (acc or di n g t o t he 
i nf or mati o n o n t he St u d y T er mi nati o n C R F pa ge), 
 W h o c o m plete d t he st u d y (acc or di n g t o t he i nf or m ati o n o n t he St u d y T er mi nati o n 
C R F pa ge). 
 N u m ber of Visits perf or me d b ef ore a n d after Start of C O VI D- 1 9 pa n de mic 
Perce nta ges will be prese nt e d wit h res pect t o t he n u m ber of eli gi bl e s u bjects. T he n u m ber of 
s u bjects i n eac h a nal ysis set will be pr o vi de d o verall, b y re gi o n, b y c o u ntr y wit hi n re gi o n, a n d 
b y site. 
T he f oll o wi n g s u bject dat a listi n gs will be pr o vi d e d: 
 Listi n g of dis c 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. 
T he n u m ber of s u bje cts wit h least o ne a vail a ble T 1 G D + l esi o n c o u nt, T 2 lesi o n c o u nt a n d 
C U A lesi o n c o u nt f or eac h St u d y Peri o d will be prese nt e d f or t he F A S t o get h er wit h t he 
statistics f or t he le n gt h of t he St u d y Peri o ds, a n d statistics of t he n u m ber of a vaila ble T 1 G d + 
lesi o n c o u nts d uri n g t he St u d y Peri o ds. 
1 0. 2  
Pr ot oc ol De vi ati o ns 
1 0. 2. 1   
I m p o rt a nt Pr ot oc ol De vi ati o ns 
T he f oll o wi n g s u m mar y t a bles a n d listi n gs of maj or pr ot oc ol d e 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 vi ati o ns f or t h e I T T: 
 Fre q u e ncies p er reas o n of maj or pr ot o c ol de viati o ns ( o verall a n d b ase d o n 
rel ati o ns hi p t o C O VI D- 1 9 p a n de mic), 
 Listi n g of maj or pr ot oc ol de vi ati o ns (i ncl u di n g i nf or mati o n re g ar di n g relati 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 g r a p hics a n d Ot her B aseli ne C h a r acteristi cs 
U nless state d ot her wis e, s u m m aries will be pres e nte d o n t he F A S. 
1 1. 1  
Me dic al Hist or y 
T he m e dical hist or y will be c o de d usi n g t he M e di cal Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A). S u m m ar y t a ble will be prese nte d b y pri m ar y s yste m or ga n class ( S O C) a n d 
preferre d ter m ( P T). 
1 1. 2  
Ot her B aseli ne C h a r acteristics 
1 1. 3  
De m o g r a p hics 
De m o gra p hic c haract eristi cs will be s u m mari ze d usi n g t he f oll o wi n g i nf or mati o n fr o m t he 
Scree ni n g/ Baseli ne Visit C R F pa ges. 
De m o gra p hic c haract eristi cs: 
 Ge n der:  
 M al e, 
 Fe male, 
 Missi n g. 
 Race:  
 W hite, 
 Bl ac k or Africa n A m eric a n, 
 Asia n, 
 A merica n I n dia n or Alas ka Nati ve, 
 Nati v e Ha waii a n or Ot her P acific Isla n d er, 
 Ot her, 
 N ot c ollecte d at t his site, 
 Missi n g. 
 Et h nicit y His pa nic or Lati n o: 
 Yes, 
 N o, 
 Missi n g. 
 Et h nicit y Ja pa nese: 
 Yes, 
 N o, 
 Missi n g. 
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 A ge ( years) 
 A ge cat e g ories: 
 ≤ 4 0 years, 
 4 0 years, < 6 5 y ears, 
 ≥ 6 5 years, 
 Missi n g. 
 Re gi o n: 
 E aster n & Ce ntral E ur o p e: A ustria, Ger ma n y, H u n gar y, P ola n d, Czec h 
Re p u blic 
 Sca n di n a via: Fi nla n d, S we de n 
 M e diterra n ea: It al y, S pai n 
 Wester n E ur o pe:  Fra nce, U nite d Ki n g d o m 
 A ustralia, 
 Ca na da, 
 Israel. 
 C o u ntr y 
 C o u ntr y 1 
 … 
 P o ole d Ce nters 
T he f oll o wi n g s u bject dat a listi n g will be pr o vi de d: 
 De m o gra p hi c Data ( C o u ntr y, Se x, Race, A ge, E D S S at B as eli ne, N u m ber of rela pses 
wit hi n 1 2 m o nt hs pri or t o Baseli ne). 
M S Dise ase C h ar acteristics 
T he d urati o n si nce o nset a n d dia g n osis of M S at Baseli ne i n m o nt hs, as w ell as t h e 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 b er of s u bj ects gr o u pe d b y t he maj or s yste ms 
affe cte d (at o ns et of M S) will be pres e nte d.  
 Ti me si nce o nset of M S ( m o nt hs) = ( Visit start date of Baseli ne Visit - d ate of first 
s y m pt o m + 1) / 3 0. 4 3 7 5, 
 Ti me si n ce dia g n osis ( m o nt hs) = ( Visit start date of Baseli ne Visit - dat e of dia g n osis 
+ 1) / 3 0. 4 3 7 5, 
 Ti me si nce first rel a pse ( m o nt hs) = ( Visit start date of Baseli n e Visit - date of first 
rela pse + 1) / 3 0. 4 3 7 5, 
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 N u m ber of pre vi o us D M Ds (i. e., n u m ber 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 dicati o n F or m ” (se e A p pe n di x 1)),  
 0 
 1 
 2 
 > 2 
 E D S S at Baseli ne, 
 E D S S at Baseli ne, 
 ≤3 
 > 3 
 Missi n g 
 N u m ber of hist orical rel a pses wit hi n 1 2 m o nt hs pri or t o Baseli ne (i.e., n u m ber of 
rela pses fr o m t he “ M S Rela pse Hist or y Baseli ne” e C R F pa ge): 
 Baseli ne Visit Start Date ≥ o ns et dat e ≥ B aseli ne Visit Start Date - 3 9 6 Da ys, 
if t he da y of t he o nset is a vail a ble, 
 M o nt h of t he Baseli ne Visit Start Date ≥ o nset m o nt h ≥ m o nt h of B as eli ne 
Visit Start Date – 1 3 m o nt hs, if o nl y t h e m o nt h of o ns et is a vaila ble. 
 N u m ber of hist ori cal rela ps es wit hi n 1 2 m o nt hs pri or t o Baseli n e cate g orize d t o: 
 0 
 1 
 2 
 > 2 
 Hi g h-rela pse acti vit y ( H R A) 
 Yes 
 N o  
Missi n g da ys or m o nt hs of t he dates of first s y m pt o m, di a g n osis, first rela ps e will be re place d 
b y 1. 
M RI B as eli ne C h a r acteristics 
T he f oll o wi n g s electe d res ults of t he i n de pe n d e nt M RI re vi e w f or t h e Bas eli ne Peri o d will be 
pres e nt e d: 
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T 1 G d + lesi o ns: 
 M ea n T 1 G d + lesi o n c o u nt f or t he Baseli ne Peri o d 
 M ea n T 1 G d + lesi o n c o u nt f or t he Baseli ne Peri o d 
 0 
 > 0 
 N o n-e val ua ble 
 Missi n g 
 T 1 G d + lesi o n c o u nt at t h e S cree ni n g Visit 
 T 1 G d + lesi o n c o u nt at t h e S cree ni n g Visit 
 0 
 1 
 > 1 
 N o n-e val ua ble 
 Missi n g 
 T 1 G d + lesi o n c o u nt at t h e B aseli ne Visit 
 T 1 G d + lesi o n c o u nt at t he Baseli ne Visit 
 0 
 1 
 > 1 
 N o n-e val ua ble 
 Missi n g 
 Ne w T 1 G d + lesi o n c o u nt at t h e Baseli ne Visit 
 Ne w T 1 G d + lesi o n c o u nt at t h e Baseli ne Visit 
 0 
 1 
 > 1 
 N o n-e val ua ble 
 Missi n g 
 
T 1 G d + lesi o n v ol u me: 
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 T 1 G d + lesi o n v ol u m e at t h e Scree ni n g Visit 
 T 1 G d + lesi o n v ol u m e at t h e Baseli ne Visit 
T 1- h y p oi nte ns e lesi o ns: 
 T 1- h y p oi nte ns e lesi o n c o u nt at t he Scree ni n g Visit 
 T 1- h y p oi nte ns e lesi o n c o u nt at t he Baseli ne Visit 
 
T 1- h y p oi nte ns e lesi o n v ol u m e: 
 T 1- h y p oi nte ns e lesi o n v ol u m e (c m 3) at t h e S cree ni n g Visit 
 T 1- h y p oi nte ns e lesi o n v ol u m e (c m 3) at t h e B as eli ne Visit 
T otal T 2 lesi o ns: 
 T otal T 2 lesi o n c o u nt at t h e Scree ni n g Visit 
 T otal T 2 lesi o n c o u nt at t h e Baseli n e Visit 
T otal T 2 lesi o n v ol u me: 
 T otal T 2 lesi o n v ol u me (c m 3) at t h e Scree ni n g Visit 
 T otal T 2 lesi o n v ol u me (c m 3) at t h e Baseli ne Visit  
Acti ve T 2 l esi o ns: 
 T otal acti ve T 2 lesi o n c o u nt d uri n g Baseli ne Peri o d  
 T otal acti ve T 2 lesi o n c o u nt d uri n g Baseli ne Peri o d  
 0 
 1 
 > 1 - < 9  
 ≥9 
 N o n-e val ua ble 
 Missi n g 
 Sta n dar dize d t otal acti ve T 2 lesi o n c o u nt d uri n g t he Baseli ne P eri o d  
 A n n uali ze d t ot al acti ve T 2 lesi o n c o u nt d uri n g t he Baseli ne Peri o d 
 Sta n dar dize d / A n n ualiz e d t otal acti ve T 2 l esi o n c o u nt d uri n g t he Baseli ne Peri o d 
 0 
 > 0 
 N o n-e val ua ble 
 Missi n g 
C CI


Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
3 6/ 9 8  
 
 
 Sta n dar dize d  t otal acti ve T 2 lesi o n c o u nt ( wit h o ut T 1 G d +) f or t he Baseli n e P eri o d 
 A n n uali ze d t ot al acti ve T 2 lesi o n c o u nt ( wit h o ut T 1 G d +) f or t he Baseli ne Peri o d 
 Sta n dar dize d / A n n uali ze d t otal acti v e T 2 l esi o n c o u nt ( wit h o ut T 1 G d +) f or t h e 
Baseli ne Peri o d 
 0 
 > 0 
 N o n-e val ua ble 
 Missi n g 
C U A lesi o ns: 
 Sta n dar dize d  C U A lesi o n c o u nt f or t h e Baseli ne P eri o d 
 A n n uali ze d C U A lesi o n c o u nt f or t he Baseli ne Peri o d 
 Sta n dar dize d / A n n ualiz e d C U A lesi o n c o u nt f or t h e Baseli ne P eri o d 
 0 
 > 0 
 N o n-e val ua ble 
 Missi n g 
N ote: W hile st a n dar di ze d lesi o n c o u nt is use d i n t he 6- m o nt h I A, t h e a n n u ali ze d lesi o n c o u nt 
is use d i n t he fi nal a nal ysis. 
Vit al Si g ns  
T he f oll o wi n g Baseli ne c haracteristics will be pr o vi d e d i n s u m mar y ta bl es: 
 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 rat e, S yst olic Bl o o d Press ure, Di ast oli c 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 0 0 
C CI


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M A G NI F Y- M S  
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1 2  
Pre vi o us or C o nc o mit a nt Me di c ati o ns/ Pr oce d ures 
C o nc o mit a nt me dic ati o ns  are m e di cati o ns, ot her t ha n st u d y me dicati o ns, w hic h are ta k e n b y 
s u bjects d uri n g t he st u d y. 
C o nc o mita nt me di cati o ns will be s u m marize d fr o m t he “ C o nc o mit a 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 b e t a b ulat e d as gi ve n fr o m t he W H O- D D di cti 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 di cati o ns e ntere d i nt o t h e “ C o nc o mita nt me dicati o n” e C R F pa ge will b e 
ass u me d t o be “c o nc o mita nt” irres pecti ve of t he act ual st art a n d e n d d ates. I n a d diti o n, all 
c o nc o mit a nt 
me dicati o ns as well as c o n c o mit a nt 
me dicati o ns gi ve n f or diseas e relate d 
c o n diti o ns will be pres e nte d b y P T a n d b y d ecreasi n g fre q ue n c y. 
Rele v a nt p re vi o us me dic ati o ns  are m e 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 m e nt (i.e. date of i nf or me d c o nse nt [I C]). D M Ds (see Se cti o n 8. 2) a d mi nist ere d 
bet wee n I C a n d start of st u d y m e dicati o n are m aj 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 pre vi o us me dicati 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 
details” e C R F pa ge. A T C- 1 st le vel a n 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 m e dicati o ns e nt ere 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 st art a n d e n d 
dates. I n a d diti o n, all rel e va nt pre vi o us m e dicati o ns a n d rele va nt pre vi o us me dicati o ns gi ve n 
f or diseas e relate d c o n diti o ns will be prese nte d b y P T a n d decreasi n g fre q u e nc y. 
All rele va nt pre vi o us m e 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 are 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 d ate 
≥ st art 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 (st art 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 st art of st u d y me di cati o n will be s u m mari ze d. T he last D M D will be d efi 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 d a y will be i m p ut e d b y 
t he 1 5t h of t he m o nt h b ut t he date will be tr u nc ate d t o I C dat e - 1 if t he i m p utati o n res ults i n a 
later date. If t he m o nt h is missi n g as well or t h e date is c o m pletel y missi n g t he e n d date will 
n ot be re pl ace d a n d it 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 st art of 
st u d y me dicati o n.  
C o nc o mit a nt p r o ce d u res  w hi c h were u n derta ke n a n y ti m e o n st u d y will b e liste d b y s u bje ct 
f or t he S A F. 
C CI


Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
3 8/ 9 8  
 
 
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 treat me nt are pla n n e d i n t his st u d y. S u bj ects will t a ke t a blets i n 
Wee k 1 
( Treat m e nt wee k 1) a n d Wee k 5 ( Tre at m e nt wee k 2) of eac h y ear. All d osi n g calc ulati o ns a n d 
s u m maries will be b as e d o n “ Treat me nt A d mi nistrati o n” a n d “ Treat me nt T er mi nati o n” e C R Fs 
pa ges. 
T he f oll o wi n g s u m m ar 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 nt a bilit y 
T he d urati o n will be pres e nte d f or Treat me nt C o urs e 1 Treat m e nt Peri o d, Treat me nt C o urse 2 
Treat m e nt Peri o d a n d t h e 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 t a blet i n Peri o d + 1) 
C o u nts of ta blets a n d c o m plia nce will be cal c ulate d first f or eac h treat me nt wee k: 
 C o m plia nce ( %) = 1 0 0 * n u m b er of ta blets ta ke n d uri n g t he tre at m e nt we e k/ n u m ber 
of pla n ne d ta blets f or t h e treat m e nt wee k  
If a s u bject disc o nti n ue d t he treat me nt bef ore t he st art of t he res pecti v e tre at m e nt wee k, 
c o m pli a nce will n ot b e deri ve d f or t his wee k. If t h e s u bject di d n ot t a ke a n y ta blet d uri n g 
t he res pecti v e treat m e nt wee k, b ut ha d n ot dis c o nti n ue d t he treat me nt bef ore, c o m plia nce 
will be 0. If t he s u bject was treate d d uri n g t he res p ecti ve treat me nt wee k, b ut t he 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 urse) a n d t otal will be cal c ulate d f or all s u bj ects t hat starte d t he 
res pecti ve treat me nt peri o d (i.e. t a ke n at le ast o n e t a blet) as a n a vera ge of a vaila ble rec or ds 
o btai ne d f or t h e c orres p o n di n g treat me nt wee ks. T hat m ea 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 treat me nt wee ks are i ncl u de d i n t he 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 p e cti ve treat me nt peri o d. 
I n a d diti o n, c o m plia nce will be cat e g oriz e d as f oll o ws: 
 < 6 0 % 
 [ 6 0 %- 8 0 %[ 
 [ 8 0 %- 9 0 %[ 
 [ 9 0 %- 1 1 0 %] 
 > 1 1 0 % 
T he n u m ber of pla n n e d ta blets is bas e d o n t he wei g ht at t he be gi n ni n g of eac h treat m e nt c o urs e 
( Ta ble 2).  
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Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
3 9/ 9 8  
 
 
T a ble 2:  D os e of M a ve ncl a d ®  p er 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 b er t a blets) per tre at me nt wee k 
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 t a blets)  
4 0 m g ( 4 ta blets)  
5 0 t o < 6 0 
5 0 m g ( 5 t a blets)  
5 0 m g ( 5 ta blets)  
6 0 t o < 7 0 
6 0 m g ( 6 t a blets)  
6 0 m g ( 6 ta blets)  
7 0 t o < 8 0 
7 0 m g ( 7 t a blets)  
7 0 m g ( 7 ta blets)  
8 0 t o < 9 0 
8 0 m g ( 8 t a blets)  
7 0 m g ( 7 ta blets)  
9 0 t o < 1 0 0 
9 0 m g ( 9 t a blets)  
8 0 m g ( 8 ta blets)  
1 0 0 t o < 1 1 0 
1 0 0 m g ( 1 0 t a 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 t a 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 pla n n e d d osi n g s c h e ma (i. e. s u bje cts e xc ha n ge d wei g ht ra n ge as defi n e d i n t h e ta ble 
a b 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 ve starte d Treat m e nt 
C o urse 2 (i. e. t a 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 h e start of t he Treat m e nt C o urse 1 Treat me nt Peri o d a n d t h e st art 
of t he Treat me nt C o urse 2 Treat me nt P eri o d will be calc ul at e d as f oll o ws: 
 Relati ve Start of Treat m e nt C o urse 2 ( da ys) = Start of Treat m e nt C o urs e 2 - St art of 
Treat m e nt C o urse 1 + 1.  
T he Relati ve Start of Treat me nt C o urse 2 will be pres e nte d t o get her wit h t he n u m b er of s u bj ects 
i n t he f oll o wi n g gr o u ps f or t he S A F: 
 Treat m e nt C o urse 2 n ot st arte 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, 
 Reas o n p ot e nti all y relate d t o C O VI D- 1 9 
 Treat m e nt C o urse 2 starte d, 
 a n d n ot dela ye d (s ee S ecti 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 yt e 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 st art of Treat me nt C o urse 2. 
 Bef ore or at / after Start of C O VI D- 1 9 p a n de mi c 
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Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
4 0/ 9 8  
 
 
T he c u m ulati ve d os e is defi ne d as t he s u m of t he n u m b er of t a blets t a ke n 1 0 m g di vi d e d b y t he 
wei g ht f or treat me nt year: 
C u m ul ati ve d os e = n u m ber of ta blets t a ke n i n Treat m e nt C o urse 1 * 1 0 m g / wei g ht i n k g at 
Baseli ne + n u m ber of ta 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 
Visit. 
T he c u m ulati ve d ose will be calc ulate d o nl y if t he wei g ht a n d n u m b er of ta bl ets are a vaila bl e. 
Ot her wis e 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 m e nt C o urse 2), t he c u m ulati ve d ose will be calc ul ate 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 pli a n ce will be pr o vi de d f or t he S A F. 
C CI


Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
4 1/ 9 8  
 
 
1 4  
Effic ac y A n al ys es 
T he f oll o wi n g s ecti o ns d escri be t he pl a n ne d a nal yses f or eac h of efficac y e n d p oi nts. 
F or t h e d etaile d defi niti o n of c o variates a n d stratificati o n fact ors t h at are use d i n t he statistical 
m o dels see Secti o n 9. Details a b o ut t he deri ve d M RI e n d p oi nts a n d ge n eral ha n dli n g of M RI 
data is des cri be d i n S ecti o n 9 (“ Data Ha n dli n g of M RI data ”). 
Descri pti v e s u m mar y st atistics will be prese nte d f or t he a bs ol ute v al ues a n d t he c ha n g es fr o m 
Baseli ne as a p pli ca bl e b y Visit [ Pr ot oc ol Sc he d ule d Visits e xc e pt f or Baseli ne ( d efi ne d i n 
Secti o n 9)], or P eri o d, f or all effi cac y e n d p oi nts (a n d t he c o m p o ne nts, w here a p plica ble) f or 
t he F A S a n d res pecti ve s u b gr o u ps or s u bsets f or w hic h t he varia bles are a nal y ze d. D etails a b o ut 
t he prese ntati o n of c o nti n u o us a n d cate g orical v aria bles are gi ve n i n Secti o n 9. 
W here v er p ossi ble, all esti m ate d res ults fr o m t he statistical m o dels will be calc ulate d wit h t he 
sa me o bser ve d mar gi n w hic h reflects t he p o p ulati o n of t he w h ole c orres p o n di n g a n al ysis s et, 
re gar dl ess of missi n g data. 
1 4. 1  
Pri m a r y E n d p oi nts: Differe nces i n t he c o u nts of C U A 
M RI l esi o ns d uri n g t he first 6 m o nt hs c o m p a re d t o 
B aseli ne 
T he pri mar y e n d p oi nts f or t h e tri al are defi ne d as t he differe nces i n c o u nts of C U A M RI lesi o ns 
d uri n g t h e first 6 m o nt hs c o m pare d t o Baseli ne, i. e., t he f oll o wi n g differe nces will b e e val uate d: 
1.  Peri o d of M o nt h 1 t o M o nt h 6 c o m pare d t o t he Baseli ne Peri o d. 
2.  Peri o d of M o nt h 2 t o M o nt h 6 c o m pare d t o t he Baseli ne Peri o d, 
3.  Peri o d of M o nt h 3 t o M o nt h 6 c o m pare d t o t h e Baseli ne P eri o d, 
F or t h e d etaile d defi niti o n of Peri o ds, please s ee S ecti o n 9 “ Dat a Ha n dli n g of M RI d ata”. 
1 4. 1. 1   
Pri m a r y O bjecti v e: A n al ysis of pri m ar y e n d p oi nts 
T he differe nces i n c o u nts of C U A l esi o ns will be e v al uate d usi n g a mi x e d-effects li near m o del, 
acc o u nti n g f or wit hi n-ce nt er/re gi o n c orrelati o n t hr o u g h a hierarc hi cal m o d el. T he a n al ysis will 
a dj ust f or B aseli ne 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: 
 C U A lesi o n c o u nt d uri n g t he Baseli ne Peri o d, 
 A ge, 
 E D S S at Baseli ne ( ≤3/ > 3). 
T he res ults of t he mi xe d-effects li n ear m o del will be use d t o des cri be t he effect si ze. A re vie w 
of B aseli ne data has s h o w n t hat t h e distri b uti o n of t he pri mar y e n d p oi nt dat a d oes n ot f oll o w 
N or mal distri b uti o n. C o nse q ue ntl y, t he h y p ot hes es will b e t este d b y a Wil c o x o n si g ne d-ra n k 
test w hic h e m pl o ys ra n ks of a bs ol ut e differe nces fr o m Baseli ne f or eac h testi n g Peri o d (i.e., p 1, 
p 2, a n d p3) usi n g a vera ge ra n ks f or tie d v al ues. 
T he a nal ysis will als o a dj ust f or t h e differe nce i n le n gt h a n d n u m ber of M RIs of t he Peri o ds t o 
be c o m pare d (s ee S ecti o n 9 “ Dat a Ha n dli n g of 
M RI data” f or details of l esi o n c o u nt 
sta n dar dizati o n). 
C CI


Cl a dri bi ne ( M a v e ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
4 2/ 9 8  
 
 
T he differe nc e i n t h e c o u nts of C U A l esi o ns d uri n g t he t hree P eri o ds c o m pare d t o t he Bas eli ne 
Peri o d will be test e d i n a s e q ue ntial or der. T h e t hree h y p ot hes es are d efi n e d as f oll o ws: 
       𝐻: ∆ C U A(p ) ≥ 0              vs.  ∆ C U A (p ) <  0,                        𝑖= 1, 2, 3  
⇔𝐻
: # C U A(p ) ≥ # C U A (p ) vs.  # C U A(p ) <  # C U A (p ),  
𝑖= 1, 2, 3  
wit h 
∆C U A( p ) =  # C U A( p ) − # C U A (p ),  
𝑖= 1, 2, 3,  
# C U A( p ): st a n d ar di z e d C U A l esi o n c o u nt d uri n g P eri o d p ,  
𝑖= 0, 1, 2, 3, 
p : B as eli n e P eri o d (P eri o d fr o m Scr e e ni n g t o B as eli n e ), 
p : P eri o d M o nt h 𝑖 t o M o nt h 6,  
𝑖= 1, 2, 3. 
T he se q ue ntial testi n g pr oce d ure will start wit h Peri o d p 3, f oll o we d b y Peri o d p2 a n d p1, i. e., 
t he h y p ot heses will be test e d i n t he f oll o wi n g or der: 
1. H 0 3  
2. H 0 2  
3. H 0 1  
T he t hree h y p ot heses will be test e d o ne-si de d o n a 2. 5 % si g nifica n ce le vel. T he t esti n g 
pr oce d ure will st o p as s o o n as o ne of t h e h y p ot h eses ca n n ot b e rejecte d f oll o wi n g t he pre-
s p ecifie d or der. D ue t o t his se q ue nti al or der of tests a n a dj ust me nt f or a p ote ntial t y pe-I-err or 
i nflati o n d ue t o t he m ulti pl e testi n g is n ot re q uire d. 
A n esti m ate f or t he differe nce i n C U A lesi o ns d uri n g t he s pecifi e d P eri o ds c o m pare d t o t he 
Baseli ne Peri o d will be re p orte d, t o g et her wit h o n e-si de d p- val ues. I n a d diti o n, 9 5 % CI a n d 2-
si de d p- val ues will be prese nt e d t o all o w f or c o m paris o n wit h t he 2-si de d s ec o n d ar y a n d 
tertiar y a n al yses. 
T he L S M ea ns will be calc ulate d wit h o bser ve d m ar gi n w hic h reflects t he distri b uti o n of a ge, 
E D S S cate g ori es at B as eli ne a n d res p ecti ve Bas eli ne Peri o d C U A Lesi o n 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 oes n’t c o n ver g e 
a varia nce c o m p o ne nts c o varia nc e str uct ure will be us e d i nstea d or t he res ults of se nsiti vit y 
a nal ysis wit h ce nter effect as a fi xe d effect will b e us e d i nstea d. 
 
 
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Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
4 4/ 9 8  
 
 
1 4. 1. 2   
Pri m ar y O bjecti ve: Se nsiti vit y A n al ys es of t he pri m ar y e n d p oi nts 
T he r o b ust ness of t he res ults of t he pri mar y a nal ysis will be e val uate d b y t h e f oll o wi n g 
 M ulti ple I m p ut ati o n t o ha n dle missi n g data usi n g differe nt ass u m pti o ns, 
 N o n- para metric fact orial m o del f or l o n git u di nal data, 
 Ge neralize d m o del ass u mi n g ne gati ve bi n o mial distri b uti o n, 
 Mi xe d-effects li near m o del wit h p o ole d-ce nters as fi xe d effects. 
T o e val uat e f urt her t he i m pact of t he p ote ntial zer o i nflati o n, t he pri mar y e n d p oi nt will be classifi e d i n differe nt res p o nse cate g ories f or 
eac h Peri o d as f oll o ws: 
 Prese nce of M RI acti vit y 
o  Yes ( C U A lesi o n c o u nt > 0) 
o  N o ( C U A lesi o n c o u nt = 0) 
 Sta n dar dize d C U A lesi o n c o u nt classifie d t o: 
o  0 (sta n dar dize d C U A lesi o n c o u nt = 0) 
o  > 0 – 1 (sta n dar dize d C U A lesi o n c o u nt > 0 a n d less or e q ual t o 1) 
o  > 1 (sta n dar dize d C U A lesi o n c o u nt > 1) 
 
C CI
C CI








Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
4 8/ 9 8  
 
 
T he f oll o wi n g reas o ns f or missi n g M RI res ults will be c o nsi dere d as M A R: 
 M RI classifi e d as n o n-e val ua ble b y t he ce ntral M RI rea di n g 
 M RI missi n g at Baseli ne 
 S u bject disc o nti n ue d t he st u d y bef ore t he M o nt h 6 Visit wit h pri mar y reas o n 
o  L ost t o f oll o w- u p 
o  A n y Pr ot oc ol n o n-c o m pli a nce re p orte d as “ Ot her” a n d classifie d as n o n-rel ate d t o st u d y treat me nt 
o  A n y wit h dra wal of c o nse nt classifie d as n o n-relate d t o st u d y treat me nt 
o  A n y pre g na n c y ( Disc o nti n uati o n Reas o n “ A d verse E ve nt” a n d “ Pre g na nc y” re p orte d as A E lea di n g t o disc o nti n uati o n. 
o  A n y “ Ot her” reas o n classifie d as n o n-relate d t o st u d y treat me nt 
All ot her missi n g M RI res ults will be ha n dle d as M N A R. 
T he f oll o wi n g pr oce d ure f or t he differe nt t y pes of missi n g data will be perf or me d:   
 C U A lesi o n c o u nts missi n g at t he Baseli ne Peri o d will be i m p ute d fr o m t he distri b uti o n of a vaila ble C U A lesi o n c o u nts at t he 
Baseli ne Peri o d.  
 C U A lesi o n c o u nts missi n g at a n y p ost- Baseli ne Peri o d t h at are c o nsi dere d M A R will be i m p ute d fr o m t he distri b uti o n of 
a vaila ble C U A lesi o n c o u nts of t he sa me p ost- Baseli ne Peri o d. 
 C U A lesi o n c o u nts missi n g at a n y p ost- Baseli n e Peri o d t hat are c o nsi dere d M N A R will be i m p ute d fr o m t he distri b uti o n of C U A 
lesi o n c o u nts of t he Baseli ne Peri o d  
T he c h a n ges fr o m t h e Baseli ne Peri o d will be calc ulate d f or all Peri o ds a n d s u bjects, a n d t he pri mar y a nal ysis (i. e. t he Wilc o x o n test as 
well as t h e mi x e d-effects li near m o del) will be re p eate d f or eac h of t he i m p utati o n re petiti o n (i.e. f or eac h of t h e i m p ute d datasets). 
Res ults c o m bi ne d usi n g R u bi n’s r ule [ 5] will be prese nte d. 
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
4 9/ 9 8  
 
 
N o n- p ar a metric f act ori al m o del 
T he pri mar y a n al ysis will be re peate d usi n g a fact orial m o del f or l o n git u di n al data acc or di n g t o Br u n ner, D o m h off a n d La n ger [ 2] 
( 2 0 0 2). F oll o wi n g t h e a ut h ors’ ter mi n ol o g y, a F x- L D- F 1 m o del will be ass u me d wit h x = 2 fi xe d fact ors (a ge, E D S S at Baseli ne) a n d o n e 
l o n git u di n al fact or (‘ L D’) w hic h is reflecti n g Baseli ne a n d o ne of t h e pri mar y p ost- Baseli ne Peri o ds. 
T he u n derl yi n g n o n para metric h y p ot hesis is defi ne d i n ter ms of t he distri b uti o n f u ncti o ns. I n a si m ple m o del wit h t w o ti me p oi nts a n d 
n o fi xe d fact ors o n e w o ul d ass u me t hat t he p airs of lesi o n c o u nt dat a ( Bas eli ne, p ost Baseli ne) w o ul d ha ve mar gi n al distri b uti o ns F s, 
s = 1, 2, a n d t he n ull h y p ot hesis w o ul d be H 0: F 1= F 2, t he alter nati v e acc or di n gl y H 0: F 1≠ F 2. I n a si m ple s hift m o del o n e w o ul d ass u me 
t hat t hese mar gi nal distri b uti o n f u ncti o ns o nl y differ t hr o u g h a ‘l ocati o n p ara meter’ µ , n a mel y o ne w o ul d ass u me t hat F 2(x) = F1(x- µ) 
a n d t he n ull h y p ot h esis w o ul d be µ = 0.  F or m ulti ple fi xe d fact ors a n d o ne ‘ L D’ fact or t h e n otati o n of h y p ot hes es is m ore c o m plicate d 
a n d ca n be f o u n d i n Br u n ner, D o m h off a n d La n g er [ 2] ( 2 0 0 2) i n s ecti o n 8. 3 a n d es peciall y i n 8. 3. 1 f or t h e n ull h y p ot hesis of ‘ n o ti me 
effect’.  
Mi dra n ks o ver all C U A lesi o ns fr o m t he B aseli ne Peri o d a n d res pecti ve p ost- Baseli ne Peri o d will be calc ulate d. T he ra n ks will be 
a nal yze d wit h a heter os ce dasti c fact orial desi g ns m o del wit h re peate d meas ures ( Baseli ne a n d o ne p ost- Baseli ne Peri o d) a n d u ns pecifie d 
c o varia n ce matrices. T he f oll o wi n g fact ors will be use d: 
 A ge gr o u ps ( ≤ 4 0, > 4 0), 
 E D S S at Baseli ne ( ≤3/ > 3). 
T he p- val ue f or t he ti me effect will be calc ul ate d as descri be d b y Br u n ner, D o m h off a n d L a n ger [ 2] ( 2 0 0 2).  
Ge ner ali ze d li ne ar m o del ass u mi n g ne g ati ve bi n o mi al distri b uti o n 
T he st a n dar dize d C U A lesi o n c o u nt will be e val uate d usi n g a ge neralize d mi xe d-effects li near m o del wit h l o g li n k f u ncti o n. Peri o d (i.e 
Baseli ne Peri o d, eac h p ost- Baseli ne Peri o d i, i = 1, 2, 3) will be a n al yze d as a re peat e d fact or acc o u nti n g f or wit hi n s u bject a n d wit hi n-
ce nter/re gi o n c orrelati o n usi n g a n u nstr uct ure d c o varia nce matri x. A g e a n d E D S S at Baseli ne ( ≤3, > 3) will be use d as fi xe d effect 
c o variates. 
T he rati o of t he sta n dar dize d C U A lesi o n c o u nt of eac h p ost- Baseli ne Peri o d vers us t he Baseli ne Peri o d will be calc ulate d as t he i n verse 
l o g of t he differe nce of t he esti mate d c o ntrast bet wee n eac h p ost- Bas eli ne Peri o d a n d t he Baseli ne Peri o d. 
T he C U A lesi o ns are alrea d y sta n d ar dize d f or t h e o bser v ati o n ti me a n d t heref ore n o offset will b e use d. T he esti mate d st a n dar dize d 
C U A lesi o n c o u nt will be calc ulate d b ase d o n t h e o bser ve d mar gi n of t he F A S at Baseli ne.  
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
5 0/ 9 8  
 
 
T he esti mates, sta n dar d de viati o n a n d 9 5 % c o nfi de nce i nt er v als f or t he st a n dar dize d C U A lesi o n c o u nt at eac h Peri o d a n d t he rati o 
bet wee n Peri o ds will be prese nte d t o get h er wit h t h e esti mate d fi xe d effects. 
If t he m o del d oes n’t c o n ver ge a v aria n ce c o m p o ne nts c o varia n ce str u ct ure will be use d i nstea d of t h e u nstr uct ure d c o vari a nce matri x. 
1 4. 2  
Sec o n d ar y E n d p oi nts: C h a r acteriz ati o n of i m m u ne cell s u bsets c o u nt at t he e n d of 3, 6, 1 2, 
1 5, 1 8 a n d 2 4 m o nt hs c o m p a re d t o B aseli ne 
List of bi o mar ker para meters per eac h p a nel is prese nte d i n A p pe n di x 3. ( F urt her, detaile d i nf or mati o n ca n be f o u n d i n t he 
c orres p o n di n g D T A [ 9] a n d Para meter M a p pi n g s pecificati o n [ 1 0]). 
A n al y si s ( A n al y si s S et) 
D eri v ati o n 
St ati sti c al A n al y si s M et h o d s 
Mi s si n g d at a h a n dli n g 
S e c o n d ar y e n d p oi nt: C h a n g e of i m m u n e c ell s u b s et c o u nt s fr o m B a s eli n e t o M o nt h 3, 6, 1 2, 1 5, 1 8 a n d 2 4 Vi sit s 
S e c o n d ar y ( F A S)  
C h a n g e fr o m B a s eli n e i n e a c h 
i m m u n e c ell s u b s et c o u nt at  
M o nt h i Vi sit, w h er e i = 3, 6, 1 2, 
1 5, 1 8 a n d 2 4. 
   
D e s cri pti v e 
s u m m ar y 
st ati sti c s i n cl u di n g 
p er c e nt a g e c h a n g e.  
   
N u m b er of s u bj e ct s wit h a v al u e b el o w L L O Q 
t o g et h er wit h t h e L L O Q li mit, if a v ail a bl e.  
   
N u m b er of s u bj e ct s wit h a v al u e o ut si d e 
r ef er e n c e r a n g e (i. e. b el o w l o w er li mit or 
a b o v e 
u p p er li mit 
of 
n or m al) 
wit h t h e 
r ef er e n c e r a n g e, if a v ail a bl e.  
  
9 5 % c o nfi d e n c e i nt er v al s of t h e m e a n 
   
Wil c o x o n si g n e d-r a n k t e st wit h t h e a s s o ci at e 
p- v al u e 
  
B o x/ s c att er/ti m e s eri e s pl ot s.    
 
If c ell c o u nt i s mi s si n g f or a Vi sit b ut 
t h e r e-t e st i s a v ail a bl e, t h e v al u e 
fr o m t h e r e-t e st will b e u s e d. 
Ot h er wi s e, t h e p o st- B a s eli n e r e-t e st 
r e s ult s will b e i g n or e d f or all 
a n al y s e s b y Vi sit.  
 
 
H a n dli n g of v al ues bel o w L o wer Li mit of Q u a ntific ati o n ( L L O Q): 
I m m u ne cell s u bsets re p orte d as bel o w t he L L O Q will be i m p ute d as f oll o ws: 
 If t he L L O Q is a vaila ble t he n half of t he L L O Q will be i m p ute d, 
 Ot her wise, a zer o will be i m p ute d. 
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
5 1/ 9 8  
 
 
1 4. 3  
Terti a r y E n d p oi nts 
 
1 4. 3. 1   
C h a n g es i n C U A lesi o n c o u nt  
T he c h a n ges i n C U A lesi o n c o u nts fr o m t he Bas eli ne Peri o d t o t he p ost- Baseli ne Peri o ds are d efi ne d i n t he Secti o n 9 “ Defi niti o n of 
St u d y Peri o ds” a n d “ Dat a Ha n dli n g of M RI data”.  
C U A lesi o n c o u nts will f urt her be classifie d f or eac h Peri o d as f oll o ws: 
 C U A lesi o n c o u nt > 0 
o  Yes ( C U A lesi o n c o u nt > 0) 
o  N o ( C U A lesi o n c o u nt = 0) 
C CI
C CI








Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
5 5/ 9 8  
 
 
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 
p 0 = B a s eli n e P eri o d 
$ = S e q u e nti al Vi sit P eri o d s 
Mi xe d-effects li n e ar m o del f or re pe ate d me as ures 
T he c ha n ge fr o m Baseli n e i n t h e a n n ualize d C U A lesi o n c o u nt b y Peri o d or Visit (i. e. t he Se q ue nti al Visit Peri o d) will be a nal yze d b y 
a re peate d mi xe d-effects li near m o del, w hic h a dj usts f or t he Baseli ne sc ore (i.e. t he a n n ualize d c o u nt), a ge (i n years), E D S S at Baseli n e 
( ≤3, > 3), p o ole d ce nter, Peri o d / or Visit, wit hi n s u bject c orrelati o n a n d ti me bet wee n sca ns (i n years), w here a p plica ble. 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 v er ge a n alter nati ve c o vari a nce str uct ure will be use d i nstea d. 
T he esti mate d a n n u alize d C U A lesi o n c o u nt will be calc ul ate d bas e d o n t he o bser ve d mar gi n of t he c orres p o n di n g a nal ysis set at 
Baseli ne.  
Mi xe d-effects li n e ar m o del 
T he c ha n ge fr o m Baseli ne i n a n n ualize d C U A lesi o n c o u nt f or eac h Peri o d se paratel y will be a nal yze d b y a mi xe d-effects li near m o del, 
w hic h a dj usts f or t he Bas eli ne sc ore (i.e., t he a n n u alize d c o u nt), a ge (i n years), E D S S at Baseli ne ( ≤3, > 3), p o ole d ce nter, ti m e bet wee n 
sca ns (i n years) a n d wit hi n s u bject c orrelati o n. 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 n alter nati v e c o varia nce str uct ure will be use d i nstea d. 
T he esti mate d a n n u alize d C U A lesi o n c o u nt will be calc ul ate d bas e d o n t he o bser ve d mar gi n of t he c orres p o n di n g a nal ysis set at 
Baseli ne.  
Ge ner ali ze d li ne ar m o del ass u mi n g ne g ati ve bi n o mi al distri b uti o n 
T he a n n u alize d C U A lesi o n c o u nt will be e v al uat e d usi n g a ge n eraliz e d mi xe d-effects li n ear m o del wit h l o g li n k f u n cti o n ass u mi n g a 
ne gati ve bi n o mial distri b uti o n. Peri o d (i.e. Baseli ne Peri o d, eac h p ost- Bas eli ne Peri o d as s pecifie d a b o ve) will be a nal yze d as: a) a 
re peate d fact or acc o u nti n g f or ti me bet wee n sca ns (i n years) if t he ti me is differe nt b et wee n sca ns, or b) ne glecte d, if t h e ti me bet wee n 
sca ns is c o nst a nt (f or e xa m ple: f or e ver y 6 m o nt hs Peri o ds, 1 yearl y Peri o ds); a n d wit hi n s u bject c orrelati o n usi n g a n u nstr uct ure d 
c o varia n ce matri x. A g e a n d E D S S at Baseli ne ( ≤3, > 3) will be use d as fi xe d effect c o variates. 
T he rati o of t he a n n ualize d C U A lesi o n c o u nt of eac h p ost- Bas eli ne Peri o d vers us t he Baseli ne Peri o d will be calc ulate d as t he i n verse 
l o g of t he differe nce of t he esti mate d c o ntrast bet wee n eac h p ost- Bas eli ne Peri o d a n d t he Baseli ne Peri o d. 
C CI
C CI




Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
5 7/ 9 8  
 
 
 
1 4. 3. 3   
T 1 G d + lesi o n c o u nt 
T 1 G D + lesi o n c o u nts b y Visit a n d Peri o d are defi ne d i n Secti o n 9 “ Defi niti o n of St u d y Peri o ds” a n d “ Data Ha n dli n g of M RI d ata”.  
T o e val uate f urt her t he c o urse of T 1 G D + lesi o n a p peara nce o ver ti me, T 1 G d + lesi o ns will be f urt her cl assifie d as f oll o ws f or eac h 
Visit:  
 T 1 G d + lesi o n c o u nt > 0  
o  Yes ( T 1 G d + lesi o n c o u nt > 0) 
o  N o ( T 1 G d + lesi o n c o u nt = 0) 
A nal o g o usl y f or ne w T 1 G d + lesi o n c o u nt. 
 
C CI
C CI








Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
6 1/ 9 8  
 
 
1 4. 3. 4   
T 1 G d + lesi o n v ol u me 
 
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 
T erti ar y e n d p oi nt: C h a n g e fr o m B a s eli n e i n t h e T 1 G d + l e si o n v ol u m e   
T erti ar y ( F A S) 
T h e a b s ol ut e v ol u m e a n d c h a n g e fr o m 
B a s eli n e t o M o nt h i Vi sit, w h er e i = 1, 2, 3, 
6, 1 2, 1 5, 1 8 a n d 2 4, i n T 1 G d + l e si o n 
v ol u m e b y Vi sit 
D e s cri pti v e s u m m ar y st ati sti c s.  
 
1 4. 3. 5   
T 1 h y p oi nte nse l esi o n c o u nt 
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 
T erti ar y e n d p oi nt: C h a n g e fr o m B a s eli n e i n t h e T 1 h y p oi nt e n s e l e si o n c o u nt 
T erti ar y ( F A S) 
T h e a b s ol ut e c o u nt a n d c h a n g e fr o m 
B a s eli n e t o M o nt h i Vi sit, w h er e i = 1, 2, 3, 
6, 1 2, 1 5, 1 8 a n d 2 4, i n T 1 h y p oi nt e n s e 
l e si o n c o u nt b y Vi sit 
D e s cri pti v e s u m m ar y st ati sti c s.  
 
1 4. 3. 6   
T 1 h y p oi nte nse l esi o n v ol u me 
 
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 
T erti ar y e n d p oi nt: C h a n g e fr o m B a s eli n e i n t h e T 1 h y p oi nt e n s e l e si o n v ol u m e 
T erti ar y ( F A S) 
T h e a b s ol ut e v ol u m e a n d c h a n g e fr o m 
B a s eli n e t o M o nt h i Vi sit, w h er e i = 1, 2, 3, 
6, 1 2, 1 5, 1 8 a n d 2 4, i n T 1 h y p oi nt e n s e 
l e si o n v ol u m e b y Vi sit 
D e s cri pti v e s u m m ar y st ati sti c s.  
 
 
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
6 2/ 9 8  
 
 
1 4. 3. 7   
Acti ve T 2 lesi o n c o u nt  
T he n u m b er a n d c ha n g es fr o m Baseli n e of t he differe nt t y pes of acti v e T 2 l esi o ns will be prese nte d b y Peri o d or Visit. 
Acti ve T 2 lesi o n c o u nt will be f urt her classifi e d as f oll o ws f or eac h Visit:  
 Acti ve T 2 lesi o n c o u nt > 0  
o  Yes ( Acti ve T 2 lesi o n c o u nt > 0) 
o  N o ( Acti ve T 2 lesi o n c o u nt = 0) 
 
C CI
C CI








Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
6 6/ 9 8  
 
 
 Res p o n der: ∆C U A (𝐻) =
# C U A (p ) − # C U A (p ) ∗6 ≥ −1, 𝑖= P eri o d 1, 2, 3,  
 N o n- Res p o n der: ot her wise. 
S u bjects wit h missi n g assess me nts will be classifie d as “ N o n- Res p o n der”. 
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 
T erti ar y e n d p oi nt: R e s p o n d er r at e d uri n g t h e diff er e nt p o st- B a s eli n e P eri o d s ( a) 
T erti ar y ( F A S) 
R e s p o n d er r at e s f or P eri o d s 1- 3.   
D e s cri pti v e s u m m ar y st ati sti c s 
a n d 9 5 % c o nfi d e n c e i nt er v al s 
Mi s si n g B a s eli n e P eri o d: 
S u bj e ct s wit h a mi s si n g C U A l e si o n c o u nt f or t h e 
B a s eli n e P eri o d will n ot b e i n cl u d e d i n a n al y si s.  
 
S u bj e ct s wit h a mi s si n g p o st- B a s eli n e P eri o d will b e 
cl a s sifi e d a s N o n- R e s p o n d er f or t h e r e s p e cti v e 
P eri o d. 
( a) 6- m o nt h i nt eri m a n al y si s 
1 4. 3. 9   
T 2 lesi o n v ol u me 
 
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 
T erti ar y e n d p oi nt: C h a n g e fr o m B a s eli n e i n T 2 l e si o n v ol u m e 
T erti ar y ( F A S) 
T h e a b s ol ut e v ol u m e a n d c h a n g e fr o m B a s eli n e t o 
t h e M o nt h i Vi sit, w h er e i = 1 2, 2 4, i n T 2 l e si o n v ol u m e 
b y Vi sit 
D e s cri pti v e s u m m ar y st ati sti c s.  
 
 
 
 
C CI
C CI




Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
6 8/ 9 8  
 
 
Mi xe d-effects li n e ar m o del f or re pe ate d me as ures 
As defi n e d i n Secti o n 1 4. 3. 1 a p pl yi n g a da ptati o ns t o t he e n d p oi nts, fact ors a n d c o variates liste d i n t h e ta ble a b o v e. 
 
1 4. 3. 1 1   
Br ai n V ol u me 
Brai n v ol u me will be pr o vi de d f or Baseli ne, M o nt h 6 Visit, a n d M o nt h 2 4 Visit b y ce ntral rea di n g f or t he f oll o wi n g v ol u me t y pes: 
 Brai n V ol u me ( B V), i.e. t he t otal brai n v ol u me 
 W hite Matter B V ( W M B V) 
 Gre y Matter B V ( G M B V) 
 Dee p Gre y Matter B V ( D G M B V) 
Perce nta g e brai n v ol u me c ha n ge ( P B V C) will be pr o vi de d f or B V fr o m j oi nt i ma ge c o m paris o n of t he ce ntral rea di n g f or t he f oll o wi n g 
c ha n ges: 
 Baseli ne t o M o nt h 1, 2, 3, 6, 1 2, 2 4 Visits 
 M o nt h 6 Visit t o M o nt h 2 4 Visit 
Perce nta g e w hit e matter / gre y matter / dee p gre y matter v ol u me c ha n g e fr o m Baseli ne t o M o nt h 2 4 will be calc ulate d as f oll o ws:   
 P W M V C = 1 0 0 * ( W M B V at M o nt h 2 4 Visit - W M B V at Baseli n e) / ( W M B V at Baseli ne). 
 P W G V C = 1 0 0 * ( G M B V at M o nt h 2 4 Visit - G M B V at Baseli ne) / ( G M B V at Baseli ne). 
 P W D G V C = 1 0 0 * ( D G M B V at M o nt h 2 4 Visit - D G M B V at Baseli ne) / ( D G M B V at Baseli ne). 
T he a n n ualize d perce nta ge brai n v ol u me c ha n ge will be calc ulate d b y di vi di n g perce nta ge brai n v ol u me c ha n ge b y t he act ual le n gt h of 
f oll o w u p bet wee n t h e 2 M RI sca ns: 
 A n n ualize d P B V C  = ( P B V C * 3 6 5. 2 5) / ( D urati o n bet wee n t he 2 M RI s ca ns i n da ys) 
 A n n ualize d P W M B V C  = ( P W M B V C * 3 6 5. 2 5) / ( D urati o n bet wee n t he 2 M RI sca ns i n da ys) 
 A n n ualize d P G M B V C  = ( P G M B V C * 3 6 5. 2 5) / ( D urati o n bet wee n t h e 2 M RI sca ns i n da ys) 
 A n n ualize d P D G M B V C  = ( P D G M B V C * 3 6 5. 2 5) / ( D urati o n bet wee n t he 2 M RI sca ns i n da ys) 
Brai n Atr o p h y is t he defi ne d b y a Brai n V ol u me L oss ( B V L) of at least 0. 4 % d uri n g t h e Treat me nt Peri o d, i.e. 
Yes: a n n ualize d P B V C f or Baseli ne t o M o nt h 2 4 ≤  - 0. 4 % 
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
6 9/ 9 8  
 
 
N o: a n n ualize d P B V C f or Baseli ne t o M o nt h 2 4 >  - 0. 4 % 
If P B V C f or Baseli ne t o M o nt h 2 4 Visit is missi n g it will be re place d b y P B V C f or Baseli ne t o M o nt h 1 2 Visit a n d if still missi n g b y 
Baseli ne t o M o nt h 6 Visit, pr o vi de d t he last a vaila ble assess me nt is at least 1 6 6 da ys ( 6 m o nt hs * 3 0 da ys - 1 4 da ys f or Visit Wi n d o w) 
after Bas eli ne. 
T he sa me c ut- off will als o be a p plie d f or P W M B V C, P G M B V C, a n d P D G M B V C at M o nt h 2 4 Visit. 
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 
T erti ar y e n d p oi nt s: A n n u ali z e d p er c e nt a g e br ai n v ol u m e c h a n g e fr o m B a s eli n e 
T erti ar y ( F A S) 
 
A n n u ali z e d P B V C at M o nt h i Vi sit, w h er e i = 1, 2, 3, 6, 
1 2 a n d 2 4.  
Mi x e d- eff e ct s li n e ar m o d el f or r e p e at e d 
m e a s ur e s f or t h e c h a n g e fr o m B a s eli n e 
wit h t h e f oll o wi n g a dj u sti n g f a ct or s: 
  
B a s eli n e v al u e,  
  
A g e (i n y e ar s),  
  
E D S S at B a s eli n e ( ≤3, > 3),  
  
Vi sit,  
  
Ti m e b et w e e n s c a n s ( y e ar s), 
   
Wit hi n- s u bj e ct c orr el ati o n. 
E sti m at e d L e a st 
S q u ar e 
M e a n s ( L S 
M e a n s) a n d c orr e s p o n di n g 
St a n d ar d 
Err or s ( S E) will b e pr e s e nt e d b y Vi sit 
i n cl u di n g 2- si d e d p- v al u e s a n d 9 5 % CI. 
 
Mi s si n g o b s er v ati o n s at B a s eli n e:  
S u bj e ct s wit h a mi s si n g B a s eli n e br ai n 
v ol u m e will n ot b e i n cl u d e d i n t h e 
li n e ar m o d el.  
Mi s si n g p o st- B a s eli n e o b s er v ati o n s: 
Mi s si n g p o st- B a s eli n e a s s e s s m e nt s 
will n ot b e i m p ut e d. T h e r e p e at e d 
m e a s ur e m e nt m o d el h a n dl e s mi s si n g 
p o st- B a s eli n e a s s e s s m e nt s u n d er t h e 
a s s u m pti o n of M A R. 
 
 
A n n u ali z e d P B V C 
  
≤  - 0. 4 % 
  
> - 0. 4 % 
d uri n g t h e Tr e at m e nt P eri o d. 
D e s cri pti v e s u m m ar y st ati sti c s.   
 
T erti ar y e n d p oi nt s: A n n u ali z e d p er c e nt a g e w hit e m att er br ai n v ol u m e c h a n g e fr o m B a s eli n e 
T erti ar y ( F A S)   
A n n u ali z e d P W M B V C at M o nt h 2 4 Vi sit.  
D e s cri pti v e s u m m ar y st ati sti c s. 
 
 
A n n u ali z e d P W B V C 
  
≤  - 0. 4 % 
  
> - 0. 4 % 
at M o nt h 2 4 Vi sit. 
 
C CI
C CI




Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
7 1/ 9 8  
 
 
 
1 4. 3. 1 2   
N o E vi de nce of Dis e ase acti vit y 
N o E vi de nce of Dis ease acti vit y ( N E D A), als o referre d t o as free d o m fr o m disease acti vit y, is a ne w g oal t h at is e mer gi n g i n M S 
treat m e nt. N E D A is a c o m p osite meas ure of disease acti vit y, i n cl u di n g rela pses, c o g niti o n a n d disa bilit y pr o gressi o n, a n d M RI acti vit y. 
Si n ce M RI acti vit y is a br oa d c o nce pt, w hic h ca n c orres p o n d t o t he M RI lesi o n l oa d or c ha n g es i n brai n v ol u me m o nit ori n g brai n 
atr o p h y, t h e disti ncti o n bet wee n N E D A- 3 a n d N E D A- 4 will be pr o vi de d. 
N E D A- 3 
N E D A- 3 at M o nt h 2 4 is defi ne d b y t h e a bs e nce of: 
 Q ualif yi n g Rela pses, 
 6- m o nt hs C o nfir me d Disa bilit y Pr o gressi o n ( 6 M C D P), 
 M RI acti vit y, 
d uri n g t he w h ole Treat m e nt Peri o d. If t h e i nf or mati o n f or o ne of t he c o m p o ne nts is u n k n o w n, a n d n o ne of t he ot her c o m p o ne nts are 
o bser ve d, N E D A- 3 will be classifie d as “ u n k n o w n”. T h us, N E D A- 3 ca n b e deri ve d fr o m its c o m p o ne nts as f oll o ws: 
 Yes: all c o m p o ne nts = “ N o”, 
 N o: at least o ne of t he c o m p o ne nts =” Yes ”, 
 U n k n o w n: Ot her wise. 
N E D A- 3 (fre q u e nt M RI) 
N E D A- 3 at M o nt h 2 4 is defi ne d b y t h e a bs e nce of: 
T erti ar y e n d p oi nt s: D e e p gr e y m att er br ai n v ol u m e 
T erti ar y ( F A S)   
D G M B V at B a s eli n e, M o nt h 6 a n d 2 4 Vi sit s. 
D e s cri pti v e s u m m ar y st ati sti c s. 
 
 
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
7 2/ 9 8  
 
 
 Q ualif yi n g Rela pses, 
 6- m o nt hs C o nfir me d Disa bilit y Pr o gressi o n ( 6 M C D P), 
 M RI acti vit y (fre q u e nt M RI), 
d uri n g t he w h ole Treat m e nt Peri o d. If t h e i nf or mati o n f or o ne of t he c o m p o ne nts is u n k n o w n, a n d n o ne of t he ot her c o m p o ne nts are 
o bser ve d, N E D A- 3 will be classifie d as “ u n k n o w n”. T h us, N E D A- 3 ca n b e deri ve d fr o m its c o m p o ne nts as f oll o ws: 
 Yes: all c o m p o ne nts = “ N o”, 
 N o: at least o ne of t he c o m p o ne nts =” Yes ”, 
 U n k n o w n: Ot her wise. 
N E D A- 4  
N E D A- 4 at 2 4 M o nt h is defi ne d as t he c o m p osite e n d p oi nt of N E D A- 3 a n d t he a bse nce of brai n atr o p h y. 
N E D A- 4 (fre q u e nt M RI) 
N E D A- 4 (fre q ue nt M RI) at M o nt h 2 4 is defi ne d b y t he c o m p osite e n d p oi nt of N E D A- 3 (fre q u e nt M RI) a n d t h e a bs e nce of brai n atr o p h y.  
Q u alif yi n g Rel a pse 
 Yes: q ualif yi n g rela ps es re p orte d d uri n g t he Treat me nt Peri o d, 
 N o: st u d y c o m plete d, a n d n o q ualif yi n g rela pse re p orte d d uri n g Treat me nt Peri o d, 
 U n k n o w n: ot her wise. 
6- M o nt hs C o nfir me d Dis a bilit y Pr o gressi o n ( 6 M C D P) 
A S ustai ne d I n crease i n E D S S sc ore, is defi ne d b y a n i ncrease of: 
 at least 1. 5 p oi nts if t he Baseli ne E D S S sc ore was 0, or  
 at least 1 p oi nt if Baseli ne E D S S sc ore was bet wee n 0. 5 a n d 4. 5 i ncl usi v el y, or  
 at least 0. 5 p oi nt if t he Baseli ne E D S S sc ore was at least 5, 
t hat occ urs o ver a 6- m o nt h ti me Peri o d. 
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
7 3/ 9 8  
 
 
T he i n crease will be defi ne d as s ustai ne d w he n it occ urs o n t w o p ost- Baseli ne Visits, w hic h are at l east 1 6 6 da ys ( 6 m o nt hs × 3 0 - 1 4 
da ys Visit Wi n d o w) a part a n d n o o bser v ati o ns at a n y ot her Visit (i ncl u di n g u nsc he d ule d Visits) i n bet wee n are less t ha n t h e defi ne d 
i ncreas e.  
T he occ urre n ce of a 6 M C D P is defi ne d as: 
 Yes: s ustai ne d i ncrease i n E D S S sc ore t hat starte d d uri n g t he Treat me nt Peri o d, 
 N o: at least 2 p ost- Baseli ne E D S S assess me nts t hat are 1 6 6 ( or m ore) d a ys a part are a v aila ble a n d n o s ustai ne d E D S S 
pr o gressi o n t hat starte d d uri n g t h e Treat me nt Peri o d, 
 U n k n o w n: Ot her wise. 
Start date of t h e 6 M C D P is t h e start date of t h e first s ustai ne d i ncreas e i n E D S S. 
M RI acti vit y: 
 Yes:  At least o n e T 1 G d + at a n y s ca n assi g ne d t o M o nt h 6, M o nt h 1 2, M o nt h 1 8, M o nt h 2 4 Visit, or at least o n e acti ve T 2 d uri n g 
a n y of t he f oll o wi n g Peri o ds: Baseli ne t o M o nt h 6, M o nt h 6 - M o nt h 1 2, M o nt h 1 2 - M o nt h 1 8, M o nt h 1 8 – M o nt h 2 4 Visits. 
 N o: T 1 G d + = 0 at all sca ns assi g ne d t o M o nt h 6, M o nt h 1 2, M o nt h 1 8, M o nt h 2 4 Visit t hat ha ve a val ue a n d at least o ne T 1 
G d + val ue fr o m M o nt h 1 8 or M o nt h 2 4 Visit a vaila ble, a n d all acti ve T 2 = 0 d uri n g a n y of t he f oll o wi n g Peri o ds: Baseli ne - 
M o nt h 6, M o nt h 6 - M o nt h 1 2, M o nt h 1 2 - M o nt h 1 8, M o nt h 1 8 - M o nt h 2 4 Visits t hat ha ve a v al ue a n d at least o n e acti ve T 2 
val ue fr o m peri o ds M o nt h 1 2 - M o nt h 1 8 or M o nt h 1 8 - M o nt h 2 4 Visits a vaila ble. 
 U n k n o w n: Ot her wise. 
 
 
  
 
 
 
  
 
 
C CI
C CI
C CI




Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
7 5/ 9 8  
 
 
 2 0 % pr o gressi o n o n T 2 5- F W,  
 2 0 % pr o gressi o n o n 9 H P T, 
d uri n g t he Treat me nt Peri o d. 
2 0 % c o nfir me d T 2 5 F W pr o gressi o n 
2 0 % c o nfir me d pr o gressi o n o n T 2 5 F W is defi ne d b y a n i ncrease of at least 2 0 % fr o m T 2 5 F W Baseli ne t hat is s ustai ne d o ver a 6- m o nt h 
ti me Peri o d. 
T he i n crease will be defi ne d as s ustai ne d w he n it occ urs o n t w o p ost- Baseli ne Visits, w hic h are at least 1 6 6 da ys ( 6 m o nt hs * 3 0 - 1 4 
da ys Visit Wi n d o w) a part a n d n o sc ore at a n y ot her Visit i ncl u di n g u nsc he d ule d Visits i n bet wee n is less t ha n t he defi n e d i n crease. 
T he occ urre n ce of a 2 0 % c o nfir me d T 2 5 F W pr o gressi o n is defi ne d as: 
 Yes: s ustai ne d T 2 5 F W pr o gressi o n t h at starte d d uri n g t h e Treat me nt Peri o d. 
 N o: at least 2 p ost- Baseli ne T 2 5 F W assess me nts t hat are 1 6 6 ( or m ore) da ys a part are a v aila ble a n d n o s ustai ne d T 2 5 F W 
pr o gressi o n t hat starte d d uri n g t h e Treat me nt Peri o d. 
 U n k n o w n: Ot her wise. 
O nl y T 2 5 F W assess me nts wit h t h e sa me assista nce de vices as at Baseli ne will be a nal y ze d. T 2 5 F W trials w hic h c o ul d n’t be fi nis he d b y 
t he s u bjects will be i m p ute d wit h 3 mi n utes (see Secti o n 1 4. 3. 1 7). 
2 0 % c o nfir me d 9 H P T pr o gressi o n 
2 0 % c o nfir me d pr o gressi o n o n 9 H P T is defi ne d b y a n i ncrease of at least 2 0 % fr o m 9 H P T Baseli n e t hat is s ustai ne d o ver a 6- m o nt h 
ti me Peri o d. 
T he i n crease will be defi ne d as s ust ai ne d w he n it occ urs o n t w o p ost- Bas eli n e Visits, w hic h are at l east 1 6 6 d a ys ( 6 m o nt hs * 3 0 - 1 4 
da ys Visit Wi n d o w) a part a n d n o sc ore at a n y ot her Visit i ncl u di n g u nsc he d ule d Visits i n bet wee n is less t ha n t he defi n e d i n crease.  
T he occ urre n ce of a 2 0 % c o nfir me d 9 H P T pr o gressi o n is defi ne d as: 
C CI
C CI




Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
7 7/ 9 8  
 
 
T he o bser ve d res ults a n d c ha n ges fr o m Baseli n e i n t h e S D M T a n d scale d sc ores of t he S D M T will be ta b ulate d b y Visit f or t he F A S 
(see Secti o n 1 8. 2). 
 
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 
T erti ar y e n d p oi nt: C h a n g e s i n S D M T o ut c o m e at t h e e n d of 6, 1 2, 1 8 a n d 2 4 m o nt h s c o m p ar e d t o B a s eli n e 
T erti ar y ( F A S) 
C h a n g e fr o m B a s eli n e i n S D M T (r a w a n d s c al e d 
s c or e s) at M o nt h i Vi sit, w h er e i = 6, 1 2, 1 8 a n d 2 4. 
D e s cri pti v e s u m m ar y st ati sti c s. 
 
Mi ni m al D e cli n e i n C o g niti v e F u n cti o n at M o nt h 2 4 
Vi sit c o m p ar e d t o B a s eli n e 
D e s cri pti v e s u m m ar y st ati sti c s 
Mi s si n g v al u e s will b e i n cl u d e d i n t h e 
d e n o mi n at or a n d pr e s e nt e d a s a 
s e p ar at e c at e g or y. 
 
1 4. 3. 1 5   
C h a n g es i n le vel of dis a bilit y as me as ure d b y E D S S  
T he E x pa n de d Dis a bilit y Stat us Scale ( E D S S) ra n ges fr o m 0 t o 1 0 i n i ncre me nts of 0. 5 o n a n or di nal scale. Hi g her sc ores re prese nt a 
hi g her le vel of disa bilit y. Details of t he E D S S sc ori n g are i ncl u d e d i n t he a p pe n di x of t he st u d y pr ot oc ol. 
T he o bser ve d E D S S a n d t he c ha n ge fr o m Baseli n e will be prese nte d b y Visits usi n g s u m mar y statisti cs ( me dia n, q uartiles, mi n, ma x) 
a n d b y t he f oll o wi n g cate g orizati o n f or eac h Visit:  
 ≤3,  
 > 3- < 6, 
 ≥6.  
 
A n al y si s 
( A n al y si s S et) 
D eri v ati o n 
St ati sti c al A n al y si s M et h o d s 
Mi s si n g d at a h a n dli n g 
S e c o n d ar y e n d p oi nt: C h a n g e s i n l e v el of di s a bilit y a s m e a s ur e d b y E D S S at M o nt h 6, 1 2, 1 8, a n d 2 4 c o m p ar e d t o B a s eli n e 
T erti ar y ( F A S)   
C h a n g e s fr o m B a s eli n e of E D S S at M o nt h i Vi sit, 
w h er e i = 6, 1 2, 1 8 a n d 2 4. 
D e s cri pti v e s u m m ar y st ati sti c s f or t h e 
m e di a n 
a n d q u artil e s.  
 
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
7 8/ 9 8  
 
 
T erti ar y ( F A S)   
E D S S c at e g ori e s ( < 3, 3- < 6, ≥6) at B a s eli n e, M o nt h 
6, 1 2, 1 8 a n d 2 4 Vi sit s. 
D e s cri pti v e s u m m ar y st ati sti c s. 
Mi s si n g v al u e s will b e i n cl u d e d i n t h e 
d e n o mi n at or a n d pr e s e nt e d a s a 
s e p ar at e c at e g or y. 
1 4. 3. 1 6   
C h a n g es i n le vel of dis a bilit y as me as ure d b y 9 H P T  
T he 9 H P T s h o ul d be c o m plete d at Baseli ne a n d t he n at M o nt h 6, 1 2 1 8, a n d 2 4 Visit t o meas ure t he le vel of disa bilit y o ver ti me. T he 
s u bjects ha ve t o stic k 9 pe gs i n 9 h oles a n d place t he m bac k. T hat will be d o ne t wice f or eac h h a n d. T he mea n of t he 4 st o p ti mes will 
be a nal yze d. At least o ne st o p ti me m ust be rec or d e d, ot her wise, t he Visit will be c o nsi dere d as missi n g. Details of t he 9 H P T are i ncl u de d 
i n t he a p pe n di x of t he st u d y pr ot oc ol. 
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 
T erti ar y e n d p oi nt: C h a n g e s i n l e v el of di s a bilit y a s m e a s ur e d b y 9 H P T at M o nt h 6, 1 2, 1 8, a n d 2 4 Vi sit c o m p ar e d t o B a s eli n e 
T erti ar y ( F A S)   
C h a n g e fr o m B a s eli n e i n m e a n ti m e of t h e 9 H P T t o 
t h e M o nt h i Vi sit, w h er e i = 6, 1 2, 1 8, a n d 2 4. 
Mi x e d- eff e ct s 
li n e ar  
m o d el 
f or 
r e p e at e d 
m e a s ur e s, s a m e a s i n T erti ar y 
A n al y si s f or 
C h a n g e fr o m B a s eli n e i n C U A l e si o n  c o u nt ( s e e 
S e cti o n 1 4. 3. 1)  
S a m e a s i n T erti ar y 
A n al y si s f or 
C h a n g e fr o m B a s eli n e i n C U A l e si o n  
c o u nt ( s e e S e cti o n 1 4. 3. 1) 
1 4. 3. 1 7   
C h a n g es i n le vel of dis a bilit y as me as ure d b y T 2 5 F W  
T 2 5 F W is a q u a ntitati ve m o bilit y a n d le g f u ncti o n perf or m a nce t est base d o n a ti me d wal k o ver 2 5 feet (a p pr o xi matel y 7. 6 meters).  
A d mi nistrati o n ti me will var y de pe n di n g u p o n t he a bilit y of t he s u bject. S u bjects ha ve t o t wice wal k a trial of 2 5 feet. T he ti me li mit f or 
eac h trial is 3 mi n utes. At least o ne tri al has t o b e c o m plete d t o calc ulate t h e mea n ti m e f or a Visit. If t he s u bjects c o ul d n’t fi nis h a trial, 
t he trial will be s c ore d wit h 3 mi n utes. T 2 5 F W p erf or me d wit h a differe nt assist a nce d e vice as c o m pare d t o w hat was use d at Baseli ne 
will be c o nsi d ere d as “c ha n ge d de vice” a n d will n ot be i ncl u de d i n t he statistical a nal ysis. Details of t he T 2 5 F W are i ncl u de d i n t he 
a p pe n di x of t he st u d y pr ot oc ol. 
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 
T erti ar y e n d p oi nt: C h a n g e s i n l e v el of di s a bilit y a s m e a s ur e d b y T 2 5 F W at M o nt h 6, 1 2, 1 8, a n d 2 4 Vi sit c o m p ar e d t o B a s eli n e 
T erti ar y ( F A S)   
C h a n g e fr o m B a s eli n e i n m e a n ti m e of t h e T 2 5 F W t o 
t h e M o nt h i Vi sit, w h er e i = 6, 1 2, 1 8, a n d 2 4. 
Mi x e d- eff e ct s li n e ar  
m o d el 
f or 
r e p e at e d 
m e a s ur e s, s a m e a s i n T erti ar y A n al y si s f or 
C h a n g e fr o m B a s eli n e i n C U A l e si o n  c o u nt ( s e e 
S e cti o n 1 4. 3. 1)  
S a m e a s i n T erti ar y 
A n al y si s f or 
C h a n g e fr o m B a s eli n e i n C U A l e si o n  
c o u nt ( s e e S e cti o n 1 4. 3. 1) 
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
7 9/ 9 8  
 
 
 
1 4. 3. 1 8   
A n n u alize d Rel a pse R ate ( A R R) bet wee n B aseli ne a n d 1 2/ 2 4 m o nt hs 
T he u na dj uste d A R R will be calc ulate d f or t he Treat me nt Peri o d, C o urse 1 Treat m e nt Peri o d a n d C o urse 2 Treat m e nt Peri o d. 
T he u na dj uste d A R R f or a s u bject i is defi ne d as t he n u m ber of rela pses p er year: 
 A R R f or s u bject i = n u m b er of rela pses d uri n g t he Peri o d / pers o n- years of s u bject i, 
 Pers o n- years f or s u bject i = Peri o d (i n da ys) / 3 6 5. 2 5. 
T he u na dj uste d p o p ulati o n A R R is t he mea n of all s u bject’s A R Rs. T he u na dj uste d A R R will be calc ulate d f or all rela pses, as well as 
t he q ualif yi n g rela pses ( A R Rq u al), as re p orte d i n t he e C R F. 
Rela pses will be c o u nte d f or t he defi n e d ti me Peri o d, if t he date of o nset of t he rela ps e is wit hi n t he defi ne d ti me Peri o d. I n c o m plete or 
missi n g o nset dates will be i m p ute d as s pecifie d i n Secti o n 9.  
T he n u m b er of s u bjects wit h ( q ualif yi n g) rela pses, t he n u m ber of ( q ualif yi n g) rela pses, pers o n- y ears a n d t he u na dj uste d p o p ulati o n A R R 
will be prese nt e d f or t h e Treat me nt Peri o d, C o urse 1 Treat me nt Peri o d a n d C o urse 2 Treat me nt Peri o d. Als o, t he n u m b er of s u bjects 
wit h rela pses a n d n u m ber of rela pses w hic h were treate d wit h ster oi ds or lea di n g t o h os pit alizati o n will be prese nte d se paratel y. F or t h e 
I nteri m A nal ysis t he differe nt rela pse c o u nts u p t o t he m o nt h 6 Visit will be prese nte d wit h o ut t he A R R.  
I n a d diti o n, t he rela pse rate will be a nal yze d usi n g a P oiss o n re gressi o n m o del wit h c o u nt of rela ps es as de pe n d e nt varia ble a n d wit h 
fi xe d effects f or a ge (i n years) a n d E D S S at Baseli ne ( ≤3, > 3). T he l o g of t he d urati o n of t he treat me nt Peri o d ( precisi o n i n da ys) will 
be t he offset v aria ble i n t he m o del. 
 
C CI
C CI




Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
8 1/ 9 8  
 
 
 
 
C CI
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
8 2/ 9 8  
 
 
 
C CI
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
8 3/ 9 8  
 
 
C CI
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
8 4/ 9 8  
 
 
C CI
C CI
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
8 5/ 9 8  
 
 
C CI
C CI
C CI


Cla dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
8 6/ 9 8  
 
 
C CI
C CI
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
8 7/ 9 8  
 
 
1 5  
S afet y A n al yses 
T he s u bsecti o ns i n t his secti o n i n cl u de s pecificati o ns f or s u m marizi n g safet y e n d p oi nts t h at 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 b e d o ne o n t he S A F. U nless ot her wise s pecifie d, t he safet y a nal ysis will be 
d o ne f or i nteri m a n d fi nal a nal ysis. 
1 5. 1  
A d vers e E ve nts 
Treat m e 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 Treat m e 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 case t h e o nset date is missi n g c o m pletel y or missi n g partiall y a n d t he o nset m o nt h a n d 
year or t h e o nset year are e q ual t o t he start of st u d y me dicati o n, t he n t he o nset d ate will 
be re pla ce d b y t h e st art date of st u d y me dicati o n or A E res ol uti o n date w hi c he ver is 
earli er. 
 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 h e last da y of t h e m o nt h (if d a y is missi n g 
o nl y), if n ot res ulti n g i n a date later t ha n t h e d ate of s u bject's deat h. I n t h e latter case t h e 
date of deat h will be use d t o i m p ute t h e i n c 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 v e nts 
T E A Es will be s u m mari ze d usi n g Me d D R A P T as e ve nt cate g or y a n d M e d D R A pri m ar y 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 H R A s u b gr o u ps ( H R A a n d n o n- H R A). 
U nless ot her wise state d, a d vers e e ve nts will be dis pla ye d i n ter ms of fre q ue nc y ta bl es: P T a n d 
pri mar y S O C i n al p ha betical or der.  
A d vers e e ve nts rel ate d t o st u d y treat m e 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. 
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
8 8/ 9 8  
 
 
T he f oll o wi n g o verall fre q ue ncies of s u bjects wit h t h e c orres p o n di n g T E A Es will be pre pare d. I n 
a d diti o n, t h e ta bles will be pr o vi de d b y P T a n d pri m ar y S O C i n al p ha beti cal 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, 
 A n y st u d y treat me nt relat e d s eri o us A Es, 
 A n y A E b y se verit y ( mil d, m o derate, se vere), 
 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 vers e e ve nts a p pl yi n g fre q ue nc y t hres h ol d of 5 % will be 
pr o vi de d b y S O C a n d P T. 
S u m mar y ta bles f or seri o us a n d n o n-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 verit y ( Mil d or w orse, m o derate or w orse, se 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 b er of s u bjects wit h A E di vi d e d 
b y t he 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 h e safet y p o p ulati o n fr o m start of 
st u d y me dicati o n t o first o nset of A E or e n d of treat me nt Peri o d, w hic he v er o cc urs first. 
T he e xact P oiss o n 9 5 % c o nfi de nce i nter vals f or t he E AI R are cal c ulate d usi n g t he relati o ns hi p 
bet wee n t h e P oiss o n a n d t he C hi-s q uare distri b uti o n ( Ul m [ 1], 1 9 9 0): 
𝐻𝑖𝐻=
𝑖
,
2 × 𝑖, 
𝑖𝑖𝑖=
𝜒
( 
),
2 × 𝑡
, 
w here t is t h e s u m of t h e i n di vi d ual ti m es i n years of all s u bjects a n d n is t h e 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 h e de grees of free d o m 
f or t h e c hi-s q u are q u a ntile f or t h e u p p er tail pr o ba bilit y χ 2.  
E x p os ure a dj uste d i nci d e 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 bl e will be pr o vi de d: 
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
8 9/ 9 8  
 
 
 E x p os ure a dj uste d i nci d e nce rat es of A Es b y S O C a n d P T. 
1 5. 1. 2   
A d vers e 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 t a bl es will b e pre pare d f or t h e a d v erse e ve nt acti o ns. 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 betic al or der: 
 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 ma 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 m e nt. 
1 5. 2  
De at hs, Ot her Seri o us A d verse E v e nts, a n d Ot her Si g nific a nt 
A d vers e 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 v e d Deat hs (fr o m “ St u d y Ter mi nati o n” e C R F p a ge) will be pr o vi de d 
t o get her wit h T E A Es wit h fatal o utc o me b y P T. 
1 5. 2. 2   
Seri o us A d verse E ve nts 
T he statistical a nal ysis a n d re p orti n g of seri o us a d vers e e v e nts are defi ne d i n Secti 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 v erse E v e 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 nt e 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 h e C o urse 1 Treat m e nt Peri o d a n d 
se parat el y f or eac h m o nt h of t h e C o urse 2 Treat m e nt P eri o d. T h e pre vale n ce at a gi v e n m o nt h is 
defi ne d as: 
( N u m ber of s u bje cts wit h fati g ue d uri n g t he m o nt h/ N u m ber of s u bjects wit h fati g ue d uri n g t h e 
m o nt h or still i n t h e st u d y at t h e e n d of t he m o nt h) * 1 0 0,  
w here s u bjects wit h fati g ue d uri n g t h e m o nt h are all s u bjects w h o h a d at least o ne re p orte d T E A E 
wit h P T e q ual t o ’ Fati 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 h e 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 d ate will be i m p ut e d as f oll o ws: 
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
9 0/ 9 8  
 
 
 Da y missi n g b ut m o nt h a n d year a v ail a ble: last da y of t he m o nt h, 
 Da y a n d m o nt h missi n g: last da y of t h e year b ut n ot later t h a n 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 
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 m e nt 
Peri o ds as well as d urati o n of a m o nt h is defi ne d i n Secti o n 9. 
1 5. 3  
Cli ni c 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 nts fr o m l ocal la b orat or y will be use d f or s u m m ar y st atistics a n d s hift ta bles. T h e y 
will b e classifie d acc or di n g t o t he N CI- C T C A E. 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 m e 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 m eas 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 yt e c o u nts at or aft er t h e Visit start 
date of t h e M o nt h 1 2 Visit a n d b ef ore or at t h e start d ate of t he Treat me nt C o urse 2 will be 
dis pla ye d as f oll o we d: 
 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 h er 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 m e nt a d mi nistrati o n) will be 
s u m marize d b y s u bject c o nsi d eri n g o nl y s u bjects 
wit h p ost- Baseli ne la b orat or y s a m ples: 
La b orat or y tests b y N CI- C T C gra de ( 0, 1, 2, 3, 4, a n y). 
L y m p h oc yte c o u nts will be e xa mi n e d f or tre n ds usi n g descri pti ve statistics ( mea n, S D, m e 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 ha n ges fr o m Bas eli n e 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 p artic ular Visit a differe nt l ocal la b orat or y t ha n 
n or mal la b orat or y w as us e d ( d ue t o C O VI D- 1 9 pa n de mi c), 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 B aseli ne vers us e n d p oi nt (as well as t he w orst v al ue at a n y p ost- Baseli n e Visit) will 
be prese nte d. A b n or malities classifie d acc or di n g t o N CI- C T C A E t o xicit y gra di n g will b e 
descri 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 res ults of t he t u berc ul osis a n d ser ol o g y tests t hat d o n ot c o m pl y wit h t he pr ot oc ol will be 
liste d.  
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
9 1/ 9 8  
 
 
1 5. 4  
Vit al Si g ns 
T he ma xi m u m c ha n ges of vital si g n m eas ure me nts fr o m Baseli n e 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:  
H e art r at e i n cr e a s e fr o m B a s eli n e  
< 1 0 0 b p m; ≥ 1 0 0 b p m 
2 0 b p m, > 2 0 – 4 0 b p m, > 4 0 b p m 
H e art r at e d e cr e a s e fr o m B a s eli n e  
< 1 0 0 b p m; ≥ 1 0 0 b p m 
2 0 b p m, > 2 0 – 4 0 b p m, > 4 0 b p m 
S B P i n cr e a s e fr o m B a s eli n e  
< 1 4 0 m m H g; ≥ 1 4 0 m m H g  
2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g 
S B P d e cr e a s e fr o m B a s eli n e  
< 1 4 0 m m H g; ≥ 1 4 0 m m H g, 
2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g 
D B P i n cr e a s e fr o m B a s eli n e  
< 9 0 m m H g; ≥ 9 0 m m H g  
2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g 
D B P d e cr e a s e fr o m B a s eli n e  
< 9 0 m m H g; ≥ 9 0 m m H g, 
2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g 
F or eac h s u bject, t h e w orst c ha n ge d uri n g t he treat m e nt Peri o d will be c o nsi dere d. Missi n g val ues 
will b e prese nte d as a se p arate cate g or y. 
T he f oll o wi n g will be pre pare d f or vital si g n p ara 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: 
 S u m mar y of Ma xi mal S hifts (c ha n ges i n cate g ories), 
 Listi n g of hi g hest c ha n ge per s u bject. 
1 5. 5  
Ot her S afet y o r 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 nal 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 nic al 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 statistical re p orti n g of 
t he Safet y M RI ce ntral 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. 
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
9 2/ 9 8  
 
 
1 6  
A n al yses of Ot her E n d p oi nts 
N ot a p plica ble. 
 
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
9 3/ 9 8  
 
 
1 7  
Refere nces 
[ 1] 
Ul m, K. “ A si m ple met h o d t o calc ulate t he c o nfi de nce i nter v al of a sta n dar dize d m ortalit y 
rati o ( S M R).” 
A meri ca n j o ur nal 
of 
e pi de mi ol o g y 
v ol. 
1 3 1, 2 ( 1 9 9 0): 
3 7 3- 5. 
d oi: 1 0. 1 0 9 3/ o xf or dj o ur nals.aje.a 1 1 5 5 0 7 
[ 2] 
Br u n ner, E., D o m h of, S. u n d La n ger, F. ( 2 0 0 2) N o n para metric A nal ysis of L o n git u di nal 
Data i n Fact orial E x p eri m e nts. Wile y, Ne w Y or k. 
[ 3] 
I n d e pe n d e nt Re vi e w C h arter f or C o u nti n g Brai n M RI L esi o ns - M S 7 0 0 5 6 8 _ 0 0 2 2, Versi o n 
2. 0, 0 7 N o ve m ber 2 0 1 9 
[ 4] 
Par me nter, Brett A et al. “ T he utilit y of re gressi o n- base d n or ms i n i nter preti n g t he mi ni mal 
assess me nt of c o g niti ve f u ncti o n i n m ulti ple scler osis ( M A C FI M S).” J o ur nal of t he 
I nter nati o nal 
Ne ur o ps yc h ol o gical 
S ociet y: 
JI N S 
v ol. 
1 6, 1 
( 2 0 1 0): 
6- 1 6. 
d oi: 1 0. 1 0 1 7/ S 1 3 5 5 6 1 7 7 0 9 9 9 0 7 5 0 
[ 5] 
R u bi n, D. B. ( 1 9 8 7). M ulti ple I m p utati o n f or N o nres p o nse i n S ur ve ys. Ne w Y or k: J o h n 
Wile y & S o ns. 
[ 6] 
I n d e pe n d e nt 
Re vi e w 
C hart er f or 
Lesi o n 
C o u nti n g f or t h e 
T ertiar y 
E n d p oi nt - 
M S 7 0 0 5 6 8 _ 0 0 2 2, Versi o n 2. 0, 2 4 Fe br u ar y 2 0 2 1 
[ 7] 
I n d e pe n d e nt Re vi e w C h arter f or A d v a nce d 
M RI - 
M S 7 0 0 5 6 8 _ 0 0 2 2, Versi o n 1. 0, 1 7 
Fe br u ar y 2 0 2 1 
[ 8] 
Data Tra nsfer S pecificati o n - M S 7 0 0 5 6 8 _ 0 0 2 2 - M RI- base d e n d p oi nt val u es, Versi o n 3. 1, 
0 8 J ul y 2 0 2 1 (s pecificati o n pr o vi de d b y SI E N A i m a gi n g) 
[ 9] 
Data Tra nsfer A gree me nt - M S 7 0 0 5 6 8 _ 0 0 2 2 - Bi o mar ker test res ults, Versi o n 1 0. 0, 0 6 
A u g ust 2 0 2 1 (s pecificati o n pr o vi de d b y Pare xel I nter nati o nal) 
[ 1 0] 
A p pe n di x Para met er 
Ma p pi n g t o 
Data Tra nsfer 
A gree me nt - 
M S 7 0 0 5 6 8 _ 0 0 2 2 – 
Bi o mar ker test res ults, Versi o n 5. 0, 0 6 A u g ust 2 0 2 1 (s pecificati o n pr o vi de d b y Pare xel 
I nter nati o nal) 
 
 
 
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
9 4/ 9 8  
 
 
1 8  
A p pe n dices 
1 8. 1  
A p pe n di x 1: List of D M Ds 
D M Ds  
Preferre d T er m  
Ale mt u z u ma b * ( Ca m pat h, Ma b Ca m pat h, 
Le mtra da) 
A L E M T U Z U M A B 
Dacliz u ma b * ( Zi n br yta) 
D A C LI Z U M A B 
Di met h yl f u marate ( Tecfi dera) 
DI M E T H Y L F U M A R A T E 
Fi n g oli m o d * ( Gile n ya) 
FI N G O LI M O D 
FI N G O LI M O D H Y D R O C H L O RI D E 
Glatira mer Acet ate ( C o pa x o ne) 
G L A TI R A M E R 
G L A TI R A M E R A C E T A T E 
I m m u n o gl o b uli ns 
I M M U N O G L O B U LI N H U M A N N O R M A L 
I M M U N O G L O B U LI N S 
I M M U N O G L O B U LI N S N O S 
I nt erfer o n bet a ( A v o ne x, Re bif, Betafer o n, 
E xta via, Pl e gri d y) 
I N T E R F E R O N 
I N T E R F E R O N B E T A 
I N T E R F E R O N B E T A- 1 A 
I N T E R F E R O N B E T A- 1 B 
P E GI N T E R F E R O N 
P E GI N T E R F E R O N B E T A- 1 A 
Mit o xa ntr o ne ( N o va ntr o ne)  
MI T O X A N T R O N E  
MI T O X A N T R O N E H Y D R O C H L O RI D E 
Nataliz u m a b * ( T ysa bri) 
N A T A LI Z U M A B 
N o n-a p pr o ve d i n vesti gati o nal D M Ds * 
( m o n ocl o nal a nti b o dies, a nti S 1 P R, la q ui ni m o d etc) 
DI R O XI M E L F U M A R A T E 
I N V E S TI G A TI O N A L D R U G 
L A Q UI NI M O D 
O F A T U M U M A B 
O PI CI N U M A B 
O T H E R A N TI N E O P L A S TI C A G E N T S 
O Z A NI M O D 
Ocreliz u m a b * ( Ocre v us) 
O C R E LI Z U M A B 
Off-l a bel i m m u n os u p pressa nts (azat hi o pri ne, 
m y c o p he n olate, c ycl o p h os p ha mi d e) 
A Z A T HI O P RI N E 
C Y C L O P H O S P H A MI D E 
M E T H O T R E X A T E 
Si p o ni m o d * 
SI P O NI M O D 
Terifl u n o mi de ( A u ba gi o) 
T E RI F L U N O MI D E 
D M Ds mar ke d wit h a * are sec o n d li ne D M Ds, w hic h are n ot all o we d as a pre vi o us me di cati o n 
acc or di n g t o t he st u d y pr ot oc ol. 
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
9 5/ 9 8  
 
 
S u bjects w h o ha ve t a ki n g a n y of t h e 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 m e nt naï ve. T h e list ma y be e xte n d e d d uri n g m e 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. 
 
 
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
9 6/ 9 8  
 
 
1 8. 2  
A p pe n di x 2: S D M T Sc al e d Sc ore 
Sc ale d sc ore 
S D M T 
2  
 
3 
< 4 3 
4 
4 3- 4 5 
5 
4 6 
6 
4 7- 5 0 
7 
5 1- 5 4 
8 
5 5- 5 6 
9 
5 7- 5 9 
1 0 
6 0- 6 3 
1 1 
6 4- 6 6 
1 2 
6 7- 6 9 
1 3 
7 0- 7 2 
1 4 
7 3- 7 4 
1 5 
7 5- 7 8 
1 6 
7 9 
1 7 
8 0- 8 7 
1 8 
> 8 7 
Par me nter et al. [ 4], JI N S 2 0 1 0; 1 6: 6- 1 6 
 
 
C CI


Cl a dri bi ne ( Ma ve ncla d ® ) 
M A G NI F Y- M S  
M S 7 0 0 5 6 8 _ 0 0 2 2   
 
Versi o n 3. 0  
 
 
 
9 7/ 9 8  
 
 
C CI
C CI


CCI



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