An Open-Label, Single-Arm, Multicenter, Phase 3 Study to Evaluate the Safety and Tolerability, and Pharmacokinetics of Diroximel Fumarate (BIIB098) in Adult Participants From the Asia-Pacific Region With Relapsing Forms of Multiple Sclerosis
Phase: PHASE3
Conditions: Relapsing Forms of Multiple Sclerosis
Sponsor: Biogen

C O V E R P A G E  
 
Offi ci al Titl e:  
A n O p e n -L a b el, Si n gl e -Ar m, M ulti c e nt er, P h a s e 3 St u d y t o E v al u at e t h e  
S af et y a n d 
T ol er a bilit y, a n d 
P h ar m a c o ki n eti c s of 
Dir o xi m el 
F u m ar at e 
( BII B 0 9 8) i n A d ult P arti ci p a nt s Fr o m t h e A si a -P a cifi c R e gi o n Wit h R el a p si n g 
F or m s of M ulti pl e S cl er o si s  
N C T n u m b er:  
N C T 0 5 0 8 3 9 2 3  
D o c u m e nt D at e:  
2 3 -M a y -2 0 2 3  
 

C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1
P R O T O C O L N U M B E R:
2 7 2 M S 3 0 3
Bi o ge n M A I nc.
2 2 5 Bi n ne y Street
Ca m bri d ge, M A  0 2 1 4 2
U nite d States
Bi o ge n I dec Researc h Li mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d, Ber ks hire
S L 6 4 A Y
U nite d Ki n g d o m
P H A S E O F D E V E L O P M E N T:
3
P R O T O C O L TI T L E: A n O pe n- La bel, Si n gle- Ar m, M ultice nter, P hase 3 St u d y t o E val uate t he 
Safet y a n d T olera bilit y, a n d P har mac o ki netics of Dir o xi mel F u marate ( BII B 0 9 8) i n A d ult 
Partici pa nts Fr o m t he Asia- Pacific Re gi o n Wit h Rela psi n g F or ms of M ulti ple Scler osis
D A T E:
2 3 Ma y 2 0 2 3
Versi o n 4
FI N A L
S u perse des pre vi o us Versi o n 3 d ate d 2 4 Fe br u ar y 2 0 2 2

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
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Bi o ge n M A I nc.
2
S P O N S O R I N F O R M A TI O N
C hi na 
Bi o ge n I dec Researc h Li mite d 
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d, Ber ks hire 
S L 6 4 A Y
U nite d Ki n g d o m
Ja pa n 
Bi o ge n Ja pa n Lt d.
Ni h o n bas hi 1-c h o me Mits ui 
B uil di n g 1 4 F
4- 1 Ni h o n bas hi 1-c h o me
C h u o- k u, T o k y o
1 0 3- 0 0 2 7 Ja pa n
F or ur ge nt me dical iss ues i n w hic h t he st u d y Me dical M o nit or s h o ul d be c o ntacte d, please refer 
t o t he St u d y C o ntact List.
T he S p o ns or ma y tra nsfer a n y or all of its st u d y-relate d res p o nsi bilities t o a c o ntract researc h 
or ga nizati o n a n d ot her t hir d parties; h o we ver, t he S p o ns or retai ns o verall acc o u nta bilit y f or t hese 
acti vities.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4
T A B L E O F C O N T E N T S
S P O N S O R I N F O R M A TI O N .......................................................................................................... 2
S P O N S O R SI G N A T U R E P A G E .................................................................................................... 3
T A B L E O F C O N T E N T S................................................................................................................. 4
LI S T O F T A B L E S........................................................................................................................... 8
LI S T O F FI G U R E S......................................................................................................................... 8
1.  
K E Y S T U D Y E L E M E N T S.......................................................................................... 9
1. 1. 
S y n o psis........................................................................................................................ 9
1. 2. 
St u d y Desi g n Sc he matic............................................................................................. 1 5
1. 3. 
Sc he d ule of Acti vities................................................................................................. 1 7
2. 
LI S T O F A B B R E VI A TI O N S..................................................................................... 2 1
3. 
I N T R O D U C TI O N...................................................................................................... 2 3
3. 1. 
St u d y Rati o nale........................................................................................................... 2 3
3. 1. 1. 
Rati o nale f or St u d y P o p ulati o n................................................................................... 2 4
3. 1. 2. 
Rati o nale f or D osi n g Re gi me n ................................................................................... 2 4
3. 2. 
Bac k gr o u n d................................................................................................................. 2 4
3. 2. 1.  
O ver vie w of M ulti ple Scler osis.................................................................................. 2 4
3. 2. 2. 
C urre nt T hera pies f or M ulti ple Scler osis ................................................................... 2 5
3. 2. 3. 
Pr ofile of Pre vi o us E x perie nce Wit h D R F ................................................................. 2 5
3. 3. 
Be nefit- Ris k Assess me nt............................................................................................ 2 6
4. 
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S.............................................................. 2 7
5. 
S T U D Y D E SI G N....................................................................................................... 2 9
5. 1. 
St u d y O ver vie w.......................................................................................................... 2 9
5. 2. 
St u d y D urati o n f or Partici pa nts.................................................................................. 3 0
5. 3. 
St u d y St o p pi n g R ules ................................................................................................. 3 1
5. 4.  
U nsc he d ule d Visits..................................................................................................... 3 1
5. 5. 
E n d of St u d y............................................................................................................... 3 1
6. 
S T U D Y P O P U L A TI O N............................................................................................. 3 2
6. 1. 
I ncl usi o n Criteria........................................................................................................ 3 2
6. 2. 
E xcl usi o n Criteria....................................................................................................... 3 2
6. 3. 
Scree ni n g, Retesti n g, a n d Scree n Fail ures.................................................................. 3 7
6. 3. 1. 
Scree ni n g .................................................................................................................... 3 7

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
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Bi o ge n M A I nc.
5
6. 3. 2. 
Retesti n g..................................................................................................................... 3 8
6. 3. 3. 
Scree n Fail ures............................................................................................................ 3 8
7. 
S T U D Y T R E A T M E N T.............................................................................................. 3 9
7. 1. 
Re gi me n...................................................................................................................... 3 9
7. 2.  
M o dificati o n of D ose a n d/ or Treat me nt Sc he d ule...................................................... 3 9
3 9
3 9
4 0
7. 3. 
St u d y Treat me nt Ma na ge me nt.................................................................................... 4 1
7. 3. 1.  
D R F............................................................................................................................. 4 1
7. 3. 1. 1. 
Pre parati o n.................................................................................................................. 4 1
7. 3. 1. 2. 
St ora ge........................................................................................................................ 4 2
7. 3. 1. 3.  
Ha n dli n g a n d Dis p osal................................................................................................ 4 2
7. 3. 1. 4.  
Acc o u nta bilit y............................................................................................................. 4 2
7. 4. 
Bli n di n g Pr oce d ures.................................................................................................... 4 2
7. 5. 
Preca uti o ns.................................................................................................................. 4 2
7. 6. 
C o m plia nce................................................................................................................. 4 2
7. 7. 
C o nc o mita nt T hera p y a n d Pr oce d ures........................................................................ 4 3
7. 7. 1. 
C o nc o mita nt T hera p y ................................................................................................. 4 3
7. 7. 1. 1.  
All o we d C o nc o mita nt T hera p y................................................................................... 4 3
7. 7. 1. 2.  
Disall o we d C o nc o mita nt T hera p y.............................................................................. 4 3
7. 7. 2. 
C o nc o mita nt Pr oce d ures............................................................................................. 4 4
7. 8. 
C o nti n uati o n of Treat me nt.......................................................................................... 4 4
8.  
DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D WI T H D R A W A L 
O F P A R TI CI P A N T S F R O M T H E S T U D Y............................................................... 4 5
8. 1.  
Disc o nti n uati o n of St u d y Treat me nt........................................................................... 4 5
8. 2. 
L ost t o F oll o w- U p....................................................................................................... 4 6
8. 3.  
Wit h dra wal of Partici pa nts fr o m t he St u d y................................................................ 4 6
9.
 P H A R M A C O KI N E TI C, A N D P H A R M A C O D Y N A MI C 
A S S E S S M E N T S......................................................................................................... 4 7
. 4 7
4 7
9. 3. 
P har mac o ki netic Assess me nts.................................................................................... 4 7

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
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Bi o ge n M A I nc.
6
1 0. 
S A F E T Y A S S E S S M E N T S ........................................................................................ 4 9
1 0. 1. 
Cli nical Safet y Assess me nts....................................................................................... 4 9
1 0. 2. 
La b orat or y Safet y Assess me nts.................................................................................. 4 9
1 1. 
S A F E T Y D E FI NI TI O N S, R E C O R DI N G, R E P O R TI N G, A N D 
R E S P O N SI BI LI TI E S................................................................................................. 5 1
1 1. 1.  
Defi niti o ns .................................................................................................................. 5 1
1 1. 1. 1.  
A d verse E ve nt............................................................................................................. 5 1
1 1. 1. 2. 
Seri o us A d verse E ve nt................................................................................................ 5 1
1 1. 1. 3. 
Presc he d ule d or Electi ve Pr oce d ures or R o uti nel y Sc he d ule d Treat me nts................ 5 2
1 1. 2. 
Safet y Classificati o ns.................................................................................................. 5 2
1 1. 2. 1. 
I n vesti gat or Assess me nt of E ve nts............................................................................. 5 2
1 1. 2. 2. 
Relati o ns hi p of E ve nts t o St u d y Treat me nt................................................................ 5 2
1 1. 2. 3. 
Se verit y of E ve nts....................................................................................................... 5 3
1 1. 2. 4. 
E x pecte d ness of E ve nts .............................................................................................. 5 3
1 1. 3.  
M o nit ori n g a n d Rec or di n g E ve nts.............................................................................. 5 3
1 1. 3. 1.  
A d verse E ve nts........................................................................................................... 5 3
1 1. 3. 2.  
A d verse E ve nts of S pecial I nterest............................................................................. 5 4
1 1. 3. 3. 
Seri o us A d verse E ve nts.............................................................................................. 5 4
1 1. 3. 4. 
I m me diate Re p orti n g of Seri o us A d verse E ve nts....................................................... 5 4
1 1. 3. 4. 1.  
Deat hs......................................................................................................................... 5 5
1 1. 3. 5. 
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns.................................................... 5 5
1 1. 4. 
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns............................................................... 5 5
1 1. 4. 1. 
Pre g na nc y ................................................................................................................... 5 5
1 1. 4. 2.  
O ver d ose..................................................................................................................... 5 6
1 1. 4. 3.  
Me dical E mer ge nc y.................................................................................................... 5 6
1 1. 5. 
C o ntrace pti o n Re q uire me nts ...................................................................................... 5 6
1 1. 6. 
Safet y Res p o nsi bilities................................................................................................ 5 8
1 1. 6. 1. 
T he I n vesti gat or.......................................................................................................... 5 8
1 1. 6. 2. 
T he S p o ns or................................................................................................................ 5 8
1 2. 
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F S A M P L E SI Z E........... 5 9
1 2. 1.  
Ge neral C o nsi derati o ns............................................................................................... 5 9
1 2. 2.  
A nal ysis Sets............................................................................................................... 5 9

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
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Bi o ge n M A I nc.
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1 2. 3.  
Met h o ds of A nal ysis................................................................................................... 5 9
5 9
1 2. 4.  
Met h o ds of A nal ysis f or P har mac o ki netic E n d p oi nts f or Part 1 ( o nl y) ..................... 6 0
1 2. 5.  
Met h o ds of A nal ysis f or Safet y E n d p oi nts................................................................. 6 1
1 2. 5. 1.  
A d verse E ve nts........................................................................................................... 6 1
1 2. 5. 2. 
Cli nical La b orat or y Res ults........................................................................................ 6 2
1 2. 5. 3.  
Vital Si g ns .................................................................................................................. 6 2
1 2. 5. 4. 
E C G............................................................................................................................ 6 2
1 2. 5. 5. 
C- S S R S....................................................................................................................... 6 2
1 2. 6. 
I nteri m A nal yses......................................................................................................... 6 2
1 2. 7. 
Sa m ple Size C o nsi derati o ns ....................................................................................... 6 2
1 3. 
E T HI C A L A N D R E G U L A T O R Y R E Q UI R E M E N T S.............................................. 6 4
1 3. 1.  
Declarati o n of Helsi n ki............................................................................................... 6 4
1 3. 2. 
Et hics C o m mittee........................................................................................................ 6 4
1 3. 3. 
C ha n ges t o Fi nal Pr ot oc ol........................................................................................... 6 5
1 3. 4. 
I nf or me d C o nse nt ....................................................................................................... 6 5
1 3. 5. 
Partici pa nt Data Pr otecti o n......................................................................................... 6 6
1 3. 6. 
C o m pe nsati o n f or I nj ur y............................................................................................. 6 6
1 3. 7. 
C o nflict of I nterest...................................................................................................... 6 6
1 3. 8. 
St u d y Re p ort Si g nat or y............................................................................................... 6 6
1 3. 9. 
Re gistrati o n of St u d y a n d Discl os ure of St u d y Res ults.............................................. 6 6
1 3. 1 0. 
Rete nti o n of St u d y Data.............................................................................................. 6 7
1 4.  
K E Y R O L E S A N D S T U D Y G O V E R N A N C E C O M MI T T E E S............................... 6 8
1 4. 1. 
Site Staff..................................................................................................................... 6 8
1 4. 2.  
Ve n d ors....................................................................................................................... 6 8
1 4. 2. 1. 
C o ntract Researc h Or ga nizati o n................................................................................. 6 8
1 4. 2. 2. 
I nteracti ve Res p o nse Tec h n ol o g y............................................................................... 6 8
1 4. 2. 3. 
Electr o nic or Re m ote Data Ca pt ure............................................................................ 6 8
1 4. 2. 4. 
Ce ntral La b orat ories f or La b orat or y Assess me nts ..................................................... 6 8
1 4. 2. 5. 
Ce ntral Facilit y f or Ot her Assess me nts...................................................................... 6 8
1 4. 2. 6. 
Ce ntral Re vie w of Raters............................................................................................ 6 8
1 4. 3. 
St u d y C o m mittees....................................................................................................... 6 9

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
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Bi o ge n M A I nc.
8
1 5.  
A D MI NI S T R A TI V E P R O C E D U R E S....................................................................... 7 0
1 5. 1. 
St u d y Site I nitiati o n.................................................................................................... 7 0
1 5. 2.  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce...................................................................... 7 0
1 5. 3.  
M o nit ori n g of t he St u d y.............................................................................................. 7 0
1 5. 3. 1. 
P u blic Healt h E mer ge ncies......................................................................................... 7 1
1 5. 4. 
St u d y F u n di n g............................................................................................................. 7 1
1 5. 5. 
P u blicati o ns................................................................................................................. 7 1
1 6. 
R E F E R E N C E S........................................................................................................... 7 2
1 7. 
SI G N E D A G R E E M E N T O F T H E S T U D Y P R O T O C O L......................................... 7 4
LI S T O F T A B L E S
Ta ble 1: 
Sc he d ule of Acti vities................................................................................................. 1 7
Ta ble 2:  
A d diti o nal F oll o w- U p f or Partici pa nts wit h L y m p h o pe nia........................................ 2 0
Ta ble 3: 
Part 1 St u d y O bjecti ves a n d E n d p oi nts ...................................................................... 2 7
Ta ble 4: 
Part 2 St u d y O bjecti ve a n d E n d p oi nts........................................................................ 2 8
Ta ble 5: 
Cli nical La b orat or y Assess me nts ............................................................................... 5 0
Ta ble 6: 
P har mac o ki netic A nal ysis Ti me p oi nts....................................................................... 6 1
LI S T O F FI G U R E S
Fi g ure 1:
St u d y Desi g n Sc he matic............................................................................................. 1 5

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
9
1.  
K E Y S T U D Y E L E M E N T S
1. 1. 
S y n o psis
Pr ot oc ol Title:
A n O pe n- La bel, Si n gle- Ar m, M ultice nter, P hase 3 St u d y t o 
E val uate t he Safet y a n d T olera bilit y, a n d P har mac o ki netics 
of Dir o xi mel F u marate ( BII B 0 9 8) i n A d ult Partici pa nts 
Fr o m t he Asia- Pacific Re gi o n Wit h Rela psi n g F or ms of 
M ulti ple Scler osis
Pr ot oc ol N u m ber:
2 7 2 M S 3 0 3
Versi o n N u m ber:
4
Na me of St u d y Treat me nt:
Researc h Na me: 
BII B 0 9 8 (als o k n o w n as A L K 8 7 0 0)
Ge neric Na me:  
Dir o xi mel F u marate ( D R F)
Tra de Na me:  
V u merit y
St u d y P hase:
3
St u d y I n dicati o n:
Rela psi n g F or ms of M ulti ple Scler osis ( R M S)
St u d y Rati o nale:
T he mai n g oal of t he c urre nt st u d y is t o assess t he  safet y 
a n d t olera bilit y, a n d P K pr ofile of D R F a d mi nistere d orall y 
i n a d ult East Asia n partici pa nts wit h R M S. 
D R F was de vel o pe d as a m o difie d-release oral treat me nt f or 
R M S. I n Oct o ber 2 0 1 9, D R F u n der t he tra de na me 
V U M E RI T Y ®  was a p pr o ve d b y t he U S F D A f or t he 
treat me nt of a d ult patie nts wit h R M S, t o i ncl u de cli nicall y 
is olate d s y n dr o me, rela psi n g-re mitti n g disease, a n d acti ve 
sec o n dar y pr o gressi ve disease.
I n partici pa nts wit h R R M S, D R F de m o nstrate d safet y a n d 
t olera bilit y, i n 2 gl o bal P hase 3 st u dies: St u d y 
A L K 8 7 0 0- A 3 0 1 ( E V O L V E- M S- 1; c urre ntl y o n g oi n g) a n d 
St u d y A L K 8 7 0 0- A 3 0 2 ( E V O L V E- M S- 2; c o m plete d). I n 
b ot h st u dies, D R F at a d ose of 2 3 1 m g t wice dail y f or 1 
wee k f oll o we d b y 4 6 2 m g t wice dail y f or 9 6 wee ks (i n 
St u d y A L K 8 7 0 0- A 3 0 1) a n d at a d ose of 4 6 2 m g t wice dail y 
f or 4 wee ks (i n St u d y A L K 8 7 0 0- A 3 0 2) ha d a n acce pta ble 
safet y pr ofile a n d was well t olerate d. Alt h o u g h t he c o m ple x 
a n d m ultifact orial pat h o ge nesis of M S is c o nsi dere d t o be 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 0
ge nerall y si milar acr oss Ca ucasia n a n d Asia n p o p ulati o ns, 
t here are c urre ntl y li mite d safet y, t olera bilit y, a n d efficac y 
data o n D R F i n t he Asia n p o p ulati o n, i ncl u di n g t he East 
Asia n M S p o p ulati o ns; t heref ore, a d diti o nal data are 
warra nte d i n t his p o p ulati o n. T his P hase 3 st u d y is desi g ne d 
t o c ollect data i n East Asia n partici pa nts wit h R M S w h o are 
treate d wit h D R F. 
D R F is a n a mi n oet h yl ester of M M F t hat u n der g oes ra pi d 
h y dr ol ysis t hr o u g h esterases t o pr o d uce M M F. M M F is als o 
t he acti ve meta b olite of t he a p pr o ve d dr u g pr o d uct, D M F. 
A n oral f or m of D M F u n der t he tra de na me Tecfi dera ™ has 
bee n a p pr o ve d b y t he U S F D A si nce 2 0 1 3 f or t he treat me nt 
of patie nts wit h R M S. T he 4 6 2 m g d ose of D R F a n d t he 
2 4 0 m g d ose of D M F a d mi nistere d orall y pr o vi de 
bi oe q ui vale nt e x p os ure of M M F. T he safet y a n d efficac y 
pr ofile of D R F is e x pecte d t o be si milar t o t hat of D M F 
base d o n t he bi oe q ui vale nce of M M F. Of n ote, D M F’s 
efficac y a n d safet y i n t he East Asia n p o p ulati o n were 
e x pl ore d i n a ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d 
P hase 3 D M F st u d y ( St u d y 1 0 9 M S 3 0 5 [ A P E X]). T he 
res ults fr o m St u d y 1 0 9 M S 3 0 5 de m o nstrate d t hat D M F was 
well t olerate d a n d s h o we d s ustai ne d efficac y at Wee k 2 4 
( d o u ble- bli n d peri o d) a n d at Wee k 4 8 i n East Asia n 
partici pa nts wit h R R M S. T hese res ults were c o m para ble t o 
t he re gistrati o n st u dies c o n d ucte d f or D M F.
Rati o nale f or D ose a n d 
Sc he d ule Selecti o n:
T he D R F d osa ge selecte d f or t his st u d y ( 2 3 1 m g t wice dail y 
f or t he first 7 da ys a n d 4 6 2 m g t wice dail y t hereafter) is t he 
a p pr o ve d d ose re gi me n i n t he U S f or t he treat me nt of 
patie nts wit h R M S a n d has bee n selecte d as t he 
rec o m me n de d d ose i n mar keti n g a p plicati o ns t o ot her healt h 
a ut h orities. T he d oses of D R F t o be use d f or i nitial d ose 
titrati o n ( 2 3 1 m g) a n d f or treat me nt mai nte na nce ( 4 6 2 m g) 
i n t his st u d y are wit hi n t he ra n ge of d oses e val uate d i n 
c o m plete d P hase 1 st u dies.
St u d y O bjecti ves a n d E n d p oi nts
Part 1
Pri mar y O bjecti ve
T o deter mi ne t he safet y a n d t olera bilit y of D R F 
a d mi nistere d f or u p t o 2 4 wee ks i n a d ult East 
Asia n partici pa nts wit h R M S
Pri mar y E n d p oi nt
•
I nci de nce of A Es a n d S A Es at 
Wee k 2 4 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 1
•
Q ua ntitati ve a n d q ualitati ve 
c ha n ges fr o m Baseli ne Visit 
( Da y 1) t o Wee k 2 4 i n cli nical 
la b orat or y para meters, E C Gs, 
a n d vital si g ns
•
I nci de nce of C- S S R S e ve nts at 
Baseli ne Visit ( Da y 1) a n d 
t hr o u g h Wee k 2 4
Sec o n dar y O bjecti ve
Sec o n dar y E n d p oi nts
T o e val uate t he P K of D R F meta b olites ( M M F 
a n d H E S) f oll o wi n g m ulti ple d oses of D R F i n a 
s u bset of a d ult East Asia n partici pa nts wit h R M S
•
Plas ma c o nce ntrati o ns of 
M M F a n d H E S
•
N o nc o m part me ntal plas ma P K 
para meters of M M F a n d H E S, 
i ncl u di n g t he f oll o wi n g:

C ma x

A U C last

T ma x

t½ ( M M F o nl y)
Part 2
Pri mar y O bjecti ve
T o deter mi ne t he safet y a n d t olera bilit y of D R F 
a d mi nistere d f or u p t o 4 8 wee ks i n a d ult East 
Asia n partici pa nts wit h R M S
Pri mar y E n d p oi nt
•
I nci de nce of A Es a n d S A Es u p 
t o Wee k 4 8
•
Q ua ntitati ve a n d q ualitati ve 
c ha n ges fr o m Baseli ne Visit 
( Da y 1) t o Wee k 4 8 i n cli nical 
la b orat or y para meters, E C Gs, 
a n d vital si g ns
•
I nci de nce of C- S S R S e ve nts at 
Baseli ne Visit ( Da y 1) a n d 
t hr o u g h Wee k 4 8
E x pl orat or y o bjecti ves a n d e n d p oi nts are liste d i n Secti o n 4 . 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 2
St u d y Desi g n:
T his is a m ultice nter, o pe n-la bel, si n gle-ar m, P hase 3 st u d y 
t o e val uate t he safet y a n d t olera bilit y, a n d P K of D R F 
a d mi nistere d orall y t o East Asia n partici pa nts wit h R M S. 
T his st u d y will be c o n d ucte d i n 2 parts:
Part 1 is desi g ne d t o e val uate t he P K, safet y, a n d t olera bilit y 
of D R F a d mi nistere d orall y. 
Part 2 is desi g ne d as a 2 4- wee k safet y e xte nsi o n peri o d f or 
partici pa nts fr o m Part 1.
St u d y L ocati o n:
A p pr o xi matel y 4 5 sites fr o m Ja pa n a n d C hi na are pla n ne d.
St u d y P o p ulati o n:
T his st u d y will be c o n d ucte d i n male a n d fe male 
partici pa nts w h o meet t he f oll o wi n g criteria:
•
a ge d 1 8 t o 6 5 years at t he ti me of i nf or me d c o nse nt
•
F or partici pa nts i n Ja pa n a ge d < 2 0 years, writte n 
i nf or me d c o nse nt s h o ul d be o btai ne d fr o m t he 
partici pa nt a n d t heir le gall y acce pta ble 
re prese ntati ve.
•
I nf or me d c o nse nt fr o m a le gall y acce pta ble 
re prese ntati ve is n ot ma n dat or y if t he partici pa nt 
is classifie d as a n a d ult base d o n t he latest 
a p plica ble l ocal la ws.
•
dia g n ose d wit h R M S acc or di n g t o st u d y eli gi bilit y 
criteria
Detaile d criteria are descri be d i n Secti o n 6.  
N u m ber of Pla n ne d 
Partici pa nts:
A p pr o xi matel y 5 0 Ja pa nese partici pa nts a n d 5 0 C hi nese 
partici pa nts are pla n ne d t o be e nr olle d. T he S p o ns or ma y 
e nr oll fe wer t ha n 5 0 partici pa nts per c o h ort base d o n t he 
o bser ve d recr uit me nt rate i n t hese re gi o ns.
Treat me nt Gr o u ps:
T he st u d y will c o nsist of 2 treat me nt c o h orts as f oll o ws:
•
C o h ort 1: a p pr o xi matel y 5 0 Ja pa nese 
partici pa nts wit h R M S

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 3
•
C o h ort 2: a p pr o xi matel y 5 0 C hi nese partici pa nts 
wit h R M S
St u d y treat me nt i ncl u des D R F 2 3 1 m g a d mi nistere d as 
1 ca ps ule t wice dail y a n d D R F 4 6 2 m g a d mi nistere d as t w o 
2 3 1 m g ca ps ules t wice dail y. Partici pa nts will titrate fr o m 
D R F 2 3 1 m g t wice dail y f or t he first wee k o n treat me nt t o 
4 6 2 m g t wice dail y fr o m Da y 8 o n war ds.
Sa m ple Size Deter mi nati o n:
A sa m ple size of a p pr o xi matel y 5 0 partici pa nts per c o h ort is 
base d o n feasi bilit y c o nsi derati o ns a n d is dee me d s ufficie nt 
t o c haracterize t he safet y a n d t olera bilit y pr ofile. Wit h t his 
sa m ple size, t he pr o ba bilit y of o bser vi n g at least 1 S A E wit h 
a bac k gr o u n d i nci de nce of 4 % w o ul d be 8 7 % base d o n data 
fr o m t he 2 4- wee k Treat me nt Peri o d i n St u d y 
A L K 8 7 0 0- A 3 0 1 ( D R F gl o bal P hase 3 st u d y) i n R R M S 
partici pa nts w h o were naï ve t o D R F treat me nt. I n a d diti o n, 
ass u mi n g t hat t he i nci de nce of GI A Es at 2 4 wee ks is 
2 7. 5 %, as o bser ve d i n de n o v o partici pa nts recr uite d i n 
St u d y A L K 8 7 0 0- A 3 0 1, t he sa m ple size of a p pr o xi matel y 
5 0 partici pa nts per c o h ort will pr o vi de a 9 6 % pr o ba bilit y of 
o bser vi n g a p oi nt esti mate of GI A E i nci de nce rate < 3 9 % i n 
Part 1 of t he st u d y (at 2 4 wee ks). A 2 4- wee k i nci de nce rate 
of 3 9 % was o bser ve d i n East Asia n partici pa nts w h o 
recei ve d D M F t wice dail y i n St u d y 1 0 9 M S 3 0 5.
Base d o n o bser ve d M M F P K para meters i n healt h y 
v ol u nteers ( St u d y A L K 8 7 0 0- A 1 0 3), a sa m ple size of 
7 partici pa nts i n t he Ja pa nese c o h ort will pr o vi de a 
reas o na ble precisi o n of t he P K para meters of M M F a n d 
H E S.
Visit Sc he d ule:
Partici pa nts will ha ve u p t o 1 5 visits d uri n g t he st u d y. 
D uri n g Part 1, partici pa nts will ha ve u p t o 8 visits d uri n g 
t he Treat me nt Peri o d (i.e., Baseli ne Visit [ Da y 1], Wee k 2, 
Wee k 4, Wee k 8, Wee k 1 2, Wee k 1 6, Wee k 2 0, a n d 
Wee k 2 4) a n d will be c o ntacte d via tele p h o ne t wice. 
D uri n g Part 2, partici pa nts will re p ort t o t he st u d y site e ver y 
4 wee ks u p t o Wee k 4 8 d uri n g t he Treat me nt Peri o d, f or a 
t otal of u p t o 7 visits, a n d will ha ve t he Safet y F oll o w- U p 
Visit 2 wee ks later ( Wee k 5 0) after t he e n d of t he Treat me nt 
Peri o d.
St u d y assess me nts c o n d ucte d at eac h visit are liste d i n t he  
Sc he d ule of Acti vities ( Ta ble 1 ).

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 4
D urati o n of St u d y Partici pati o n:
St u d y d urati o n f or partici pa nts w h o c o m plete t he st u d y will 
be u p t o 5 4 wee ks:
•
4- wee k Scree ni n g Peri o d
•
2 4- wee k Treat me nt Peri o d i n Part 1
•
2 4- wee k Treat me nt Peri o d i n Part 2
•
2- wee k Safet y F oll o w- U p Peri o d
Be nefit- Ris k A nal ysis:
T he p ote ntial be nefits of partici pati o n i n t his st u d y are 
e x pecte d t o o ut wei g h t he ris ks.
T he safet y pr ofile of D R F relies o n t he well- k n o w n safet y 
pr ofile of t he refere nce dr u g, D M F. T he safet y of D M F has 
bee n esta blis he d i n 2 ra n d o mize d, place b o-c o ntr olle d, 
d o u ble- bli n d, pi v otal P hase 3 st u dies ( St u d y 1 0 9 M S 3 0 1 a n d 
St u d y 1 0 9 M S 3 0 2) a n d f urt her esta blis he d i n e xte nsi ve 
p ost mar keti n g e x perie nce. Data fr o m D R F st u dies ha ve 
s h o w n c o m para bilit y t o t he D M F safet y pr ofile, wit h n o 
ne w safet y iss ues i de ntifie d t o date.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
1 5
1. 2. 
St u d y Desi g n Sc he m atic
Fi g ure 1: 
St u d y Desi g n Sc he m atic

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
1 6
B L = baseli ne; E T = earl y ter mi nati o n; F U = f oll o w- u p; M S = m ulti ple scler osis; P K = p har mac o ki netic; S C R = scree ni n g; T C = tele p h o ne c o ntact
aL y m p h oc yte m o nit ori n g f oll o w- u p visits ( ma xi m u m 3 visits wit hi n 6 m o nt hs) ma y be re q uire d after t his visit
b Tele p h o ne c o ntact at Da y 8 ( Wee k 1) a n d Da y 2 2 ( Wee k 3) f or safet y a n d t olera bilit y assess me nts 
cC hi nese partici pa nts will n ot ha ve i nte nsi ve P K sa m pli n g.
d I n t he e ve nt t hat a partici pa nt is e nr olle d i n b ot h t he s parse a n d i nte nsi ve P K c o h orts a n d i nte nsi ve P K sa m pli n g was c o m plete d o n Da y 2 9 or Da y 5 7 f or a 
partici pa nt, s parse P K sa m pli n g will n ot be re q uire d f or t h ose da ys. H o we ver, if it is deter mi ne d t hat i nte nsi ve P K is n ot feasi ble b y Da y 5 7, s parse P K sa m pli n g 
will be c o m plete d acc or di n g t o pr ot oc ol, a n d i nte nsi ve P K s h o ul d be c o m plete d at later visits.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
1 7
1. 3. 
Sc he d ule of Acti vities
T a ble 1: 
Sc he d ule of Acti vities
P art 1: 2 4- Wee k O pe n- L a bel Tre at me nt 1
P art 2: 2 4- Wee k O pe n- L a bel 
Tre at me nt 1  
S afet y 
F U 2
Visit
S C R
B L
1
T C 3
2
T C 3
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4/
E T
1 5
D a y
- 2 8 
t o - 1
1
8 
( ± 2)
1 5 
( ± 3)
2 2 
( ± 2)
2 9 
( ± 3)
5 7 
( ± 5)
8 5 
( ± 5)
1 1 3 
( ± 5)
1 4 1 
( ± 5)
1 6 9 
( ± 5)
1 9 7 
( ± 5)
2 2 5 
( ± 5)
2 5 3 
( ± 5)
2 8 1 
( ± 5)
3 0 9 
( ± 5)
3 3 7 
( ± 5)
3 5 1 
( ± 5)
Wee k
- 4 t o 
- 1
1
2
3
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
5 0
I nf or me d C o nse nt 
X
I ncl usi o n/
E xcl usi o n Criteria
X
X 4
De m o gra p hics a n d 
Me dical Hist or y
X
P h ysical E xa mi nati o n 5  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hei g ht
X
Wei g ht
X
X 4
X
X
X
X
X
X
X
X
X
F S H Test 6
X
 
Ser u m Pre g na nc y Test 7, 8 
X
X
Uri ne Pre g na nc y Test 7 ,9
X 4
X  
X
X
X
X
X
X
X
X
X
X
X
X
HI V/ He patitis Scree n
X
T S H Test
X
Scree ni n g f or T B (I G R A)
X
Bi oc he mistr y, Uri nal ysis, 
a n d He mat ol o g y 1 0
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
P K Sa m pli n g
X 1 1, 
1 2, 1 3, 
1 4
X 1 1, 
1 2 , 1 3, 
1 4
X 1 1, 
1 2, 1 3, 
1 4
X 1 1, 
1 2, 1 3, 
1 4
X 1 1, 
1 2, 1 3, 
1 4
X 1 1, 
1 2, 1 3, 
1 4
Vital Si g ns 1 5
X
X 4
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
1 8
P art 1: 2 4- Wee k O pe n- L a bel Tre at me nt 1
P art 2: 2 4- Wee k O pe n- L a bel 
Tre at me nt 1  
S afet y 
F U 2
Visit
S C R
B L
1
T C 3
2
T C 3
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4/
E T
1 5
D a y
- 2 8 
t o - 1
1
8 
( ± 2)
1 5 
( ± 3)
2 2 
( ± 2)
2 9 
( ± 3)
5 7 
( ± 5)
8 5 
( ± 5)
1 1 3 
( ± 5)
1 4 1 
( ± 5)
1 6 9 
( ± 5)
1 9 7 
( ± 5)
2 2 5 
( ± 5)
2 5 3 
( ± 5)
2 8 1 
( ± 5)
3 0 9 
( ± 5)
3 3 7 
( ± 5)
3 5 1 
( ± 5)
Wee k
- 4 t o 
- 1
1
2
3
4
8
1 2
1 6
2 0
2 4
2 8
3 2
3 6
4 0
4 4
4 8
5 0
1 2- Lea d E C G
X
X 4
X
X
X
X
X
X
X
X
X
X
X
C- S S R S 1 9
X
X 4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
A E Rec or di n g
----------------------------------------------------------------------------------------------- X---------------------------------------------------------------------
S A E Rec or di n g
--------------------------------------------------------------------------------------------------------- X---------------------------------------------------------------------
C o nc o mita nt T hera p y 
a n d Pr oce d ure Rec or di n g
--------------------------------------------------------------------------------------------------------- X---------------------------------------------------------------------
St u d y Treat me nt 
Dis pe nsati o n
X
X
X
X
X
X
X
X
X
X
X
X
X
1 U nsc he d ule d visits ma y occ ur at a n y ti me as per pr ot oc ol re q uire me nt.
2 A n y partici pa nt w h o pre mat urel y disc o nti n ues st u d y treat me nt or wit h dra ws fr o m t he st u d y will be as ke d t o ret ur n t o t he cli nic t o c o m plete all st u d y 
assess me nts f or Visit 1 4/ E T Visit a n d f or t he Safet y F oll o w- U p Visit 2 wee ks later ( Visit 1 5).
3 Safet y a n d t olera bilit y assess me nts (i ncl u di n g A Es a n d c o nc o mita nt me dicati o ns) will be c o n d ucte d b y tele p h o ne o n t hese da ys.
4 T o be c o n d ucte d pre d ose at Visit 1.
5 F ull p h ysical e xa mi nati o n at Scree ni n g. Brief p h ysical e xa mi nati o n, s y m pt o m- directe d, at all ot her visits.
6 T o c o nfir m p ost me n o pa usal stat us (i n p ost me n o pa usal fe male partici pa nts o nl y).
7 T o be perf or me d o nl y i n w o me n of c hil d beari n g p ote ntial; res ults m ust be ne gati ve t o c o nti n ue partici pati o n i n st u d y.
8 Sa m ples f or ser u m pre g na nc y test are t o be a nal yze d b y t he ce ntral la b orat or y. Res ults m ust be k n o w n pri or t o st u d y treat me nt distri b uti o n.
9 Sa m ples f or uri ne pre g na nc y test are t o be a nal yze d b y t he l ocal la b orat or y.
1 0 La b orat or y assess me nt as per Ta ble 5 .
1 1 I nte nsi ve P K sa m ples will be c ollecte d i n a s u bset of P K p o p ulati o n ( n = 7 Ja pa nese c o h ort o nl y) at a n y ti me p oi nt i n t he peri o d bet wee n Wee k 4 ( Da y 2 9, Visit 
3 ± 3 da ys) a n d Wee k 2 4 ( Da y 1 6 9, Visit 8 ± 5 da ys), b ot h i ncl usi ve; see t he P K sa m pli n g ti me p oi nts i n Ta ble 6 . 
1 2 I n b ot h Ja pa nese a n d C hi nese partici pa nts, o n Da ys 2 9 a n d 5 7, P K sa m ples will be ta ke n - 3 0 t o 0 mi n utes pre d ose a n d a p pr o xi matel y 2 t o 3 h o urs p ost d ose f or 
t h ose partici pa nts w h ose i nte nsi ve P K sa m ples are n ot c ollecte d o n t his da y ( n o n- P K p o p ulati o n).
1 3 N o i nte nse P K sa m pli n g will be c o n d ucte d i n C hi nese M S partici pa nts. C hi nese M S partici pa nts will ha ve s parse P K o n Da ys 2 9 a n d 5 7.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
1 9
1 4 I n t he e ve nt t hat a partici pa nt is e nr olle d i n b ot h t he s parse a n d i nte nsi ve P K c o h orts a n d i nte nsi ve P K sa m pli n g was c o m plete d o n Da y 2 9 or Da y 5 7 f or a 
partici pa nt, s parse P K sa m pli n g will n ot be re q uire d f or sai d da ys. H o we ver, if it is deter mi ne d t hat i nte nsi ve P K is n ot feasi ble b y Da y 5 7, s parse P K sa m pli n g 
will be c o m plete d acc or di n g t o pr ot oc ol a n d i nte nsi ve P K s h o ul d be c o m plete d at later visits.
1 5 Vital si g n meas ure me nts i ncl u de te m perat ure, res pirat or y rate, bl o o d press ure, a n d p ulse rate. Bl o o d press ure, res pirat or y rate, a n d p ulse rate will be meas ure d 
after t he partici pa nt has bee n i n a seate d or s u pi ne p ositi o n f or at least 5 mi n utes.
1 9 Use t he " Baseli ne Scree ni n g" versi o n at Scree ni n g; use t he " Si nce Last Visit" versi o n at all ot her sc he d ule d visits.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of Bi o ge n M A I nc.
2 0
T a ble 2:  
A d diti o n al F oll o w- U p f or P artici p a nts wit h L y m p h o pe ni a
L M Visits 1
Assess me nts
L M Visit 1
( 2 m o nt hs after Safet y F oll o w- U p 
Visit ± 7 da ys)
L M Visit 2
( 4 m o nt hs after Safet y F oll o w- U p 
Visit ± 7 da ys)
L M Visit 3
( 6 m o nt hs after Safet y F oll o w- U p 
Visit ± 7 da ys)
L y m p h oc yte C o u nt
X
X
X
C o nc o mita nt Me dicati o n
X
X
X
1 Partici pa nts w h o c o m plete t he st u d y or w h o ter mi nate t he st u d y earl y a n d ha ve a last meas ure d l y m p h oc yte c o u nt < L L N will ret ur n t o t he cli nic f or a d diti o nal 
L M visits e ver y 2 m o nt hs starti n g fr o m Visit 1 5 ( or fr o m t he E T visit f or partici pa nts w h o ter mi nate t he st u d y earl y) f or a peri o d of 6 m o nt hs (i.e., a ma xi m u m 
of 3 visits), u ntil l y m p h oc yte c o u nts reac h n or mal li mits ( ≥ L L N), or u ntil a n ot her D M T is starte d t hat ma y affect l y m p h oc yte c o u nts (i n t his case, l y m p h oc yte 
m o nit ori n g f or t hat D M T will a p pl y), w hic he ver occ urs first. All assess me nts re q uire d f or t he Safet y F oll o w- U p Visit ( Visit 1 5, Ta ble 1 ) s h o ul d be c o m plete d 
f or t hese partici pa nts pri or t o i nitiati o n of t he L M visits.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2 1
2. 
LI S T O F A B B R E VI A TI O N S
A E
a d verse e ve nt
A E SI
a d verse e ve nt of s pecial i nterest
A L C
a bs ol ute l y m p h oc yte c o u nt
A L T
ala ni ne a mi n otra nsferase 
a nti- H Bc
he patitis B c ore a nti b o d y
a nti- H Bs
he patitis B s urface a nti b o d y
A S T
as partate a mi n otra nsferase
A U C
area u n der t he c o nce ntrati o n-ti me c ur ve
A U C last
area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me zer o t o ti me of 
last meas ura ble c o nce ntrati o n
A U C ta u
area u n der t he c o nce ntrati o n-ti me c ur ve wit hi n a d osi n g i nter val
B L
baseli ne
C D 1 9
cl uster of differe ntiati o n 1 9
CI
c o nfi de nce i nter val
CI S
cli nicall y is olate d s y n dr o me
C L/ F
a p pare nt t otal b o d y cleara nce
C ma x
ma xi m u m o bser ve d c o nce ntrati o n
C R F
case re p ort f or m
C R O
c o ntract researc h or ga nizati o n
C- S S R S
C ol u m bia S uici de Se verit y Rati n g Scale
C V of A U C
cr oss vali date d area u n der t he c ur ve
D H A
Directi o ns f or Ha n dli n g a n d A d mi nistrati o n
D M F
di met h yl f u marate
D M T
disease- m o dif yi n g t hera p y
D R F
dir o xi mel f u marate
E C G
electr ocar di o gra m 
e G F R
esti mate d gl o mer ular filtrati o n rate 
E Q- 5 D
E ur o Q o L- 5 Di me nsi o ns q uesti o n naire
E T
earl y ter mi nati o n
E U
E ur o pea n U ni o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
F S
f u ncti o nal s yste m
F S H
f ollicle-sti m ulati n g h or m o ne
F U
F oll o w- U p Visit
G A
glatira mer acetate
G C P
G o o d Cli nical Practice
G G T
ga m ma- gl uta m yl tra nsferase 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2 2
GI
gastr oi ntesti nal
H Bs A g
he patitis B s urface a nti ge n
H E S
2- h y dr o x yet h yl s ucci ni mi de
H C V
he patitis C vir us
H D P E
hi g h de nsit y p ol yet h yle ne
HI V
h u ma n i m m u n o deficie nc y vir us
H P M C
h y dr o x y pr o p yl met h ylcell ul ose
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I F N- α
i nterfer o n-al p ha
I F N- β
i nterfer o n- beta
I G R A
i nterfer o n- ga m ma release assa y
I M P
i n vesti gati o nal me dici nal pr o d uct
I R T
i nteracti ve res p o nse tec h n ol o g y
I V
i ntra ve n o us(l y)
I V M P
i ntra ve n o us met h yl pre d nis ol o ne
L D H
lactate de h y dr o ge nase 
L L N
l o wer li mit of n or mal
L M
l y m p h oc yte m o nit ori n g
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
M M F
m o n o met h yl f u marate
M S
m ulti ple scler osis
P C S
p ote ntiall y cli nicall y seri o us
P K
p har mac o ki netic(s)
P M L
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y
R M S
rela psi n g f or ms of M S
R N A
ri b o n ucleic aci d
R R M S
rela psi n g-re mitti n g M S
S 1 P
s p hi n g osi ne 1- p h os p hate
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S C
s u bc uta ne o us(l y)
S C R
scree ni n g
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
t½
eli mi nati o n half-life
T B
t u berc ul osis
T C
tele p h o ne c o ntact
T la g
la g ti me
T ma x
ti me t o reac h Cma x
T S H
t h yr oi d sti m ulati n g h or m o ne
U L N
u p per li mit of n or mal 
U S
U nite d States
V Z / F
a p pare nt v ol u me of distri b uti o n

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2 3
3. 
I N T R O D U C TI O N 
Dir o xi mel f u marate ( D R F; BII B 0 9 8) was de vel o pe d as a m o difie d-release oral treat me nt f or 
R M S. I n Oct o ber 2 0 1 9, D R F, u n der t he tra de na me V U M E RI T Y ® , was a p pr o ve d b y t he 
U S F D A f or t he treat me nt of a d ults wit h R M S, i ncl u di n g CI S, rela psi n g-re mitti n g disease, a n d 
acti ve sec o n dar y pr o gressi ve M S. D R F is a n a mi n oet h yl ester of M M F t hat u n der g oes 
pres yste mic h y dr ol ysis t hr o u g h esterases t o pr o d uce M M F [ T E C FI D E R A ®   U S PI 2 0 2 2]. M M F 
is als o t he acti ve meta b olite of t he a p pr o ve d dr u g pr o d uct D M F, als o k n o w n as Tecfi dera™ 
[T E C FI D E R A ®  U S PI 2 0 2 2 ].
3. 1.
St u d y R ati o n ale
T he mai n g oal of t he c urre nt st u d y is t o assess t he safet y a n d t olera bilit y, a n d P K pr ofile of D R F 
a d mi nistere d orall y i n a d ult East Asia n partici pa nts wit h R M S. 
D R F was de vel o pe d as a m o difie d-release oral treat me nt f or R M S. I n Oct o ber 2 0 1 9, D R F u n der 
t he tra de na me V U M E RI T Y®  was a p pr o ve d b y t he U S F D A f or t he treat me nt of a d ult patie nts 
wit h R M S, t o i ncl u de cli nicall y is olate d s y n dr o me, rela psi n g-re mitti n g disease, a n d acti ve 
sec o n dar y pr o gressi ve disease.
I n partici pa nts wit h R R M S, D R F de m o nstrate d safet y a n d t olera bilit y i n 2 gl o bal P hase 3 st u dies, 
St u d y A L K 8 7 0 0- A 3 0 1 ( E V O L V E- M S- 1; c urre ntl y o n g oi n g) a n d St u d y A L K 8 7 0 0- A 3 0 2 
( E V O L V E- M S- 2; c o m plete d). I n b ot h st u dies, D R F at a d ose of 2 3 1 m g t wice dail y f or 1 wee k 
f oll o we d b y 4 6 2 m g t wice dail y f or 9 6 wee ks (i n St u d y A L K 8 7 0 0- A 3 0 1) a n d at a d ose of 
4 6 2 m g t wice dail y f or 4 wee ks (i n St u d y A L K 8 7 0 0- A 3 0 2) ha d a n acce pta ble safet y pr ofile a n d 
was well t olerate d.
D R F is a n a mi n oet h yl ester of M M F t hat u n der g oes ra pi d h y dr ol ysis t hr o u g h esterases t o 
pr o d uce M M F. M M F is als o t he acti ve meta b olite of t he a p pr o ve d dr u g pr o d uct, D M F. A n oral 
f or m of D M F u n der t he tra de na me Tecfi dera® has bee n a p pr o ve d b y t he U S F D A si nce 2 0 1 3 f or 
t he treat me nt of patie nts wit h R M S. T he 4 6 2 m g d ose of D R F a n d t he 2 4 0 m g d ose of D M F 
a d mi nistere d orall y pr o vi de bi oe q ui vale nt e x p os ure of M M F. T he o verall safet y a n d efficac y 
pr ofile of D R F is e x pecte d t o be si milar t o t hat of D M F base d o n t he bi oe q ui vale nce of M M F. 
D R F de m o nstrate d cli nicall y si g nifica nt i m pr o ve d GI t olera bilit y c o m pare d wit h D M F i n t he 
5- wee k, ra n d o mize d, P hase 3 St u d y A L K 8 7 0 0- A 3 0 2. D R F pr o vi des a n M M F e x p os ure pr ofile 
t hat ma y li mit t he GI effects ass ociate d wit h D M F treat me nt w hile mai ntai ni n g efficac y 
c o m para ble t o t hat de m o nstrate d b y D M F. T heref ore, D R F has t he p ote ntial t o a d dress a n u n met 
me dical nee d f or patie nts wit h rela psi n g f or ms of M S w h o are u na ble t o t olerate D M F, 
partic ularl y d ue t o GI effects.
Of n ote, D M F’s efficac y a n d safet y i n t he East Asia n p o p ulati o n were e x pl ore d i n a ra n d o mize d, 
d o u ble- bli n d, place b o-c o ntr olle d P hase 3 D M F st u d y ( St u d y 1 0 9 M S 3 0 5 [ A P E X]). T he res ults 
fr o m St u d y 1 0 9 M S 3 0 5 de m o nstrate d t hat D M F was well t olerate d a n d s h o we d s ustai ne d efficac y 
at Wee k 2 4 ( d o u ble- bli n d peri o d) a n d at Wee k 4 8 i n East Asia n partici pa nts wit h R R M S. T hese 
res ults were c o m para ble t o t he re gistrati o n st u dies c o n d ucte d f or D M F.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2 4
3. 1. 1.  
R ati o n ale f or St u d y P o p ul ati o n
Alt h o u g h t he c o m ple x a n d m ultifact orial pat h o ge nesis of M S is c o nsi dere d t o be ge nerall y 
si milar acr oss Ca ucasia n a n d Asia n p o p ulati o ns, t here are c urre ntl y li mite d safet y a n d 
t olera bilit y, a n d efficac y data o n D R F i n t he Asia n p o p ulati o n, i ncl u di n g t he East Asia n M S 
p o p ulati o ns. T heref ore, a d diti o nal data are warra nte d i n t his p o p ulati o n. T his P hase 3 st u d y is 
desi g ne d t o c ollect data i n East Asia n partici pa nts wit h R M S w h o are treate d wit h D R F.
3. 1. 2.  
R ati o n ale f or D osi n g Re gi me n
T he D R F d osa ge selecte d f or t his st u d y ( 2 3 1 m g t wice dail y f or t he first 7 da ys a n d 4 6 2 m g 
t wice dail y t hereafter) is t he a p pr o ve d d ose re gi me n i n t he U S f or t he treat me nt of patie nts wit h 
R M S a n d has bee n selecte d as t he rec o m me n de d d ose i n mar keti n g a p plicati o ns t o ot her healt h 
a ut h orities. T he d oses of D R F t o be use d f or i nitial d ose titrati o n ( 2 3 1 m g) a n d f or treat me nt 
mai nte na nce ( 4 6 2 m g) i n t his st u d y are wit hi n t he ra n ge of d oses e val uate d i n c o m plete d P hase 1 
st u dies.
As n ote d a b o ve, D R F s hares t he c o m m o n acti ve meta b olite M M F wit h D M F. I n t he P hase 1 
st u d y of D R F a n d D M F i n healt h y v ol u nteers ( A L K 8 7 0 0- A 1 0 3), at differe nt stre n gt hs, D R F 
( 4 6 2 m g) a n d D M F ( 2 4 0 m g) s h o we d bi oe q ui vale nt e x p os ures of M M F a n d are t heref ore 
e x pecte d t o ha ve si milar efficac y a n d safet y pr ofiles. Res ults of t he D M F P K, safet y, a n d 
t olera bilit y st u d y i n Ja pa nese, C hi nese, a n d Ca ucasia n a d ult healt h y v ol u nteers 
( St u d y 1 0 9 H V 1 0 8) i n dicate t hat t he P K be ha vi or of D M F acr oss t he 3 et h nic gr o u ps is si milar 
a n d c o nsiste nt wit h t he o bser ve d e x p os ure i n mi xe d-race p o p ulati o ns i n pre vi o us st u dies wit h 
eit her healt h y v ol u nteers or M S patie nts. T hese o bser vati o ns f urt her s u p p ort t he i m ple me ntati o n 
of a 4 6 2 m g t wice dail y d osi n g re gi me n of D R F i n t he c urre nt st u d y.
3. 2. 
B ac k gr o u n d
3. 2. 1.  
O ver vie w of M ulti ple Scler osis
M S is a c hr o nic i nfla m mat or y, de m yeli nati n g, a n d ne ur o de ge nerati ve disease of t he C N S i n 
w hic h acti vate d i m m u ne cells i n va de t he C N S a n d ca use i nfla m mati o n, de m yeli nati o n, a x o nal 
l oss, a n d gli osis [ P o pesc u 2 0 1 3a; P o pesc u 2 0 1 3 b]. M S is t he m ost c o m m o n disa bli n g 
ne ur ol o gical disease of y o u n g a d ults [ Br o w ne 2 0 1 4], wit h first s y m pt o ms ma nifesti n g i n 
a p pr o xi matel y 7 0 % of patie nts bet wee n 2 0 a n d 4 0 years of a ge [ Flac he nec ker a n d St u ke 2 0 0 8; 
Wei ns he n ker 1 9 8 9] . T he disease is m ore c o m m o n i n w o me n t ha n me n [ Har b o 2 0 1 3], a n d 
pre vale nce ge nerall y i ncreases wit h latit u de [ Br o w ne 2 0 1 4]. M S is a maj or ca use of t he o verall 
ne ur ol o gical disease b ur de n [ Gr o u p 2 0 1 7], wit h a p pr o xi matel y 2. 3 milli o n i n di vi d uals affecte d 
w orl d wi de a n d a me dia n gl o bal M S pre vale nce of 3 3 per 1 0 0, 0 0 0 [ Br o w ne 2 0 1 4].
M ost M S patie nts prese nt i nitiall y wit h t he CI S or rela psi n g-re mitti n g f or m of t he disease ( 8 5 %), 
wit h rela pses a n d re missi o ns ca use d b y f ocal de m yeli nati n g lesi o ns, or “ pla q ues,” disse mi nate d 
i n ti me a n d s pace i n t he C N S. A b o ut 1 0 % t o 1 5 % of M S patie nts prese nt wit h a n i nsi di o us 
pr o gressi ve c o urse fr o m o nset, ter me d pri mar y pr o gressi ve M S [ H ur witz 2 0 0 9]. Wit h o ut 
treat me nt, R R M S i n maj orit y of patie nts e v ol ves t o sec o n dar y pr o gressi ve M S c haracterize d b y 
pr o gressi ve accr ual of disa bilit y [ Gi o va n n o ni 2 0 1 6]. P h ysical disa bilit y t y picall y ma nifests 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2 5
wit hi n 1 5 t o 2 0 years after prese ntati o n wit h M S [ Tre mlett 2 0 1 0]. Wit h treat me nt, t he me dia n 
life s pa n of c o m merciall y i ns ure d M S patie nts i n t he U S is a p pr o xi matel y 6 years s h orter t ha n 
n o n- M S i n di vi d uals fr o m t he sa me p o p ulati o n [ Ka uf ma n 2 0 1 4].
3. 2. 2.  
C urre nt T her a pies f or M ulti ple Scler osis
T he c urre nt sta n dar d of care i n rela psi n g M S uses 2 ge neral a p pr oac hes: ( 1) i m m u n o m o d ulat or y 
dr u gs ai me d at re d uci n g t he fre q ue nc y a n d se verit y of rela pses as well as t he acc u m ulati o n of 
p h ysical disa bilit y a n d ( 2) dr u gs/i nter ve nti o ns t hat pr o vi de s y m pt o matic treat me nt as nee de d f or 
de pressi o n, bla d der d ysf u ncti o n, m o bilit y i m pair me nt, s pasticit y, a n d ot her c o m m o n 
c o m or bi dities/se q uelae of M S disease. I m m u n o m o d ulat or y dr u gs c urre ntl y a vaila ble f or M S var y 
b y c o u ntr y a n d i ncl u de i nterfer o n- beta pr o d ucts ( A v o ne x ® , Re bif® , 
Betaser o n ® / Betafer o n® / E xta via® , a n d Ple gri d y® ), G A ( C o pa x o ne® ), fi n g oli m o d ( Gile n ya® ), 
terifl u n o mi de ( A u ba gi o® ), D M F ( Tecfi dera), nataliz u ma b ( T ysa bri™), ale mt uz u ma b 
( Le mtra da® ), ocreliz u ma b ( Ocre v us® ), ofat u m u ma b ( Kesi m pta® ), mit o xa ntr o ne ( N o va ntr o ne® ), 
cla dri bi ne ( Ma ve ncla d ® ), a n d si p o ni m o d ( Ma yze nt® ).
3. 2. 3. 
Pr ofile of Pre vi o us E x perie nce Wit h D R F
T he pri mar y e val uati o n of D R F efficac y is base d o n a P K bri d gi n g a p pr oac h, w hic h 
de m o nstrate d c o m para ble M M F P K para meters f or D R F a n d D M F after oral a d mi nistrati o n of 
4 6 2 m g a n d 2 4 0 m g, res pecti vel y. T he P K bri d gi n g was esta blis he d b y ge nerati n g c o m parati ve 
M M F bi oa vaila bilit y P K data f or D R F a n d D M F u n der a n u m ber of dietar y c o n diti o ns i n 
differe nt cli nical st u dies. C o n diti o ns were i de ntifie d t hat res ulte d i n M M F e x p os ures t hat fell 
wit hi n t he ra n ge of e x p os ures ge nerate d w he n D M F was ta ke n wit h a n d wit h o ut f o o d.
T he effect of f o o d o n M M F P K after a d mi nistrati o n of D R F is nearl y i de ntical t o t he effect t hat 
f o o d has o n D M F P K. D R F a n d D M F pr o d uce bi oe q ui vale nt e x p os ure ( A U C) of M M F acr oss all 
teste d dietar y c o n diti o ns, w hile t he M M F Cma x  after D R F a d mi nistrati o n is wit hi n t he Cma x  ra n ge 
deter mi ne d f or D M F.
T he effect of f o o d o n M M F o verall e x p os ure ( A U C) after D R F a d mi nistrati o n was si milar t o t hat 
of D M F. T he i m pact of meal t y pe o n t he M M F C ma x  was relate d t o t he fat or cal oric c o nte nt, as 
reflecte d b y re d ucti o ns of a p pr o xi matel y 1 2 %, 2 5 %, a n d 4 4 % wit h l o w-fat, me di u m-fat, a n d 
hi g h-fat meals, res pecti vel y [ T E C FI D E R A ®   U S PI 2 0 2 2].
I n t he o n g oi n g o pe n-la bel St u d y A L K 8 7 0 0- A 3 0 1 ( N = 1 0 5 7 partici pa nts recei ve d st u d y 
treat me nt) e val uati n g t he l o n g-ter m effects of D R F i n partici pa nts wit h R R M S, i nteri m res ults 
ha ve s h o w n t hat D R F is ge nerall y well t olerate d f or u p t o 9 6 wee ks, a n d n o ne w safet y si g nals 
ha ve bee n i de ntifie d. I n a c o m plete d P hase 3 st u d y, St u d y A L K 8 7 0 0- A 3 0 2 ( N = 5 0 4 partici pa nts 
recei ve d st u d y treat me nt), w hic h was a ra n d o mize d, d o u ble- bli n d, c o ntr olle d st u d y, t he GI 
t olera bilit y of D R F a n d D M F i n partici pa nts wit h R R M S was c o m pare d. T he res ults ha ve s h o w n 
t hat t he d urati o n, i nci de nce, a n d se verit y of partici pa nt-re p orte d GI s y m pt o ms were si g nifica ntl y 
l o wer i n t he gr o u p treate d wit h D R F c o m pare d wit h t he gr o u p treate d wit h D M F.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2 6
See t he I n vesti gat or’s Br oc h ure f or detaile d i nf or mati o n o n rele va nt n o ncli nical a n d cli nical 
st u dies.
3. 3. 
Be nefit- Ris k Assess me nt
T he p ote ntial ris ks relate d t o partici pati o n i n t his st u d y are j ustifie d b y t he a ntici pate d be nefit t o 
partici pa nts.
Detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y e x pecte d 
A Es of D R F is pr o vi de d i n t he I n vesti gat or’s Br oc h ure a n d I C F. A hi g h-le vel s u m mar y of t h ose 
be nefits a n d ris ks k n o w n d uri n g st u d y desi g n is pr o vi de d here.
T he safet y pr ofile of D R F relies o n t he well- k n o w n safet y pr ofile of t he refere nce dr u g, D M F.
T he safet y of D M F has bee n esta blis he d i n 2 ra n d o mize d, place b o-c o ntr olle d, d o u ble- bli n d, 
pi v otal P hase 3 st u dies ( St u d y 1 0 9 M S 3 0 1 a n d St u d y 1 0 9 M S 3 0 2) a n d f urt her esta blis he d i n 
e xte nsi ve p ost mar keti n g e x perie nce. Fl us hi n g a n d GI e ve nts (a b d o mi nal pai n, na usea, diarr hea, 
a n d v o miti n g) were a m o n g t he m ost c o m m o nl y e x perie nce d A Es wit h D M F i n t he 2 pi v otal 
P hase 3 st u dies [ P hilli ps 2 0 1 7]. St u d y 1 0 9 M S 3 0 5 s h o we d t hat D M F ha d a n acce pta ble safet y 
pr ofile i n East Asia n partici pa nts t hat was c o nsiste nt wit h t he pr ofile esta blis he d i n t he st u dies 
wit h gl o bal partici pa nts. I m p orta nt i de ntifie d ris ks f or D M F a n d, he nce, D R F i ncl u de decreases 
i n l y m p h oc yte c o u nts a n d P M L. Data fr o m D R F st u dies ha ve s h o w n c o m para bilit y t o t he D M F 
safet y pr ofile, wit h n o ne w safet y iss ues i de ntifie d t o date. 
I n St u d y A L K 8 7 0 0- A 3 0 2, w hic h was a 5- wee k pr os pecti ve, ra n d o mize d, bli n de d c o ntr ol st u d y 
i n partici pa nts wit h R R M S t hat f or mall y e x pl ore d differe nces i n GI t olera bilit y bet wee n D R F 
( N = 2 5 3) a n d D M F ( N = 2 5 1), t he d urati o n, i nci de nce, a n d se verit y of partici pa nt-re p orte d GI 
s y m pt o ms were si g nifica ntl y l o wer acr oss a m ultit u de of e n d p oi nts (i ncl u di n g t he pri mar y 
e n d p oi nt) i n t he gr o u p of partici pa nts treate d wit h D R F c o m pare d wit h t he gr o u p of partici pa nts 
treate d wit h D M F. T he i nci de nce of GI A Es i n t he D R F gr o u p was l o wer c o m pare d wit h t he 
D M F gr o u p ( 3 4. 8 % a n d 4 9. 0 %, res pecti vel y), a n d disc o nti n uati o ns d uri n g t he Treat me nt Peri o d 
d ue t o GI e ve nts were als o n ota bl y less i n t he D R F gr o u p c o m pare d wit h t he D M F gr o u p ( 0. 8 % 
a n d 4. 8 %, res pecti vel y) [ Nais mit h 2 0 2 0]. I n St u d y A L K 8 7 0 0- A 3 0 1 ( N = 1 0 5 7), i nteri m res ults 
s h o we d t hat D R F is ge nerall y well t olerate d f or u p t o 9 6 wee ks, a n d n o ne w safet y si g nals ha ve 
bee n i de ntifie d. T he i nci de nce of GI A Es i n de n o v o recr uite d partici pa nts at Wee k 2 4 was 
2 7. 5 %.
T hese res ults fr o m t he P hase 3 D R F st u dies s u p p ort a fa v ora ble safet y a n d efficac y pr ofile i n 
patie nts wit h R R M S. It is a ntici pate d t hat t he a b o ve fa v ora ble res ults re p orte d i n gl o bal P hase 3 
st u dies wit h D R F will als o be nefit partici pa nts w h o recei ve D R F treat me nt i n t his st u d y.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2 7
4. 
S T U D Y O B J E C TI V E S A N D E N D P OI N T S
T a ble 3: 
P art 1 St u d y O bjecti ves a n d E n d p oi nts
Pri m ar y O bjecti ve
Pri m ar y E n d p oi nts
T o deter mi ne t he safet y a n d t olera bilit y 
of D R F a d mi nistere d f or u p t o 
2 4 wee ks i n a d ult East Asia n 
partici pa nts wit h R M S
•
I nci de nce of A Es a n d S A Es at Wee k 2 4 
•
Q ua ntitati ve a n d q ualitati ve c ha n ges 
fr o m Baseli ne Visit ( Da y 1) t o Wee k 2 4 
i n cli nical la b orat or y para meters, E C Gs, 
a n d vital si g ns
•
I nci de nce of C- S S R S e ve nts at Baseli ne 
Visit ( Da y 1) a n d t hr o u g h Wee k 2 4
Sec o n d ar y O bjecti ve
Sec o n d ar y E n d p oi nts
T o e val uate t he P K of D R F meta b olites 
( M M F a n d H E S) f oll o wi n g m ulti ple 
d oses of D R F i n a s u bset of a d ult East 
Asia n partici pa nts wit h R M S
•
Plas ma c o nce ntrati o ns of M M F a n d H E S
•
N o nc o m part me ntal plas ma P K 
para meters of M M F a n d H E S, i ncl u di n g 
t he f oll o wi n g:

C ma x

A U C last

T ma x

t½ ( M M F o nl y)

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2 8
T a ble 4: 
P art 2 St u d y O bjecti ve a n d E n d p oi nts
Pri m ar y O bjecti ve
Pri m ar y E n d p oi nts
T o deter mi ne t he safet y a n d t olera bilit y 
of D R F a d mi nistere d f or u p t o 
4 8 wee ks i n a d ult East Asia n 
partici pa nts wit h R M S
•
I nci de nce of A Es a n d S A Es u p t o 
Wee k 4 8
•
Q ua ntitati ve a n d q ualitati ve c ha n ges 
fr o m Baseli ne Visit ( Da y 1) t o Wee k 4 8 
i n cli nical la b orat or y para meters, E C Gs, 
a n d vital si g ns
•
I nci de nce of C- S S R S e ve nts at Baseli ne 
Visit ( Da y 1) a n d t hr o u g h Wee k 4 8

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2 9
5. 
S T U D Y D E SI G N
5. 1. 
St u d y O ver vie w
T his is a m ultice nter, o pe n-la bel, si n gle-ar m, P hase 3 st u d y t o e val uate t he safet y a n d t olera bilit y, 
a n d P K of D R F a d mi nistere d orall y t o East Asia n partici pa nts wit h R M S. T his st u d y will be 
c o n d ucte d i n 2 parts:
Part 1 is desi g ne d t o e val uate t he P K, safet y, a n d t olera bilit y of D R F a d mi nistere d orall y.
Part 2 is desi g ne d as a 2 4- wee k safet y e xte nsi o n peri o d i n partici pa nts fr o m Part 1.
St u d y assess me nts c o n d ucte d at eac h visit are liste d i n Ta ble 1 .
After eli gi bilit y f or t he st u d y has bee n c o nfir me d d uri n g Scree ni n g, all eli gi ble, c o nse nti n g 
partici pa nts will be gi n o pe n-la bel treat me nt at t he Baseli ne Visit ( Da y 1). Partici pa nts will 
i nitiate treat me nt wit h D R F 2 3 1 m g t wice dail y o n Da y 1 t hr o u g h Da y 7, f oll o we d b y 4 6 2 m g 
t wice dail y fr o m Da y 8 o n war ds, wit h all o wa ble d ose re d ucti o n f or t olera bilit y fr o m Da y 8 
o n war ds. St u d y staff will a d mi nister t he first d ose of D R F at t he Baseli ne Visit ( Da y 1).
Starti n g o n Da y 8 of treat me nt, d ose re d ucti o n t o D R F 2 3 1 m g t wice dail y is per mitte d at t he 
I n vesti gat or’s discreti o n f or partici pa nts w h o are u na ble t o t olerate D R F 4 6 2 m g t wice dail y d ue 
t o fl us hi n g or GI dist ur ba nces. O nce a partici pa nt has sta bilize d after d ose re d ucti o n, atte m pts 
s h o ul d a gai n be ma de t o ac hie ve a n d mai ntai n t he tar get mai nte na nce d ose of D R F 4 6 2 m g t wice 
dail y. If a partici pa nt re mai ns u na ble t o t olerate D R F 4 6 2 m g t wice dail y after 1 m o nt h o n 
treat me nt, f urt her d ose re d ucti o n will n ot be per mitte d, a n d t he partici pa nt will be disc o nti n ue d 
fr o m t he st u d y.
Partici pa nts will u n der g o peri o dic safet y assess me nts t hat are sc he d ule d e ver y 2 wee ks u p t o 
Wee k 4 a n d t he n e ver y 4 wee ks u ntil t he e n d of t he Treat me nt Peri o d at Wee k 4 8 ( Visit 1 4) a n d 
will ha ve a Safet y F oll o w- U p Visit 2 wee ks later at Wee k 5 0 ( Visit 1 5).
A n y partici pa nt w h o pre mat urel y disc o nti n ues st u d y treat me nt or wit h dra ws fr o m t he st u d y will 
be as ke d t o ret ur n t o t he cli nic t o c o m plete all st u d y assess me nts f or Visit 1 4/ E T Visit a n d f or t he 
Safet y F oll o w- U p Visit 2 wee ks later ( Visit 1 5). 
Partici pa nts w h o c o m plete t he st u d y or w h o ter mi nate t he st u d y earl y a n d ha ve a last meas ure d 
l y m p h oc yte c o u nt < L L N will ret ur n t o t he cli nic f or a d diti o nal L M visits e ver y 2 m o nt hs 
starti n g fr o m Visit 1 5 ( or fr o m t he E T visit f or partici pa nts w h o ter mi nate t he st u d y earl y) f or a 
peri o d of 6 m o nt hs (i.e., a ma xi m u m of 3 visits), u ntil l y m p h oc yte c o u nts reac h n or mal li mits 
( ≥ L L N), or t he partici pa nt c o m me nces t hera p y wit h a n ot her D M T, w hic he ver occ urs first 
(Ta ble 2 ).
At e ver y visit  (e xcl u di n g Visits 1 4 a n d 1 5), t he st u d y staff will dis pe nse D R F f or partici pa nts’ 
self-a d mi nistrati o n. Partici pa nts will be i nstr ucte d t o ta ke st u d y treat me nt wit h or wit h o ut f o o d.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
3 0
I nte nsi ve bl o o d sa m ples will be c ollecte d pre d ose (- 3 0 t o 0 mi n utes pre d ose) a n d at vari o us 
ti me p oi nts p ost d ose ( 0. 5, 1, 2, 3, 4, 6, a n d 8 h o urs p ost d ose) at a n y ti me p oi nt i n t he peri o d 
bet wee n Wee k 4 ( Da y 2 9, Visit 3 ± 3 da ys) a n d Wee k 2 4 ( Da y 1 6 9, Visit 8 ± 5 da ys), b ot h 
i ncl usi ve, f or 7 Ja pa nese partici pa nts w h o will ta ke D R F after 1 0 h o urs of fasti n g, a n d n o f o o d 
will be all o we d f or at least 4 h o urs after t he d ose of D R F. Partici pa nts will be all o we d water a d 
li bit u m, e xce pt f or 1 h o ur bef ore a n d 2 h o urs after a d mi nistrati o n of t he d ose of D R F. S parse 
bl o o d sa m ples will be c ollecte d f or all re mai ni n g partici pa nts (as well as f or t h ose partici pa nts 
w h o are e nr olle d b ot h i n t he i nte nsi ve P K a n d t he s parse P K c o h orts) pre d ose (- 3 0 t o 0 mi n utes 
pre d ose) a n d 2 t o 3 h o urs p ost d ose o n Da y 2 9 ( Visit 3) a n d Da y 5 7 ( Visit 4).
Partici pati o n i n t he s parse P K c o h ort d oes n ot precl u de e nr oll me nt i n t he i nte nsi ve P K c o h ort as 
well. I n t he e ve nt t hat a partici pa nt is e nr olle d i n b ot h t he s parse a n d i nte nsi ve P K c o h orts a n d 
i nte nsi ve P K sa m pli n g was c o m plete d o n Da y 2 9 or Da y 5 7 f or a partici pa nt, s parse P K 
sa m pli n g will n ot be re q uire d f or t h ose da ys. H o we ver, if it is deter mi ne d t hat i nte nsi ve P K is n ot 
feasi ble b y Da y 5 7, s parse P K sa m pli n g will be c o m plete d acc or di n g t o pr ot oc ol a n d i nte nsi ve 
P K s h o ul d be c o m plete d at later visits.
See Fi g ure 1  f or a sc he matic of t he st u d y desi g n.
5. 2. 
St u d y D ur ati o n f or P artici p a nts
St u d y d urati o n f or partici pa nts w h o c o m plete t he st u d y will be u p t o 5 4 wee ks:  
•
4- wee k Scree ni n g Peri o d
•
2 4- wee k Treat me nt Peri o d i n Part 1
•
2 4- wee k Treat me nt Peri o d i n Part 2
•
2- wee k Safet y F oll o w- U p Peri o d
D uri n g Part 1, partici pa nts will ha ve u p t o 8 visits d uri n g t he Treat me nt Peri o d (i.e., Baseli ne 
Visit [ Da y 1], Wee k 2, Wee k 4, Wee k 8, Wee k 1 2, Wee k 1 6, Wee k 2 0, a n d Wee k 2 4) a n d will 
be c o ntacte d via tele p h o ne t wice. 
D uri n g Part 2, partici pa nts will re p ort t o t he st u d y site e ver y 4 wee ks u p t o Wee k 4 8 d uri n g t he 
Treat me nt Peri o d, f or a t otal of 7 visits, a n d will ha ve t he Safet y F oll o w- U p Visit 2 wee ks later 
( Wee k 5 0) after t he e n d of t he Treat me nt Peri o d.
All visits s h o ul d be perf or me d wit hi n t he ti me fra me fr o m t he n o mi nal visit da y, as s h o w n i n 
Ta ble 1 . Visit da ys are calc ulate d wit h res pect t o Da y 1 (t he date of first d ose).
T he e n d of st u d y date f or a partici pa nt ma y be t he last st u d y visit, last f oll o w- u p tele p h o ne 
c o n versati o n, or last pr ot oc ol-s pecifie d assess me nt; if t he partici pa nt has o n g oi n g A Es t hat are 
bei n g f oll o we d, t he date ma y be t he date of A E res ol uti o n.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
3 2
6. 
S T U D Y P O P U L A TI O N
T o be eli gi ble t o partici pate i n t his st u d y, ca n di dates m ust meet t he f oll o wi n g eli gi bilit y criteria 
at Scree ni n g.
6. 1. 
I ncl usi o n Criteri a
1.
A bilit y of t he partici pa nt t o u n dersta n d t he p ur p ose a n d ris ks of t he st u d y, t o pr o vi de 
i nf or me d c o nse nt, a n d t o a ut h orize t he use of c o nfi de ntial healt h i nf or mati o n i n 
acc or da nce wit h nati o nal a n d l ocal pri vac y re g ulati o ns. 
2.
Male a n d fe male partici pa nts a ge d 1 8 t o 6 5 years ol d, i ncl usi ve, at t he ti me of i nf or me d 
c o nse nt.
•
F or partici pa nts i n Ja pa n a ge d < 2 0 years, writte n i nf or me d c o nse nt s h o ul d be 
o btai ne d fr o m t he partici pa nt a n d t heir le gall y acce pta ble re prese ntati ve. 
•
I nf or me d c o nse nt fr o m a le gall y acce pta ble re prese ntati ve is n ot ma n dat or y if t he 
partici pa nt is classifie d as a n a d ult base d o n t he latest a p plica ble l ocal la ws.
3.
All w o me n of c hil d beari n g p ote ntial a n d all me n m ust practice c o ntrace pti o n d uri n g t he 
st u d y a n d f or at least 3 0 da ys after t heir last d ose of st u d y treat me nt (see Secti o n 1 1. 5 ). I n 
a d ditio n, partici pa nts s h o ul d n ot d o nate s per m or e g gs d uri n g t he st u d y a n d f or at least 
3 0 da ys after t heir last d ose of st u d y treat me nt.
4.
M ust ha ve a dia g n osis of R M S, as defi ne d b y re vise d 2 0 1 7 Mc D o nal d’s criteria [ L u bli n 
2 0 1 4; T h o m ps o n 2 0 1 8] .
5.
E D S S sc ore bet wee n 0. 0 a n d 5. 0, i ncl usi ve, at Scree ni n g a n d Baseli ne Visit ( Da y 1).
6.
Ne ur ol o gicall y sta ble wit h n o e vi de nce of rela pse wit hi n 3 0 da ys pri or t o Baseli ne Visit 
( Da y 1).
7.
F or Ja pa nese partici pa nts:
a.
Was b or n i n Ja pa n a n d bi ol o gical pare nts a n d gra n d pare nts were of Ja pa nese ori gi n. If 
pre vi o usl y li ve d o utsi de of Ja pa n f or m ore t ha n 5 years, m ust n ot ha ve ha d a 
si g nifica ntl y m o difie d diet si nce lea vi n g Ja pa n.
8.
F or C hi nese partici pa nts:
a.
Was b or n i n C hi na, a n d bi ol o gical pare nts a n d gra n d pare nts were of C hi nese ori gi n. 
If pre vi o usl y li ve d o utsi de of C hi na f or m ore t ha n 5 years, m ust n ot ha ve ha d a 
si g nifica ntl y m o difie d diet si nce lea vi n g C hi na.
6. 2. 
E xcl usi o n Criteri a
Me dical Hist or y a n d C urre nt Healt h Stat us

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
3 3
1.
Has a n M S rela pse t hat has occ urre d wit hi n t he 3 0 da ys pri or t o ra n d o mizati o n a n d/ or t he 
partici pa nt has n ot sta bilize d fr o m a pre vi o us rela pse pri or t o ra n d o mizati o n.
2.
Hist or y of a n y cli nicall y si g nifica nt car diac, e n d ocri n ol o gic, he mat ol o gic, he patic, 
i m m u n ol o gic, i nfecti o us, meta b olic, ur ol o gic, p ul m o nar y, ne ur ol o gic, der mat ol o gic, 
ps yc hiatric, a n d re nal or ot her maj or disease t hat w o ul d precl u de partici pati o n i n a 
cli nical trial, as deter mi ne d b y t he I n vesti gat or.
3.
Hist or y of se vere aller gic or a na p h ylactic reacti o ns or of a n y aller gic reacti o ns t hat, i n t he 
o pi ni o n of t he I n vesti gat or, are li kel y t o be e xacer bate d b y a n y c o m p o ne nt of t he st u d y 
treat me nt.
4.
Hist or y of, or o n g oi n g, mali g na nt disease, i ncl u di n g s oli d t u m ors a n d he mat ol o gic 
mali g na ncies ( wit h t he e xce pti o n of basal cell carci n o mas a n d s q ua m o us cell carci n o mas 
of t he s ki n t hat ha ve bee n c o m pletel y e xcise d a n d c o nsi dere d c ure d at least 1 year pri or t o 
Da y - 1). Partici pa nts wit h ca ncers i n re missi o n f or greater t ha n 5 years pri or t o Baseli ne 
Visit ( Da y 1) ma y be i ncl u de d after disc ussi o n wit h/a p pr o val b y t he S p o ns or.
5.
Has a hist or y of GI s ur ger y (e xce pt a p pe n dect o m y or c h olec ystect o m y t hat occ urre d 
m ore t ha n 6 m o nt hs pri or t o Scree ni n g), irrita ble b o wel s y n dr o me, i nfla m mat or y b o wel 
disease ( Cr o h n’s disease, ulcerati ve c olitis), or ot her cli nicall y si g nifica nt a n d acti ve GI 
c o n diti o n per t he I n vesti gat or’s discreti o n.
6.
Hist or y of cli nicall y si g nifica nt rec urri n g or acti ve GI s y m pt o ms (e. g., na usea, diarr hea, 
d ys pe psia, c o nsti pati o n) wit hi n 9 0 da ys of Scree ni n g, i ncl u di n g s y m pt o ms t hat re q uire 
t he i nitiati o n of s y m pt o matic me dical treat me nt (e. g., i nitiati o n of a me dicati o n t o treat 
gastr oes o p ha geal refl u x disease) or a c ha n ge i n s y m pt o matic me dical treat me nt (e. g., a n 
i ncrease i n d ose) wit hi n 9 0 da ys pri or t o Scree ni n g.
7.
Partici pa nt has a me ntal or p h ysical c o n diti o n t hat w o ul d precl u de perf or mi n g  
 
a n d safet y assess me nts.
8.
S yst olic bl o o d press ure > 1 5 0 m m H g or < 9 0 m m H g after sitti n g f or 5 mi n utes at 
Scree ni n g or pri or t o d osi n g. If o ut of ra n ge, testi n g ma y be re peate d o nce at Scree ni n g 
a n d o nce pri or t o d osi n g. Partici pa nts m ust n ot be d ose d if t he re peate d val ue is still o ut 
of ra n ge.
9.
Partici pa nt has sec o n d- or t hir d- de gree atri o- ve ntric ular bl oc k or sic k si n us s y n dr o me, 
u nc o ntr olle d atrial fi brillati o n, se vere or u nsta ble a n gi na, c o n gesti ve heart fail ure, 
m y ocar dial i nfarcti o n wit hi n 3 m o nt hs of t he Scree ni n g visit, or si g nifica nt E C G 
a b n or malit y, i ncl u di n g Q Tc > 4 5 0 msec ( males) or 4 7 0 msec (fe males), w here Q Tc is 
base d o n Fri dericia’s c orrecti o n met h o d.
1 0. Pla ns t o u n der g o electi ve pr oce d ures or s ur geries at a n y ti me after si g ni n g t he I C F 
t hr o u g h t he F oll o w- U p Visit.
1 1. A n y c o n diti o n affecti n g st u d y treat me nt a bs or pti o n (e. g., gastrect o m y). 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
3 4
1 2. Hist or y of se nsiti vit y t o he pari n or he pari n-i n d uce d t hr o m b oc yt o pe nia. 
1 3. Hist or y of s yste mic h y perse nsiti vit y reacti o n t o D R F, D M F, M M F or ot her f u maric 
esters, t he e xci pie nts c o ntai ne d i n t he f or m ulati o n, a n d if a p pr o priate, a n y dia g n ostic 
a ge nts t o be a d mi nistere d d uri n g t he st u d y.
1 4. Partici pa nt has a n a b n or malit y t hat t he i n vesti gat or dee ms t o be cli nicall y si g nifica nt o n 
me dical hist or y, p h ysical e xa mi nati o n, E C G, or a dia g n ostic la b orat or y test t hat ma y 
c o nf o u n d st u d y res ults or p ose ris k t o t he s u bject t hr o u g h partici pati o n i n t he st u d y, i n t he 
o pi ni o n of t he I n vesti gat or.
I nfecti o n Ris k
1 5. E vi de nce of c urre nt S A R S- C o V- 2 i nfecti o n wit hi n 1 4 da ys pri or t o Scree ni n g, bet wee n 
Scree ni n g a n d Baseli ne Visit ( Da y 1), or at Baseli ne Visit ( Da y 1), i ncl u di n g b ut n ot 
li mite d t o a fe ver (te m perat ure > 3 7. 5° C), ne w a n d persiste nt c o u g h, breat hless ness, or 
l oss of taste a n d/ or s mell.
N ote: If a S A R S- C o V- 2 test ( P C R or ot her re g ulat or y a p pr o ve d met h o d) is perf or me d per t he 
discreti o n of t he I n vesti gat or i n acc or da nce wit h l ocal site practice, t he test res ult m ust be 
ne gati ve i n or der f or t he partici pa nt t o be e nr olle d i n t he trial.
Partici pa nts wit h e vi de nce of c urre nt S A R S- C o V- 2 i nfecti o n wit hi n 1 4 da ys pri or t o 
Scree ni n g or d uri n g Scree ni n g, will be eli gi ble f or rescree ni n g, pr o vi de d t hat t he partici pa nt 
is as y m pt o matic f or 1 4 da ys pri or t o rescree ni n g.
1 6. Ha ve cl ose c o ntact wit hi n 1 4 da ys pri or t o Da y 1 wit h i n di vi d ual(s) wit h s us pecte d 
S A R S- C o V- 2 i nfecti o n. Cl ose c o ntact is defi ne d as:
a.
face-t o-face c o ntact wit h a pr o ba ble or c o nfir me d case wit hi n 1 meter a n d f or at least 
1 5 mi n utes; 
b.
direct p h ysical c o ntact wit h a pr o ba ble or c o nfir me d case; 
c.
direct care f or a patie nt wit h pr o ba ble or c o nfir me d C O VI D- 1 9 disease wit h o ut t he 
use of rec o m me n de d P P E; or 
d.
ot her sit uati o ns as i n dicate d b y l ocal ris k assess me nts.
Partici pa nts w h o ha d cl ose c o ntact wit h i n di vi d ual(s) wit h s us pecte d S A R S- C o V- 2 i nfecti o n 
wit hi n 1 4 da ys pri or t o Da y 1, as deter mi ne d b y t he I n vesti gat or, will be eli gi ble f or 
rescree ni n g, pr o vi de d t hat t he partici pa nt is as y m pt o matic f or 1 4 da ys after t he c o ntact.
1 7. Hist or y or p ositi ve test res ult at Scree ni n g f or HI V. 
1 8. C urre nt he patitis C i nfecti o n ( defi ne d as p ositi ve H C V a nti b o d y a n d detecta ble H C V 
R N A). Partici pa nts wit h p ositi ve H C V a nti b o d y a n d u n detecta ble H C V R N A are eli gi ble 
t o partici pate i n t he st u d y ( U nite d States Ce nters f or Disease C o ntr ol a n d Pre ve nti o n).
1 9. C urre nt he patitis B i nfecti o n ( defi ne d as p ositi ve f or H Bs A g a n d/ or t otal a nti- H Bc). 
Partici pa nts wit h i m m u nit y t o he patitis B fr o m pre vi o us nat ural i nfecti o n ( defi ne d as 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
3 5
ne gati ve H Bs A g, p ositi ve a nti- H Bc, a n d p ositi ve a nti- H Bs) or vacci nati o n ( defi ne d as 
ne gati ve H Bs A g, ne gati ve a nti- H Bc, a n d p ositi ve a nti- H Bs) are eli gi ble t o partici pate i n 
t he st u d y.
2 0. C hr o nic, rec urre nt, or seri o us i nfecti o n (e. g., p ne u m o nia, se ptice mia) wit hi n t he 9 0 da ys 
pri or t o Baseli ne Visit ( Da y 1).
2 1. Partici pa nts wit h a n y of t he f oll o wi n g T B-relate d criteria: 
a.
Acti ve T B i nfecti o n.
b.
Hist or y of acti ve T B i nfecti o n i n v ol vi n g a n y or ga n s yste m or fi n di n gs i n ot her or ga n 
s yste ms c o nsiste nt wit h T B, u nless a de q uatel y treate d acc or di n g t o W H O/ C D C 
t hera pe utic g ui da nce a n d pr o ve n t o be f ull y rec o vere d u p o n c o ns ult wit h a T B 
s pecialist.
c.
Late nt T B i nfecti o n ( defi ne d as a c o nfir me d p ositi ve I G R A res ult or 2 s uccessi ve 
i n deter mi nate I G R A res ults) u nless a p pr o priate pr o p h yla xis is i nitiate d at least 
4 wee ks pri or t o st u d y me dicati o n d osi n g o n Baseli ne Visit ( Da y 1) a n d will be 
c o nti n ue d t o c o m pleti o n of pr o p h yla xis.
2 2. S y m pt o ms of bacterial, f u n gal, or viral i nfecti o n(s) (i ncl u di n g u p per res pirat or y tract 
i nfecti o n) wit hi n 2 8 da ys pri or t o Baseli ne Visit ( Da y 1), u nless t he partici pa nts rec o vere d 
c o m pletel y pri or t o Baseli ne Visit ( Da y 1) a n d t he i nfecti o ns were c o nsi dere d mil d per 
I n vesti gat or’s j u d g me nt. Partici pa nts w h o ha ve n ot rec o vere d pri or t o Baseli ne Visit ( Da y 1), 
as j u d ge d b y t he I n vesti gat or, will be eli gi ble f or rescree ni n g.
Me dicati o ns
2 3. Pre vi o us partici pati o n i n t his st u d y or pre vi o us st u dies wit h D R F, D M F, or M M F.
2 4. Use of a n y tra diti o nal a n d/ or u nlice nse d me dici nes a n d/ or t hera pies a n d/ or her bal 
pre parati o ns, w hic h are k n o w n or c o nsi dere d b y t he treati n g ne ur ol o gist t o affect M S a n d 
e n d p oi nts t hat are bei n g c o nsi dere d i n t he st u d y, i ncl u di n g safet y, P K, a n d  
.
2 5. Partici pa nt recei ve d treat me nt wit h o pi oi ds wit hi n 2 8 da ys pri or t o t he scree ni n g visit.
2 6. A n y li ve or atte n uate d i m m u nizati o n or vacci nati o n gi ve n wit hi n 2 8 da ys pri or t o 
Baseli ne Visit ( Da y 1) or pla n ne d t o be gi ve n d uri n g t he st u d y peri o d.
2 7. Has a hist or y of treat me nt wit h or has recei ve d t he f oll o wi n g:
a.
T otal l y m p h oi d irra diati o n, cla dri bi ne, T-cell or T-cell rece pt or vacci nati o n, or t otal 
b o d y irra diati o n at a n y ti me
b.
Ste m cell tra ns pla ntati o n at a n y ti me
c.
Mit o xa ntr o ne or ot her i m m u n os u p pressa nt a ge nts (e. g., c ycl os p ori ne, 
c ycl o p h os p ha mi de, met h otre xate, m yc o p he n olate) wit hi n 1 2 m o nt hs pri or t o Baseli ne 
Visit ( Da y 1); azat hi o pri ne wit hi n 6 m o nt hs pri or t o Baseli ne Visit ( Da y 1).
d.
Treat me nt wit h a n y of t he f oll o wi n g me dicati o ns or pr oce d ures wit hi n 6 m o nt hs pri or 
t o Baseli ne Visit ( Da y 1): plas ma p heresis, I V i m m u n o gl o b uli n, or c yta p heresis

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
3 6
e.
Terifl u n o mi de wit hi n 1 2 m o nt hs of Baseli ne Visit ( Da y 1), u nless t he ser u m/ plas ma 
c o nce ntrati o n of terifl u n o mi de is < 0. 0 2 0 μ g/ m L ( < 2 0 n g/ m L) pri or t o Baseli ne Visit 
( Da y 1) or a n accelerate d eli mi nati o n pr oce d ure f or terifl u n o mi de wit h 
c h olest yra mi ne is s uccessf ull y c o m plete d d uri n g scree ni n g.
f.
Nataliz u ma b wit hi n 6 0 da ys pri or t o Baseli ne Visit ( Da y 1)
g.
A n y pri or use of ale mt uz u ma b
h.
S 1 P rece pt or m o d ulat ors (fi n g oli m o d, si p o ni m o d or oza ni m o d) wit hi n 9 0 da ys pri or 
t o Baseli ne Visit ( Da y 1)
i.
B-cell tar gete d t hera pies f or t he treat me nt of M S (e. g., ocreliz u ma b, rit u xi ma b) wit hi n 
1 2 m o nt hs pri or t o Baseli ne Visit ( Da y 1). Partici pa nts w h o ha ve recei ve d B-cell 
tar gete d t hera pies m ore t ha n 1 2 m o nt hs pri or t o Baseli ne Visit ( Da y 1) will re q uire 
C D 1 9 testi n g t o c o nfir m t hat C D 1 9 cells ha ve ret ur ne d t o wit hi n n or mal ra n ge. 
Partici pa nts w h o ha ve recei ve d B-cell tar gete d t hera pies less t ha n 1 2 m o nt hs pri or t o 
Baseli ne Visit ( Da y 1) will be e xcl u de d fr o m t he st u d y.
j.
Has pre vi o usl y disc o nti n ue d treat me nt wit h Tecfi dera d ue t o t olera bilit y iss ues a n d/ or 
lac k of efficac y
k.
Eli gi bilit y relate d t o pri or treat me nt wit h a n i n vesti gati o nal dr u g a n d/ or a 
c o m merciall y a vaila ble dr u g f or t he treat me nt of M S n ot liste d a b o ve wit hi n t he past 
2 years will be deter mi ne d o n a case- b y-case basis b y t he Me dical M o nit or
l.
Ster oi ds, wit h t he e xce pti o n of t o pical or i n hale d ster oi ds wit hi n 3 0 da ys pri or t o 
Baseli ne Visit ( Da y 1)
La b orat or y Val ues
2 8. Cli nicall y si g nifica nt a b n or mal la b orat or y test val ues (t h ose t hat ma y c o nf o u n d st u d y 
res ults or p ose ris k t o t he s u bject t hr o u g h partici pati o n i n t he st u d y), as deter mi ne d b y t he 
I n vesti gat or, at Scree ni n g or Baseli ne Visit ( Da y 1).
2 9. Has a n y of t he f oll o wi n g a b n or mal bl o o d tests at Scree ni n g:
a.
A L T, A S T, or G G T ≥ 3 × U L N or bilir u bi n > 2 × U L N. 
b.
T S H le vel > 1 0 % of t he U L N 
c.
e G F R ≤ 6 0 m L/ mi n/ 1. 7 3 m 2 ( usi n g t he C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b orati o n e q uati o n) [ Le ve y 2 0 0 9 ]
d.
L y m p h oc yte c o u nt < L L N
3 0. Has a n y of t he f oll o wi n g a b n or mal uri ne tests at Scree ni n g:
a.
Beta- 2 micr o gl o b uli n > 0. 3 μ g/ m L
b.
Al b u mi n t o creati ni ne rati o > 2 2. 6 m g/ m m ol
F or t he para meters liste d i n E xcl usi o n Criteria 2 9 d a n d 3 0, o ut- of-ra n ge val ues t hat are 
cli nicall y n ot si g nifica nt, as deter mi ne d b y t he I n vesti gat or, ma y be re peate d o nce, a n d t he 
partici pa nt ma y be e nr olle d o nl y if t he re peate d val ue is wit hi n t he n or mal ra n ge.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
3 7
Ot her
3 1. Bl o o d d o nati o n ( 1 u nit or m ore) wit hi n 9 0 da ys pri or t o Scree ni n g, plas ma d o nati o n 
wit hi n 1 wee k pri or t o Scree ni n g, a n d platelet d o nati o n wit hi n 6 wee ks pri or t o 
Scree ni n g.
3 2. Hist or y of alc o h ol or s u bsta nce a b use wit hi n t he past year (as deter mi ne d b y t he 
I n vesti gat or). 
3 3. Partici pa nts w h o are pre g na nt or c urre ntl y breastfee di n g a n d t h ose i nte n di n g t o bec o me 
pre g na nt or be gi n breastfee di n g at a n y p oi nt d uri n g t he st u d y a n d f or 3 0 da ys after 
c o m pleti n g st u d y treat me nt.
3 4. C urre nt or pri or partici pati o n i n a cli nical trial wit hi n 9 0 da ys of Scree ni n g. Partici pa nts 
w h o ha ve pre vi o usl y partici pate d i n a cli nical trial b ut ha ve n ot recei ve d a n y I M P 
treat me nt wit hi n 9 0 da ys of Scree ni n g will be eli gi ble if t he I n vesti gat or c o nfir ms t hat t he 
partici pa nt meets all ot her I ncl usi o n a n d E xcl usi o n criteria a n d t here are n o ot her safet y 
c o ncer ns.
3 5. Has a cli nicall y si g nifica nt hist or y of s uici dal i deati o n or s uici dal be ha vi or occ urri n g i n 
t he past 1 2 m o nt hs as assesse d b y t he C‑ S S R S at Scree ni n g.
3 6. U n willi n g ness or i na bilit y t o c o m pl y wit h st u d y re q uire me nts.
3 7. Ot her u ns pecifie d reas o ns t hat, i n t he o pi ni o n of t he I n vesti gat or or S p o ns or, ma ke t he 
partici pa nt u ns uita ble f or e nr oll me nt.
6. 3. 
Scree ni n g, Retesti n g, a n d Scree n F ail ures
6. 3. 1. 
Scree ni n g
O nce i nf or me d c o nse nt is o btai ne d, scree ni n g assess me nts ca n occ ur. At t his ti me, a u ni q ue 
i de ntificati o n n u m ber is assi g ne d t hat will be use d o n st u d y-relate d d oc u me nts pertai ni n g t o t he 
partici pa nt. A n y i de ntificati o n n u m bers t hat are assi g ne d will n ot be re use d, e ve n if t he 
partici pa nt d oes n ot recei ve treat me nt or c o nti n ue i n t he st u d y. St u d y sites are re q uire d t o 
d oc u me nt all scree ne d partici pa nts i nitiall y c o nsi dere d f or i ncl usi o n i n t he st u d y. 
T he scree ni n g peri o d ca n be e xte n de d u p t o a ma xi m u m of 4 2 da ys (i.e., a n a d diti o nal 2 wee ks) 
wit h pri or a p pr o val of t he me dical m o nit or if t he testi n g of terifl u n o mi de le vels or c o nfir mati o n 
of accelerate d eli mi nati o n ( per e xcl usi o n criteri o n 2 7e; Secti o n 6. 2 ) or mi ni m u m of 4 wee ks’ T B 
pr o p h yla xis ( per e xcl usi o n criteri o n 2 1c; Secti o n 6. 2 ) ca n n ot be c o m plete d wit hi n t he 2 8- da y 
scree ni n g peri o d.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
3 8
6. 3. 2.  
Retesti n g
F or t he para meters liste d i n e xcl usi o n criteria 2 9 d a n d 3 0, o ut- of-ra n ge val ues t hat are n ot 
cli nicall y si g nifica nt, as deter mi ne d b y t he I n vesti gat or, ma y be re peate d o nce, a n d t he 
partici pa nt ma y be e nr olle d o nl y if t he re peate d val ue is wit hi n t he n or mal ra n ge.
Partici pa nts w h o ha ve a b n or mal la b orat or y test val ues as descri be d i n e xcl usi o n criteria 2 9a, 2 9 b, 
a n d 2 9c s h o ul d n ot be reteste d.
6. 3. 3. 
Scree n F ail ures
Scree n fail ures are defi ne d as partici pa nts w h o si g n t he I C F b ut are n ot s u bse q ue ntl y d ose d. If a 
partici pa nt is c o nsi dere d a scree n fail ure, t he reas o ns f or e xcl usi o n m ust be d oc u me nte d i n t he 
partici pa nt’s s o urce d oc u me nts a n d o n t he scree ni n g l o g. A mi ni mal set of scree n fail ure 
i nf or mati o n is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure partici pa nts t o meet t he 
C o ns oli date d Sta n dar ds of Re p orti n g Trials p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries 
fr o m re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure details, 
eli gi bilit y criteria, a n d a n y S A Es.
All partici pa nts wit h i nc o m plete e nr oll me nt d ue t o a p u blic healt h e mer ge nc y (e. g., tra vel 
restricti o ns, partici pa nts w h o rec o vere d after getti n g i nfecte d) will be eli gi ble f or rescree ni n g 
pr o vi de d t hat t he partici pa nts met all eli gi bilit y criteria d uri n g t he i nitial scree ni n g peri o d, a n d 
t hat t he reas o n f or rescree ni n g is i nc o m plete e nr oll me nt d ue t o a p u blic healt h e mer ge nc y. T hese 
partici pa nts will be re p orte d as scree n faile d a n d t he n rescree ne d. Partici pa nts ma y ha ve bee n 
pr o vi de d wit h a u ni q ue i de ntificati o n n u m ber d uri n g Scree ni n g. T he pre vi o usl y iss ue d u ni q ue 
i de ntificati o n n u m ber will n o l o n ger be use d, a n d a se parate u ni q ue i de ntificati o n n u m ber will be 
pr o vi de d d uri n g rescree ni n g.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4 2
7. 3. 1. 2. 
St or a ge
D R F is t o be st ore d at r o o m te m perat ure ( n ot t o e xcee d 2 5° C) i n a m o nit ore d a n d l oc ke d ca bi net, 
wit h li mite d access. F or t he m ost u p-t o- date st ora ge re q uire me nts, f oll o w t he i nstr ucti o ns 
pr o vi de d i n t he D H A.
7. 3. 1. 3.  
H a n dli n g a n d Dis p os al
T he I n vesti gat or m ust ret ur n all use d a n d u n use d b ottles of D R F as i nstr ucte d b y t he S p o ns or 
u nless a p pr o ve d f or o nsite destr ucti o n.
If a n y D R F s u p plies are t o be destr o ye d at t he st u d y site, t he i nstit uti o n or a p pr o priate site staff 
m ust o btai n pri or a p pr o val fr o m t he S p o ns or, b y pr o vi di n g, i n writi n g, t he destr ucti o n p olic y or 
details of t he met h o d of destr ucti o n. After s uc h destr ucti o n, t he S p o ns or m ust be n otifie d, i n 
writi n g, of t he details of t he st u d y treat me nt destr o ye d (e. g., l ot or kit n u m bers, q ua ntities), t he 
date of destr ucti o n, a n d pr o of of destr ucti o n.
7. 3. 1. 4.  
Acc o u nt a bilit y
Acc o u nta bilit y f or st u d y treat me nt is t he res p o nsi bilit y of t he I n vesti gat or. T he st u d y site m ust 
mai ntai n acc urate rec or ds de m o nstrati n g dates a n d a m o u nt of st u d y treat me nt recei ve d, t o w h o m 
dis pe nse d, a m o u nt ret ur ne d b y t he partici pa nt, a n d acc o u nts of a n y st u d y treat me nt acci de ntall y 
or deli beratel y destr o ye d or l ost. 
U nless ot her wise n otifie d, all b ottles b ot h use d a n d u n use d, m ust be sa ve d f or st u d y treat me nt 
acc o u nta bilit y. B y t he e n d of t he st u d y, rec o nciliati o n m ust be ma de a m o n g t he a m o u nt of D R F 
s u p plie d, dis pe nse d, a n d s u bse q ue ntl y destr o ye d, l ost, or ret ur ne d t o t he S p o ns or. A writte n 
e x pla nati o n m ust be pr o vi de d f or a n y discre pa ncies.
7. 4. 
Bli n di n g Pr oce d ures
T his is a n o pe n-la bel st u d y.
7. 5. 
Prec a uti o ns
Me dicati o ns f or t he treat me nt of se vere h y perse nsiti vit y reacti o ns (e. g., e pi ne p hri ne f or 
S C i njecti o ns, di p he n h y dra mi ne f or i njecti o n) m ust be a vaila ble f or i m me diate use.
See t he D H A f or detaile d i nstr ucti o ns.
7. 6.  
C o m pli a nce
C o m plia nce wit h treat me nt d osi n g is t o be m o nit ore d a n d rec or de d b y site staff.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4 3
7. 7.  
C o nc o mit a nt T her a p y a n d Pr oce d ures
7. 7. 1.  
C o nc o mit a nt T her a p y
A c o nc o mita nt t hera p y is a n y dr u g or s u bsta nce a d mi nistere d bet wee n t he partici pa nt’s Baseli ne 
Visit ( Da y 1) a n d last st u d y visit.
7. 7. 1. 1.  
All o we d C o nc o mit a nt T her a p y
Partici pa nts s h o ul d be i nstr ucte d t o c o ntact t heir I n vesti gat ors bef ore ta ki n g a n y ne w 
me dicati o ns, i ncl u di n g n o n prescri pti o n dr u gs a n d her bal pre parati o ns.
S y m pt o matic t hera p y s uc h as treat me nt f or s pasticit y, de pressi o n, or fati g ue is n ot restricte d b ut 
s h o ul d be o pti mize d as earl y as p ossi ble d uri n g scree ni n g t o mai ntai n c o nsiste nt treat me nt f or t he 
d urati o n of t he st u d y.
7. 7. 1. 2.  
Dis all o we d C o nc o mit a nt T her a p y
C o nc o mita nt treat me nt wit h a n y of t he f oll o wi n g is n ot all o we d w hile recei vi n g st u d y treat me nt, 
u nless a p pr o ve d b y t he Me dical M o nit or:
•
A n y o pi oi ds.
•
A n y alter nati ve dr u g treat me nts directe d t o war d t he treat me nt of M S s uc h as 
l o n g-ter m i m m u n os u p pressa nt t hera p y or ot her i m m u n o m o d ulat or y treat me nts 
(i ncl u di n g b ut n ot li mite d t o I F N- β, I F N- α, G A, nataliz u ma b, ale mt uz u ma b, B-cell 
de pleti n g a ge nts, c ycl o p h os p ha mi de, met h otre xate, azat hi o pri ne, m yc o p he n olate 
m ofetil, D M F, terifl u n o mi de, 4-a mi n o p yri di ne, S 1 P rece pt or m o d ulat ors s uc h as 
fi n g oli m o d, or relate d pr o d ucts).
•
A n y i n vesti gati o nal pr o d uct, i ncl u di n g i n vesti gati o nal s y m pt o matic t hera pies f or M S 
a n d i n vesti gati o nal t hera pies f or n o n- M S i n dicati o ns.
•
A n y s yste mic ster oi d t hera p y i ncl u di n g, b ut n ot li mite d t o, oral c ortic oster oi ds 
(e. g., pre d nis o ne) or peri o dic (e. g., m o nt hl y) treat me nt wit h I V M P. S yste mic ster oi d 
t hera p y is per missi ble f or t he treat me nt of 
 as per l ocal re g ulati o ns 
a n d/ or prescri bi n g practice, f or u p t o 5 da ys ma xi m u m d urati o n. Refer t o 
Secti o n 7. 2. 2  f or all o we d use of treat me nts f or  
. Ster oi ds t hat are a d mi nistere d 
b y n o ns yste mic r o utes (e. g., t o pical, i n hale d) are all o we d.
•
A n y li ve or atte n uate d i m m u nizati o n or vacci nati o n.
•
T otal l y m p h oi d ra diati o n, cla dri bi ne, T-cell or T-cell rece pt or vacci nati o n, a n y 
t hera pe utic m o n ocl o nal a nti b o d y, mit o xa ntr o ne, c ycl os p ori ne, I V i m m u n o gl o b uli n, 
plas ma p heresis, or c yta p heresis.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4 4
If a n ot her M S treat me nt is i nitiate d ( or if D R F is restarte d) bef ore t he l y m p h oc yte c o u nt ret ur ns 
t o L L N d uri n g t he pr ot oc ol-re q uire d A L C f oll o w- u p m o nit ori n g peri o d, t he partici pa nt m ust be 
disc o nti n ue d fr o m t he st u d y.
Partici pa nts w h o recei ve a n y of t hese restricte d me dicati o ns wit h o ut a p pr o val fr o m t he Me dical 
M o nit or will be re q uire d t o per ma ne ntl y disc o nti n ue st u d y treat me nt a n d will be wit h dra w n fr o m 
t he st u d y as descri be d i n Secti o n 8. 3 . Partici pa nts w h o i nitiate a pr ot oc ol- defi ne d disall o we d 
c o nc o mita nt t hera p y m ust c o m plete a n E T Visit a n d wit h dra w fr o m t he st u d y.
7. 7. 2.  
C o nc o mit a nt Pr oce d ures
A c o nc o mita nt pr oce d ure is a n y t hera pe utic i nter ve nti o n (e. g., s ur ger y/ bi o ps y, p h ysical t hera p y) 
or dia g n ostic assess me nt (e. g., bl o o d gas meas ure me nt, bacterial c ult ures) perf or me d bet wee n 
t he ti me of t he partici pa nt’s Baseli ne Visit a n d last st u d y visit.
7. 8.  
C o nti n u ati o n of Tre at me nt 
N o f urt her pr o visi o ns are ma de f or access t o t he st u d y treat me nt. 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4 5
8.  
DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D 
WI T H D R A W A L O F P A R TI CI P A N T S F R O M T H E S T U D Y
8. 1.  
Disc o nti n u ati o n of St u d y Tre at me nt
A partici pa nt m ust per ma ne ntl y disc o nti n ue st u d y treat me nt f or a n y of t he f oll o wi n g reas o ns: 
•
T he partici pa nt bec o mes pre g na nt. St u d y treat me nt m ust be disc o nti n ue d i m me diatel y 
( N ote: I nstr ucti o ns f or re p orti n g t he pre g na nc y are pr o vi de d i n Secti o n 1 1. 4. 1 ).
•
T he partici pa nt wit h dra ws c o nse nt t o c o nti n ue st u d y treat me nt. 
•
T he partici pa nt e x perie nces a n A E t hat re q uires per ma ne nt disc o nti n uati o n of st u d y 
treat me nt.
•
T he partici pa nt is u n willi n g or u na ble t o c o m pl y wit h t he pr ot oc ol.
•
At t he discreti o n of t he I n vesti gat or f or me dical reas o ns.
•
At t he discreti o n of t he S p o ns or or u p o n re q uest of a re g ulat or y a ut h orit y. 
•
L y m p h oc yte c o u nt < 0. 5 × 1 0 3/ µ L persisti n g f or > 6 m o nt hs.  A n i nitial l y m p h oc yte 
c o u nt < 0. 5 × 1 0 3/ µ L s h o ul d be c o nfir me d b y re peat testi n g. If t he val ue re mai ns 
< 0. 5 × 1 0 3/ µ L f or > 6 m o nt hs, t he partici pa nt m ust per ma ne ntl y disc o nti n ue st u d y 
treat me nt. Partici pa nts w h o per ma ne ntl y disc o nti n ue t he st u d y wit h a last meas ure d 
l y m p h oc yte c o u nt < L L N will re q uire a d diti o nal f oll o w- u p t o m o nit or t heir 
l y m p h oc yte c o u nts; see Ta ble 2 .
T he reas o n f or disc o nti n uati o n of st u d y treat me nt m ust be rec or de d i n t he C R F. 
I n a d diti o n t o t he reas o ns pr o vi de d a b o ve f or per ma ne nt disc o nti n uati o n of st u d y treat me nt, 
st u d y treat me nt m ust be te m p oraril y wit h hel d if a n y of t he f oll o wi n g la b orat or y para meters meet 
t he f oll o wi n g t hres h ol d li mits:
•
A S T or A L T > 3 × U L N; c o nfir me d b y re peat testi n g. If t he val ue re mai ns > 3 × U L N 
f or ≥ 4 wee ks after i nterr u pti o n of st u d y treat me nt, t he partici pa nt m ust per ma ne ntl y 
disc o nti n ue st u d y treat me nt.
•
e G F R < 6 0 m L/ mi n/ 1. 7 3 m 2; c o nfir me d b y re peat testi n g as s o o n as p ossi ble. If t he 
e G F R re mai ns < 6 0 m L/ mi n/ 1. 7 3 m 2 f or ≥ 4 wee ks after i nterr u pti o n of st u d y 
treat me nt, t he partici pa nt m ust per ma ne ntl y disc o nti n ue st u d y treat me nt.
•
Uri ne al b u mi n t o uri ne creati ni ne rati o > 2 2. 6 m g/ m m ol; c o nfir me d b y re peat testi n g 
as s o o n as p ossi ble. If t he uri ne al b u mi n t o uri ne creati ni ne rati o re mai ns 
> 2 2. 6 m g/ m m ol f or ≥ 4 wee ks after i nterr u pti o n of st u d y treat me nt, t he partici pa nt 
m ust per ma ne ntl y disc o nti n ue st u d y treat me nt.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4 6
Res u mi n g st u d y treat me nt after it has bee n te m p oraril y wit h hel d is t o be c o nsi dere d o n a case-
b y-case basis a n d m ust be disc usse d wit h t he Me dical M o nit or. 
8. 2. 
L ost t o F oll o w- U p
Partici pa nts will be c o nsi dere d l ost t o f oll o w- u p if t he y re peate dl y fail t o ret ur n f or sc he d ule d 
visits a n d are u na ble t o be c o ntacte d b y t he st u d y site. 
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he st u d y site f or a re q uire d 
st u d y visit:
•
T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble, c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule, a n d ascertai n w het her t he partici pa nt wis hes t o a n d/ or s h o ul d c o nti n ue i n t he 
st u d y.
•
I n cases i n w hic h t he partici pa nt is dee me d l ost t o f oll o w- u p, t he i n vesti gat or or desi g nee 
m ust ma ke e ver y eff ort t o re gai n c o ntact wit h t he partici pa nt. T hese c o ntact atte m pts 
s h o ul d be d oc u me nte d i n t he partici pa nt’s me dical rec or d.
•
S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, t hat partici pa nt will be c o nsi dere d t o 
ha ve wit h dra w n fr o m t he st u d y wit h a pri mar y reas o n of l ost t o f oll o w- u p.
8. 3.  
Wit h dr a w al of P artici p a nts fr o m t he St u d y
Partici pa nts m ust be wit h dra w n fr o m t he st u d y f or a n y o ne of t he f oll o wi n g reas o ns:
•
T he partici pa nt wit h dra ws c o nse nt f or partici pati o n i n t he st u d y. 
•
T he partici pa nt e nr olls i nt o a n ot her i nter ve nti o nal cli nical st u d y i n w hic h a n 
i n vesti gati o nal treat me nt or a p pr o ve d t hera p y f or i n vesti gati o nal use is a d mi nistere d.
•
T he partici pa nt is u n willi n g or u na ble t o c o m pl y wit h t he pr ot oc ol.
T he pri mar y reas o n f or t he partici pa nt’s wit h dra wal fr o m t he st u d y m ust be rec or de d i n t he 
partici pa nt’s C R F. A n y partici pa nt w h o pre mat urel y disc o nti n ues st u d y treat me nt or wit h dra ws 
fr o m t he st u d y will be as ke d t o ret ur n t o t he cli nic t o c o m plete all st u d y assess me nts f or 
Visit 1 4/ E T Visit as well as t he Safet y F oll o w- U p Visit 2 wee ks later ( Visit 1 5). 
Partici pa nts s h o ul d u n der g o a n E T visit u nless wit h dra wal is d ue t o deat h or wit h dra wal of 
c o nse nt. Partici pa nts w h o wit h dra w fr o m t he st u d y f or reas o ns ot her t ha n safet y ma y be re place d 
at t he discreti o n of t he S p o ns or.
Partici pa nts wit h i nte nse P K sa m pli n g w h o wit h dra w earl y or re q uire d ose re d ucti o n or sa m ples 
n ot c ollecte d per pr ot oc ol or la b orat or y ma n ual, ma y be re place d at t he discreti o n of t he S p o ns or.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4 8
I n a d diti o n, s parse bl o o d sa m ples will be c ollecte d f or P K a nal ysis of t he meta b olites M M F a n d 
H E S as f oll o ws:
•
O n Da y 2 9, bl o o d sa m ples will be c ollecte d - 3 0 t o 0 mi n utes ( pre d ose) a n d 2 t o 
3 h o urs ( p ost d ose) f or partici pa nts wit h s parse bl o o d sa m ple c ollecti o n 
(a p pr o xi matel y 4 3 per Ja pa nese c o h ort a n d 5 0 per C hi nese c o h ort). 
•
O n Da y 5 7, bl o o d sa m ples will be c ollecte d - 3 0 t o 0 mi n utes ( pre d ose) a n d 2 t o 
3 h o urs ( p ost d ose) f or all partici pa nts wit h s parse bl o o d sa m ple c ollecti o n 
(a p pr o xi matel y 5 0 per c o h ort).
•
Partici pati o n i n t he s parse P K c o h ort d oes n ot precl u de e nr oll me nt i n t he i nte nsi ve P K 
c o h ort as well. I n t he e ve nt t hat a partici pa nt is e nr olle d i n b ot h t he s parse a n d 
i nte nsi ve P K c o h orts a n d i nte nsi ve P K sa m pli n g was c o m plete d o n Da y 2 9 or Da y 5 7 
f or a partici pa nt, s parse P K sa m pli n g will n ot be re q uire d f or sai d da ys. H o we ver, if it 
is deter mi ne d t hat i nte nsi ve P K is n ot feasi ble b y Da y 5 7, s parse P K sa m pli n g will be 
c o m plete d acc or di n g t o pr ot oc ol a n d i nte nsi ve P K s h o ul d be c o m plete d at later visits. 
T he P K sa m ple v ol u me will be a p pr o xi matel y 6 m L f or eac h i n di vi d ual sa m ple. F or t he i nte nsi ve 
P K sa m pli n g gr o u p, t here are a ma xi m u m of 1 0 P K sa m ple c ollecti o n ti me p oi nts pla n ne d ( 8 
ti me p oi nts o n Da y 2 9 f or t he i nte nsi ve P K sa m pli n g a n d 2 ti me p oi nts o n Da y 5 7 f or t he s parse 
P K sa m pli n g). I n t he a d ve nt t hat i nte nsi ve P K sa m pli n g is n ot feasi ble b y Da y 5 7, t here are a 
ma xi m u m of 1 2 P K sa m ple c ollecti o n ti me p oi nts pla n ne d ( 2 ti me p oi nts o n Da y 2 9 a n d o n Da y 
5 7 f or t he s parse P K sa m pli n g, res pecti vel y a n d 8 ti me p oi nts f or t he i nte nsi ve P K sa m pli n g at a 
later visit). T heref ore, t he ma xi m u m P K sa m ple v ol u me f or a gi ve n partici pa nt i n t he i nte nsi ve 
P K sa m pli n g gr o u p will be a p pr o xi matel y 7 2 m L. T his v ol u me will be l o wer f or patie nts 
partici pati n g o nl y i n t he s parse P K sa m ple c ollecti o n a n d will be a p pr o xi matel y 2 4 m L ( 2 
sa m ples o n Da y 2 9 a n d 2 sa m ples o n Da y 5 7).

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4 9
1 0. 
S A F E T Y A S S E S S M E N T S
See Secti o n  1. 3 f or t he ti mi n g of all safet y assess me nts.
Tests a n d e val uati o ns affecti n g pri mar y e n d p oi nts a n d/ or a nal yses ma y nee d t o be re peate d if t he 
ori gi nal res ults are l ost or da ma ge d. I n t hese cases, partici pa nts will be as ke d t o ret ur n t o t he 
st u d y site t o ha ve t he e val uati o ns re peate d.
1 0. 1.  
Cli nic al S afet y Assess me nts
T he f oll o wi n g cli nical assess me nts will be perf or me d t o e val uate t he safet y pr ofile of D R F:
•
A E a n d S A E rec or di n g 
•
Me dical hist or y
•
P h ysical e xa mi nati o ns: F ull p h ysical e xa mi nati o ns will be perf or me d at Scree ni n g. 
A n a b bre viate d p h ysical e xa mi nati o n (i.e., e xa mi nati o n of ge neral a p peara nce a n d t he 
f oll o wi n g b o d y s yste ms: l y m p h n o des, t h ora x a n d l u n gs, car di o vasc ular s yste m, 
a b d o me n, a n d s ki n) will be perf or me d at ot her ti me p oi nts. 
•
Vital si g n meas ure me nts: te m perat ure, p ulse rate, s yst olic a n d diast olic bl o o d 
press ure, a n d res pirat or y rate 
•
Wei g ht a n d hei g ht meas ure me nts 
•
1 2-lea d E C Gs 
•
C- S S R S 
•
C o nc o mita nt t hera p y a n d pr oce d ure rec or di n g
1 0. 2. 
L a b or at or y S afet y Assess me nts
Sa m ples will be a nal yze d usi n g G o o d La b orat or y Practice- vali date d assa ys.
T he f oll o wi n g la b orat or y assess me nts will be perf or me d t o e val uate t he safet y pr ofile of D R F:

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
5 0
T a ble 5:  
Cli nic al L a b or at or y Assess me nts
He m at ol o g y 1
Bi oc he mistr y
Uri n al ysis
He mat ocrit
He m o gl o bi n
Re d bl o o d cell c o u nt
T otal a n d differe ntial (a bs ol ute) 
w hite bl o o d cell c o u nt
Platelets
S o di u m
P otassi u m
C hl ori de
Bicar b o nate
Gl uc ose
Calci u m
Uric aci d
Creati ni ne 2
T otal pr otei n
Bl o o d urea nitr o ge n
Al b u mi n
T otal bilir u bi n
A L T
A S T
L D H
Al kali ne p h os p hatase
G G T
Creati ne p h os p h o ki nase
Li pi d pr ofile: bl o o d c h olester ol, 
hi g h- de nsit y li p o pr otei n, 
l o w- de nsit y li p o pr otei n, a n d 
tri gl yceri des
Ser u m F S H (t o c o nfir m 
p ost me n o pa usal stat us) 3
Vita mi n D ( 1, 2 5-( O H) 2)
T S H 3
Ser u m pre g na nc y 4
HI V/ He patitis scree n 3
T B test 3
C ol or
p H
S pecific gra vit y
Ket o nes
Pr otei n
Gl uc ose
Bilir u bi n
Nitrite
Ur o bili n o ge n
Occ ult bl o o d
Micr osc o pic e xa mi nati o n of 
se di me nt o nly if uri n alysis di pstick 
res ults are a b n or m al
Uri ne al b u mi n
Uri ne beta- 2- micr o gl o b uli n
Uri ne creati ni ne
1 A d diti o nal he mat ol o g y assess me nts will be c ollecte d f or partici pa nts re q uiri n g f oll o w- u p f or l y m p h o pe nia at t he 
ti me of st u d y c o m pleti o n or E T.
2 Ser u m creati ni ne will be use d t o calc ulate e G F R at eac h ti me p oi nt t hat a creati ni ne res ult is ge nerate d. 
Partici pa nt’s latest wei g ht assess me nt will be use d t o calc ulate e G F R.
3 O nl y at Scree ni n g.
4 O nl y at Scree ni n g a n d Safet y F oll o w- U p ( Visit 1 5).

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
5 1
1 1. 
S A F E T Y D E FI NI TI O N S, R E C O R DI N G, R E P O R TI N G, A N D 
R E S P O N SI BI LI TI E S
T hr o u g h o ut t he c o urse of t he st u d y, e ver y eff ort m ust be ma de t o re mai n vi gila nt t o p ossi ble 
A Es. If a n A E occ urs, t he first c o ncer n s h o ul d be f or t he safet y of t he partici pa nt. If necessar y, 
a p pr o priate me dical i nter ve nti o n s h o ul d be pr o vi de d.
At t he si g ni n g of t he I C F, eac h partici pa nt a n d/ or his/ her le gall y a ut h orize d re prese ntati ve a n d/ or 
mai n care gi ver m ust be gi ve n t he na mes a n d tele p h o ne n u m bers of site staff f or re p orti n g S A Es, 
pre g na ncies, o ver d oses, a n d me dical e mer ge ncies. T hr o u g h o ut t he pr ot oc ol, t he S p o ns or is 
na me d, b ut re p orti n g ma y be d o ne t hr o u g h a C R O.
1 1. 1.  
Defi niti o ns
1 1. 1. 1.  
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or cli nical i n vesti gati o n partici pa nt 
( partici pa nt) a d mi nistere d a p har mace utical pr o d uct a n d t hat d oes n ot necessaril y ha ve a ca usal 
relati o ns hi p wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal assess me nt s uc h as a n a b n or mal la b orat or y val ue), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or n ot 
relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct.
Deter mi nati o n of w het her a n a b n or mal assess me nt (e. g., la b orat or y val ue, vital si g n, a n d E C G) 
res ult meets t he defi niti o n of a n A E will be ma de b y t he I n vesti gat or. A b n or mal res ults are n ot 
c o nsi dere d A Es u nless o ne or m ore of t he f oll o wi n g criteria are met:
•
T he res ult meets t he criteria f or a n S A E.
•
T he res ult re q uires t he partici pa nt t o recei ve s pecific c orrecti ve t hera p y.
•
T he res ult is c o nsi dere d b y t he I n vesti gat or t o be cli nicall y si g nifica nt.
1 1. 1. 2. 
Seri o us A d verse E ve nt
A n S A E is a n y u nt o war d me dical occ urre nce t hat at a n y d ose:
•
Res ults i n deat h.
•
I n t he vie w of t he I n vesti gat or, places t he partici pa nt at i m me diate ris k of deat h (a 
life-t hreate ni n g e ve nt); h o we ver, t his d oes n ot i ncl u de a n e ve nt t hat, ha d it occ urre d 
i n a m ore se vere f or m, mi g ht ha ve ca use d deat h.
•
Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n.
•
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
5 2
•
Res ults i n a c o n ge nital a n o mal y/ birt h defect.
•
Is a me dicall y i m p orta nt e ve nt.
A me dicall y i m p orta nt e ve nt is a n A E t hat, i n t he o pi ni o n of t he I n vesti gat or, ma y je o par dize t he 
partici pa nt or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he 
defi niti o n a b o ve. ( E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or c o n v ulsi o ns occ urri n g at h o me t hat d o n ot re q uire 
a n i n patie nt h os pitalizati o n.)
1 1. 1. 3. 
Presc he d ule d or Electi ve Pr oce d ures or R o uti nel y Sc he d ule d Tre at me nts
A presc he d ule d or electi ve pr oce d ure or a r o uti nel y sc he d ule d treat me nt will n ot be c o nsi dere d 
a n S A E, e ve n if t he partici pa nt is h os pitalize d. T he st u d y site m ust d oc u me nt all t he f oll o wi n g:
•
T he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt was 
sc he d ule d ( or was o n a waiti n g list t o be sc he d ule d) pri or t o o btai ni n g t he 
partici pa nt’s c o nse nt t o be i n t he st u d y.
•
T he c o n diti o n re q uiri n g t he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d 
treat me nt was prese nt bef ore a n d di d n ot w orse n or pr o gress i n t he o pi ni o n of t he 
I n vesti gat or bet wee n t he partici pa nt’s c o nse nt t o be i n t he st u d y a n d t he ti me of t he 
pr oce d ure or treat me nt.
•
T he presc he d ule d or electi ve pr oce d ure or r o uti nel y sc he d ule d treat me nt is t he s ole 
reas o n f or t he i nter ve nti o n or h os pital a d missi o n.
o
If a partici pa nt is h os pitalize d d ue t o l ocal re q uire me nts f or a d mi nistrati o n of 
t he st u d y treat me nt, t he h os pitalizati o n s h o ul d n ot be c o nsi dere d a n S A E 
u nless o ne of t he re q uire me nts i n Secti o n 1 1. 1. 2  is met.
1 1. 2. 
S afet y Cl assific ati o ns
1 1. 2. 1. 
I n vesti g at or Assess me nt of E ve nts
All e ve nts m ust be assesse d t o deter mi ne t he f oll o wi n g:
•
If t he e ve nt meets t he criteria f or a n S A E as defi ne d i n Secti o n 1 1. 1. 2
•
T he relati o ns hi p of t he e ve nt t o st u d y treat me nt as defi ne d i n Secti o n 1 1. 2. 2
•
T he se verit y of t he e ve nt as defi ne d i n Secti o n 1 1. 2. 3
1 1. 2. 2.  
Rel ati o ns hi p of E ve nts t o St u d y Tre at me nt
T he f oll o wi n g defi niti o ns s h o ul d be c o nsi dere d w he n e val uati n g t he relati o ns hi p of A Es a n d 
S A Es t o t he st u d y treat me nt.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
5 3
Rel ati o ns hi p of E ve nt t o St u d y Tre at me nt
N ot relate d
A n A E will be c o nsi dere d “ n ot relate d” t o t he use of t he i n vesti gati o nal pr o d uct if t here 
is n ot a reas o na ble p ossi bilit y t hat t he e ve nt has bee n ca use d b y t he pr o d uct u n der 
i n vesti gati o n. Fact ors p oi nti n g t o war d t his assess me nt i ncl u de b ut are n ot li mite d t o t he 
lac k of reas o na ble te m p oral relati o ns hi p bet wee n a d mi nistrati o n of t he i n vesti gati o nal 
pr o d uct a n d t he A E, t he prese nce of a bi ol o gicall y i m pla usi ble relati o ns hi p bet wee n t he 
pr o d uct a n d t he A E, or t he prese nce of a m ore li kel y alter nati ve e x pla nati o n f or t he A E.
Relate d
A n A E will be c o nsi dere d “relate d” t o t he use of t he i n vesti gati o nal pr o d uct if t here is a 
reas o na ble p ossi bilit y t hat t he e ve nt ma y ha ve bee n ca use d b y t he pr o d uct u n der 
i n vesti gati o n. Fact ors t hat p oi nt t o war d t his assess me nt i ncl u de b ut are n ot li mite d t o a 
p ositi ve rec halle n ge, a reas o na ble te m p oral se q ue nce bet wee n a d mi nistrati o n of t he 
i n vesti gati o nal pr o d uct a n d t he A E, a k n o w n res p o nse patter n of t he s us pecte d pr o d uct, 
i m pr o ve me nt f oll o wi n g disc o nti n uati o n or d ose re d ucti o n, a bi ol o gicall y pla usi ble 
relati o ns hi p bet wee n t he pr o d uct a n d t he A E, or a lac k of a n alter nati ve e x pla nati o n f or 
t he A E.
1 1. 2. 3. 
Se verit y of E ve nts
T he f oll o wi n g defi niti o ns s h o ul d be c o nsi dere d w he n e val uati n g t he se verit y of A Es a n d S A Es:
Se verit y of E ve nt
Mil d
S y m pt o ms barel y n oticea ble t o partici pa nt or d oes n ot ma ke partici pa nt u nc o mf orta ble; 
d oes n ot i nfl ue nce perf or ma nce or f u ncti o ni n g; prescri pti o n dr u g n ot or di naril y nee de d 
f or relief of s y m pt o ms b ut ma y be gi ve n beca use of pers o nalit y of partici pa nt.
M o derate
S y m pt o ms of a s ufficie nt se verit y t o ma ke partici pa nt u nc o mf orta ble; perf or ma nce of 
dail y acti vit y is i nfl ue nce d; partici pa nt is a ble t o c o nti n ue i n st u d y; treat me nt f or 
s y m pt o ms ma y be nee de d.
Se vere
S y m pt o ms ca use se vere disc o mf ort; s y m pt o ms ca use i nca pacitati o n or si g nifica nt 
i m pact o n partici pa nt’s dail y life; se verit y ma y ca use cessati o n of treat me nt wit h st u d y 
treat me nt; treat me nt f or s y m pt o ms ma y be gi ve n a n d/ or partici pa nt h os pitalize d.
1 1. 2. 4. 
E x pecte d ness of E ve nts
E x pecte d ness of all S A Es will be deter mi ne d b y t he S p o ns or acc or di n g t o t he D R F I B.
1 1. 3.  
M o nit ori n g a n d Rec or di n g E ve nts
1 1. 3. 1.  
A d verse E ve nts
A n y A E e x perie nce d b y t he partici pa nt bet wee n t he ti me of first d ose of st u d y treat me nt a n d 
u ntil t he c o m pleti o n of t he safet y f oll o w- u p visit is t o be rec or de d o n t he C R F, re gar dless of t he 
se verit y of t he e ve nt or its relati o ns hi p t o st u d y treat me nt. At eac h st u d y visit, t he I n vesti gat or 
will assess t he partici pa nt f or A Es a n d will rec or d a n y ne w A Es or u p dates t o pre vi o usl y re p orte d 
A Es o n t he C R F.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
5 5
I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t he S A E re p orti n g i nf or mati o n a n d pr oce d ures are 
use d a n d f oll o we d a p pr o priatel y.
Re p orti n g I nf or m ati o n f or S A Es
A re p ort m ust be s u b mitte d  t o t he S p o ns or re gar dless of t he f oll o wi n g:
•
W het her or n ot t he partici pa nt has u n der g o ne st u d y-relate d pr oce d ures
•
W het her or n ot t he partici pa nt has recei ve d st u d y treat me nt
•
T he se verit y of t he e ve nt
•
T he relati o ns hi p of t he e ve nt t o st u d y treat me nt
T o re p ort i nitial or f oll o w- u p i nf or mati o n o n a n S A E, fa x or e mail a c o m plete d S A E f or m t o 
t he S p o ns or; refer t o t he St u d y Refere nce G ui de’s Official St u d y C o ntact List f or c o m plete 
c o ntact i nf or mati o n. 
1 1. 3. 4. 1.
De at hs
Deat h is a n o utc o me of a n e ve nt. T he e ve nt t hat res ulte d i n deat h s h o ul d be rec or de d o n t he 
a p pr o priate C R F. All ca uses of deat h m ust be re p orte d as S A Es wit hi n 2 4 h o urs of t he site 
bec o mi n g a ware of t he e ve nt. T he I n vesti gat or s h o ul d ma ke e ver y eff ort t o o btai n a n d se n d deat h 
certificates a n d a ut o ps y re p orts t o t he S p o ns or. T he ter m deat h s h o ul d be re p orte d as a n S A E 
o nl y if t he ca use of deat h is n ot k n o w n a n d ca n n ot be deter mi ne d.
1 1. 3. 5. 
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns
S U S A Rs are S A Es t hat are u ne x pecte d a n d j u d ge d b y t he I n vesti gat or or t he S p o ns or t o be 
relate d t o t he st u d y treat me nt a d mi nistere d.
T he S p o ns or will re p ort S U S A Rs t o t he a p pr o priate re g ulat or y a ut h orities a n d I n vesti gat ors as 
re q uire d, acc or di n g t o l ocal la w.
1 1. 4. 
Pr oce d ures f or H a n dli n g S peci al Sit u ati o ns
1 1. 4. 1. 
Pre g n a nc y
P artici p a nts s h o ul d n ot bec o me pre g n a nt or i m pre g n ate t heir p art ners d uri n g t he st u d y 
a n d f or 3 0 d a ys after t heir l ast d ose of st u d y tre at me nt. If a fe male partici pa nt bec o mes 
pre g na nt, st u d y treat me nt m ust be disc o nti n ue d i m me di ately.
T he I n vesti gat or m ust re p ort a pre g na nc y occ urri n g i n a fe male partici pa nt a n d fe male part ner of 
a male partici pa nt fr o m first d ose of st u d y dr u g t o 3 0 da ys after t heir last d ose of st u d y treat me nt 
b y fa xi n g t he a p pr o priate f or m t o t he S p o ns or wit hi n 2 4 h o urs of t he site staff bec o mi n g a ware of 
t he pre g na nc y. Refer t o t he St u d y Refere nce G ui de’s Official St u d y C o ntact List f or c o m plete 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
5 6
c o ntact i nf or mati o n. T he I n vesti gat or or site staff m ust re p ort t he o utc o me of t he pre g na nc y t o 
t he S p o ns or. A pre g na nc y is n ot c o nsi dere d a n A E a n d s h o ul d n ot be rec or de d o n t he A E C R F.
C o n ge nital a b n or malities a n d birt h defects i n t he offs pri n g of male or fe male partici pa nts s h o ul d 
be re p orte d as a n S A E if c o nce pti o n occ urre d d uri n g t he st u d y treat me nt peri o d or wit hi n 3 0 da ys 
fr o m t heir last d ose of st u d y treat me nt.
1 1. 4. 2.  
O ver d ose
A n o ver d ose is a n y d ose of st u d y treat me nt a d mi nistere d t o a partici pa nt or ta ke n b y a partici pa nt 
t hat e xcee ds t he d ose assi g ne d t o t he partici pa nt acc or di n g t o t he pr ot oc ol. O ver d oses are n ot 
c o nsi dere d A Es a n d s h o ul d n ot be rec or de d as a n A E o n t he C R F; h o we ver, all o ver d oses m ust 
be rec or de d o n a n O ver d ose f or m a n d fa xe d or e maile d t o t he S p o ns or wit hi n 2 4 h o urs of t he site 
bec o mi n g a ware of t he o ver d ose. A n o ver d ose m ust be re p orte d t o t he S p o ns or e ve n if t he 
o ver d ose d oes n ot res ult i n a n A E. If a n o ver d ose res ults i n a n A E, t he A E m ust be rec or de d. If 
a n o ver d ose res ults i n a n S A E, b ot h t he S A E a n d O ver d ose f or ms m ust be c o m plete d a n d fa xe d 
or e maile d t o t he S p o ns or. All st u d y treat me nt-relate d d osi n g i nf or mati o n m ust be rec or de d o n 
t he d osi n g C R F.
1 1. 4. 3.  
Me dic al E mer ge nc y
I n a me dical e mer ge nc y re q uiri n g i m me diate atte nti o n, site staff will a p pl y a p pr o priate me dical 
i nter ve nti o n, acc or di n g t o c urre nt sta n dar ds of care. T he I n vesti gat or ( or desi g nee) s h o ul d 
c o ntact t he st u d y’s Me dical M o nit or. Refer t o t he St u d y Refere nce G ui de’s Official St u d y 
C o ntact List f or c o m plete c o ntact i nf or mati o n. 
1 1. 5.  
C o ntr ace pti o n Re q uire me nts
All w o me n of c hil d beari n g p ote ntial m ust e ns ure t hat hi g hl y effecti ve c o ntrace pti o n is use d 
d uri n g t he st u d y a n d f or 3 0 da ys after t heir last d ose of st u d y treat me nt. All me n m ust e ns ure t hat 
effecti ve c o ntrace pti o n is use d d uri n g t he st u d y a n d f or 3 0 da ys after t heir last d ose of st u d y 
treat me nt. I n a d diti o n, partici pa nts s h o ul d n ot d o nate s per m or e g gs f or t he d urati o n of t he st u d y 
a n d f or at least 3 0 da ys after t heir last d ose of st u d y treat me nt.
F or t he p ur p oses of t his st u d y, w o me n of c hil d beari n g p ote ntial are defi ne d as all w o me n 
p h ysi ol o gicall y ca pa ble of bec o mi n g pre g na nt, U N L E S S t he y meet o ne of t he f oll o wi n g 
c o n diti o ns: 
•
P ost me n o pa usal

5 2 c o nti n u o us wee ks of nat ural (s p o nta ne o us) a me n orr hea wit h o ut a n alter nati ve 
me dical ca use a n d a ser u m F S H le vel > 4 0 mI U/ m L 

6 wee ks after s ur gical bilateral o o p h orect o m y wit h or wit h o ut h ysterect o m y
•
P ost h ysterect o m y

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
5 7
•
Fe male s ur gical sterilizati o n (e. g., bilateral t u bal li gati o n) w here a p plica ble acc or di n g t o 
l ocal g ui deli nes
F or t he p ur p oses of t he st u d y, hi g hl y effecti ve c o ntrace pti o n f or fe males is defi ne d as use of at 
least 1 of t he f oll o wi n g: 
F or fe males:
•
Esta blis he d use of oral, i ntra va gi nal 1, or tra ns der mal1 c o m bi ne d (estr o ge n a n d 
pr o gest o ge n c o ntai ni n g) h or m o nal met h o ds of c o ntrace pti o n ass ociate d wit h t he 
i n hi biti o n of o v ulati o n.
•
Esta blis he d use of oral, i njecte d 1, or i m pla nte d1 pr o gest o ge n- o nl y h or m o nal met h o ds of 
c o ntrace pti o n ass ociate d wit h t he i n hi biti o n of o v ulati o n.
•
Place me nt of a n i ntra uteri ne de vice or i ntra uteri ne h or m o ne-releasi n g s yste m.
•
Bilateral t u bal occl usi o n.
•
Se x wit h a male w h o has u n der g o ne s ur gical sterilizati o n ( wit h t he a p pr o priate 
p ost vasect o m y d oc u me ntati o n of t he a bse nce of s per m i n t he ejac ulate).
F or t he p ur p oses of t he st u d y, effecti ve c o ntrace pti o n f or males is defi ne d as:
•
Vasect o m y wit h ne gati ve se me n a nal ysis at f oll o w- u p. If d oc u me ntati o n is n ot a vaila ble, 
t he partici pa nt m ust use c o ntrace pti o n.
•
C o n d o ms wit h or wit h o ut s per mici de.
Tr ue a bsti ne nce, w he n t his is c o nsiste nt wit h t he preferre d a n d us ual lifest yle of t he partici pa nt, 
ca n be c o nsi dere d a n acce pta ble met h o d of c o ntrace pti o n base d o n t he e val uati o n of t he 
I n vesti gat or w h o s h o ul d als o ta ke i nt o c o nsi derati o n t he d urati o n of t he cli nical st u d y. Peri o dic 
a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, p ost o v ulati o n met h o ds) a n d wit h dra wal are 
n ot c o nsi dere d acce pta ble met h o ds of c o ntrace pti o n.
Pre g na nc y re p orti n g is descri be d i n Secti o n 1 1. 4. 1 .
1 I ntra va gi nal a n d tra ns der mal c o m bi ne d h or m o nal met h o ds of c o ntrace pti o n a n d i njecte d a n d i m pla nte d h or m o nal 
met h o ds of c o ntrace pti o n are n ot a p pr o ve d f or use i n Ja pa n.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
5 8
1 1. 6. 
S afet y Res p o nsi bilities
1 1. 6. 1. 
T he I n vesti g at or
T he I n vesti gat or’s res p o nsi bilities i ncl u de t he f oll o wi n g:
•
M o nit or a n d rec or d all A Es, i ncl u di n g S A Es, o n t he C R F re gar dless of t he se verit y or 
relati o ns hi p t o st u d y treat me nt.
•
Deter mi ne t he seri o us ness, relati o ns hi p, a n d se verit y of eac h e ve nt.
•
Deter mi ne t he o nset a n d res ol uti o n dates of eac h e ve nt.
•
M o nit or a n d rec or d all pre g na ncies i n fe male partici pa nts a n d fe male part ners of male 
partici pa nts a n d f oll o w u p o n t he o utc o me of all pre g na ncies.
•
C o m plete a n S A E f or m f or eac h S A E a n d fa x or e mail it t o t he S p o ns or wit hi n 
2 4 h o urs of t he site staff bec o mi n g a ware of t he e ve nt.
•
P urs ue S A E f oll o w- u p i nf or mati o n acti vel y a n d persiste ntl y. F oll o w- u p i nf or mati o n 
m ust be re p orte d t o t he S p o ns or wit hi n 2 4 h o urs of t he site staff bec o mi n g a ware of 
ne w i nf or mati o n.
•
E ns ure all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntati o n i n t he partici pa nts’ 
me dical rec or ds.
•
P urs ue A E f oll o w- u p i nf or mati o n, if p ossi ble, u ntil t he e ve nt has res ol ve d or bec o me 
sta ble. Rec or d A E f oll o w- u p i nf or mati o n, i ncl u di n g res ol uti o n, o n t he C R F, as 
a p plica ble.
•
Re p ort S A Es t o l ocal et hics c o m mittees, as re q uire d b y l ocal la w.
1 1. 6. 2. 
T he S p o ns or 
T he S p o ns or’s res p o nsi bilities i ncl u de t he f oll o wi n g:
•
Bef ore a site ca n e nr oll a n y partici pa nts, t he Cli nical M o nit or is res p o nsi ble f or 
re vie wi n g wit h site staff t he defi niti o ns of A E a n d S A E, as well as t he i nstr ucti o ns f or 
m o nit ori n g, rec or di n g, a n d re p orti n g A Es a n d S A Es.
•
T he S p o ns or is t o n otif y all a p pr o priate re g ulat or y a ut h orities, ce ntral et hics 
c o m mittees, a n d I n vesti gat ors of S A Es, as re q uire d b y l ocal la w, wit hi n re q uire d ti me 
fra mes.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6 0
1 2. 4.  
Met h o ds of A n al ysis f or P h ar m ac o ki netic E n d p oi nts f or P art 1 ( o nl y)
T he P K p o p ulati o n wit h i nte nsi ve bl o o d sa m ple c ollecti o n will c o nsist of a s u bset of 
7 partici pa nts i n Ja pa nese c o h ort ( 7 of t he 5 0 partici pa nts).
If a partici pa nt i n t he P K s u bset wit h i nte nsi ve bl o o d sa m ple c ollecti o n ( 7 of t he 5 0 partici pa nts) 
disc o nti n ues t he st u d y bef ore c o m pleti n g t he 8- h o ur P K sa m pli n g peri o d or re q uires d ose 
re d ucti o n or sa m ples n ot c ollecte d per pr ot oc ol or la b orat or y ma n ual, t he partici pa nt ma y be 
re place d wit h o ne of t he ot her e nr olle d partici pa nts. If t his is n ot feasi ble, a d diti o nal partici pa nts 
a b o ve t he a ntici pate d sa m ple size of 5 0 ma y be e nr olle d t o e ns ure a de q uate n u m ber of 
partici pa nts are a vaila ble f or i nte nsi ve P K sa m pli n g.
T he P K p o p ulati o n wit h s parse bl o o d sa m ple c ollecti o n will c o nsist of 4 3 partici pa nts ( 4 3 of t he 
a p pr o xi matel y 5 0 partici pa nts i n t he Ja pa nese c o h ort) a n d 5 0 partici pa nts ( 5 0 of t he 
a p pr o xi matel y 5 0 partici pa nts i n t he C hi nese c o h ort).
M M F a n d H E S plas ma c o nce ntrati o ns will be s u m marize d usi n g descri pti ve statistics ( mea n, 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m), a n d t he mea n val ues wit h sta n dar d err ors 
will be pl otte d o ver ti me b ot h o n a li near a n d a l o garit h mic scale ( w here a p plica ble). T he M M F 
a n d H E S c o nce ntrati o ns o btai ne d t hr o u g h i nte nsi ve bl o o d sa m ple c ollecti o n will als o be use d t o 
calc ulate t he f oll o wi n g P K para meters usi n g n o nc o m part me ntal met h o ds.
T he f oll o wi n g P K para meters will be calc ulate d:
•
C ma x
•
A U C last
•
T ma x
•
t½  ( M M F o nl y)
•
Ot her P K para meters ca n be calc ulate d if feasi ble ( C L/ F, Vz/ F, T la g).
Eac h of t hese P K para meters will be s u m marize d usi n g descri pti ve statistics ( mea n, sta n dar d 
de viati o n, ge o metric mea n, 9 5 % CI, c oefficie nt of variati o n, me dia n, mi ni m u m a n d ma xi m u m 
f or A U Clast, Cma x , t½ , C L/ F, Vz/ F; me dia n, mi ni m u m, a n d ma xi m u m f or Tma x  a n d Tla g).
T hese P K para meters will als o be descri pti vel y c o m pare d t o P K para meters fr o m n o n-Ja pa nese 
partici pa nts i n St u d y A L K 8 7 0 0- A 3 0 1 wit h res pect t o et h nic se nsiti vit y a n d res ults will be 
disc usse d i n t he Part 1 a n d 2 st u d y re p orts.
M M F a n d H E S plas ma c o nce ntrati o ns pre d ose a n d at 2 t o 3 h o urs p ost d ose o n Da y 2 9 a n d 
Da y 5 7 will be s u m marize d usi n g descri pti ve statistics ( mea n, sta n dar d de viati o n, ge o metric 
mea n, 9 5 % CI, c oefficie nt of variati o n, me dia n, mi ni m u m a n d ma xi m u m).

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6 1
T he plas ma c o nce ntrati o ns i n 4 3 Ja pa nese partici pa nts will be c o m pare d wit h t h ose i n 
St u d y A L K 8 7 0 0- A 3 0 1 usi n g ta b ular data a n d gra p hics. T hese res ults will be disc usse d i n st u d y 
re p orts f or Parts 1 a n d 2.
P o p ulati o n P K a nal ysis will be perf or me d b y usi n g i nte grate d plas ma c o nce ntrati o n data, 
i ncl u di n g all plas ma c o nce ntrati o n data fr o m St u d y 2 7 2 M S 3 0 3, t o assess et h nic se nsiti vit y i n 
ter ms of H E S P K. Detaile d p o p ulati o n P K a nal ysis will be descri be d i n a se parate re p ort. 
T a ble 6: 
P h ar m ac o ki netic A n al ysis Ti me p oi nts
I nte nsi ve P K Ti me p oi nts 1
Pre d ose
0. 5 h 
1 h
2 h 
3 h
4 h
6 h
8 h 
p ost d ose
Ti me 
Wi n d o w
- 3 0 t o 
0 mi n
± 5 mi n
± 5 mi n
± 1 5 mi n
± 1 5 mi n
± 1 5 mi n
± 1 5 mi n
± 1 5 mi n
1 P K a nal ysis will be perf or me d i n a s u bset of 7 partici pa nts i n t he Ja pa nese c o h ort at a n y ti me p oi nt i n t he peri o d 
bet wee n Wee k 4 ( Da y 2 9, Visit 3 ± 3 da ys) a n d Wee k 2 4 ( Da y 1 6 9, Visit 8 ± 5 da ys), b ot h i ncl usi ve. If a 
partici pa nt fr o m t he P K s u bset p o p ulati o n disc o nti n ues t he st u d y d uri n g t he s peci me n sa m pli n g peri o d, t he n t he 
partici pa nt ma y be re place d wit h o ne of t he e nr olle d partici pa nts.
1 2. 5.  
Met h o ds of A n al ysis f or S afet y E n d p oi nts
T he safet y a nal ysis will be perf or me d usi n g t he safet y a nal ysis set ( Secti o n 1 2. 2 ). A Es a n d S A Es 
will be c o de d usi n g t he Me d D R A.
Safet y assess me nts will be s u m marize d usi n g descri pti ve statistics al o n g wit h s u p p orti ve listi n gs.
Listi n gs will be pr o vi de d f or all safet y e n d p oi nts.
T he selecte d safet y data ma y als o be descri pti vel y c o m pare d t o t he si milar data fr o m St u d y 
A L K 8 7 0 0- A 3 0 1 a n d St u d y 1 0 9 M S 3 0 5. T he p oi nt esti mates wit h ass ociate d CIs f or selecte d 
safet y data fr o m t he af ore me nti o ne d st u dies will be refere nce d i n t he st u d y re p orts w he ne ver 
p ossi ble.
F urt her details will be pr o vi de d i n t he S A P.
1 2. 5. 1.  
A d verse E ve nts
T he n u m ber a n d perce nta ge of T E A Es a n d S A Es will be s u m marize d b y s yste m or ga n class a n d 
preferre d ter ms wit hi n eac h s yste m or ga n class. S A Es a n d A Es res ulti n g i n treat me nt 
disc o nti n uati o n will be s u m marize d.
T he i nci de nce rates of T E A Es a n d S A Es will be s u m marize d b y s yste m or ga n class a n d 
preferre d ter ms wit hi n eac h s yste m or ga n class a n d prese nte d as n u m ber of A Es per partici pa nt 
per year. 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6 2
F urt her details will be pr o vi de d i n t he S A P.
1 2. 5. 2.  
Cli nic al L a b or at or y Res ults
N u m ber a n d perce nta ge of partici pa nts wit h val ues c o nsi dere d P C S occ urri n g at a n y p ost baseli ne 
visit f or selecte d para meters will be s u m marize d.
I n a d diti o n, s hifts fr o m baseli ne t o a n y p ost baseli ne visits d uri n g treat me nt peri o d will be 
pr o vi de d f or selecte d c he mistr y, he mat ol o g y, a n d uri nal ysis para meters.
1 2. 5. 3.  
Vit al Si g ns
Vital si g n res ults ( baseli ne a n d c ha n ge fr o m baseli ne) f or eac h para meter a n d visit d uri n g t he 
e ntire st u d y will be s u m marize d.
T he n u m ber a n d perce nta ge of partici pa nts wit h val ues c o nsi dere d P C S occ urri n g at a n y 
p ost baseli ne visit f or selecte d para meters will be s u m marize d.
1 2. 5. 4. 
E C G
E C G res ults ( baseli ne a n d c ha n ge fr o m baseli ne) f or eac h para meter a n d visit d uri n g t he e ntire 
st u d y will be s u m marize d.
T he n u m ber a n d perce nta ge of partici pa nts wit h val ues c o nsi dere d P C S occ urri n g at a n y 
p ost baseli ne visit f or selecte d para meters will be s u m marize d.
1 2. 5. 5.  
C- S S R S
T he n u m ber a n d perce nta ge of partici pa nts meeti n g o ne of t he criteria occ urri n g at baseli ne a n d 
a n y p ost baseli ne visit f or selecte d para meters will be s u m marize d.
1 2. 6. 
I nteri m A n al yses
I nteri m a nal yses ma y be c o n d ucte d f or Part 1, f or Part 2, a n d/ or f or Part 1 a n d Part 2 c o m bi ne d, 
as necessar y.
1 2. 7. 
S a m ple Size C o nsi der ati o ns
A sa m ple size of a p pr o xi matel y 5 0 partici pa nts per c o h ort is base d o n feasi bilit y c o nsi derati o ns 
a n d is dee me d s ufficie nt t o c haracterize t he safet y a n d t olera bilit y pr ofile. Wit h t his sa m ple size, 
t he pr o ba bilit y of o bser vi n g at least 1 S A E wit h a bac k gr o u n d i nci de nce of 4 % w o ul d be 8 7 % 
base d o n data fr o m t he 2 4- wee k Treat me nt Peri o d i n St u d y A L K 8 7 0 0- A 3 0 1 (a D R F gl o bal 
P hase 3 st u d y) i n R R M S partici pa nts w h o were naï ve t o D R F treat me nt. 
I n a d diti o n, ass u mi n g t he i nci de nce of GI A Es at 2 4 wee ks of 2 7. 5 % as o bser ve d i n partici pa nts 
naï ve t o D R F treat me nt recr uite d i n St u d y A L K 8 7 0 0- A 3 0 1, t he sa m ple size of a p pr o xi matel y 
5 0 partici pa nts per c o h ort will pr o vi de a 9 6 % pr o ba bilit y of o bser vi n g a p oi nt esti mate of GI A E 

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6 3
i nci de nce rate < 3 9 % i n Part 1 of t he st u d y (at 2 4 wee ks). T he 2 4- wee k i nci de nce rate of 3 9 % 
was o bser ve d i n East Asia n partici pa nts w h o recei ve d D M F t wice dail y i n St u d y 1 0 9 M S 3 0 5.
Base d o n t he o bser ve d D R F P K para meters i n faste d partici pa nts fr o m A L K 8 7 0 0- A 1 0 3 st u d y, 
C V of A U C (last) was esti mate d t o be 3 0. 9; t heref ore, a sa m ple size of 7 Ja pa nese partici pa nts 
w o ul d be nee de d t o e val uate t he M M F P K para meters wit h s ufficie nt precisi o n, w hic h is defi ne d 
as a n e val uati o n of t he P K para meters of M M F wit h at least 8 0 % p o wer t o ac hie ve a 9 5 % CI 
wit hi n 6 0 % t o 1 4 0 % of t he ge o metric mea n. Si nce t he varia bilit y of H E S para meters is 
si g nifica ntl y l o wer, t he data fr o m 7 partici pa nts will als o pr o vi de a r o b ust assess me nt of A U C last 
a n d C ma x  of H E S i n Ja pa nese M S partici pa nts.
T he S p o ns or ma y e nr oll fe wer t ha n 5 0 partici pa nts per c o h ort base d o n t he o bser ve d recr uit me nt 
rate i n t hese re gi o ns.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6 4
1 3. 
E T HI C A L A N D R E G U L A T O R Y R E Q UI R E M E N T S
T he S p o ns or, a n y c o ntracte d t hir d part y, a n d t he I n vesti gat or m ust c o m pl y wit h all i nstr ucti o ns, 
re g ulati o ns, a n d a gree me nts i n t his pr ot oc ol a n d a p plica ble I C H a n d G C P g ui deli nes a n d c o n d uct 
t he st u d y acc or di n g t o l ocal re g ulati o ns.
T he I n vesti gat ors are res p o nsi ble f or de m o nstrati n g ti mel y o versi g ht of all cli nical trial data fr o m 
t heir site, i ncl u di n g data e xter nal t o t he electr o nic data ca pt ure s yste m, s uc h as la b orat or y, 
 a n d electr o nic cli nical o utc o mes assess me nt data. I n vesti gat ors m ust a p pr o ve all t heir 
data o n c o m plete d C R Fs b y si g ni n g electr o nicall y, at t he partici pa nt, visit, or case b o o k le vel, at 
a n y ti me pri or t o a n i nteri m l oc k or data base l oc k, as well as bef ore a n y s u bse q ue nt re-l oc k. T he 
electr o nic data ca pt ure s yste m d oes n ot pr o hi bit I n vesti gat or a p pr o val or si g ni n g i n a n y wa y.
T he I n vesti gat or ma y dele gate res p o nsi bilities f or st u d y-relate d tas ks w here a p pr o priate t o 
i n di vi d uals s ufficie ntl y q ualifie d b y e d ucati o n, trai ni n g, a n d e x perie nce, i n acc or da nce wit h 
a p plica ble I C H a n d G C P g ui deli nes. T he I n vesti gat or s h o ul d mai ntai n a list of t he a p pr o priatel y 
q ualifie d pers o ns t o w h o m si g nifica nt st u d y-relate d d uties ha ve bee n dele gate d. T he I n vesti gat or 
is res p o nsi ble f or s u per visi n g t h ose i n di vi d uals a n d f or i m ple me nti n g pr oce d ures t o e ns ure t he 
i nte grit y of t he tas ks perf or me d a n d a n y data ge nerate d.
1 3. 1.  
Decl ar ati o n of Helsi n ki
T his st u d y will be perf or me d i n ali g n me nt wit h t he et hical pri nci ples o utli ne d i n t he Declarati o n 
of Helsi n ki.
1 3. 2. 
Et hics C o m mittee
T he I n vesti gat or m ust o btai n et hics c o m mittee a p pr o val of t he pr ot oc ol, I C F, a n d ot her re q uire d 
st u d y d oc u me nts pri or t o starti n g t he st u d y. T he S p o ns or will s u b mit d oc u me nts o n be half of t he 
st u d y sites i n c o u ntries ot her t ha n t he U S.
If t he I n vesti gat or ma kes a n y c ha n ges t o t he I C F, t he S p o ns or m ust a p pr o ve t he c ha n ges bef ore 
t he I C F is s u b mitte d t o t he et hics c o m mittee. A c o p y of t he a p pr o ve d I C F m ust be pr o vi de d t o 
t he S p o ns or. After a p pr o val, t he I C F m ust n ot be altere d wit h o ut t he a gree me nt of t he rele va nt 
et hics c o m mittee a n d t he S p o ns or.
It is t he res p o nsi bilit y of t he I n vesti gat ors t o e ns ure t hat all as pects of i nstit uti o nal re vie w are 
c o n d ucte d i n acc or da nce wit h c urre nt a p plica ble re g ulati o ns.
T he S p o ns or m ust recei ve a letter d oc u me nti n g et hics c o m mittee a p pr o val, w hic h s pecificall y 
i de ntifies t he pr ot oc ol, pr ot oc ol n u m ber, a n d I C F, pri or t o t he i nitiati o n of t he st u d y. Pr ot oc ol 
a me n d me nts will be s u bject t o t he sa me re q uire me nts as t he ori gi nal pr ot oc ol.
A pr o gress re p ort m ust be s u b mitte d t o t he et hics c o m mittee at re q uire d i nter vals a n d n ot less 
t ha n a n n uall y.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6 6
1 3. 5. 
P artici p a nt D at a Pr otecti o n
Pri or t o a n y testi n g u n der t his pr ot oc ol, i ncl u di n g scree ni n g tests a n d assess me nts, ca n di dates 
m ust als o pr o vi de all a ut h orizati o ns re q uire d b y a p plica ble nati o nal a n d l ocal pri vac y re g ulati o ns 
(e. g., Pr otecte d Healt h I nf or mati o n a ut h orizati o n i n N ort h A merica).
D uri n g t he st u d y, partici pa nts’ race a n d et h nicit y will be c ollecte d ( u nless t he c ollecti o n is n ot 
per mitte d b y a p plica ble la w or n ot a p pr o ve d b y t he g o ver ni n g et hics c o m mittee). T hese data will 
be use d i n t he a nal ysis of t he safet y a n d/ or P K pr ofile of t he st u d y treat me nt. Si nce it is n ot 
al wa ys k n o w n w het her t he effects of t he st u d y treat me nt are i nfl ue nce d b y race or et h nicit y, t his 
i nf or mati o n will be of val ue i n t he a nal ysis of safet y. 
St u d y re p orts will be use d f or researc h p ur p oses o nl y. T he partici pa nt will n ot be i de ntifie d b y 
na me i n C R Fs, st u d y-relate d f or ms, st u d y re p orts, or a n y relate d p u blicati o ns. T he S p o ns or, its 
part ners a n d desi g nees, et hics c o m mittees, a n d vari o us g o ver n me nt healt h a ge ncies ma y i ns pect 
t he rec or ds of t his st u d y. E ver y eff ort will be ma de t o kee p t he partici pa nt’s pers o nal me dical 
data c o nfi de ntial.
1 3. 6.  
C o m pe ns ati o n f or I nj ur y
T he S p o ns or mai ntai ns a p pr o priate i ns ura nce c o vera ge f or cli nical st u dies a n d will f oll o w 
a p plica ble l ocal c o m pe nsati o n la ws.
1 3. 7.  
C o nflict of I nterest
T he I n vesti gat ors s h o ul d a d dress a n y p ote ntial c o nflicts of i nterest (e. g., fi na ncial i nterest i n t he 
S p o ns or) wit h t he partici pa nt bef ore t he partici pa nt ma kes a decisi o n t o partici pate i n t he st u d y.
1 3. 8. 
St u d y Re p ort Si g n at or y
T he S p o ns or will desi g nate o ne of t he partici pati n g I n vesti gat ors as a si g nat or y f or t he st u d y 
re p ort. T his deter mi nati o n will be ma de b y se veral fact ors, i ncl u di n g b ut n ot li mite d t o, t he 
I n vesti gat or's e x perie nce a n d re p utati o n i n t he st u die d i n dicati o n; t he I n vesti gat or's c o ntri b uti o n 
t o t he st u d y i n ter ms of desi g n, ma na ge me nt, a n d/ or partici pa nt e nr oll me nt; or b y ot her fact ors 
deter mi ne d t o be rele va nt b y t he S p o ns or.
T he S p o ns or will f oll o w all a p plica ble l ocal re g ulati o ns pertai ni n g t o st u d y re p ort si g nat ories.
1 3. 9.  
Re gistr ati o n of St u d y a n d Discl os ure of St u d y Res ults
T he S p o ns or will re gister t he st u d y a n d p ost st u d y res ults re gar dless of o utc o me o n a p u blicl y 
accessi ble we bsite i n acc or da nce wit h t he a p plica ble la ws a n d re g ulati o ns.
T he S p o ns or als o will n otif y, w he n re q uire d, t he re g ulat or y a ut h orities a n d et hics c o m mittees 
a b o ut t he c o m pleti o n or ter mi nati o n of t his st u d y a n d se n d a c o p y of t he st u d y s y n o psis i n 
acc or da nce wit h necessar y ti meli nes.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6 7
1 3. 1 0.
Rete nti o n of St u d y D at a
T he mi ni m u m rete nti o n ti me f or st u d y rec or ds will meet t he strictest sta n dar d a p plica ble t o t hat 
site, as dictate d b y a n y i nstit uti o nal re q uire me nts or l ocal, nati o nal, or re gi o nal la ws or 
re g ulati o ns. Pri or t o pr ocee di n g wit h destr ucti o n of rec or ds, t he I n vesti gat or m ust n otif y t he 
S p o ns or i n writi n g a n d recei ve writte n a ut h orizati o n fr o m t he S p o ns or t o destr o y st u d y rec or ds. 
I n a d diti o n, t he I n vesti gat or m ust n otif y t he S p o ns or of a n y c ha n ges i n t he arc hi val arra n ge me nts 
i ncl u di n g b ut n ot li mite d t o arc hi val at a n offsite facilit y or tra nsfer of o w ners hi p if t he 
I n vesti gat or lea ves t he site.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6 8
1 4.  
K E Y R O L E S A N D S T U D Y G O V E R N A N C E C O M MI T T E E S
1 4. 1. 
Site St aff
T he I n vesti gat or of t he site will desi g nate t he a p pr o priate site pers o n nel a n d t heir r ole i n t he 
st u d y. See t he St u d y Refere nce G ui de f or details.
1 4. 2.  
Ve n d ors
T he S p o ns or will e ns ure o versi g ht of a n y st u d y-relate d d uties a n d f u ncti o ns carrie d o ut o n its 
be half a n d will s pecif y i n writi n g all d uties a n d f u ncti o ns t hat are tra nsferre d. 
1 4. 2. 1.  
C o ntr act Rese arc h Or g a niz ati o n 
At least 2 C R Os ha ve bee n selecte d b y t he S p o ns or t o be res p o nsi ble f or a d mi nistrati ve as pects 
of t he st u d y i ncl u di n g b ut n ot li mite d t o st u d y i nitiati o n, ma na ge me nt of S A E re p orts, 
m o nit ori n g, a n d data ma na ge me nt. 
1 4. 2. 2. 
I nter acti ve Res p o nse Tec h n ol o g y
I R T will be use d i n t his st u d y. Bef ore partici pa nts are scree ne d or e nr olle d, t he I R T ve n d or will 
pr o vi de eac h st u d y site wit h t he necessar y trai ni n g, a user ma n ual, a n d access ri g hts t o t he 
s yste m.
1 4. 2. 3. 
Electr o nic or Re m ote D at a C a pt ure
Partici pa nt i nf or mati o n will be ca pt ure d a n d ma na ge d b y st u d y sites o n electr o nic C R Fs b y a 
We b- base d electr o nic data ca pt ure t o ol c o nfi g ure d b y t he S p o ns or or t he C R O a n d h oste d b y t he 
electr o nic/re m ote data ca pt ure ve n d or. 
1 4. 2. 4.  
Ce ntr al L a b or at ories f or L a b or at or y Assess me nts
Ce ntral la b orat ories ha ve bee n selecte d b y t he S p o ns or t o a nal yze t he he mat ol o g y, bl o o d 
c he mistr y, a n d uri ne sa m ples c ollecte d f or t his st u d y. P K sa m ples will be a nal yze d at a 
la b orat or y selecte d b y t he S p o ns or.
1 4. 2. 5.  
Ce ntr al F acilit y f or Ot her Assess me nts
Ce ntral facilities ha ve bee n selecte d b y t he S p o ns or t o rea d a n d i nter pret 
 a n d E C G 
rea di n gs f or t his st u d y.
1 4. 2. 6.  
Ce ntr al Re vie w of R aters
T he S p o ns or has selecte d a rater ma na ge me nt gr o u p t o esta blis h rater q ualificati o ns, pr o vi de 
st u d y-s pecific trai ni n g a b o ut t he rater pr ocess, a n d pr o vi de o versi g ht. As part of t he o versi g ht 
pr ocess, t he rater ma na ge me nt gr o u p will i nc or p orate a ce ntral re vie w of t he raters t o e ns ure t hat 
data are c o nsiste ntl y rate d acr oss sites.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6 9
1 4. 3. 
St u d y C o m mittees
N ot a p plica ble.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
7 0
1 5.  
A D MI NI S T R A TI V E P R O C E D U R E S
1 5. 1. 
St u d y Site I niti ati o n
T he I n vesti gat or m ust n ot scree n a n y partici pa nts pri or t o t he S p o ns or c o m pleti n g a st u d y 
i nitiati o n visit. T his i nitiati o n visit wit h t he I n vesti gat or a n d ot her site staff, as a p pr o priate, will 
i ncl u de a detaile d re vie w of t he pr ot oc ol, st u d y pr oce d ures, a n d st u d y res p o nsi bilities.
1 5. 2.  
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce
Q ualit y c o ntr ol pr oce d ures will be i m ple me nte d at eac h sta ge of data ha n dli n g t o e ns ure t hat all 
data are relia ble a n d ha ve bee n pr ocesse d c orrectl y. Data a n o malies will be c o m m u nicate d t o t he 
sites f or clarificati o n a n d res ol uti o n, as a p pr o priate. T he I n vesti gat or is res p o nsi ble f or e n d orsi n g 
all C R F data pri or t o a n y i nteri m or fi nal data base l oc k.
D uri n g a n d/ or after c o m pleti o n of t he st u d y, q ualit y ass ura nce officers na me d b y t he S p o ns or or 
t he re g ulat or y a ut h orities ma y wis h t o perf or m o nsite a u dits or i ns pecti o ns. T he I n vesti gat or will 
be e x pecte d t o c o o perate wit h a n y a u dit or i ns pecti o n a n d t o pr o vi de assista nce a n d 
d oc u me ntati o n (i ncl u di n g s o urce data) as re q ueste d.
1 5. 3.  
M o nit ori n g of t he St u d y
T he I n vesti gat or m ust per mit st u d y-relate d m o nit ori n g b y pr o vi di n g direct access t o s o urce data 
a n d t o t he partici pa nts’ me dical hist ories. S o urce data m ust be attri b uta ble, le gi ble, 
c o nte m p ora ne o us, ori gi nal, acc urate, a n d c o m plete. C ha n ges t o s o urce data m ust be tracea ble, 
n ot o bsc ure t he ori gi nal e ntr y, a n d be e x plai ne d if necessar y (e. g., wit h a n a u dit trail). T he 
I n vesti gat or s h o ul d mai ntai n a rec or d of t he l ocati o n(s) of esse ntial d oc u me nts.
T he Cli nical M o nit or will visit t he st u d y site at re g ular i nter vals d uri n g t he st u d y a n d after t he 
st u d y has c o m plete d, as a p pr o priate. A cli nical site m o nit ori n g pla n will detail w h o perf or ms t he 
m o nit ori n g, h o w ofte n, a n d t he e xte nt of re vie w. It als o will pr o vi de t he m o nit ori n g strate g y, 
wit h e m p hasis o n partici pa nt safet y, data i nte grit y, a n d critical data a n d pr ocesses.
D uri n g t hese visits, C R Fs, s u p p orti n g d oc u me ntati o n, a n d esse ntial d oc u me ntati o n relate d t o t he 
st u d y will be re vie we d a n d a n y discre pa ncies or o missi o ns will be res ol ve d. D oc u me ntati o n of 
res ults will be pr o vi de d t o t he S p o ns or i n a ti mel y fas hi o n t o all o w f oll o w- u p a n d verificati o n of 
c o m plia nce wit h t he m o nit ori n g pla n. Re m ote e val uati o n of data (ce ntralize d m o nit ori n g) ma y 
als o be c o n d ucte d a n d re p orte d as defi ne d i n t he m o nit ori n g pla n.
M o nit ori n g visits m ust be c o n d ucte d acc or di n g t o t he a p plica ble I C H a n d G C P g ui deli nes t o 
e ns ure t he pr otecti o n of partici pa nt ri g hts a n d well- bei n g, pr ot oc ol a d here nce, q ualit y of data 
(acc urate, c o m plete, a n d verifia ble), st u d y treat me nt acc o u nta bilit y, c o m plia nce wit h re g ulat or y 
re q uire me nts, a n d c o nti n ue d a de q uac y of t he i n vesti gati o nal site a n d its facilities.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
7 1
1 5. 3. 1. 
P u blic He alt h E mer ge ncies
I n t he e ve nt of a p u blic healt h e mer ge nc y t hat res ults i n site cl os ure, tra vel restricti o ns, a n d/ or t he 
st u d y bei n g de pri oritize d at t he site s uc h t hat cli nic visit(s) ca n n ot occ ur, a pr ot oc ol de viati o n 
w o ul d be i nc urre d f or a n y de viati o n fr o m t he pr ot oc ol-s pecifie d visits a n d assess me nts, wit h 
a d diti o nal n otati o n t hat t his pr ot oc ol de viati o n is d ue t o t he p u blic healt h e mer ge nc y. If a 
pr ot oc ol-s pecifie d cli nical visit ca n n ot occ ur d ue t o a p u blic healt h e mer ge nc y, o ne or m ore of 
t he f oll o wi n g miti gati n g o pti o ns s h o ul d be p urs ue d i n c o ns ultati o n wit h t he me dical m o nit or: 1) 
tra nsfer t o a n ot her acti ve st u d y site t hat is o pe n, 2) tele me dici ne visit (e. g., b y tele p h o ne or we b 
c o nfere nce), a n d 3) l ocal la b orat or y visit. T hese miti gati n g o pti o ns o nl y a p pl y i n t he setti n g of a 
p u blic healt h e mer ge nc y i n w hic h a pr ot oc ol-s pecifie d cli nic visit ca n n ot occ ur a n d s h o ul d n ot be 
p urs ue d s olel y d ue t o partici pa nt’s prefere nce. If t he partici pa nt d oes n ot partici pate i n o ne or 
m ore of t hese o pti o ns, a safet y tele p h o ne call m ust be c o n d ucte d wit hi n 1 4 da ys of t he last 
d osi n g visit.
If t he partici pa nt is u na ble t o pic k u p st u d y treat me nt d uri n g t he 4 8- wee k Treat me nt Peri o d 
beca use of a p u blic healt h e mer ge nc y, arra n ge me nts ma y be ma de t o s hi p st u d y treat me nt 
directl y t o t he partici pa nt, w here all o we d per c o u ntr y or l ocal re g ulati o ns.
1 5. 4. 
St u d y F u n di n g
T he S p o ns or is res p o nsi ble f or setti n g u p t he f u n di n g of t he st u d y. All fi na ncial details are 
pr o vi de d i n t he se parate c o ntracts bet wee n t he i nstit uti o n, I n vesti gat or, a n d t he S p o ns or 
or ga nizati o n. 
1 5. 5. 
P u blic ati o ns
Details are i ncl u de d i n t he cli nical trial a gree me nt f or t his st u d y.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
7 2
1 6.  
R E F E R E N C E S
Br o w ne P, C ha n drarat na D, A n g o o d C, et al. Atlas of M ulti ple Scler osis 2 0 1 3: A gr o wi n g gl o bal 
pr o ble m wit h wi des prea d i ne q uit y. Ne ur ol o g y. 2 0 1 4; 8 3( 1 1): 1 0 2 2- 4.
Flac he nec ker P, St u ke K. Nati o nal M S Re gistries. J Ne ur ol. 2 0 0 8; 2 5 5( S u p pl 6): 1 0 2- 8. E p u b 
2 0 0 9/ 0 3/ 2 8.
Gi o va n n o ni G, B utz k ue ve n H, D hi b-Jal b ut S, et al. Brai n healt h: ti me matters i n m ulti ple 
scler osis. M ult Scler Relat Dis or d. 2 0 1 6; 9 S u p pl 1: S 5- S 4 8.
Gr o u p G N D C. Gl o bal, re gi o nal, a n d nati o nal b ur de n of ne ur ol o gical dis or ders d uri n g 1 9 9 0-
2 0 1 5: a s yste matic a nal ysis f or t he Gl o bal B ur de n of Disease St u d y 2 0 1 5. La ncet Ne ur ol. 
2 0 1 7; 1 6( 1 1): 8 7 7- 8 9 7. E p u b 2 0 1 7/ 0 9/ 1 7.
Har b o H F, G ol d R, Ti nt oré M. Se x a n d ge n der iss ues i n m ulti ple scler osis. T her A d v Ne ur ol 
Dis or d. 2 0 1 3; 6( 4): 2 3 7- 4 8.
H ur witz BJ. T he dia g n osis of m ulti ple scler osis a n d t he cli nical s u bt y pes. A n n I n dia n Aca d 
Ne ur ol. 2 0 0 9; 1 2( 4): 2 2 6- 3 0.
Ka uf ma n D W, Res hef S, G ol u b H L, et al. S ur vi val i n c o m merciall y i ns ure d m ulti ple scler osis 
patie nts a n d c o m parat or s u bjects i n t he U. S. M ult Scler Relat Dis or d. 2 0 1 4; 3( 3): 3 6 4- 7 1. E p u b 
2 0 1 3/ 1 2/ 2 5.
Le ve y A S, Ste ve ns L A, Sc h mi d C H, et al. A ne w e q uati o n t o esti mate gl o mer ular filtrati o n rate. 
A n n I nter n Me d. 2 0 0 9; 1 5 0( 9): 6 0 4- 1 2.
L u bli n F D, Rei n g ol d S C, C o he n J A, et al. Defi ni n g t he cli nical c o urse of m ulti ple scler osis: t he 
2 0 1 3 re visi o ns. Ne ur ol o g y. 2 0 1 4; 8 3( 3): 2 7 8- 8 6.
Nais mit h R T, W u n des A, Zie msse n T, et al. Dir o xi mel F u marate De m o nstrates a n I m pr o ve d 
Gastr oi ntesti nal T olera bilit y Pr ofile C o m pare d wit h Di met h yl F u marate i n Patie nts wit h 
Rela psi n g- Re mitti n g M ulti ple Scler osis: Res ults fr o m t he Ra n d o mize d, D o u ble- Bli n d, P hase III 
E V O L V E- M S- 2 St u d y. C N S Dr u gs. 2 0 2 0; 3 4( 2): 1 8 5- 1 9 6.
P hilli ps J T, A grella S, F o x RJ. Di met h yl F u marate: A Re vie w of Efficac y a n d Practical 
Ma na ge me nt Strate gies f or C o m m o n A d verse E ve nts i n Patie nts wit h M ulti ple Scler osis. 
I nter nati o nal J o ur nal of M S Care. 2 0 1 7; 1 9.
P o pesc u B F, Pir k o I, L ucc hi netti C F. Pat h ol o g y of m ulti ple scler osis: w here d o we sta n d? 
C o nti n u u m ( Mi n nea p Mi n n). 2 0 1 3a; 1 9( 4 M ulti ple Scler osis): 9 0 1- 2 1.
P o pesc u V, A g osta F, H ulst H E, et al. Brai n atr o p h y a n d lesi o n l oa d pre dict l o n g ter m disa bilit y 
i n m ulti ple scler osis. J Ne ur ol Ne ur os ur g Ps yc hiatr y. 2 0 1 3 b; 8 4( 1 0): 1 0 8 2- 9 1. E p u b 2 0 1 3/ 0 3/ 2 3.
T E C FI D E R A ®  ( di met h yl f u marate) Pac ka ge I nsert. Ca m bri d ge, M A: Bi o ge n, I nc.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
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Bi o ge n M A I nc.
7 3
T h o m ps o n AJ, Ba n well B L, Bar k h of F, et al. Dia g n osis of m ulti ple scler osis: 2 0 1 7 re visi o ns of 
t he Mc D o nal d criteria. La ncet Ne ur ol. 2 0 1 8; 1 7( 2): 1 6 2- 1 7 3. E p u b 2 0 1 7/ 1 2/ 2 1.
Tre mlett H, Z ha o Y, Riec k ma n n P, et al. Ne w pers pecti ves i n t he nat ural hist or y of m ulti ple 
scler osis. Ne ur ol o g y. 2 0 1 0; 7 4( 2 4): 2 0 0 4- 1 5.
Wei ns he n ker B G, Bass B, Rice G P, et al. T he nat ural hist or y of m ulti ple scler osis: a 
ge o gra p hicall y base d st u d y. I. Cli nical c o urse a n d disa bilit y. Brai n. 1 9 8 9; 1 1 2( Pt 1): 1 3 3- 1 4 6.

Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
P hase 3 St u d y t o E val uate Safet y a n d T olera bilit y, a n d P K of D R F i n A d ults i n Asia- Pacific Re gi o n
C O N FI D E N TI A L
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Bi o ge n M A I nc.
7 4
1 7. 
SI G N E D A G R E E M E N T O F T H E S T U D Y P R O T O C O L
I ha ve rea d t he f ore g oi n g pr ot oc ol, “ A n O pe n- La bel, Si n gle- Ar m, M ultice nter, P hase 3 St u d y t o 
E val uate t he Safet y a n d T olera bilit y, a n d P har mac o ki netics of Dir o xi mel F u marate ( BII B 0 9 8) i n 
A d ult Partici pa nts Fr o m t he Asia- Pacific Re gi o n Wit h Rela psi n g F or ms of M ulti ple Scler osis,” 
a n d a gree t o c o n d uct t he st u d y acc or di n g t o t he pr ot oc ol a n d t he a p plica ble I C H g ui deli nes a n d 
G C P re g ulati o ns, a n d t o i nf or m all w h o assist me i n t he c o n d uct of t his st u d y of t heir 
res p o nsi bilities a n d o bli gati o ns.
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I n vesti gat or’s Si g nat ure
Date
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I n vesti gat or’s Na me ( Pri nt)
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St u d y Site ( Pri nt)

C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1
Bi o ge n M A I nc.
2 2 5 Bi n ne y Street
Ca m bri d ge, M A  0 2 1 4 2
U nite d States
Bi o ge n I dec Researc h Li mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d, Ber ks hire
S L 6 4 A Y
U nite d Ki n g d o m
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A M E N D M E N T S U M M A R Y
Bi o ge n Pr ot oc ol 2 7 2 M S 3 0 3
A n O pe n- La bel, Si n gle- Ar m, M ultice nter, P hase 3 St u d y t o E val uate t he Safet y a n d T olera bilit y, 
a n d P har mac o ki netics of Dir o xi mel F u marate ( BII B 0 9 8) i n A d ult Partici pa nts Fr o m t he 
Asia- Pacific Re gi o n Wit h Rela psi n g F or ms of M ulti ple Scler osis
Versi o n 4
Date: 2 3 Ma y 2 0 2 3
Versi o n 4 of t he pr ot oc ol has bee n pre pare d f or t his a me n d me nt, w hic h s u perse des Versi o n 3.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
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Bi o ge n M A I nc.
2
P RI M A R Y R E A S O N F O R A M E N D M E N T
T he pri mar y reas o n f or t his a me n d me nt t o Pr ot oc ol 2 7 2 M S 3 0 3 is t o i ncl u de alter nati ve 
ti me p oi nts f or i nte nsi ve P K sa m pli n g f or ne wl y e nr olle d partici pa nts a n d f or partici pa nts alrea d y 
e nr olle d i n t he s parse P K c o h ort w h o ha ve n ot yet reac he d Wee k 2 4.
Ne w te xt is s h o w n i n b ol d t y pe; delete d te xt is s h o w n wit h a stri ket hr o u g h.
Secti o n 5. 1, St u d y O ver vie w
N o w re a ds:
I nte nsi ve bl o o d sa m ples will be c ollecte d pre d ose (- 3 0 t o 0 mi n utes pre d ose) a n d at vari o us 
ti me p oi nts p ost d ose ( 0. 5, 1, 2, 3, 4, 6, a n d 8 h o urs p ost d ose) o n at a n y ti me p oi nt i n t he peri o d 
bet wee n Wee k 4 ( Da y 2 9, Visit 3 ± 3 da ys)  a n d Wee k 2 4 ( D a y 1 6 9, Visit 8 ± 5 d a ys), b ot h 
i ncl usi ve, f or 7 Ja pa nese partici pa nts w h o will ta ke D R F after 1 0 h o urs of fasti n g, a n d n o f o o d 
will be all o we d f or at least 4 h o urs after t he d ose of D R F. Partici pa nts will be all o we d water a d 
li bit u m, e xce pt f or 1 h o ur bef ore a n d 2 h o urs after a d mi nistrati o n of t he d ose of D R F. S parse 
bl o o d sa m ples will be c ollecte d f or all re mai ni n g partici pa nts (e xcl u di n g as well as f or  t h ose 
w h ose sa m ples p artici p a nts w h o  are c ollecte d f or e nr olle d b ot h i n t he  i nte nsi ve P K sa m pli n g 
a n d t he s p arse P K c o h orts ) pre d ose (- 3 0 t o 0 mi n utes pre d ose) a n d 2 t o 3 h o urs p ost d ose o n 
Da y 2 9 ( Visit 3) a n d Da y 5 7 ( Visit 4).
R ati o n ale:  Alter nati ve ti me p oi nts f or i nte nsi ve P K sa m pli n g w he n stea d y state is g uara ntee d 
were a d de d t o i ntr o d uce fle xi bilit y i n P K ti me p oi nts, t here b y re d uci n g restricti o ns t hat ma y 
affect partici pa nt recr uit me nt. La n g ua ge was re vise d t o clarif y eli gi bilit y f or e nr oll me nt i n 
i nte nsi ve P K c o h ort. G ui da nce f or partici pa nts w h o ma y be e nr olle d i n b ot h t he s parse a n d 
i nte nsi ve P K c o h orts was i ncl u de d t o pr o vi de clarit y f or t he c o n d uct of st u d y pr oce d ures.
T his c ha n ge als o affects t he f oll o wi n g secti o ns: Secti o n 1. 2, St u d y Desi g n Sc he matic; Secti o n 
1. 3, Sc he d ule of Acti vities; Secti o n 9. 3, P K Assess me nts; Secti o n 1 2. 4, Met h o ds of A nal ysis of 
A nal ysis f or P K E n d p oi nts f or Part 1 ( o nl y).

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
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Bi o ge n M A I nc.
3
S U M M A R Y O F M A J O R C H A N G E S T O T H E P R O T O C O L
T he f oll o wi n g maj or c ha n ges were ma de t o t he pr ot oc ol.
C ha n ges t o t he pr ot oc ol are prese nte d c hr o n ol o gicall y. Ne w te xt is s h o w n i n b ol d t y pe; delete d 
te xt is s h o w n wit h a stri ket hr o u g h.
Secti o n 1. 1, S y n o psis
T he s y n o psis was re vise d t o reflect c ha n ges ma de t hr o u g h o ut t he pr ot oc ol.
Secti o n 6. 1, I ncl usi o n Criteria
C h a n ge:  A d de d te xt t o state t hat i nf or me d c o nse nt fr o m a le gall y acce pta ble re prese ntati ve is 
ma n dat or y f or partici pa nts i n Ja pa n, if t he partici pa nt is a ge d < 2 0 years.
N o w re a ds:  
2. Male a n d fe male partici pa nts a ge d 1 8 t o 6 5 years ol d, i ncl usi ve, at t he ti me of i nf or me d 
c o nse nt. 
•
F or p artici p a nts i n J a p a n a ge d < 2 0 ye ars, writte n i nf or me d c o nse nt s h o ul d be 
o bt ai ne d fr o m t he p artici p a nt a n d t heir le g all y acce pt a ble re prese nt ati ve.
•
I nf or me d c o nse nt fr o m a le g all y acce pt a ble re prese nt ati ve is n ot m a n d at or y if 
t he p artici p a nt is cl assifie d as a n a d ult b ase d o n t he l atest a p plic a ble l oc al l a ws.
R ati o n ale:  T his i ncl usi o n criteri o n was u p date d t o clarif y t hat, as of n o w f or partici pa nts i n 
Ja pa n, i nf or me d c o nse nt fr o m a le gall y acce pta ble re prese ntati ve is ma n dat or y if t he partici pa nt 
is a ge d < 2 0 years. T his criteri o n is s u bject t o c ha n ge per t he latest a p plica ble l ocal la ws.
Secti o n 6. 2, E xcl usi o n Criteria
C h a n ge: La n g ua ge was re vise d i n e xcl usi o n criteri o n 1 5 re gar di n g rescree ni n g eli gi bilit y of 
partici pa nts wit h e vi de nce of c urre nt S A R S- C o V- 2 i nfecti o n. N o w re a ds:
1 5. E vi de nce of c urre nt S A R S- C o V- 2 i nfecti o n wit hi n 1 4 da ys pri or t o Scree ni n g, bet wee n 
Scree ni n g a n d Baseli ne Visit ( D a y 1), or at Baseli ne Visit ( D a y 1), i ncl u di n g b ut n ot li mite d t o a 
fe ver (te m perat ure > 3 7. 5° C), ne w a n d persiste nt c o u g h, breat hless ness, or l oss of taste a n d/ or 
s mell.
N ote: If a S A R S- C o V- 2 test ( P C R or ot her re g ulat or y a p pr o ve d met h o d) is perf or me d per t he 
discreti o n of t he I n vesti gat or i n acc or da nce wit h l ocal site practice, t he test res ult m ust be 
ne gati ve i n or der f or t he partici pa nt t o be e nr olle d i n t he trial.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4
P artici p a nts wit h e vi de nce of c urre nt S A R S- C o V- 2 i nfecti o n wit hi n 1 4 d a ys pri or t o 
Scree ni n g or d uri n g Scree ni n g, will be eli gi ble f or rescree ni n g, pr o vi de d t h at t he 
p artici p a nt is as y m pt o m atic f or 1 4 d a ys pri or t o rescree ni n g.
R ati o n ale:  La n g ua ge i n e xcl usi o n criteri o n 1 5 was re vise d t o all o w rescree ni n g of partici pa nts 
wit h e vi de nce of c urre nt S A R S- C o V- 2 i nfecti o n after rec o ver y fr o m s y m pt o ms.
C h a n ge: La n g ua ge was re vise d i n e xcl usi o n criteri o n 1 6 re gar di n g rescree ni n g eli gi bilit y of 
partici pa nts w h o ha d cl ose c o ntact wit h i n di vi d ual(s) wit h s us pecte d S A R S- C o V- 2 i nfecti o n 
wit hi n 1 4 da ys pri or t o Da y 1.
N o w re a ds:
1 6. Ha ve cl ose c o ntact wit hi n 1 4 da ys pri or t o Da y 1 wit h i n di vi d ual(s) wit h a S A R S- C o V- 2 
p ositi ve i n di vi d ual s us pecte d S A R S- C o V- 2 i nfecti o n. Cl ose c o ntact is defi ne d as:
a.
face-t o-face c o ntact wit h a pr o ba ble or c o nfir me d case wit hi n 1 meter a n d f or at least 
1 5 mi n utes; 
b.
direct p h ysical c o ntact wit h a pr o ba ble or c o nfir me d case; 
c.
direct care f or a patie nt wit h pr o ba ble or c o nfir me d C O VI D- 1 9 disease wit h o ut t he 
use of rec o m me n de d P P E; or 
d.
ot her sit uati o ns as i n dicate d b y l ocal ris k assess me nts.
P artici p a nts w h o h a d cl ose c o nt act wit h i n di vi d u al(s) wit h s us pecte d S A R S- C o V- 2 i nfecti o n 
wit hi n 1 4 d a ys pri or t o D a y 1, as deter mi ne d b y t he I n vesti g at or, will be eli gi ble f or 
rescree ni n g, pr o vi de d t h at t he p artici p a nt is as y m pt o m atic f or 1 4 d a ys after t he c o nt act.
R ati o n ale:  La n g ua ge i n e xcl usi o n criteri o n 1 6 was re vise d t o all o w rescree ni n g of partici pa nts 
w h o ha d cl ose c o ntact wit h i n di vi d ual(s) wit h s us pecte d S A R S- C o V- 2 i nfecti o n wit hi n 1 4 da ys 
pri or t o Da y 1 .
C h a n ge: La n g ua ge was re vise d i n e xcl usi o n criteri o n 2 1 re gar di n g hist or y of or o n g oi n g 
t u berc ul osis i nfecti o n.
N o w re a ds:
2 1. A hist or y of dia g n osis of T B or a p ositi ve late nt T B test res ult, defi ne d as a p ositi ve I G R A 
res ult or 2 s uccessi ve i n deter mi nate I G R A res ults.
P artici p a nts wit h a n y of t he f oll o wi n g T B-rel ate d criteri a:
a.
Acti ve T B i nfecti o n.
b.
Hist or y of acti ve T B i nfecti o n i n v ol vi n g a n y or g a n s yste m or fi n di n gs i n ot her 
or g a n s yste ms c o nsiste nt wit h T B, u nless a de q u atel y tre ate d acc or di n g t o 
W H O/ C D C t her a pe utic g ui d a nce a n d pr o ve n t o be f ull y rec o vere d u p o n c o ns ult 
wit h a T B s peci alist.
c.
L ate nt T B i nfecti o n ( defi ne d as a  c o nfir me d p ositi ve I G R A res ult or 2 s uccessi ve 
i n deter mi nate I G R A res ults) u nless a p pr o pri ate pr o p h yl a xis is i niti ate d at le ast 4 

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
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Bi o ge n M A I nc.
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wee ks pri or t o st u d y me dic ati o n d osi n g o n B aseli ne Visit ( D a y 1) a n d will be 
c o nti n ue d t o c o m pleti o n of pr o p h yl a xis.
R ati o n ale:  La n g ua ge i n e xcl usi o n criteri o n 2 1 was re vise d t o pr o vi de a d diti o nal details o n t he 
eli gi bilit y criteria f or partici pa nts wit h T B i nfecti o n.
C h a n ge: La n g ua ge i n e xcl usi o n criteri o n 2 2 re gar di n g bacterial, f u n gal, or viral i nfecti o n was 
re vise d.
N o w re a ds:
2 2. S y m pt o ms of bacterial, f u n gal, or viral i nfecti o n (i ncl u di n g u p per res pirat or y tract i nfecti o n) 
wit hi n 2 8 da ys pri or t o Baseli ne ( Visit 1)  ( D a y 1). Partici pa nts wit h l ocal f u n gal i nfecti o n 
(e. g., ca n di diasis, ti nea) are eli gi ble t o be rescree ne d after s uccessf ul treat me nt of t he i nfecti o n, 
u nless t he p artici p a nts rec o vere d c o m pletel y pri or t o B aseli ne Visit ( D a y 1) a n d t he 
i nfecti o ns were c o nsi dere d mil d per I n vesti g at or’s j u d g me nt. P artici p a nts w h o h a ve n ot 
rec o vere d pri or t o B aseli ne Visit ( D a y 1), as j u d ge d b y t he I n vesti g at or, will be eli gi ble f or 
rescree ni n g.
R ati o n ale:  La n g ua ge i n e xcl usi o n criteri o n 2 2 was re vise d t o all o w e nr oll me nt or rescree ni n g of 
partici pa nts wit h mil d bacterial a n d viral i nfecti o ns.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
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C h a n ge: E xcl usi o n criteri o n 2 7c re gar di n g partici pa nts w h o ma y ha ve recei ve d mit o xa ntr o ne or 
ot her i m m u n os u p pressa nt a ge nts was re vise d.
N o w re a ds:
2 7. Has a hist or y of treat me nt wit h or has recei ve d t he f oll o wi n g:
c. Mit o xa ntr o ne or ot her i m m u n os u p pressa nt a ge nts (e. g., c ycl os p ori ne, 
c ycl o p h os p ha mi de, met h otre xate, m yc o p he n olate) wit hi n 2 years 1 2 m o nt hs  pri or t o 
Baseli ne ( Visit ( D a y 1);  az at hi o pri ne wit hi n 6 m o nt hs pri or t o Baseli ne ( Visit ( D a y 1) .
R ati o n ale:  T he was h o ut peri o ds f or partici pa nts w h o ma y ha ve recei ve d treat me nt wit h 
mit o xa ntr o ne, ot her i m m u n os u p pressa nt a ge nts, a n d azat hi o pri ne were re vise d w hile still 
e ns uri n g t hat effects of treat me nt d o n ot i nterfere wit h t he safet y pr ofile of D R F a n d t o a v oi d 
u n necessar y ris ks ass ociate d wit h M S t hera p y use.
C h a n ge: E xcl usi o n criteri o n 2 7 d re gar di n g partici pa nts w h o ma y ha ve recei ve d plas ma p heresis, 
I V i m m u n o gl o b uli n, or c yta p heresis treat me nt was a d de d.
N o w re a ds:
2 7. Has a hist or y of treat me nt wit h or has recei ve d t he f oll o wi n g:
d. Tre at me nt wit h a n y of t he f oll o wi n g me dic ati o ns or pr oce d ures wit hi n 6 m o nt hs 
pri or t o B aseli ne Visit ( D a y 1): pl as m a p heresis, I V i m m u n o gl o b uli n, or 
c yt a p heresis .
R ati o n ale: T he was h o ut peri o ds f or partici pa nts w h o ma y ha ve recei ve d treat me nt wit h 
plas ma p heresis, I V i m m u n o gl o b uli n, or c yta p heresis treat me nt were i ncl u de d t o e ns ure t hat 
effects of treat me nt wit h plas ma p heresis, I V i m m u n o gl o b uli n, or c yta p heresis d o n ot i nterfere 
wit h t he safet y pr ofile of D R F a n d t o a v oi d u n necessar y ris ks ass ociate d wit h M S t hera p y use.
C h a n ge: E xcl usi o n criteri o n 2 7e re gar di n g partici pa nts w h o ma y ha ve terifl u n o mi de treat me nt 
was re vise d.
N o w re a ds:
2 7. Has a hist or y of treat me nt wit h or has recei ve d t he f oll o wi n g:
e. Terifl u n o mi de wit hi n 2 years 1 2 m o nt hs  of Baseli ne ( Visit ( D a y 1), u nless t he 
ser u m/ plas ma c o nce ntrati o n of terifl u n o mi de is < 0. 0 2 0 μ g/ m L ( < 2 0 n g/ m L) pri or t o 
Baseli ne ( Visit ( D a y 1) or a n accelerate d eli mi nati o n pr oce d ure f or terifl u n o mi de wit h 
c h olest yra mi ne is s uccessf ull y c o m plete d d uri n g scree ni n g.
R ati o n ale: T he was h o ut peri o d f or i n di vi d uals w h o ma y ha ve recei ve d terifl u n o mi de treat me nt 
was re vise d w hile still e ns uri n g t hat effects of treat me nt d o n ot i nterfere wit h t he safet y pr ofile of 
D R F a n d t o a v oi d u n necessar y ris ks ass ociate d wit h M S t hera p y use
C h a n ge: La n g ua ge i n e xcl usi o n criteri o n 2 7i re gar di n g t he was h o ut peri o d f or partici pa nts w h o 
ma y ha ve recei ve d B-cell tar gete d t hera pies was re vise d.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
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Bi o ge n M A I nc.
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N o w re a ds:
2 7. Has a hist or y of treat me nt wit h or has recei ve d t he f oll o wi n g:
i. B-cell tar gete d t hera pies f or t he treat me nt of M S (e. g., ocreliz u ma b, rit u xi ma b) wit hi n 
1 2 m o nt hs of pri or t o  Baseli ne ( Visit ( D a y 1); wit hi n). P artici p a nts w h o h a ve recei ve d 
B-cell t ar gete d t her a pies  m ore t ha n 1 2 m o nt hs of Scree ni n g is per missi ble wit h 
e vi de nce pri or t o B aseli ne Visit ( D a y 1) will re q uire C D 1 9 testi n g t o c o nfir m t hat t he 
C D 1 9 cells ha ve ret ur ne d t o wit hi n n or mal ra n ge ( per l ocal la b orat or y refere nce ra n ge). 
P artici p a nts w h o h a ve recei ve d B-cell t ar gete d t her a pies less t h a n 1 2 m o nt hs pri or 
t o B aseli ne Visit ( D a y 1) will be e xcl u de d fr o m t he st u d y.
R ati o n ale:  La n g ua ge i n e xcl usi o n criteri o n 2 7i was re vise d d ue t o t he discre pa nc y bet wee n 1 2 
m o nt hs t o Baseli ne or t o Scree ni n g.
C h a n ge: E xcl usi o n criteri o n 2 7l re gar di n g partici pa nts w h o ma y ha ve recei ve d treat me nt wit h 
ster oi ds was re vise d.
N o w re a ds:
2 7. Has a hist or y of treat me nt wit h or has recei ve d t he f oll o wi n g:
l. Ster oi ds, wit h t he e xce pti o n of t o pical or i n hale d ster oi ds, or I V i m m u n o gl o b uli n wit hi n 
3 0 da ys pri or t o Baseli ne ( Visit 1)  ( D a y 1).
R ati o n ale:  T his e xcl usi o n criteri o n was re vise d beca use g ui da nce f or partici pa nts w h o ma y ha ve 
recei ve d treat me nt wit h I V i m m u n o gl o bi n is disc usse d i n e xcl usi o n criteri o n 2 7 d.
C h a n ge: La n g ua ge i n e xcl usi o n criteria 2 9 d a n d 3 0 re gar di n g retesti n g of partici pa nts w h o ma y 
ha ve o ut- of-ra n ge la b orat or y res ults was a d de d.
N o w re a ds:
2 9. Has a n y of t he f oll o wi n g a b n or mal bl o o d tests at Scree ni n g:
a.
A L T, A S T, or G G T ≥ 3 × U L N or bilir u bi n > 2 × U L N. 
b.
T S H le vel > 1 0 % of t he U L N 
c.
e G F R ≤ 6 0 m L/ mi n/ 1. 7 3 m 2 ( usi n g t he C hr o nic Ki d ne y Disease E pi de mi ol o g y 
C olla b orati o n e q uati o n) [ Le ve y 2 0 0 9]
d.
L y m p h oc yte c o u nt < L L N 
3 0. Has a n y of t he f oll o wi n g a b n or mal uri ne tests at Scree ni n g:
a.
Beta- 2 micr o gl o b uli n > 0. 3 μ g/ m L
b.
Al b u mi n t o creati ni ne rati o > 2 2. 6 m g/ m m ol
F or t he p ar a meters liste d i n e xcl usi o n criteri a 2 9 d a n d 3 0, o ut- of-r a n ge v al ues t h at are 
cli nic all y n ot si g nific a nt, as deter mi ne d b y t he I n vesti g at or, m a y be re pe ate d o nce, a n d t he 
p artici p a nt m a y be e nr olle d o nl y if t he re pe ate d v al ue is wit hi n t he n or m al r a n ge.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
8
R ati o n ale:  La n g ua ge was i ncl u de d t o clarif y t he para meters f or retesti n g of partici pa nts wit h 
o ut- of-ra n ge la b orat or y res ults para meters liste d i n e xcl usi o n criteria 2 9 d a n d 3 0.
C h a n ge: La n g ua ge was i ncl u de d i n e xcl usi o n criteri o n 3 4 re gar di n g t he e nr oll me nt of 
partici pa nts w h o ma y ha ve pri or or c urre nt partici pati o n i n a cli nical trial wit hi n 9 0 da ys of 
Scree ni n g.
N o w re a ds:
3 4. C urre nt or pri or partici pati o n i n a cli nical trial wit hi n 9 0 da ys of Scree ni n g. P artici p a nts 
w h o h a ve pre vi o usl y p artici p ate d i n a cli nic al tri al b ut h a ve n ot recei ve d a n y I M P 
tre at me nt wit hi n 9 0 d a ys of Scree ni n g will be eli gi ble if t he I n vesti g at or c o nfir ms t h at t he 
p artici p a nt meets all ot her i ncl usi o n a n d e xcl usi o n criteri a a n d t here are ot her s afet y 
c o ncer ns.
R ati o n ale:  La n g ua ge was i ncl u de d i n e xcl usi o n criteri o n 3 4 t o all o w e nr oll me nt of partici pa nts 
w h o ma y ha ve partici pate d i n a cli nical trial b ut ha ve n ot recei ve d a n y I M P treat me nt wit hi n 9 0 
da ys of Scree ni n g, as e nr oll me nt of s uc h partici pa nt will n ot c o m pr o mise St u d y 2 7 2 M S 3 0 3 
res ults.
Secti o n 6. 3. 1, Scree ni n g
C h a n ge: La n g ua ge f or rescree ni n g criteria was u p date d f oll o wi n g re visi o n t o e xcl usi o n 
criteria 2 1c re gar di n g e xte nsi o n of scree ni n g wi n d o w i n t he e ve nt t hat a partici pa nt re q uires 4 
wee ks’ T B pr o p h yla xis.
N o w re a ds:
T he scree ni n g peri o d ca n be e xte n de d u p t o a ma xi m u m of 4 2 da ys (i.e., a n a d diti o nal 2 wee ks) 
wit h pri or a p pr o val of t he me dical m o nit or if t he testi n g of terifl u n o mi de le vels or c o nfir mati o n 
of accelerate d eli mi nati o n ( per e xcl usi o n criteri o n 2 7 d 2 7e; Secti o n 6. 2)  or mi ni m u m of 
4 wee ks’ T B pr o p h yl a xis ( per e xcl usi o n  criteri o n 2 1c ; Secti o n 6. 2) ca n n ot be c o m plete d 
wit hi n t he 2 8- da y scree ni n g peri o d.
R ati o n ale:  W or di n g was u p date d t o ali g n wit h t he re visi o n ma de t o e xcl usi o n criteria 2 1c t o 
pr o vi de g ui da nce re gar di n g partici pa nts wit h a late nt T B i nfecti o n.
Secti o n 6. 3. 2, Retesti n g
C h a n ge: La n g ua ge f or retesti n g criteria was u p date d f oll o wi n g re visi o n t o e xcl usi o n criteria 2 9 d 
a n d 3 0 re gar di n g partici pa nts wit h o ut- of-ra n ge la b orat or y res ults.
N o w re a ds:
Partici pa nts w h o ha ve a n o ut- of-ra n ge la b orat or y res ult t hat is n ot cli nicall y si g nifica nt ca n be 
reteste d o nce, as per e xcl usi o n criteria, at t he discreti o n of t he I n vesti gat or.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
9
F or t he p ar a meters liste d i n e xcl usi o n criteri a 2 9 d a n d 3 0, o ut- of-r a n ge v al ues t h at are 
cli nic all y n o nsi g nific a nt, as deter mi ne d b y t he I n vesti g at or, m a y be re pe ate d o nce, a n d t he 
p artici p a nt m a y be e nr olle d o nl y if t he re pe ate d v al ue is wit hi n t he n or m al r a n ge.
Partici pa nts w h o ha ve cli nicall y si g nifica nt a b n or mal la b orat or y test val ues as descri be d i n 
e xcl usi o n criteri a 2 9 a, 2 9 b, a n d 2 9c  s h o ul d n ot be reteste d.
R ati o n ale:  W or di n g was u p date d t o ali g n wit h t he clarificati o n ma de f or e xcl usi o n criteria 2 9 d 
a n d 3 0 t o pr o vi de g ui da nce re gar di n g o ut- of-ra n ge la b orat or y test res ults.
Secti o n 6. 3. 3, Scree n Fail ures
C h a n ge: La n g ua ge was re vise d t o i ncl u de partici pa nts w h o ma y ha ve bee n c o nsi dere d scree n 
fail ures d ue t o i nc o m plete e nr oll me nt i n t he e ve nt of a p u blic healt h e mer ge nc y.
N o w re a ds:
Scree n fail ures are defi ne d as partici pa nts w h o si g n t he I C F b ut are n ot s u bse q ue ntl y d ose d. If a 
partici pa nt is c o nsi dere d a scree n fail ure, t he reas o ns f or e xcl usi o n m ust be d oc u me nte d i n t he 
partici pa nt’s s o urce d oc u me nts a n d o n t he scree ni n g l o g. A mi ni mal set of scree n fail ure 
i nf or mati o n is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure partici pa nts t o meet t he 
C o ns oli date d Sta n dar ds of Re p orti n g Trials p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries 
fr o m re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure details, 
eli gi bilit y criteria, a n d a n y S A Es.
All p artici p a nts wit h i nc o m plete e nr oll me nt d ue t o a p u blic he alt h e mer ge nc y (e. g., tr a vel 
restricti o ns, p artici p a nts w h o rec o vere d after getti n g i nfecte d) will be eli gi ble f or 
rescree ni n g pr o vi de d t h at t he p artici p a nts met all eli gi bilit y criteri a d uri n g t he i niti al 
scree ni n g peri o d, a n d t h at t he re as o n f or rescree ni n g is i nc o m plete e nr oll me nt d ue t o a 
p u blic he alt h e mer ge nc y. T hese p artici p a nts will be re p orte d as scree n f aile d a n d t he n 
rescree ne d. P artici p a nts m a y h a ve bee n pr o vi de d wit h a u ni q ue i de ntific ati o n n u m ber 
d uri n g Scree ni n g. T he pre vi o usl y iss ue d u ni q ue i de ntific ati o n n u m ber will n o l o n ger be 
use d, a n d a se p ar ate u ni q ue i de ntific ati o n n u m ber will be pr o vi de d d uri n g rescree ni n g.
R ati o n ale:  La n g ua ge was a d de d t o s pecif y t he re q uire me nts f or rescree ni n g of partici pa nts wit h 
i nc o m plete e nr oll me nt d ue t o a p u blic healt h e mer ge nc y.
Secti o n 9. 3, P har mac o ki netic Assess me nts
C h a n ge:  La n g ua ge re gar di n g t he P K sa m ple v ol u me f or eac h i n di vi d ual sa m ple was a d de d.
N o w re a ds: T he P K s a m ple v ol u me will be a p pr o xi m atel y 6 m L f or e ac h i n di vi d u al s a m ple. 
F or t he i nte nsi ve P K s a m pli n g gr o u p, t here are a m a xi m u m of 1 0 P K s a m ple c ollecti o n 
ti me p oi nts pl a n ne d ( 8 ti me p oi nts o n D a y 2 9 f or t he i nte nsi ve P K s a m pli n g a n d 2 ti me p oi nts 
o n D a y 5 7 f or t he s p arse P K s a m pli n g). I n t he a d ve nt t h at i nte nsi ve P K s a m pli n g is n ot 
fe asi ble b y D a y 5 7, t here are a m a xi m u m of 1 2 P K s a m ple c ollecti o n ti me p oi nts pl a n ne d ( 2 

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 0
ti me p oi nts o n D a y 2 9 a n d o n D a y 5 7 f or t he s p arse P K s a m pli n g, res pecti vel y a n d 8 
ti me p oi nts f or t he i nte nsi ve P K s a m pli n g at a l ater visit). T heref ore, t he m a xi m u m P K 
s a m ple v ol u me f or a gi ve n p artici p a nt i n t he i nte nsi ve P K s a m pli n g gr o u p will be 
a p pr o xi m atel y 7 2 m L. T his v ol u me will be l o wer f or p atie nts p artici p ati n g o nl y i n t he 
s p arse P K s a m ple c ollecti o n a n d will be a p pr o xi m atel y 2 4 m L ( 2 s a m ples o n D a y 2 9 a n d 2 
s a m ples o n D a y 5 7).
R ati o n ale:  T his la n g ua ge was a d de d t o pr o vi de g ui da nce re gar di n g P K sa m ple v ol u me f or t he 2 
sa m pli n g gr o u ps.
Secti o n 1 0. 2, La b orat or y Safet y Assess me nts
C h a n ge:  F o ot n ote 2 i n Ta ble 5, o utli ni n g g ui da nce t o calc ulate t he e G F R rate, was re vise d.
N o w re a ds :
2 Ser u m creati ni ne will be use d t o calc ulate e G F R at eac h ti me p oi nt t hat a creati ni ne res ult is 
ge nerate d. P artici p a nt’s l atest wei g ht assess me nt will be use d t o c alc ul ate e G F R.
R ati o n ale:  T his c ha n ge was ma de t o clarif y t hat t he partici pa nt’s m ost rece nt wei g ht assess me nt 
is t o be use d t o calc ulate e G F R.
Secti o n 1 1. 3. 2, A d verse E ve nts of S pecial I nterest
C h a n ge:  La n g ua ge was a d de d t o i ncl u de pa ncreatitis as a n A E SI.
N o w re a ds :
P M L a n d p a ncre atitis  will be c o nsi dere d A E SIs . T he st u d y site m ust f or mall y n otif y t he 
S p o ns or wit hi n 2 4 h o urs of t he site staff bec o mi n g a ware of t he A E SI.
R ati o n ale:  Pa ncreatitis was a d de d as a n A E SI t o better e val uate t he safet y pr ofile of D R F.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 1
S U M M A R Y O F MI N O R C H A N G E S T O T H E P R O T O C O L
T he f oll o wi n g mi n or c ha n ges were ma de t o t he pr ot oc ol, as a p pr o priate:
•
T he versi o n n u m ber a n d date were u p date d t hr o u g h o ut t he pr ot oc ol.
•
O n t he S p o ns or Si g nat ure Pa ge, t he Bi o ge n si g nat or y’s title was u p date d.
•
Refere nce t o t he T E C FI D E R A ®  ( di met h yl f u marate) Pac ka ge I nsert was u p date d t o 
t he latest a vaila ble refere nce ( 2 0 2 2).
•
I n Secti o n 1. 1, S y n o psis, c orrecti o ns were ma de t o f or matti n g.
•
T he ter m “ Baseli ne ( Visit 1)”, “ Baseli ne Visit” a n d “ Baseli ne Visit ( Da y 1)” ha d bee n 
use d i nterc ha n gea bl y i n t he d oc u me nt. T hese were re vise d t o “ Baseli ne Visit ( Da y 
1)” f or c o nsiste nc y, w here a p plica ble.
•
I n Secti o n 6. 2, E xcl usi o n criteria, u n der criteri o n 2 7a, w hic h disc usses hist or y of 
treat me nt, treat me nt wit h t otal l y m p h oi d irra diati o n was re peate d. T his re petiti o n was 
re m o ve d.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 4
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 2
LI S T O F A B B R E VI A TI O N S
A L T
ala ni ne a mi n otra nsferase 
C D 1 9
cl uster of differe ntiati o n 1 9
C D C
Ce nters f or Disease C o ntr ol a n d Pre ve nti o n
C O VI D- 1 9
c or o na vir us disease 2 0 1 9
D R F
dir o xi mel f u marate
e G F R
esti mate d gl o mer ular filtrati o n rate 
G G T
ga m ma- gl uta m yl tra nsferase 
H E S
2- h y dr o x yet h yl s ucci ni mi de
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I G R A
i nterfer o n- ga m ma release assa y
I M P
i n vesti gati o nal me dici nal pr o d uct
L L N
l o wer li mit of n or mal
M S
m ulti ple scler osis
P C R
p ol y merase c hai n reacti o n
P K
p har mac o ki netic(s)
P P E
pers o nal pr otecti ve e q ui p me nt
S A E
seri o us a d verse e ve nt
T B
t u berc ul osis
T S H
t h yr oi d sti m ulati n g h or m o ne
U L N
u p per li mit of n or mal 
W H O
W orl d Healt h Or ga nizati o n

C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
1  
 
 
 
 
 
 
Bi o ge n M A I nc.  
2 2 5 Bi n ne y Street  
Ca m bri d ge, M A  0 2 1 4 2  
U nite d States  
 
Bi o ge n I dec Researc h Li mite d  
I n n o vati o n H o use 
7 0 N or de n R oa d  
Mai de n hea d, Ber ks hire  
S L 6  4 A Y  
U nite d Ki n g d o m  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
A M E N D M E N T S U M M A R Y  
Bi o ge n Pr ot oc ol 2 7 2 M S 3 0 3  
A n O pe n -La bel, Si n gle -Ar m, M ultice nter, P hase 3 St u d y t o E val uate t he Safet y a n d T olera bilit y, 
a n d P har mac o ki netics of Dir o xi mel F u marate ( BII B 0 9 8) i n A d ult Partici pa nts Fr o m t he 
Asia -Pacific Re gi o n Wit h Rela psi n g F or ms of M ulti ple Scler osis  
Versi o n 3  
Date: 2 4 Fe br uar y 2 0 2 2  
Versi o n 3 of t he pr ot oc ol has bee n pre pare d f or t his a me n d me nt, w hic h s u perse des Versi o n 2.  

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 3  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
2  
P RI M A R Y R E A S O N F O R A M E N D M E N T  
T he pri mar y reas o n f or t his a me n d me nt t o Pr ot oc ol 2 7 2 M S 3 0 3 is t o pr o vi de g ui da nce i n case of 
a p u blic healt h e mer ge nc y t hat res ults i n st u d y site cl os ure, tra vel restricti o ns, a n d/ or t he st u d y 
bei n g de pri oritize d at t he st u d y site. As a res ult, a ne w secti o n ( Secti o n 1 5. 3. 1) was a d de d.  
Ne w te xt is s h o w n i n b ol d t y pe; delete d te xt is s h o w n wit h a stri ket hr o u g h. 
Secti o n 1 5. 3. 1, P u blic Healt h E mer ge nc y  
N o w re a ds:  
I n t he e ve nt of a p u blic he alt h e mer ge nc y t h at res ults i n site cl os ure, tr a vel restricti o ns, 
a n d/ or t he st u d y bei n g de pri oritize d at t he site s uc h t h at cli nic visit(s) c a n n ot occ ur, a 
pr ot oc ol de vi ati o n w o ul d be i nc urre d f or a n y de vi ati o n fr o m t he pr ot oc ol -s pecifie d visits 
a n d assess me nts, wit h a d diti o n al n ot ati o n t h at t his pr ot oc ol de vi ati o n is d ue t o t he p u blic 
he alt h e mer ge nc y. If a pr ot oc ol -s pecifie d cli nic al visit c a n n ot occ ur d ue t o a p u blic he alt h 
e mer ge nc y, o ne or m ore of t he f oll o wi n g miti g ati n g o pti o ns s h o ul d be p urs ue d i n 
c o ns ult ati o n wit h t he me dic al m o nit or: 1) tr a nsfer t o a n ot her acti ve st u d y site t h at is o pe n, 
2) tele me dici ne visit (e. g., b y tele p h o ne or we b c o nfere nce), a n d 3) l oc al l a b or at or y visit. 
T hese miti g ati n g o pti o ns o nl y a p pl y i n t he setti n g of a p u blic he alt h e mer ge nc y i n w hic h a 
pr ot oc ol -s pecifie d cli nic visit c a n n ot occ ur a n d s h o ul d n ot be p urs ue d s olel y d ue t o 
p artici p a nt’s prefere nce. If t he p artici p a nt d oes n ot p artici p ate i n o ne or m ore of t hese 
o pti o ns, a s afet y tele p h o ne c all m ust be c o n d ucte d wit hi n 1 4  d a ys of t he l ast d osi n g visit.  
If t he p artici p a nt is u n a ble t o pic k u p st u d y tre at me nt d uri n g t he 4 8-wee k Tre at me nt 
Peri o d bec a use of a p u blic he alt h e mer ge nc y, arr a n ge me nts m a y be m a de t o s hi p st u d y 
tre at me nt directl y t o t he p artici p a nt, w here all o we d per c o u ntr y or l oc al re g ul ati o ns. 
R ati o n ale:  I nstr ucti o nal la n g ua ge was a d de d t o pr o vi de g ui da nce as t o h o w st u d y disr u pti o ns 
s h o ul d be ha n dle d d ue t o t he o n g oi n g p u blic healt h e mer ge nc y a n d i n t he e ve nt of a f ut ure p u blic 
healt h e mer ge nc y.  
 

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 3  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
3  
S U M M A R Y O F M A J O R C H A N G E S T O T H E P R O T O C O L  
C ha n ges t o t he pr ot oc ol are prese nte d c hr o n ol o gicall y. Ne w te xt is s h o w n i n b ol d t y pe; delete d 
te xt is s h o w n wit h a stri ket hr o u g h. 
 
S p o ns or I nf or mati o n  
C h a n ge:  C ha n ges were ma de t o t he S p o ns or i nf or mati o n t o i ncl u de Bi o ge n I dec Researc h 
Li mite d a n d re m o ve Bi o ge n M A I nc.  
N o w re a ds:  
Bi o ge n is res p o nsi ble f or i nitiati n g a n d ma na gi n g t he st u d y.  
C hi n a  
Bi o ge n M A I nc.  
2 2 5 Bi n ne y Street  
Ca m bri d ge, M A 0 2 1 4 2  
U nite d States  
Bi o ge n I dec Rese arc h Li mite d  
I n n o v ati o n H o use 
7 0 N or de n R o a d  
M ai de n he a d, Ber ks hire  
S L 6 4 A Y  
U nite d Ki n g d o m  
J a p a n  
Bi o ge n Ja pa n Lt d.  
Ni h o n bas hi 1 -c h o me Mits ui 
B uil di n g 1 4 F  
4 -1 Ni h o n bas hi 1 -c h o me 
C h u o -k u, T o k y o  
1 0 3 -0 0 2 7 Ja pa n  
F or ur ge nt me dical iss ues i n w hic h t he st u d y Me dical M o nit or s h o ul d be c o ntacte d, please refer 
t o t he St u d y C o ntact List. 
Bi o ge n T he S p o ns or  ma y tra nsfer a n y or all of its st u d y -relate d res p o nsi bilities t o a c o ntract 
researc h or ga nizati o n a n d ot her t hir d parties; h o we ver, Bi o ge n  t he S p o ns or retai ns o verall 
acc o u nta bilit y f or t hese acti vities.  
R ati o n ale:  Bi o ge n I dec Researc h Li mite d is t he S p o ns or of t he cli nical trial i n C hi na.  
T his c ha n ge als o affects Secti o n 1 1. 2. 4, E x pecte d ness of E ve nts; Secti o n 1 1. 3. 1, A d verse E ve nts; 
Secti o n 1 1. 3. 5, S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns; Secti o n 1 4. 2, Ve n d ors; 
Secti o n 1 4. 2. 3, Electr o nic or Re m ote Data Ca pt ure; a n d Secti o n 1 5. 4, St u d y F u n di n g.  
 

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 3  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
4  
Secti o n 1. 1, S y n o psis  
T he s y n o psis was re vise d t o reflect c ha n ges ma de t hr o u g h o ut t he pr ot oc ol.  
 
Secti o n 6. 2, E xcl usi o n Criteria  
C h a n ge:  E xcl usi o n criteria 1 4, 2 7 d, a n d 2 8 were u p date d.  
N o w re a ds:  
…  
1 4. Partici pa nt has a n a b n or malit y t hat t he i n vesti gat or dee ms t o be cli nicall y rele va nt 
si g nific a nt o n me dical hist or y, p h ysical e xa mi nati o n, E C G, or a dia g n ostic la b orat or y 
test t h at m a y c o nf o u n d st u d y res ults or p ose ris k t o t he s u bject t hr o u g h 
p artici p ati o n i n t he st u d y, i n t he o pi ni o n of t he I n vesti g at or.  
…  
2 7. Has a hist or y of treat me nt wit h or has recei ve d t he f oll o wi n g:  
a. T otal l y m p h oi d irra diati o n, cla dri bi ne, T -cell or T-cell rece pt or vacci nati o n, t otal 
b o d y irra diati o n, or t otal l y m p h oi d irra diati o n at a n y ti me  
b.  Ste m cell tra ns pla ntati o n at a n y ti me  
c. Mit o xa ntr o ne or ot her i m m u n os u p pressa nt a ge nts (e. g., c ycl os p ori ne, 
c ycl o p h os p ha mi de, met h otre xate, m yc o p he n olate) wit hi n 2 years pri or t o Baseli ne 
( Visit 1) 
d.  Terifl u n o mi de wit hi n 2 years of Baseli ne ( Visit 1), u nless t he ser u m/ plas ma 
c o nce ntrati o n of terifl u n o mi de is < 0. 0 2 0 μ g/ m L ( < 2 0 n g/ m L) pri or t o Baseli ne 
( Visit 1) or [a n accelerate d eli mi nati o n pr oce d ure f or terifl u n o mi de wit h 
c h olest yra mi ne is per mitte d  s uccessf ull y c o m plete d d uri n g scree ni n g ] 
…  
2 8. Cli nicall y si g nifica nt a b n or mal la b orat or y test val ues t h at m a y c o nf o u n d st u d y res ults 
or p ose ris k t o t he s u bject t hr o u g h p artici p ati o n i n t he st u d y , as deter mi ne d b y t he 
I n vesti gat or, at Scree ni n g or Baseli ne ( Visit 1). 
R ati o n ale:  E dit orial c ha n ges were ma de, a n d a d diti o nal la n g ua ge was a d de d t o e xcl usi o n criteria 
1 4 a n d 2 8 t o pr o vi de clarificati o n of t he ter m “cli nicall y si g nifica nt” w hile lea vi n g t he 
deter mi nati o n t o t he I n vesti gat or’s cli nical j u d ge me nt.  
Mi n or e dits were ma de t o  e xcl usi o n criteri o n 2 7 d t o e ns ure clarit y re gar di n g t he nee d t o meas ure 
t he ser u m/ plas ma terifl u n o mi de c o nce ntrati o n or c o m plete t he accelerate d eli mi nati o n pr oce d ure 
f or partici pa nts w h o wis h t o partici pate i n t he st u d y b ut ha ve ta ke n terifl u n o mi de wit hi n 2 years 
of t he st u d y Baseli ne Visit.  

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 3  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
5  
 
Secti o n 6. 3. 1, Scree ni n g  
C h a n ge:  C ha n ge was ma de t o all o w t he scree ni n g peri o d t o be e xte n de d if t he testi n g of 
terifl u n o mi de le vels or c o nfir mati o n of accelerate d eli mi nati o n was n ot c o m plete d wit hi n t he 
2 8 -da y scree ni n g peri o d  
N o w re a ds:  
O nce i nf or me d c o nse nt is o btai ne d, scree ni n g assess me nts ca n occ ur. At t his ti me, a u ni q ue 
i de ntificati o n n u m ber is assi g ne d t hat will be use d o n st u d y-relate d d oc u me nts pertai ni n g t o t he 
partici pa nt. A n y i de ntificati o n n u m bers t hat are assi g ne d will n ot be re use d, e ve n if t he 
partici pa nt d oes n ot recei ve treat me nt or c o nti n ue i n t he st u d y. St u d y sites are re q uire d t o 
d oc u me nt all scree ne d partici pa nts i nitiall y c o nsi dere d f or i ncl usi o n i n t he st u d y.  
T he scree ni n g peri o d c a n be e xte n de d u p t o a m a xi m u m of 4 2 d a ys (i.e., a n a d diti o n al 
2  wee ks) wit h pri or a p pr o v al of t he me dic al m o nit or if t he testi n g of terifl u n o mi de le vels or 
c o nfir m ati o n of acceler ate d eli mi n ati o n ( per e xcl usi o n criteri o n 2 7 d; Secti o n 6. 2) c a n n ot be 
c o m plete d wit hi n t he 2 8 -d a y scree ni n g peri o d.  
R ati o n ale:  T his c ha n ge was ma de t o all o w a d diti o nal ti me a n d fle xi bilit y f or sites t o recei ve 
terifl u n o mi de c o nce ntrati o n res ults nee de d f or e xcl usi o n criteri o n 2 7 d, d ue t o t he le n gt h of ti me 
re q uire d f or testi n g. 
 
 
C h a n ge: 
 
N o w re a ds:  
 
 
 
 
 
 
 
 
R ati o n ale: 
 
 
 

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 3  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
6  
 
 
 
  
 
Secti o n 8. 1, Disc o nti n uati o n of St u d y Treat me nt  
C h a n ges: E dit orial c ha n ges were ma de.  
N o w re a ds:  
A partici pa nt m ust per ma ne ntl y disc o nti n ue st u d y treat me nt f or a n y of t he f oll o wi n g reas o ns:  
•  T he partici pa nt bec o mes pre g na nt. St u d y treat me nt m ust be disc o nti n ue d i m me diatel y 
( N ote: I nstr ucti o ns f or re p orti n g t he pre g na nc y are pr o vi de d i n Secti o n 1 1. 4. 1). 
•  T he partici pa nt wit h dra ws c o nse nt t o c o nti n ue st u d y treat me nt.  
•  T he partici pa nt e x perie nces a n A E t hat re q uires per ma ne nt disc o nti n uati o n of st u d y 
treat me nt. 
•  T he partici pa nt is u n willi n g or u na ble t o c o m pl y wit h t he pr ot oc ol.  
•  At t he discreti o n of t he I n vesti gat or f or me dical reas o ns.  
•  At t he discreti o n of t he S p o ns or or u p o n re q uest of a re g ulat or y a ut h orit y.  
•  L y m p h oc yte c o u nt < 0. 5 × 1 0 3 / µ L persisti n g f or > 6 m o nt hs. A n i niti al 
l y m p h oc yte c o u nt < 0. 5 × 1 03/ µ L s h o ul d be, c o nfir me d b y re pe at testi n g  as s o o n 
as p ossi ble . If t he v al ue re m ai ns < 0. 5 × 1 0 3 / µ L f or > 6 m o nt hs after treat me nt 
i nterr u pti o n, t he p artici p a nt m ust per m a ne ntl y disc o nti n ue st u d y tre at me nt. 
P artici p a nts w h o per m a ne ntl y disc o nti n ue t he st u d y wit h a l ast me as ure d 
l y m p h oc yte c o u nt < L L N will re q uire a d diti o n al f oll o w-u p t o m o nit or t heir 
l y m p h oc yte c o u nts; see T a ble 2.  
T he reas o n f or disc o nti n uati o n of st u d y treat me nt m ust be rec or de d i n t he C R F.  
I n a d diti o n t o t he reas o ns pr o vi de d a b o ve f or per ma ne nt disc o nti n uati o n of st u d y treat me nt, 
st u d y treat me nt m ust be te m p oraril y wit h hel d if a n y of t he f oll o wi n g la b orat or y para meters meet 
t he f oll o wi n g t hres h ol d li mits: 
•  A S T or A L T > 3 × U L N; c o nfir me d b y re peat testi n g. If t he val ue re mai ns > 3  ×  U L N 
f or ≥ 4 wee ks after disc o nti n uati o n  i nterr u pti o n of st u d y treat me nt, t he partici pa nt 
m ust per ma ne ntl y disc o nti n ue st u d y treat me nt.  

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 3  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
7  
•  L y m p h oc yte c o u nt < 0. 5 × 1 0 3 / µ L, c o nfir me d b y re peat testi n g as s o o n as p ossi ble. If 
t he val ue re mai ns < 0. 5 × 1 03 / µ L f or > 6 m o nt hs after treat me nt i nterr u pti o n, t he 
partici pa nt m ust per ma ne ntl y disc o nti n ue st u d y treat me nt. Partici pa nts w h o 
per ma ne ntl y disc o nti n ue t he st u d y wit h a last meas ure d l y m p h oc yte c o u nt < L L N will 
re q uire a d diti o nal f oll o w u p t o m o nit or t heir l y m p h oc yte c o u nts; see Ta ble 2.  
•  e G F R < 6 0 m L/ mi n/ 1. 7 3 m 2; c o nfir me d b y re peat testi n g as s o o n as p ossi ble. If t he 
e G F R re mai ns < 6 0 m L/ mi n/ 1. 7 3 m 2 f or ≥ 4 wee ks after disc o nti n uati o n  i nterr u pti o n 
of st u d y treat me nt, t he partici pa nt m ust per ma ne ntl y disc o nti n ue st u d y treat me nt.  
•  Uri ne al b u mi n t o uri ne creati ni ne rati o > 2 2. 6 m g/ m m ol; c o nfir me d b y re peat testi n g 
as s o o n as p ossi ble. If t he uri ne al b u mi n t o uri ne creati ni ne rati o re mai ns 
>  2 2. 6  m g/ m m ol f or ≥ 4 wee ks after disc o nti n uati o n  i nterr u pti o n of st u d y treat me nt, 
t he partici pa nt m ust per ma ne ntl y disc o nti n ue st u d y treat me nt 
R ati o n ale:  E dits were ma de f or clarificati o n. F or e xa m ple, t he ter m “ disc o nti n uati o n” was 
re place d wit h “i nterr u pti o n” as a p pr o priate t o hel p a v oi d c o nf usi o n bet wee n te m p orar y 
i nterr u pti o n a n d per ma ne nt treat me nt disc o nti n uati o n. T he sec o n d b ullet (i.e., pr ol o n ge d 
l y m p h o pe nia) was re vise d t o ali g n t he pr ot oc ol la n g ua ge m ore cl osel y t o t he g ui da nce pr o vi de d 
i n t he dir o xi mel f u marate c ore data s heet. As a res ult of t his c ha n ge, t he sec o n d b ullet was 
m o ve d t o t he treat me nt disc o nti n uati o n secti o n i m me diatel y a b o ve t o ali g n wit h t he re vise d 
g ui da nce.  
 
Secti o n 1 1. 5, C o ntrace pti o n Re q uire me nts  
C h a n ges: C ha n ge was ma de t o all o w c o n d o m use wit h o ut s per mici de as a n effecti ve 
c o ntrace pti o n f or males.  
N o w re a ds:  
F or t he p ur p oses of t he st u d y, effecti ve c o ntrace pti o n f or males is defi ne d as:  
•  Vasect o m y wit h ne gati ve se me n a nal ysis at f oll o w -u p. If d oc u me ntati o n is n ot a vaila ble, 
t he partici pa nt m ust use c o ntrace pti o n. 
•  C o n d o ms wit h or wit h o ut  s per mici de. 
R ati o n ale:  C o n d o ms wit h s per mici de ma y n ot be a vaila ble i n all c o u ntries. I m p orta ntl y, t he 
pr ot oc ol re q uires effecti ve c o ntrace pti o n f or male partici pa nts a n d hi g hl y effecti ve c o ntrace pti o n 
f or fe male partici pa nts. C o n d o ms wit h or wit h o ut s per mici de w o ul d be c o nsi dere d a n acce pta ble 
met h o d of c o ntrace pti o n f or male partici pa nts i n t his st u d y. T he rati o nale is base d o n t he 
g ui deli nes pr o vi de d i n t he Cli nical Trials Facilitati o n a n d C o or di nati o n Gr o u p of t he E ur o pea n 
Hea ds of Me dici nes A ge ncies, Secti o n 4. 2.  

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 3  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
8  
S U M M A R Y O F MI N O R C H A N G E S T O T H E P R O T O C O L  
T he f oll o wi n g mi n or c ha n ges were ma de t o t he pr ot oc ol, as a p pr o priate:  
•  T he versi o n n u m ber a n d date were u p date d t hr o u g h o ut t he pr ot oc ol.  
•  Mi n or e dit orial u p dates were ma de t hr o u g h o ut t he d oc u me nt.  
 
 
 
•  I n Secti o n 6. 2, E xcl usi o n Criteria, f or matti n g c ha n ges were ma de f or clarit y. 
 
 
 
 
 
•  Secti o n 1 0. 2, La b orat or y Safet y Assess me nts, Ta ble 5, Cli nical La b orat or y 
Assess me nts, was u p date d t o a d d ser u m pre g na nc y testi n g at Scree ni n g a n d Safet y 
F oll o w -u p ( Visit 1 5) as well as HI V/ he patis a n d T B testi n g at Scree ni n g. T hese 
c ha n ges were ma de t o ali g n wit h Secti o n 1. 3, Sc he d ule of Acti vities, Ta ble  1, 
Sc he d ule of Acti vities.  
•  Secti o n 1 4. 2. 1, Cli nical Researc h Or ga nizati o n, was u p date d t o reflect t hat m ore t ha n 
1  cli nical researc h or ga nizati o n is utilize d i n t he st u d y.  
•  Secti o n 1 4. 2. 4, Ce ntral La b orat ories f or La b orat or y Assess me nts, was u p date d t o 
reflect t hat m ore t ha n 1 ce ntral la b orat or y is utilize d i n t he st u d y. 
•  Secti o n 1 4. 2. 5, Ce ntral Facilit y f or Ot her Assess me nts, was u p date d t o reflect t hat 
m ore t ha n 1 ce ntral facilit y is utilize d i n t he st u d y.  
 

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 3  
 
C O N FI D E N TI A L  
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n  M A I nc.  
9  
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
A L T  
ala ni ne a mi n otra nsferase  
A S T  
as partate a mi n otra nsferase  
E C G  
electr ocar di o gra m  
e G F R 
esti mate d gl o mer ular filtrati o n rate  
I V 
i ntra ve n o us i njecti o n  
L L N  
l o wer li mits of n or mal 
T B  
t u berc ul osis 
U L N  
u p per li mits of n or mal  
 

C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1
Bi o ge n M A I nc.
2 2 5 Bi n ne y Street
Ca m bri d ge, M A  0 2 1 4 2
U nite d States
Bi o ge n I dec Researc h Li mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d, Ber ks hire
S L 6 4 A Y
U nite d Ki n g d o m
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
A M E N D M E N T S U M M A R Y
Bi o ge n Pr ot oc ol 2 7 2 M S 3 0 3
A n O pe n- La bel, Si n gle- Ar m, M ultice nter, P hase 3 St u d y t o E val uate t he Safet y a n d T olera bilit y, 
a n d P har mac o ki netics of Dir o xi mel F u marate ( BII B 0 9 8) i n A d ult Partici pa nts Fr o m t he 
Asia- Pacific Re gi o n Wit h Rela psi n g F or ms of M ulti ple Scler osis
Versi o n 2
Date: 1 4 J u ne 2 0 2 1
Versi o n 2 of t he pr ot oc ol has bee n pre pare d f or t his a me n d me nt, w hic h s u perse des Versi o n 1.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 2
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
2
P RI M A R Y R E A S O N F O R A M E N D M E N T
T he pri mar y reas o n f or t his a me n d me nt t o Pr ot oc ol 2 7 2 M S 3 0 3 is t o u p date t he c o ntrace pti o n 
re q uire me nts.
Ne w te xt is s h o w n i n b ol d t y pe; delete d te xt is s h o w n wit h a stri ket hr o u g h.
Secti o n 1 1. 5, C o ntrace pti o n Re q uire me nts
N o w re a ds:
All w o me n of c hil d beari n g p ote ntial a n d all me n m ust e ns ure t hat hi g hl y effecti ve c o ntrace pti o n 
is use d d uri n g t he st u d y a n d f or 3 0 da ys after t heir last d ose of st u d y treat me nt. All me n m ust 
e ns ure t h at effecti ve c o ntr ace pti o n is use d d uri n g t he st u d y a n d f or 3 0 d a ys after t heir l ast 
d ose of st u d y tre at me nt. I n a d diti o n, partici pa nts s h o ul d n ot d o nate s per m or e g gs f or t he 
d urati o n of t he st u d y a n d f or at least 3 0 da ys after t heir last d ose of st u d y treat me nt.
[ …]
F or t he p ur p oses of t he st u d y, hi g hl y effecti ve c o ntrace pti o n f or fe m ales is defi ne d as use of at 
le ast 1 ( or 2) of t he f oll o wi n g:
F or fe males:

Esta blis he d use of oral, i ntra va gi nal 1, or tra ns der mal1 c o m bi ne d (estr o ge n a n d 
pr o gest o ge n c o ntai ni n g) h or m o nal met h o ds of c o ntrace pti o n ass ociate d wit h t he 
i n hi biti o n of o v ulati o n.

Esta blis he d use of oral, i njecte d 1, or i m pla nte d1 pr o gest o ge n- o nl y  h or m o nal met h o ds 
of c o ntrace pti o n ass ociate d wit h t he i n hi biti o n of o v ulati o n.

Place me nt of a n i ntra uteri ne de vice or i ntra uteri ne h or m o ne-releasi n g s yste m.

Barrier met h o ds of c o ntrace pti o n w here a p plica ble acc or di n g t o l ocal g ui deli nes.

Bilateral t u bal occl usi o n.

Se x wit h a male w h o has u n der g o ne s ur gical sterilizati o n ( wit h t he a p pr o priate 
p ost vasect o m y d oc u me ntati o n of t he a bse nce of s per m i n t he ejac ulate).
F or males:
F or t he p ur p oses of t he st u d y, effecti ve c o ntr ace pti o n f or m ales is defi ne d as:

Vasect o m y wit h ne gati ve se me n a nal ysis at f oll o w u p. If d oc u me ntati o n is n ot 
a vaila ble, t he partici pa nt m ust use c o ntrace pti o n.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 2
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
3

C o n d o ms wit h s per mici de w here a p plica ble acc or di n g t o l ocal g ui deli nes.

Se x wit h a w o ma n w h o uses t he met h o ds descri be d f or fe males if s he is of 
c hil d beari n g p ote ntial.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
1 I ntr a v a gi n al a n d tr a ns der m al c o m bi ne d h or m o n al met h o ds of c o ntr ace pti o n a n d i njecte d a n d i m pl a nte d 
h or m o n al met h o ds of c o ntr ace pti o n are n ot a p pr o ve d f or use i n J a p a n.
R ati o n ale:  Te xt i n t he sec o n d b ullet was re vise d t o differe ntiate bet wee n t he c o m bi ne d 
h or m o nal met h o ds me nti o ne d i n t he first b ullet a n d pr o gest o ge n- o nl y h or m o nal met h o ds. Ot her 
c ha n ges were ma de t o ali g n wit h t he rec o m me n dati o ns fr o m t he Cli nical Trials Facilitati o n a n d 
C o or di nati o n Gr o u p a n d t o i n dicate w hic h c o ntrace pti o n met h o ds are n ot a p pr o ve d f or use i n 
Ja pa n.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 2
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
4
S U M M A R Y O F M A J O R C H A N G E S T O T H E P R O T O C O L
C ha n ges t o t he pr ot oc ol are prese nte d c hr o n ol o gicall y. Ne w te xt is s h o w n i n b ol d t y pe; delete d 
te xt is s h o w n wit h a stri ket hr o u g h.
Secti o n 1. 1, S y n o psis
T he s y n o psis was re vise d t o reflect c ha n ges ma de t hr o u g h o ut t he pr ot oc ol.
Secti o n 1. 3, Sc he d ule of Acti vities
C h a n ge: T he ta ble f o ot n ote was re vise d t o ali g n wit h i nf or mati o n pr o vi de d i n Secti o n 5. 1, St u d y 
O ver vie w.
T a ble 1:  
A d diti o n al F oll o w- U p f or P artici p a nts wit h L y m p h o pe ni a
L M Visits 1
Assess me nts
L M Visit 1
( 2 m o nt hs after Safet y 
F oll o w- U p Visit ± 7 da ys)
L M Visit 2
( 4 m o nt hs after Safet y 
F oll o w- U p Visit ± 7 da ys)
L M Visit 3
( 6 m o nt hs after Safet y 
F oll o w- U p Visit ± 7 da ys)
L y m p h oc yte C o u nt
X
X
X
C o nc o mita nt Me dicati o n
X
X
X
1 Partici pa nts w h o c o m plete t he st u d y or w h o ter mi nate t he st u d y earl y a n d ha ve a last meas ure d l y m p h oc yte c o u nt 
< L L N will ret ur n t o t he cli nic f or a d diti o nal L M visits e ver y 2 m o nt hs starti n g fr o m Visit 1 5 ( or fr o m t he E T visit 
f or partici pa nts w h o ter mi nate t he st u d y earl y) f or a peri o d of 6 m o nt hs (i.e., a ma xi m u m of 3 visits), u ntil 
l y m p h oc yte c o u nts reac h n or mal li mits ( ≥ L L N), or u ntil a n ot her D M T is st arte d t h at m a y affect l y m p h oc yte 
c o u nts (i n t his c ase, l y m p h oc yte m o nit ori n g f or t h at D M T will a p pl y),  w hic he ver occ urs first. All assess me nts 
re q uire d f or t he Safet y F oll o w- U p Visit ( Visit 1 5, Ta ble 1) s h o ul d be c o m plete d f or t hese partici pa nts pri or t o 
i nitiati o n of t he L M visits.
R ati o n ale: T he f o ot n ote was u p date d t o e ns ure c o nsiste nt i nstr ucti o ns t hr o u g h o ut t he pr ot oc ol 
re gar di n g f oll o w- u p f or partici pa nts w h o de vel o p l y m p h o pe nia a n d s witc h t o a differe nt 
treat me nt o pti o n.
Secti o n 5. 1, St u d y O ver vie w
C h a n ge:  D ose re d ucti o n was clarifie d t o o nl y be all o we d d ue t o fl us hi n g or GI dist ur ba nces, t he 
Da y 2 9 visit wi n d o w was c orrecte d t o ± 3 da ys, a n d t he fasti n g re q uire me nts f or P K bl o o d 
sa m ple c ollecti o n were clarifie d.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 2
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
7
1 6. Hist or y of a n y cli nicall y si g nifica nt car diac, e n d ocri n ol o gic, he mat ol o gic, he patic, 
i m m u n ol o gic, meta b olic, ur ol o gic, p ul m o nar y, ne ur ol o gic, der mat ol o gic, ps yc hiatric, a n d re nal, 
or ot her maj or disease, as deter mi ne d b y t he I n vesti gat or.
[ …]
2 5. C urre nt e nr oll me nt or a pla n t o e nr oll i n a n y i nter ve nti o nal cli nical st u d y i n w hic h a n 
i n vesti gati o nal treat me nt or a p pr o ve d t hera p y f or i n vesti gati o nal use is a d mi nistere d wit hi n 3 0 
da ys pri or t o Baseli ne ( Visit 1) or 5 half-li ves, w hic he ver is l o n ger.
[ …]
2 7. Use of a ge nts k n o w n t o si g nifica ntl y i n hi bit or i n d uce dr u g- meta b olizi n g e nz y mes (e. g., 
bar bit urates, p he n ot hiazi nes), wit hi n 2 8 da ys pri or t o t he Scree ni n g Visit. 
R ati o n ale:  E xcl usi o n criteri o n 2 was re vise d t o clarif y t hat t he liste d c o n diti o ns are e xcl usi o nar y 
base d o n I n vesti gat or discreti o n, n ot si m pl y d ue t o lac k of c o ntr ol. E xcl usi o n criteri o n 1 6 was 
delete d beca use it was a d u plicate of e xcl usi o n criteri o n 2. E xcl usi o n criteri o n 1 1 was delete d t o 
clarif y t hat me n o pa usal h ot flas hes are n ot e xcl usi o nar y a n d n ot a c o ntrai n dicati o n i n t he c ore 
data s heet a n d t he U S PI. T he pr ot oc ol all o ws te m p orar y d ose re d ucti o n t o re d uce occ urre nce of 
fl us hi n g. E xcl usi o n criteri o n 2 5 was delete d beca use it was re d u n da nt wit h e xcl usi o n criteri o n 
3 0 j a n d c o ntra dict or y t o e xcl usi o n criteri o n 3 8. E xcl usi o n criteri o n 2 7 was delete d beca use D R F 
is meta b olize d b y esterases a n d is n ot i n d uce d or i n hi bite d b y maj or dr u g meta b olizi n g e nz y mes 
(e. g., C Y P e nz y mes). 
T his c ha n ge als o affects Secti o n 7. 7. 1. 2, Disall o we d C o nc o mita nt T hera p y.
Secti o n 6. 3. 2, Retesti n g
C h a n ge: I nf or mati o n o n bl o o d press ure, e xte n di n g t he scree ni n g peri o d, a n d te xt relate d t o 
c o nc o mita nt me dicati o n criteria were re m o ve d.
N o w re a ds:  Partici pa nts w h o ha ve a n o ut- of-ra n ge la b orat or y res ult or bl o o d press ure res ult t hat 
is n ot cli nicall y si g nifica nt ca n be reteste d o nce, as per e xcl usi o n criteria, at t he discreti o n of t he 
I n vesti gat or. T he scree ni n g peri o d ma y be e xte n de d f or eli gi ble i n di vi d uals w h o ca n n ot c o m plete 
t he Da y 1 Visit wit hi n 2 8 da ys of si g ni n g t he I C F. I n di vi d uals w h o si g ne d t he I C F a n d 
s u bse q ue ntl y d o n ot meet c o nc o mita nt me dicati o n criteria ca n ha ve t heir Scree ni n g peri o d 
e xte n de d t o e ns ure t he re q uire me nts f or c o nc o mita nt me dicati o n sta bilizati o n ha ve bee n met.
Partici pa nts w h o ha ve cli nicall y si g nifica nt a b n or mal la b orat or y test val ues s h o ul d n ot be 
reteste d.
R ati o n ale:  T he rele va nt i nf or mati o n f or bl o o d press ure is pr o vi de d i n e xcl usi o n criteri o n 8. T he 
Scree ni n g Peri o d e xte nsi o n was re m o ve d t o a v oi d c o nf usi o n a n d p ote ntial de viati o ns a n d t o 
mai ntai n c o nsiste nc y acr oss partici pa nts. T he i nf or mati o n o n c o nc o mita nt me dicati o n 
sta bilizati o n was re m o ve d t o ali g n wit h Secti o n 7, C o nc o mita nt T hera p y a n d Pr oce d ures.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 2
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 0
Secti o n 1 2. 4, Met h o ds of A nal ysis f or P har mac o ki netic E n d p oi nts f or Part 1 ( o nl y)
C h a n ge: T he reas o ns f or re placi n g a P K s u bset partici pa nt were clarifie d.
N o w re a ds: If a partici pa nt i n t he P K s u bset wit h i nte nsi ve bl o o d sa m ple c ollecti o n ( 7 of t he 
5 0 partici pa nts) disc o nti n ues t he st u d y o n Da y 2 9 bef ore c o m pleti n g t he 8- h o ur P K sa m pli n g 
peri o d or re q uire d ose re d ucti o n or s a m ples n ot c ollecte d per pr ot oc ol or l a b or at or y 
m a n u al,  t he partici pa nt ma y be re place d wit h o ne of t he ot her e nr olle d partici pa nts. If t his is n ot 
feasi ble, a d diti o nal partici pa nts a b o ve t he a ntici pate d sa m ple size of 5 0 ma y be e nr olle d t o 
e ns ure a de q uate n u m ber of partici pa nts are a vaila ble f or i nte nsi ve P K sa m pli n g.
R ati o n ale:  Te xt was a d de d t o clarif y t hat partici pa nts i n t he P K s u bset ca n be re place d u n der 
s pecific circ u msta nces t o e ns ure t hat e n o u g h data are c ollecte d t o deter mi ne t he P K of D R F i n 
t he st u die d partici pa nt p o p ulati o n.
T his c ha n ge als o affects Secti o n 8. 3, Wit h dra wal of Partici pa nts Fr o m t he St u d y.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 2
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 1
S U M M A R Y O F MI N O R C H A N G E S T O T H E P R O T O C O L
T he f oll o wi n g mi n or c ha n ges were ma de t o t he pr ot oc ol, as a p pr o priate:

T he versi o n n u m ber a n d date were u p date d t hr o u g h o ut t he pr ot oc ol.

" Me dical Direct or" was re vise d t o " Me dical M o nit or" t hr o u g h o ut t he pr ot oc ol t o 
c o nf or m wit h S p o ns or ter mi n ol o g y.

Secti o n 2, List of A b bre viati o ns was u p date d.

T y p o gra p hical a n d e dit orial err ors a n d f or matti n g were c orrecte d.

T he Tecfi dera a n d V u merit y U S PI versi o ns were u p date d fr o m 2 0 2 0 t o 2 0 2 1.

I n Ta ble 1, Sc he d ule of Acti vities, t he uri ne pre g na nc y test was re m o ve d o n Da y 5 0 
beca use t he ser u m pre g na nc y test pr o vi des a m ore acc urate res ult f or t his para meter.

T he f o ot n otes i n Ta ble 1, Sc he d ule of Acti vities, were u p date d t o ali g n wit h t he 
c orres p o n di n g descri pti o ns of t he assess me nts i n t he te xt of t he pr ot oc ol a n d t o clarif y 
assess me nt res ults t hat m ust be k n o w n bef ore st u d y treat me nt d osi n g.

T he u nits use d t hr o u g h o ut t he pr ot oc ol were re vise d t o SI u nits t o e ns ure c o nsiste nc y 
acr oss st u d y sites.

Heart rate was re vise d t o p ulse rate f or c o nsiste nc y of ter mi n ol o g y acr oss st u d y sites 
i n differe nt re gi o ns.

I n Ta ble 5, Cli nical La b orat or y Assess me nts, f o ot n otes were a d de d f or clarit y.

T he na me of t he C R O was re m o ve d fr o m t he pr ot oc ol.

I n Secti o n 1 1. 3. 3, Seri o us A d verse E ve nts, d u plicate te xt was delete d a n d t he 
f oll o w- u p f or S A Es t hat occ ur after t he F oll o w- U p Safet y Visit was clarifie d.

Secti o n 1 1. 4. 1, Pre g na nc y a n d Secti o n 1 1. 6. 1, T he I n vesti gat or's Safet y 
Res p o nsi bilities were u p date d t o clarif y t hat t he I n vesti gat or m ust re p ort a pre g na nc y 
occ urri n g i n a fe male partici pa nt as well as i n a fe male part ner of a male partici pa nt. 

Secti o n 1 2. 2, A nal ysis Sets, t he Safet y a nal ysis defi niti o n was u p date d fr o m “all 
e nr olle d partici pa nts” t o “all partici pa nts”.

I n Secti o n 1 2. 5. 1, A d verse E ve nts, T E A Es was re vise d t o A Es f or c o nsiste nc y i n 
ter mi n ol o g y wit h t he S A P.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 2
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 2

I n Ta ble 6, P har mac o ki netic A nal ysis Ti me p oi nts, t he Pre d ose r o w hea der was 
a me n de d, a n d t he sa m pli n g wi n d o w was a d de d i n t he Ti me Wi n d o w r o w f or 
c o nsiste nc y a n d clarit y. T his c ha n ge als o affects Fi g ure 1, St u d y Desi g n Sc he matic.

A me n d me nt S u m mar y f or Pr ot oc ol 2 7 2 M S 3 0 3, Versi o n 2
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 3
LI S T O F A B B R E VI A TI O N S
A E
a d verse e ve nt
A E SI
a d verse e ve nt of s pecial i nterest
C D S
c ore data s heet
C R F
case re p ort f or m
C R O
c o ntract researc h or ga nizati o n
C Y P
c yt oc hr o me P 4 5 0
D R F
dir o xi mel f u marate
GI
gastr oi ntesti nal
M S
m ulti ple scler osis
P K
p har mac o ki netic(s)
P M L
pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y
S A P
statistical a nal ysis pla n
T E A E
treat me nt e mer ge nt a d verse e ve nt
U S PI
U nite d States Prescri bi n g I nf or mati o n