A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of BIIB122/DNL151 in Participants With Parkinson's Disease and Pathogenic LRRK2 Variants
Phase: PHASE3
Conditions: Parkinson Disease
Sponsor: Biogen

C O V E R P A G E  
Offi ci al Titl e:  
A P h a s e 3, M ulti c e nt er, R a n d o mi z e d, D o u bl e -Bli n d, Pl a c e b o -
C o ntr oll e d  St u d y t o D et er mi n e t h e Effi c a c y a n d S af et y of 
BII B 1 2 2/ D N L 1 5 1 i n P arti ci p a nt s wit h P ar ki n s o n’ s  Di s e a s e a n d 
P at h o g e ni c L R R K 2 V ari a nt s  
N C T N u m b er:  
N C T 0 5 4 1 8 6 7 3  
D o c u m e nt  D at e : 
Pr ot o c ol  V er si o n 2. 0 : 0 9 -A pril -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
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
P R O T O C O L N U M B E R:
2 8 3 P D 3 0 2
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 P hase 3, M ultice nter, Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d 
St u d y t o Deter mi ne t he Efficac y a n d Safet y of BII B 1 2 2/ D N L 1 5 1 i n Partici pa nts wit h Par ki ns o n’s 
Disease a n d Pat h o ge nic L R R K 2 Varia nts
E U D R A C T N U M B E R:
2 0 2 2- 0 0 0 7 4 7- 7 7
I N D N U M B E R: 
1 3 5 7 4 3
D A T E:
0 9 A pril 2 0 2 3
Versi o n 2. 0
Fi n al
S u perse des pre vi o us Versi o n 1. 0 d ate d 2 1 A pril 2 0 2 2

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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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S P O N S O R I N F O R M A TI O N
T his st u d y is a c olla b orati o n bet wee n Bi o ge n a n d De nali. Bi o ge n is res p o nsi ble f or t he st u d y.
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
F or ur ge nt me dical iss ues i n w hic h t he St u d y Me dical Direct 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 f or c o m plete c o ntact i nf or mati o n.
Bi o ge n 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 retai ns o verall acc o u nta bilit y f or t hese 
acti vities.

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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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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........................................................................................................................... 9
LI S T O F FI G U R E S....................................................................................................................... 1 0
1.  
K E Y S T U D Y E L E M E N T S........................................................................................ 1 1
1. 1. 
S y n o psis...................................................................................................................... 1 1
1. 2. 
St u d y Desi g n Sc he matic............................................................................................. 1 6
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 7
3. 
I N T R O D U C TI O N...................................................................................................... 3 1
3. 1. 
St u d y Rati o nale........................................................................................................... 3 1
3. 1. 1. 
Rati o nale f or St u d y P o p ulati o n................................................................................... 3 1
3. 1. 2. 
Rati o nale f or D osi n g Re gi me n ................................................................................... 3 2
3. 2. 
Bac k gr o u n d................................................................................................................. 3 3
3. 2. 1.  
O ver vie w of Par ki ns o n’s Disease............................................................................... 3 3
3. 2. 2. 
C urre nt T hera pies f or Par ki ns o n’s Disease ................................................................ 3 3
3. 2. 3. 
Pr ofile of Pre vi o us E x perie nce Wit h BII B 1 2 2........................................................... 3 3
3. 3. 
Be nefit- Ris k Assess me nt............................................................................................ 3 4
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.............................................................. 3 7
5. 
S T U D Y D E SI G N....................................................................................................... 4 0
5. 1. 
St u d y O ver vie w.......................................................................................................... 4 0
5. 2. 
St u d y D urati o n f or Partici pa nts.................................................................................. 4 1
5. 3. 
St u d y St o p pi n g R ules ................................................................................................. 4 2
5. 4.  
U nsc he d ule d Visits..................................................................................................... 4 2
5. 5. 
E n d of St u d y............................................................................................................... 4 2
5. 6.
4 2
6. 
S T U D Y P O P U L A TI O N............................................................................................. 4 4
6. 1. 
I ncl usi o n Criteria........................................................................................................ 4 4
6. 2. 
E xcl usi o n Criteria....................................................................................................... 4 5
6. 3. 
Scree ni n g, Retesti n g, a n d Scree n Fail ures.................................................................. 5 0

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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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6. 3. 1. 
Scree ni n g .................................................................................................................... 5 0
6. 3. 2. 
Retesti n g..................................................................................................................... 5 0
6. 3. 3. 
Scree n Fail ures............................................................................................................ 5 1
5 1
7. 
S T U D Y T R E A T M E N T.............................................................................................. 5 3
7. 1. 
Re gi me n...................................................................................................................... 5 3
7. 2. 
St u d y Treat me nt I nterr u pti o n ..................................................................................... 5 3
7. 3. 
St u d y Treat me nt Ma na ge me nt.................................................................................... 5 3
7. 3. 1. 
BII B 1 2 2...................................................................................................................... 5 3
7. 3. 1. 1. 
St u d y Treat me nt I nstr ucti o ns f or Partici pa nts............................................................ 5 4
7. 3. 1. 2. 
Pre parati o n.................................................................................................................. 5 4
7. 3. 1. 3. 
St ora ge........................................................................................................................ 5 4
7. 3. 1. 4.  
Ha n dli n g a n d Dis p osal................................................................................................ 5 4
7. 3. 1. 5.  
Acc o u nta bilit y............................................................................................................. 5 4
7. 3. 2. 
Place b o a n d/ or C o m parat or or Refere nce Pr o d uct ..................................................... 5 5
7. 4. 
Bli n di n g Pr oce d ures.................................................................................................... 5 5
7. 5. 
Preca uti o ns.................................................................................................................. 5 5
7. 6. 
C o m plia nce................................................................................................................. 5 5
7. 7. 
C o nc o mita nt T hera p y a n d Pr oce d ures........................................................................ 5 5
7. 7. 1. 
C o nc o mita nt T hera p y ................................................................................................. 5 5
7. 7. 1. 1. 
I nitiati o n of or C ha n ge i n P D Me dicati o n .................................................................. 5 6
7. 7. 1. 2.  
All o we d C o nc o mita nt T hera p y................................................................................... 5 6
7. 7. 1. 3.  
Disall o we d C o nc o mita nt T hera p y.............................................................................. 5 7
7. 7. 2. 
Ca uti o nar y C o nc o mita nt S u bsta nces.......................................................................... 5 8
7. 7. 3. 
C o nc o mita nt Pr oce d ures............................................................................................. 5 8
7. 8. 
C o nti n uati o n of Treat me nt after St u d y C o m pleti o n................................................... 5 8
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............................................................... 5 9
8. 1.  
Disc o nti n uati o n of St u d y Treat me nt........................................................................... 5 9
8. 2. 
L ost t o F oll o w- U p....................................................................................................... 5 9
8. 3.  
Wit h dra wal of Partici pa nts Fr o m t he St u d y ............................................................... 6 0
9. 
E F FI C A C Y, 
 
A S S E S S M E N T S......................................................................................................... 6 1

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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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9. 1. 
Cli nical Efficac y Assess me nts.................................................................................... 6 1
9. 2. 
La b orat or y Efficac y Assess me nts............................................................................... 6 3
9. 3.
6 3
9. 4.
6 3
9. 5.
6 3
9. 6.
6 4
1 0. 
S A F E T Y A S S E S S M E N T S ........................................................................................ 6 6
1 0. 1. 
Cli nical Safet y Assess me nts....................................................................................... 6 6
1 0. 2. 
La b orat or y Safet y Assess me nts.................................................................................. 6 6
1 0. 3. 
Pr o d uct- S pecific Safet y Assess me nts......................................................................... 6 7
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................................................................................................. 6 8
1 1. 1.  
Defi niti o ns .................................................................................................................. 6 8
1 1. 1. 1.  
A d verse E ve nt............................................................................................................. 6 8
1 1. 1. 2. 
Seri o us A d verse E ve nt................................................................................................ 6 8
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................ 6 9
1 1. 2. 
Safet y Classificati o ns.................................................................................................. 6 9
1 1. 2. 1. 
I n vesti gat or Assess me nt of E ve nts............................................................................. 6 9
1 1. 2. 2. 
Relati o ns hi p of E ve nts t o St u d y Treat me nt................................................................ 7 0
1 1. 2. 3. 
Se verit y of E ve nts....................................................................................................... 7 1
1 1. 2. 4. 
E x pecte d ness of E ve nts .............................................................................................. 7 1
1 1. 3.  
M o nit ori n g a n d Rec or di n g E ve nts.............................................................................. 7 1
1 1. 3. 1.  
A d verse E ve nts........................................................................................................... 7 1
7 2
1 1. 3. 3. 
Seri o us A d verse E ve nts.............................................................................................. 7 2
1 1. 3. 4. 
I m me diate Re p orti n g of Seri o us A d verse E ve nts a n d A E SIs .................................... 7 3
1 1. 3. 4. 1.  
Deat hs......................................................................................................................... 7 3
1 1. 3. 5. 
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns.................................................... 7 3
1 1. 4. 
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns............................................................... 7 4
1 1. 4. 1. 
Pre g na nc y ................................................................................................................... 7 4
1 1. 4. 2.  
O ver d ose..................................................................................................................... 7 4
1 1. 4. 3.  
Me dical E mer ge nc y.................................................................................................... 7 4

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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 1. 4. 3. 1.  
U n bli n di n g f or Me dical E mer ge nc y........................................................................... 7 4
1 1. 5.  
De vice Safet y Defi niti o ns a n d Re p orti n g Re q uire me nts............................................ 7 5
1 1. 5. 1.  
De vice Deficie nc y ...................................................................................................... 7 5
1 1. 5. 2.  
De vice A d verse E ve nt a n d A d verse De vice Effect.................................................... 7 5
1 1. 5. 3.  
De vice Seri o us A d verse E ve nt a n d U na ntici pate d A d verse De vice Effect................ 7 5
1 1. 5. 4. 
Relati o ns hi p of E ve nts a n d Effects t o St u d y De vices ................................................ 7 6
1 1. 5. 5. 
Se verit y of De vice E ve nts a n d Effects ....................................................................... 7 7
7 7
1 1. 6. 
C o ntrace pti o n Re q uire me nts ...................................................................................... 7 7
1 1. 7. 
Safet y Res p o nsi bilities................................................................................................ 7 8
1 1. 7. 1. 
T he I n vesti gat or.......................................................................................................... 7 8
1 1. 7. 2. 
T he S p o ns or................................................................................................................ 7 9
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........... 8 0
1 2. 1.  
Ge neral C o nsi derati o ns............................................................................................... 8 0
1 2. 2.  
A nal ysis Sets............................................................................................................... 8 0
1 2. 3.  
Met h o ds of A nal ysis f or Efficac y E n d p oi nts.............................................................. 8 0
1 2. 3. 1.  
A nal ysis of t he Pri mar y E n d p oi nts............................................................................. 8 0
1 2. 3. 2.  
A nal ysis of Sec o n dar y E n d p oi nts............................................................................... 8 1
8 1
8 1
8 2
8 2
1 2. 7.  
Met h o ds of A nal ysis f or Safet y E n d p oi nts................................................................. 8 2
1 2. 7. 1.  
A d verse E ve nts........................................................................................................... 8 2
1 2. 7. 2. 
Cli nical La b orat or y Res ults........................................................................................ 8 2
1 2. 7. 3.  
Vital Si g ns .................................................................................................................. 8 3
1 2. 7. 4. 
C- S S R S....................................................................................................................... 8 3
1 2. 7. 5. 
E C G............................................................................................................................ 8 3
1 2. 7. 6. 
P F T ............................................................................................................................. 8 3
1 2. 7. 7. 
P h ysical a n d Ne ur ol o gical E xa mi nati o ns................................................................... 8 3
1 2. 8.  
Met h o ds of A nal ysis f or I m m u n o ge nicit y Data ......................................................... 8 3
1 2. 9. 
I nteri m A nal yses......................................................................................................... 8 3

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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. 1 0. 
Sa m ple Size C o nsi derati o ns ....................................................................................... 8 3
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.............................................. 8 5
1 3. 1.  
Declarati o n of Helsi n ki............................................................................................... 8 5
1 3. 2. 
Et hics C o m mittee........................................................................................................ 8 5
1 3. 3. 
C ha n ges t o Fi nal Pr ot oc ol........................................................................................... 8 6
1 3. 4. 
I nf or me d C o nse nt ....................................................................................................... 8 6
1 3. 5. 
Partici pa nt Data Pr otecti o n......................................................................................... 8 7
1 3. 6. 
C o m pe nsati o n f or I nj ur y............................................................................................. 8 7
1 3. 7. 
C o nflict of I nterest...................................................................................................... 8 7
1 3. 8. 
St u d y Re p ort Si g nat or y............................................................................................... 8 7
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.............................................. 8 8
1 3. 1 0. 
Rete nti o n of St u d y Data.............................................................................................. 8 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............................... 8 9
1 4. 1. 
Site Staff..................................................................................................................... 8 9
1 4. 2.  
Ve n d ors....................................................................................................................... 9 0
1 4. 2. 1. 
C o ntract Researc h Or ga nizati o n................................................................................. 9 0
1 4. 2. 2. 
I nteracti ve Res p o nse Tec h n ol o g y............................................................................... 9 0
1 4. 2. 3. 
Electr o nic or Re m ote Data Ca pt ure............................................................................ 9 0
1 4. 2. 4.  
Di gital O utc o me Assess me nt Data Ca pt ure ............................................................... 9 0
1 4. 2. 5. 
Ce ntral La b orat ories f or La b orat or y Assess me nts ..................................................... 9 0
1 4. 2. 6. 
Ce ntral Facilit y f or Ot her Assess me nts...................................................................... 9 1
1 4. 2. 7. 
Rater Ma na ge me nt...................................................................................................... 9 1
1 4. 3. 
St u d y C o m mittees....................................................................................................... 9 1
1 4. 3. 1.  
A d vis or y C o m mittee................................................................................................... 9 1
1 4. 3. 2. 
I n de pe n de nt Data M o nit ori n g C o m mittee.................................................................. 9 1
1 5.  
A D MI NI S T R A TI V E P R O C E D U R E S....................................................................... 9 2
1 5. 1. 
St u d y Site I nitiati o n.................................................................................................... 9 2
1 5. 2.  
Q ualit y C o ntr ol a n d Q ualit y Ass ura nce...................................................................... 9 2
1 5. 3.  
M o nit ori n g of t he St u d y.............................................................................................. 9 2
1 5. 4. 
St u d y F u n di n g............................................................................................................. 9 3
1 5. 5. 
P u blicati o ns................................................................................................................. 9 3

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
C O N FI D E N TI A L
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A P P E N DI X A.
C O N TI N G E N C Y M E A S U R E S T O E N A B L E S T U D Y C O N D U C T I N 
E X C E P TI O N A L CI R C U M S T A N C E S...................................................................... 9 4
1 6. 
C O M M U NI C A TI O N O F MI TI G A TI O N I M P L E M E N T A TI O N.............................. 9 4
1 6. 1. 
I n vesti gat or a n d I nstit uti o nal Re vie w B oar d N otificati o n.......................................... 9 4
1 6. 2. 
Partici pa nt N otificati o n/I nf or me d C o nse nt F or m U p dates......................................... 9 4
1 7. 
P O T E N TI A L MI TI G A TI O N S................................................................................... 9 5
1 7. 1.  
Virt ual Visits............................................................................................................... 9 5
1 7. 2. 
C ha n ges t o Treat me nt A d mi nistrati o n........................................................................ 9 5
1 7. 2. 1. 
St u d y Treat me nt A d mi nistrati o n via Alter nati ve St u d y Site a n d/ or Pers o n nel.......... 9 5
1 7. 2. 2.  
H o me Deli ver y of St u d y Treat me nt ........................................................................... 9 5
1 7. 3.  
Use of Alter nati ve Me dical Facilities......................................................................... 9 5
1 7. 4. 
Re m ote M o nit ori n g..................................................................................................... 9 5
1 7. 5.  
M o dificati o n t o Per missi ble C o nc o mita nt Me dicati o ns............................................. 9 5
1 7. 6.  
Ot her U nf oresee n Miti gati o ns .................................................................................... 9 6
A P P E N DI X B.
S A F E T Y M O NI T O RI N G P L A N...................................................................... 9 7
1 0 5
1 0 8
1 8. 
R E F E R E N C E S......................................................................................................... 1 0 9
1 9. 
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....................................... 1 1 2
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: 
Safet y Mar gi ns............................................................................................................ 3 5
9 8
1 0 2
1 0 3
1 0 5
1 0 6
1 0 8
1 0 8

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
LI S T O F FI G U R E S
Fi g ure 1:
Sa m ple St u d y Desi g n.................................................................................................. 1 6

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
safe a n d well t olerate d d ose t o rest ore l ys os o mal f u ncti o n a n d 
m o dif y cli nical pr o gressi o n of P D.
St u d y O bjecti ves a n d E n d p oi nts
Pri mar y O bjecti ve
Pri mar y E n d p oi nt
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n t he ti me t o 
c o nfir me d w orse ni n g i n M D S U P D R S 
Parts II a n d III c o m bi ne d sc ore
Ti me t o c o nfir me d w orse ni n g i n M D S 
U P D R S Parts II a n d III o ver t he treat me nt 
peri o d ( mi ni m u m 9 6 wee ks a n d ma xi m u m 
1 8 0 wee ks)
Sec o n dar y O bjecti ves
Sec o n dar y E n d p oi nts
T o e val uate t he safet y a n d t olera bilit y of 
BII B 1 2 2 2 2 5 m g c o m pare d wit h place b o 
w he n a d mi nistere d f or 9 6 t o 1 8 0 wee ks i n 
partici pa nts wit h L R R K 2- P D
I nci de nce of A Es a n d S A Es 
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n t he ti me t o 
c o nfir me d w orse ni n g i n M D S U P D R S Part II 
sc ore
Ti me t o c o nfir me d w orse ni n g i n M D S 
U P D R S Part II sc ore o ver t he treat me nt peri o d
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n c ha n ge i n 
t he M D S- U P D R S Parts II a n d III c o m bi ne d 
sc ore, w he n a d mi nistere d f or 9 6 wee ks i n 
partici pa nts wit h L R R K 2- P D
C ha n ge i n M D S- U P D R S Parts II a n d III 
c o m bi ne d sc ore fr o m Baseli ne t o Wee k 9 6
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n c ha n ge i n 
m S E- A D L sc ore
Ti me t o c o nfir me d w orse ni n g i n m S E- A D L 
sc ore o ver t he treat me nt peri o d
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n c ha n ge i n 
M D S- U P D R S Parts I, II, a n d III c o m bi ne d 
sc ore
C ha n ge i n M D S- U P D R S Parts I, II, a n d III 
c o m bi ne d sc ore fr o m Baseli ne t o Wee k 9 6 
 
St u d y Desi g n:
T his P hase 3, m ultice nter, ra n d o mize d, d o u ble- bli n d, 
place b o-c o ntr olle d st u d y is desi g ne d t o deter mi ne t he efficac y 
a n d safet y of BII B 1 2 2 i n partici pa nts wit h L R R K 2- P D w h o are 
i n t he earl y sta ge of t he disease. T he st u d y p o p ulati o n is defi ne d 
as partici pa nts wit h a cli nical dia g n osis of earl y-sta ge P D w h o 

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
de m o nstrate t hat BII B 1 2 2 is ge nerall y safe a n d well t olerate d. 
F urt her m ore, t hese d oses (a n d t heir ass ociate d A U C) e xcee d t he 
BII B 1 2 2 2 2 5 m g Q D d ose pr o p ose d f or t his c urre nt st u d y. T he 
safet y of BII B 1 2 2 was als o s u p p orte d i n t he 
- wee k a n d 
- wee k c hr o nic t o xic ol o g y st u dies i n rats a n d m o n ke ys, 
res pecti vel y. T he safet y mar gi ns were esta blis he d at  
× (rats) 
a n d  
 × ( m o n ke ys) of h u ma n t otal dr u g plas ma e x p os ure at 
2 2 5 m g Q D. T heref ore, t he be nefit-ris k assess me nt is p ositi ve 
a n d s u p p orts t he de vel o p me nt of BII B 1 2 2 f or t he treat me nt of 
P D.
See Secti o n 3. 3  f or a m ore detaile d descri pti o n.

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
  
Pl ace b o C o ntr olle d, D o u ble- Bli n d Tre at me nt Peri o d
Visit
Scree ni n g 2
B aseli ne 3
E O T/ E T 4
S F U
Visit N u m ber
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
2 3
U V 1
 
Dr u g Scree n
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hei g ht
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral Ser ol o g y
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F S H 7
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser u m Pre g na nc y 
Test 8 
X
 
 
 
 
 
 
 
 
 
X
 
 
 
X
 
 
 
X
X
X
 
Uri ne Pre g na nc y 
Test 8
 
X
X
X
X
 
X
 
X
 
 
X
X
X 
X 
X
 X
X
X
X
 
 
 
Ge netic Testi n g 9
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ra n d o mizati o n
 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St u d y Dr u g 
Dis pe nsati o n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
  
Pl ace b o C o ntr olle d, D o u ble- Bli n d Tre at me nt Peri o d
Visit
Scree ni n g 2
B aseli ne 3
E O T/ E T 4
S F U
Visit N u m ber
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
2 3
U V 1
 
St u d y Dr u g 
A d mi nistrati o n
 
X 1 0
 
 
X
Effic ac y Assess me nts 1 1
M D S- U P D R S 
( Parts I t o I V)1 2
X 1 3
X
 
 
X
 
X
 
X
 
X
X
X
X
X
X
X
X
X
X
X
X
X
 
X
m S E- A D L
 
X
 
 
X
 
X
 
X
 
X
X
X
X
X
X
X
X
X
X
X
X
X
 
X

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
2 7 Perf or m P F Ts ( F V C, F E V 1, F E V 1-t o- F V C rati o, a n d he m o gl o bi n-a dj uste d D L C O ) as descri be d i n t he P F T ma n ual (e. g., a d diti o nal P F Ts ma y be perf or me d f or 
partici pa nts wit h p ul m o nar y s y m pt o ms of u n k n o w n eti ol o g y). E ver y eff ort s h o ul d be ma de t o perf or m t he P F Ts at a si milar ti me of da y ( ± 4 h o urs) of t he 
i n-cli nic visits a n d t o ha ve t he sa me res pirat or y t hera pist or q ualifie d staff me m ber c o n d uct all P F Ts f or a gi ve n partici pa nt. U nsc he d ule d P F Ts ma y als o be 
perf or me d f or partici pa nts w h o de vel o p res pirat or y s y m pt o ms d uri n g partici pati o n i n t he st u d y ( A p pe n di x B ).
2 8 I ncl u des ser u m c he mistr y (i ncl u di n g re nal f u ncti o n tests a n d L F Ts), he mat ol o g y, uri nal ysis, a n d c oa g ulati o n.
2 9 Perf or m 1 2-lea d E C Gs pre d ose a n d 4 h o urs ( ± 1. 5 h o urs) p ost d ose 
 visits. I n a d diti o n, perf or m 1 2-lea d E C Gs at 
, at a n y ti me d uri n g t he visit, irres pecti ve of st u d y treat me nt a d mi nistrati o n.
3 0 At Baseli ne, use t he Baseli ne/ Scree ni n g versi o n of t he C- S S R S a n d assess f or lifeti me a n d prece di n g 6 m o nt hs s uici dal i deati o n a n d be ha vi or. At all ot her 
visits, use t he Si nce Last Visit versi o n of t he C- S S R S.
3 1 N o nseri o us A Es t hat occ ur d uri n g t he Scree ni n g peri o d a n d t hat are assesse d b y t he I n vesti gat or as relate d t o 
 will be ca pt ure d b y t he sites o n 
t he A E e C R F. After t he first d ose of st u d y treat me nt, all A Es are c ollecte d, b ot h relate d a n d u nrelate d t o t he li ga n d.

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
2. 
LI S T O F A B B R E VI A TI O N S
A C R
al b u mi n-t o-creati ni ne rati o
A D E
a d verse de vice effect
A D L
acti vities of dail y li vi n g
A E
a d verse e ve nt
A E SI
a d verse e ve nts of s pecial i nterest
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 P T T
acti vate d partial t hr o m b o plasti n ti me
A R
acc u m ulati o n rati o
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
B C R P
breast ca ncer resista nce pr otei n
BI D
t wice dail y
BI O
bi o mar kers
B P
bl o o d press ure
B U N
bl o o d urea nitr o ge n
C ma x
ma xi m u m o bser ve d c o nce ntrati o n
C mi n
mi ni m u m o bser ve d c o nce ntrati o n
C N S
ce ntral ner v o us s yste m
C O M T
catec h ol O- met h yl tra nsferase
C O VI D- 1 9
c or o na vir us disease
C R O
cli nical researc h or ga nizati o n
C S F
cere br os pi nal fl ui d
C- S S R S
C ol u m bia S uici de Se verit y Rati n g Scale
C T
c o m p ute d t o m o gra p h y

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I D M C
i n de pe n de nt data m o nit ori n g c o m mittee
I g M
i m m u n o gl o b uli n M
I N R
i nter nati o nal n or malize d rati o
I R B
I nstit uti o nal Re vie w B oar d
I R T
i nteracti ve res p o nse tec h n ol o g y 
I V
i ntra ve n o us(l y)
L F T
li ver f u ncti o n test
L P
l u m bar p u nct ure
L R R K 2
le uci ne-ric h re peat ki nase 2
M A D
m ulti ple asce n di n g d ose
M A O- B
m o n oa mi ne o xi dase B
M C P
m ulti plicit y c o ntr ol pr oce d ure
M D S- U P D R S
M o ve me nt Dis or der S ociet y U nifie d Par ki ns o n’s 
Disease Rati n g Scale
M D Z
Mi daz ola m
M M R M
mi xe d m o del f or re peate d meas ures
m S E- A D L
m o difie d Sc h wa b a n d E n gla n d Acti vities of Dail y 
Li vi n g Scale
N O A E L
n o- o bser ve d-a d verse-effect le vel
N S AI D
n o nster oi dal a nti-i nfla m mat or y dr u gs
P D
Par ki ns o n’s disease
P F T
p ul m o nar y f u ncti o n test
PI
Pri nci pal I n vesti gat or

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
P K
p har mac o ki netic(s)
P P MI
Par ki ns o n’s Pr o gressi o n Mar kers I nitiati ve
p Ra b 1 0
p h os p h or ylate d Ra b 1 0
P T
pr ot hr o m bi n ti me
Q A L Y
q ualit y-a dj uste d life- year
Q D
o nce dail y
Ra b 1 0
Ra b G T Pase i n v ol ve d i n vesic ular traffic ki n g
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S Cr
ser u m creati ni ne
S F U
safet y f oll o w- u p
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
U A D E
u na ntici pate d a d verse de vice effect
U L N
u p per li mit of n or mal
U S
U nite d States
U V
u nsc he d ule d visit

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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 1
3. 
I N T R O D U C TI O N 
3. 1. 
St u d y R ati o n ale
BII B 1 2 2 is a selecti ve, orall y bi oa vaila ble, ce ntral ner v o us s yste m- pe netra nt, re versi ble i n hi bit or 
of L R R K 2 t hat is bei n g c o de vel o pe d b y Bi o ge n, I nc., a n d De nali T hera pe utics I nc. as a p ote ntial 
treat me nt f or patie nts wit h P D. I n hi biti o n of L R R K 2 ki nase, a ge neticall y vali date d tar get, is 
e x pecte d t o i m pr o ve l ys os o mal f u ncti o n i n patie nts wit h P D w h o d o ( L R R K 2- P D) a n d d o n ot 
ha ve pat h o ge nic L R R K 2 varia nts. L R R K 2 varia nts are a n esta blis he d ca use of P D, acc o u nti n g 
f or a p pr o xi matel y 4 % t o 5 % of fa milial P D [ C hai a n d Li m 2 0 1 3; Heal y 2 0 0 8]. Fa milial L R R K 2 
varia nts are tra ns mitte d i n a n a ut os o mal d o mi na nt patter n of i n herita nce wit h i nc o m plete 
pe netra nce [ Mar der 2 0 1 5]. I n a d diti o n, l o w fre q ue nc y pat h o ge nic varia nts wit hi n t he L R R K 2 
ge ne are a ge netic ris k fact or a n d acc o u nt f or 1 % t o 2 % of ‘s p ora dic’ P D cases [ C hai a n d Li m 
2 0 1 3; C o o ks o n 2 0 1 5; Heal y 2 0 0 8; Her na n dez 2 0 1 6]  a n d c o m m o n n o nc o di n g P D ge netic ris k 
fact or varia nts i n a n d ar o u n d L R R K 2 ha ve als o bee n i de ntifie d [ Lill 2 0 1 2; Nalls 2 0 1 9]. T he 
maj orit y of i de ntifie d pat h o ge nic varia nts i n L R R K 2 are l ocate d wit hi n its catal ytic d o mai ns, 
i ncl u di n g t he m ost c o m m o n varia nt ass ociate d wit h L R R K 2- P D, G 2 0 1 9 S . T hese varia nts are 
h y p ot hesize d t o i ncrease L R R K 2 ki nase acti vit y, eit her t hr o u g h direct mec ha nis ms wit hi n t he 
ki nase d o mai n, or t hr o u g h i n direct mec ha nis ms [ S he n g 2 0 1 2; West 2 0 0 7]. W hile t he e xact 
pat h o ge nic mec ha nis ms re mai n u n k n o w n, L R R K 2 is belie ve d t o pla y a r ole i n i ntracell ular 
traffic ki n g i n t he e n d ol ys os o mal s yste m [ C o o ks o n 2 0 1 6; He nr y 2 0 1 5]. BII B 1 2 2 ma y i nter ve ne i n 
a n i m p orta nt disease pat h wa y i n P D a n d pre ve nt or c ur b t he acc u m ulati o n of m ot or a n d 
n o n m ot or disa bilities t hat defi ne t he pr o gressi o n of P D.
T his P hase 3, m ultice nter, ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d st u d y is desi g ne d t o 
deter mi ne t he efficac y a n d safet y of BII B 1 2 2 i n partici pa nts wit h a cli nical dia g n osis of P D w h o 
carr y a pat h o ge nic L R R K 2 varia nt a n d are i n t he earl y sta ge of t he disease. Use of place b o is 
j ustifie d as n o disease m o dif yi n g t hera pies are a p pr o ve d f or P D at t his ti me.
3. 1. 1.  
R ati o n ale f or St u d y P o p ul ati o n
T his st u d y will e nr oll partici pa nts wit h a cli nical dia g n osis of P D w h o are i n t he earl y sta ges of 
t he disease a n d carr y a pat h o ge nic varia nt i n t he L R R K 2 ge ne (e. g., G 2 0 1 9 S , N 1 4 3 7 H , R 1 4 4 1 G , 
R 1 4 4 1 C , R 1 4 4 1 H , Y 1 6 9 9 C , or I 2 0 2 0 T). Beca use L R R K 2 ge netic stat us ma y i nfl ue nce patie nt 
res p o nse t o BII B 1 2 2 treat me nt, o nl y patie nts wit h L R R K 2 pat h o ge nic ge netic variati o n will 
e nr oll i n t his st u d y.
Partici pa nts wit h earl y-sta ge P D were selecte d beca use BII B 1 2 2 is h y p ot hesize d t o ha ve greater 
effect o n P D s y m pt o ms a n d pr o gressi o n w he n a d mi nistere d earlier i n t he disease. I n earl y-sta ge 
disease, w he n t here is less ne ur o de ge nerati o n i n t he d o pa mi ner gic ne ur o ns, t he p ote ntial e xists t o 
rest ore or preser ve l ys os o mal f u ncti o n i n a hi g her perce nta ge of ne ur o ns t ha n i n later-sta ge 
disease. Pat h ol o gical st u dies ha ve s h o w n t hat, 4 years after a cli nical dia g n osis of P D, t here is 
alrea d y a s u bsta ntial re d ucti o n i n stai ni n g f or d o pa mi ne ter mi nals i n t he d orsal striat u m 
[ K or d o wer 2 0 1 3]. T heref ore, treat me nts a d mi nistere d i n later P D sta ges ma y be less effecti ve i n 
rest ori n g f u ncti o n of d o pa mi ner gic ne ur o ns a n d re d uci n g f urt her ne ur o de ge nerati o n.

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
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
Pri mar y O bjecti ve
Pri mar y E n d p oi nt
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n t he ti me t o 
c o nfir me d w orse ni n g i n M D S- U P D R S Parts II 
a n d III c o m bi ne d sc ore
Ti me t o c o nfir me d w orse ni n g i n 
M D S- U P D R S Parts II a n d III o ver t he 
treat me nt peri o d ( mi ni m u m 9 6 wee ks a n d 
ma xi m u m 1 8 0 wee ks)
Sec o n dar y O bjecti ves
Sec o n dar y E n d p oi nts
T o e val uate t he safet y a n d t olera bilit y of BII B 1 2 2 
2 2 5 m g c o m pare d wit h place b o w he n 
a d mi nistere d f or 9 6 t o 1 8 0 wee ks 
I nci de nce of A Es a n d S A Es 
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n t he ti me t o 
c o nfir me d w orse ni n g i n M D S- U P D R S Part II 
sc ore
Ti me t o c o nfir me d w orse ni n g i n 
M D S- U P D R S Part II sc ore o ver t he 
treat me nt peri o d
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n c ha n ge i n t he 
M D S- U P D R S Parts II a n d III c o m bi ne d sc ore, 
w he n a d mi nistere d f or 9 6 wee ks 
C ha n ge i n M D S- U P D R S Parts II a n d III 
c o m bi ne d sc ore fr o m Baseli ne t o Wee k 9 6
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n c ha n ge i n 
m S E- A D L sc ore
Ti me t o c o nfir me d w orse ni n g i n 
m S E- A D L sc ore o ver t he treat me nt peri o d
T o e val uate t he efficac y of BII B 1 2 2 2 2 5 m g 
c o m pare d wit h place b o, base d o n c ha n ge i n 
M D S- U P D R S Parts I, II, a n d III c o m bi ne d sc ore
C ha n ge i n M D S- U P D R S 
Parts I, II, a n d III c o m bi ne d sc ore fr o m 
Baseli ne t o Wee k 9 6 

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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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Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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.
Scree ni n g ge netic test res ults verif yi n g t he prese nce of a pat h o ge nic L R R K 2 varia nt (e. g., 
G 2 0 1 9 S , N 1 4 3 7 H , R 1 4 4 1 G , R 1 4 4 1 C , R 1 4 4 1 H , Y 1 6 9 9 C , or I 2 0 2 0 T). Partici pa nts wit h 
a d diti o nal L R R K 2 varia nts ma y be i ncl u de d if data e mer ge t o c o n vi nci n gl y s u p p ort a n 
ass ociati o n of t he varia nts wit h L R R K 2- P D pat h o ge nicit y. C o nfir mati o n of t his eli gi bilit y 
re q uire me nt ma y c o me fr o m a n accre dite d ge netic test (see Secti o n 9. 5 ).
9.
O nl y w he n a vaila ble, hist orical Da T/ S P E C T res ults de m o nstrati n g acti vit y i n t he striat u m 
is eit her as y m metric, a bse nt i n t he p uta me n a n d/ or o ne or b ot h ca u date n uclei, c o nsiste nt 
wit h ne ur o de ge nerati ve Par ki ns o nis m, as assesse d wit h q ualitati ve, vis ual assess me nt. 
A d diti o nal details are pr o vi de d i n Secti o n 6. 3. 4 .
1 0. All w o me n of c hil d beari n g p ote ntial m ust practice effecti ve c o ntrace pti o n d uri n g t he 
st u d y a n d f or 3 m o nt hs after t heir last d ose of st u d y treat me nt as descri be d i n 
Secti o n 1 1. 6 . I n a d diti o n, partici pa nts s h o ul d n ot d o nate e g gs d uri n g t he st u d y a n d f or at 
least 3 m o nt hs after t heir last d ose of st u d y treat me nt.
6. 2. 
E xcl usi o n Criteri a
Me dic al Hist or y a n d C urre nt He alt h St at us
1.
Cli nicall y si g nifica nt ne ur ol o gic dis or der ot her t ha n P D, i ncl u di n g, b ut n ot li mite d t o, 
str o ke, de me ntia, or seiz ure wit hi n 5 years of Scree ni n g Visit, i n t he o pi ni o n of t he 
I n vesti gat or.
2.
Cli nical e vi de nce of at y pical par ki ns o nis m (e. g., m ulti ple-s yste m atr o p h y or pr o gressi ve 
s u pra n uclear pals y) or e vi de nce of dr u g-i n d uce d par ki ns o nis m.
3.
Pre vi o us or c urre nt partici pati o n i n a ge ne t hera p y trial f or P D.
4.
Hist or y of brai n s ur gical i nter ve nti o n f or P D (e. g., dee p- brai n sti m ulati o n, palli d ot o m y).
5.
A n y p h ysical c o n diti o n t hat ma y c o nf o u n d t he m ot or assess me nt ( M D S- U P D R S) o ver 
ti me (e. g., se vere art hritis, se vere d ys ki nesias, tra u matic i nj uries wit h per ma ne nt p h ysical 
disa bilit y).
7.
Cli nicall y si g nifica nt a b n or mal la b orat or y test val ues, as deter mi ne d b y t he I n vesti gat or, 
d uri n g Scree ni n g. Details re gar di n g retesti n g are pr o vi de d i n Secti o n 6. 3. 2 . Details 
re gar di n g rescree ni n g are pr o vi de d i n Secti o n 6. 3. 3 .
8.
H os pitalizati o n f or a n y reas o n d uri n g t he 4 wee ks bef ore Scree ni n g.
9.
A n y of t he f oll o wi n g vital si g n a b n or malities at t he Scree ni n g or Baseli ne Visit (if vital 
si g n val ues are o ut of ra n ge, testi n g ma y be re peate d o nce):
•

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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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A L T, A S T, or t otal bilir u bi n > 1. 5 × U L N ( u nless d ue t o Gil bert’s s y n dr o me base d o n 
bilir u bi n fracti o nati o n) wit hi n 6 m o nt hs of t he Scree ni n g Visit.
1 6. Hist or y or p ositi ve test res ult at Scree ni n g f or h u ma n i m m u n o deficie nc y vir us.
1 7. 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 ≥ 1 year pri or t o 
Baseli ne). Partici pa nts wit h ca ncers i n re missi o n f or > 5 years pri or t o Baseli ne ma y be 
i ncl u de d after disc ussi o n wit h t he S p o ns or.
1 8. C urre nt or hist or y of cli nicall y si g nifica nt car di o vasc ular disease or a b n or mal 
assess me nts, i ncl u di n g a n y of t he f oll o wi n g:
•
M y ocar dial i nfarcti o n or u nsta ble a n gi na wit hi n 6 m o nt hs pri or t o Scree ni n g.
•
Ve ntric ular tac h ycar dia, fa mil y or pers o nal hist or y of l o n g Q T s y n dr o me, atrial 
fi brillati o n or fl utter, or ot her si g nifica nt arr yt h mias.
•
Ne w Y or k Heart Ass ociati o n Class III or I V c o n gesti ve heart fail ure. 
•
Hist or y of car diac s y nc o pe, or s y nc o pe/ near s y nc o pe of u n k n o w n eti ol o g y i n t he past 
6 years or a n y s y nc o pe/ near s y nc o pe i n t he last 3 years.
•
Cli nicall y si g nifica nt (as deter mi ne d b y t he I n vesti gat or) 1 2-lea d E C G a b n or malities.
•
C o nfir me d de m o nstrati o n of c orrecte d Q T i nter val, usi n g Fri dericia’s c orrecti o n 
met h o d, of > 4 5 0 ms f or male partici pa nts a n d > 4 6 0 ms f or fe male partici pa nts. If 
o ut of ra n ge, t he E C 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. A 
partici pa nt m ust n ot be ra n d o mize d/ d ose d if t he re peat val ue is still o ut of ra n ge.
1 9. Partici pa nts wit h u nc o ntr olle d h y perte nsi o n. Partici pa nts wit h a hist or y of sta ble 
h y perte nsi o n treate d wit h all o we d a nti h y perte nsi ve a ge nts ma y be i ncl u de d, pr o vi de d t he 
d oses of c o nc o mita nt a nti h y perte nsi ve a ge nts are sta ble f or > 3 m o nt hs pri or t o Baseli ne 
a n d n o m ore t ha n t hree a nti h y perte nsi ve a ge nts are re q uire d.
2 0. U nsta ble ps yc hiatric ill ness, i ncl u di n g ps yc h osis, s uici dal i deati o n, or u ntreate d maj or 
de pressi o n, wit hi n 9 0 da ys bef ore Scree ni n g, as deter mi ne d b y t he I n vesti gat or.
2 1. Hist or y of dr u g or alc o h ol a b use wit hi n t he past 5 years (as defi ne d b y t he I n vesti gat or), a 
p ositi ve uri ne dr u g test at Scree ni n g ( e xce pti o n : partici pa nts w h o test p ositi ve f or 
be nz o diaze pi nes ma y be i ncl u de d i n t he st u d y, at t he discreti o n of t he I n vesti gat or), or a n 
u n willi n g ness t o a bstai n fr o m t hese s u bsta nces d uri n g i n-cli nic visit da ys. Partici pa nts 
w h o test p ositi ve f or ca n na bi n oi ds d ue t o occasi o nal marij ua na use, as deter mi ne d b y t he 
I n vesti gat or, a n d w h o a gree t o refrai n fr o m usi n g marij ua na f or t he d urati o n of t he st u d y 
ma y be e nr olle d at I n vesti gat or’s discreti o n, after a c o ns ultati o n wit h t he S p o ns or. T he 

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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
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 
ra n d o mize d/ 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.
Partici pa nts w h o fail scree ni n g criteria ca n be rescree ne d o nce after re vie w b y t he Me dical 
M o nit or, at t he discreti o n of t he S p o ns or.
Scree n-faile d partici pa nts will be rec o nse nte d if t he y are t o be rescree ne d a n d will recei ve a ne w 
scree ni n g n u m ber. All scree ni n g assess me nts will be re peate d e xce pt f or c o nfir mati o n of P D 
dia g n osis, hei g ht meas ure me nt, a n d bl o o d sa m pli n g f or D N A, u nless deter mi ne d ot her wise b y 
t he S p o ns or. F or fe male partici pa nts, if t he i nitial F S H le vel c o nfir me d p ost me n o pa usal state, it 
d oes n ot nee d t o be re peate d.

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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
U nless ot her wise n otifie d, all 
 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 bet wee n t he 
a m o u nt of BII B 1 2 2 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. 3. 2. 
Pl ace b o a n d/ or C o m p ar at or or Refere nce Pr o d uct
T he sa me pac ka gi n g, st ora ge te m perat ure, a n d e xci pie nt material a p plies t o t he place b o as f or 
BII B 1 2 2. 
7. 4. 
Bli n di n g Pr oce d ures
T he I n vesti gat or, S p o ns or, st u d y staff, a n d partici pa nts will re mai n bli n de d t o t he treat me nt 
assi g n me nts. T o mai ntai n t he st u d y bli n d, it is i m perati ve t hat treat me nt assi g n me nts are n ot 
s hare d wit h t he partici pa nts, t heir fa milies, or a n y me m ber of t he bli n de d st u d y tea m, at t he site, 
S p o ns or, a n d C R O. 
At t he e n d of t he st u d y (i.e., o nce t he cli nical st u d y re p ort is fi nalize d), if u n bli n di n g will n ot 
je o par dize t he res ults of o n g oi n g relate d st u dies, t he S p o ns or will pr o vi de t he ra n d o mizati o n 
c o des t o I n vesti gat ors, w h o t he n ca n i nf or m t heir partici pa nts a b o ut t he treat me nt recei ve d. 
I n t he e ve nt of a me dical e mer ge nc y t hat re q uires u n bli n di n g of a partici pa nt’s treat me nt 
assi g n me nt, refer t o Secti o n 1 1. 4. 3 .
7. 5. 
Prec a uti o ns
N ot a p plica ble
7. 6.  
C o m pli a nce
T he n u m ber of ta blets ta ke n a n d dates of a d mi nistrati o n will be d oc u me nte d t hr o u g h di gital 
a d here nce m o nit ori n g usi n g di gital blister wallets a n d t he c orres p o n di n g m o bile a p plicati o n a n d 
tra nsferre d t o t he data base electr o nicall y. 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. Ma n ual a d here nce m o nit ori n g, e. g., pill c o u nti n g, ma y be 
i m ple me nte d i n c o nj u ncti o n wit h or as a n alter nati ve t o t he di gital blister wallet w here necessar y.
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 fr o m t he ti me of scree ni n g t hr o u g h 
S F U, as well as U Vs.
Partici pa nts m ust 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, vita mi ns, a n d her bal pre parati o ns. Partici pa nts e nr olli n g i n t he 

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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
st u d y s h o ul d n ot be e x pecte d t o start or c ha n ge P D me dicati o ns fr o m Scree ni n g t hr o u g h t he first 
 wee ks after e nr oll me nt (as j u d ge d b y t he I n vesti gat or).
7. 7. 1. 1. 
I niti ati o n of or C h a n ge i n P D Me dic ati o n
I n vesti gat ors s h o ul d ma ke e ver y atte m pt t o c o n d uct a n i n-cli nic visit (sc he d ule d or u nsc he d ule d) 
t o assess safet y a n d efficac y meas ures pri or t o i nitiati n g or c ha n gi n g P D me dicati o ns (e. g., 
le v o d o pa, d o pa mi ne a g o nists, M A O- B i n hi bit ors, a ntic h oli ner gics, a de n osi ne rece pt or 
a nta g o nists, C O M T i n hi bit ors). See Secti o n 5. 4  f or a d diti o nal details.
7. 7. 1. 2.  
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 nti n ue t he me dicati o ns t hat t he y were recei vi n g at 
e nr oll me nt a n d t o a v oi d starti n g a n y ne w me dicati o ns or her bal pre parati o ns d uri n g t he st u d y 
peri o d, si nce t he y ma y c o nf o u n d t he res ults of t he st u d y. T he f oll o wi n g c o nc o mita nt t hera pies 
are all o we d d uri n g st u d y partici pati o n:
•
P D me dicati o ns t hat ha ve bee n sta ble f or at least 
 da ys pri or t o Scree ni n g. P D 
me dicati o ns s h o ul d n ot be e x pecte d t o c ha n ge fr o m Scree ni n g t hr o u g h at least 
wee ks after e nr oll me nt as j u d ge d b y t he I n vesti gat or.
•
Sta n dar d of care me dicati o ns f or P D (i.e., le v o d o pa, d o pa mi ne a g o nists, M A O- B 
i n hi bit ors, a ntic h oli ner gics, a de n osi ne rece pt or a nta g o nists, C O M T i n hi bit ors) ma y be 
i nitiate d d uri n g a partici pa nt’s partici pati o n i n t he st u d y at t he discreti o n of t he 
I n vesti gat or t o ma na ge P D s y m pt o ms. T he S p o ns or rec o m me n ds mi ni mizi n g c ha n ges 
t o P D me dicati o ns d uri n g t he trial, as me dicall y a p pr o priate i n t he o pi ni o n of 
I n vesti gat or.  
•
Me dicati o ns f or a nti h y perte nsi ve a ge nts ( n o m ore t ha n 3 a ge nts use d) a n d ot her 
c hr o nic c o n diti o ns are all o we d pr o vi de d t hat t he partici pa nt is o n a sta ble d ose f or 
> 3 m o nt hs pri or t o baseli ne a n d t he d ose e x pecte d t o re mai n sta ble f or t he d urati o n of 
t he st u d y.
•
As piri n ≤ 1 0 0 m g dail y.
•
Aceta mi n o p he n a n d N S AI Ds are all o we d if use d acc or di n g t o t he l ocal la bel 
g ui deli nes. N S AI Ds a n d cl o pi d o grel m ust be a v oi de d bef ore a n d after L P pr oce d ures, 
as descri be d i n Secti o n 7. 7. 1. 3 .
•
Vacci nati o ns, i ncl u di n g wit h li ve or atte n uate d vacci nes, are all o we d d uri n g t he 
st u d y; h o we ver, a d mi nistrati o n of a n y vacci nati o n or b o oster s h o ul d n ot be gi ve n 
wit hi n 1 0 da ys bef ore a st u d y visit a n d f or 1 0 da ys after a st u d y visit.
•
R o uti ne vita mi n t hera p y is all o we d. Partici pa nts s h o ul d n ot c ha n ge a d mi nistrati o n of 
vita mi ns, s u p ple me nts, her bal/alter nati ve healt h pre parati o ns, or o ver-t he-c o u nter 

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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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7. 7. 2.  
C a uti o n ar y C o nc o mit a nt S u bst a nces 
•
Ca uti o n s h o ul d be e xercise d f or st u d y partici pa nts w h o ta ke  
 s u bstrate dr u gs. 
Partici pa nts s h o ul d be m o nit ore d f or c ha n ges i n t olera bilit y or efficac y of t his dr u g class. 
Partici pa nts are rec o m me n de d t o sta g ger 
 dr u gs a n d st u d y treat me nt b y at 
least 8 h o urs.
A partial list of 
 ca n be f o u n d i n 
  
•
Ca uti o n s h o ul d be e xercise d f or st u d y partici pa nts w h o ta ke se nsiti ve 
 
dr u gs wit h a narr o w t hera pe utic i n de x. Partici pa nts s h o ul d be m o nit ore d f or c ha n ges i n 
t olera bilit y or efficac y of t his dr u g class.
A partial list of dr u gs i n t his class ca n be f o u n d i n 
 
•
Partici pa nts s h o ul d refrai n fr o m e xcessi ve use of alc o h ol d uri n g t he st u d y; n o m ore t ha n 
2 u nits of alc o h ol at a gi ve n ti me, or > 1 4 u nits per wee k f or males a n d > 7 u nits per wee k 
f or fe males. O ne u nit of alc o h ol e q uals 1 2 oz ( 3 6 0 m L) beer, 1 ½ oz ( 4 5 m L) li q u or, or 
5 oz ( 1 5 0 m L) wi ne. 
7. 7. 3.  
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 fr o m t he 
ti me of partici pa nt scree ni n g t o t he S F U a n d a n y U Vs.
7. 8.  
C o nti n u ati o n of Tre at me nt after St u d y C o m pleti o n 
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 after t he st u d y. If st u d y 
treat me nt is pr o ve n t o be be neficial, all re g ulat or y re q uire me nts re gar di n g p ostst u d y access will 
be met.

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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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•
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 a n d 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 e C R F.
Partici pa nts w h o wit h dra w fr o m t he st u d y 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. Fi nal f oll o w- u p visit assess me nts will be perf or me d at t he E T 
Visit. If a n E T Visit ca n n ot be perf or me d, e ver y eff ort m ust be ma de b y t he st u d y site t o c o ntact 
t he partici pa nt (e. g., b y p h o ne) t o c ollect safet y f oll o w- u p assess me nts re m otel y a n d t he reas o n 
f or disc o nti n uati o n. T he meas ures ta ke n t o f oll o w- u p m ust be d oc u me nte d.
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 a safet y or t olera bilit y e ve nt, 
ma y be re place d at discreti o n of t he S p o ns or.

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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 
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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.
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 BII B 1 2 2. 
At t he baseli ne visit, all safet y assess me nts m ust be perf or me d bef ore BII B 1 2 2 d osi n g.
•
A E a n d S A E rec or di n g
•
P h ysical (i ncl u di n g wei g ht) a n d ne ur ol o gical e xa mi nati o ns 
•
Vital si g n meas ure me nts (te m perat ure, H R, B P, a n d res pirat or y rate). Bl o o d press ure 
will be meas ure d after t he partici pa nt has bee n resti n g i n a seate d p ositi o n f or at least 
5 mi n utes. Ort h ostatic vital si g n meas ure me nts will be o btai ne d w he ne ver bl o o d 
press ure is rea d, i n t he f oll o wi n g ma n ner: after s u pi ne bl o o d press ure a n d heart rate 
are meas ure d, t he partici pa nt s h o ul d sta n d, a n d bl o o d press ure a n d heart rate s h o ul d 
be meas ure d after sta n di n g 1 mi n ute a n d a gai n after 3 t otal mi n utes. 
•
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
•
P F Ts 
•
P ulse o xi metr y 
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 
BII B 1 2 2. At t he baseli ne visit, all safet y assess me nts m ust be perf or me d bef ore BII B 1 2 2 d osi n g.
•
He mat ol o g y: C o m plete bl o o d c o u nt wit h differe ntial a n d platelet c o u nt 
•
Ser u m c he mistr y: Electr ol ytes, t otal pr otei n, al b u mi n, creati ni ne, bl o o d urea nitr o ge n, 
uric aci d, bilir u bi n (t otal a n d direct), al kali ne p h os p hatase, ala ni ne a mi n otra nsferase, 
as partate a mi n otra nsferase, ga m ma- gl uta m yl tra nsferase, gl uc ose, calci u m, a n d 
p h os p h or us
•
C oa g ulati o n: I N R, P T, a n d A P T T
•
Uri nal ysis: Di pstic k f or bl o o d, pr otei n, a n d gl uc ose ( micr osc o pic e xa mi nati o n ma y 
als o be perf or me d) a n d uri ne A C R

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•
Ser u m a n d/ or uri ne pre g na nc y tests
1 0. 3. 
Pr o d uct- S pecific S afet y Assess me nts
N ot a p plica ble.

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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 alert t o p ossi ble A Es, 
de vice A Es, A D Es, a n d de vice deficie ncies. If a n A E, de vice A E, A D E, or de vice deficie nc y 
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, i n 
acc or da nce wit h l ocal practice a n d re g ulati o ns, 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, de vice S A Es, U A D Es, re p orta ble de vice deficie ncies, 
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.
F or t he classificati o n of  
, refer t o t he  
I n vesti gat or's Br oc h ure. Safet y 
m o nit ori n g, rec or di n g, a n d re p orti n g are descri be d i n t he secti o ns bel o w.
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 
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 
electr ocar di o gra m) 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.

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•
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.
•
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 .

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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
Partici pa nts s h o ul d n ot bec o me pre g na nt d uri n g a n d f or 3 m o nt hs after t heir last d ose of st u d y 
treat 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 diatel y.
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 fr o m first d ose of 
st u d y dr u g t o 3 m o nt hs after t heir last d ose b y fa xi n g or e maili 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 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 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 m o nt hs fr o m t heir last d ose of st u d y treat me nt, w hic he ver is l o n ger.
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 e 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 e 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 Direct 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. 4. 3. 1.
U n bli n di n g f or Me dic al E mer ge nc y
I n a me dical e mer ge nc y w he n k n o wle d ge of t he partici pa nt’s treat me nt assi g n me nt ma y 
i nfl ue nce t he partici pa nt’s cli nical care, t he I n vesti gat or ma y access t he partici pa nt’s treat me nt 
assi g n me nt b y I R T. T he I n vesti gat or m ust d oc u me nt t he reas o ns f or u n bli n di n g i n t he 
partici pa nt’s s o urce d oc u me nts. T he I n vesti gat or is str o n gl y a d vise d n ot t o di v ul ge t he 
partici pa nt’s treat me nt assi g n me nt t o a n y i n di vi d ual n ot directl y i n v ol ve d i n ma na gi n g t he 
me dical e mer ge nc y, or t o pers o n nel i n v ol ve d wit h t he a nal ysis a n d c o n d uct of t he st u d y. T he 
I n vesti gat or ca n c o ntact t he S p o ns or t o disc uss s uc h sit uati o ns.

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1 1. 5.  
De vice S afet y Defi niti o ns a n d Re p orti n g Re q uire me nts
F oll o w t his secti o n f or re p orti n g e ve nts d uri n g t he use of  
.
1 1. 5. 1.  
De vice Deficie nc y
De vice deficie nc y is defi ne d as a n y i na de q uac y i n t he i de ntit y, q ualit y, d ura bilit y, relia bilit y, 
safet y, or perf or ma nce of a n i n vesti gati o nal de vice, i ncl u di n g malf u ncti o n, use err ors, or 
i na de q uac y i n i nf or mati o n s u p plie d b y t he ma n ufact urer.
A n y case of a de vice deficie nc y t hat mi g ht ha ve le d t o a n S A E if a n a p pr o priate acti o n ha d n ot 
bee n ta ke n, a n i nter ve nti o n ha d n ot occ urre d, or circ u msta nces ha d bee n less f ort u nate a n d t hat 
occ urre d after t he first use of t he de vice b y partici pa nt a n d bef ore st u d y c o m pleti o n or pre mat ure 
st u d y wit h dra wal is t o a d diti o nall y be rec or de d o n a Cli nical Trial De vice Re p orti n g F or m. T he 
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 bec o mi n g a ware of t he de vice 
deficie nc y. F oll o w- u p i nf or mati o n re gar di n g s uc h de vice deficie nc y als o m ust be re p orte d wit hi n 
2 4 h o urs.
1 1. 5. 2.  
De vice A d verse E ve nt a n d A d verse De vice Effect
A de vice A E is a n y u nt o war d me dical occ urre nce, u ni nte n de d disease or i nj ur y, or a n y u nt o war d 
cli nical si g ns, i ncl u di n g a n a b n or mal la b orat or y fi n di n g, i n partici pa nts, users, or ot her pers o ns, 
i n t he c o nte xt of a cli nical i n vesti gati o n, w het her or n ot relate d t o t he i n vesti gati o nal de vice.
A n A D E is defi ne d as a n y A E relate d t o t he use of a n i n vesti gati o nal me dical de vice.
A n y de vice A E or A D E e x perie nce d b y a partici pa nt after t he first use of t he de vice b y 
partici pa nt a n d bef ore st u d y c o m pleti o n or pre mat ure st u d y wit h dra wal is t o be rec or de d o n t he 
A E e C R F.
1 1. 5. 3.  
De vice Seri o us A d verse E ve nt a n d U n a ntici p ate d A d verse De vice Effect
A de vice S A E mea ns a n y A E t hat le d t o a n y of t he f oll o wi n g:
•
Deat h
•
Seri o us deteri orati o n i n t he healt h of t he partici pa nts t hat res ulte d i n a n y of t he f oll o wi n g:
o
Life-t hreate ni n g ill ness or i nj ur y
o
Per ma ne nt i m pair me nt of a b o d y str uct ure or a b o d y f u ncti o n
o
H os pitalizati o n or pr ol o n gati o n of patie nt h os pitalizati o n
o
Me dical or s ur gical i nter ve nti o n t o pre ve nt life-t hreate ni n g ill ness or i nj ur y or 
per ma ne nt i m pair me nt t o a b o d y str uct ure or a b o d y f u ncti o n
o
C hr o nic disease
•
Fetal distress, fetal deat h, or a c o n ge nital p h ysical or me ntal i m pair me nt or birt h defect
A U A D E is defi ne d as a n y seri o us a d verse effect o n healt h or safet y or a n y life-t hreate ni n g 
pr o ble m or deat h ca use d b y or ass ociate d wit h a de vice, if t hat effect, pr o ble m, or deat h was n ot 
pre vi o usl y i de ntifie d i n nat ure, se verit y, or de gree of i nci de nce i n t he i n vesti gati o nal pla n or 

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a p plicati o n, or a n y ot her u na ntici pate d seri o us pr o ble m ass ociate d wit h a de vice t hat relates t o 
t he ri g hts, safet y, or welfare of partici pa nts.
T he criteria f or seri o us ness i ncl u de t he f oll o wi n g:
•
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
•
Ca uses disa bilit y or per ma ne nt da ma ge
•
Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y
•
Re q uires i nter ve nti o n t o pre ve nt per ma ne nt i m pair me nt/ da ma ge
•
Res ults i n c o n ge nital a n o mal y/ birt h defect
•
Is a n y ot her me dicall y i m p orta nt e ve nt 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
A n y de vice S A E or U A D E e x perie nce d b y a partici pa nt after t he first use of t he de vice b y 
partici pa nt a n d bef ore st u d y c o m pleti o n or pre mat ure st u d y wit h dra wal is t o be rec or de d o n t he 
A E e C R F a n d o n a Cli nical Trial De vice Re p orti n g F or m wit hi n 2 4 h o urs of a ware ness of t he 
e ve nt. A d diti o nall y, i n t he U S, t he st u d y site m ust f or mall y n otif y t he I R B of U A D Es wit hi n 1 0 
w or ki n g da ys of site a ware ness of t he e ve nt.
Partici pa nts will be f oll o we d f or t hese e ve nts u ntil st u d y c o m pleti o n or pre mat ure st u d y 
wit h dra wal. A n y e ve nt t hat is o n g oi n g w he n t he partici pa nt c o m pletes or disc o nti n ues t he st u d y 
will be f oll o we d b y t he I n vesti gat or u ntil t he e ve nt has res ol ve d, sta bilize d, or ret ur ne d t o 
baseli ne stat us.
1 1. 5. 4.  
Rel ati o ns hi p of E ve nts a n d Effects t o St u d y De vices
T he f oll o wi n g s h o ul d be c o nsi dere d w he n e val uati n g if a n effect or de vice deficie nc y is ca use d 
b y or ass ociate d wit h  
:
•
A n e ve nt has a te m p oral relati o ns hi p wit h i n vesti gati o nal de vice use/a p plicati o n or 
pr oce d ures
•
A n e ve nt i n v ol ves a b o d y site or or ga n t hat:
o
T he i n vesti gati o nal de vice or pr oce d ures are a p plie d t o
o
T he i n vesti gati o nal de vice or pr oce d ures ha ve a n effect o n
•
A seri o us e ve nt f oll o ws a k n o w n res p o nse patter n t o t he me dical de vice (if t he res p o nse 
patter n is pre vi o usl y k n o w n)
•
Disc o nti n uati o n of me dical de vice a p plicati o n ( or a re d ucti o n i n t he le vel of 
acti vati o n/e x p os ure) a n d rei ntr o d ucti o n of its use ( or a n i ncrease i n t he le vel of 
acti vati o n/e x p os ure) a n d i m pact o n t he seri o us e ve nt ( w he n cli nicall y feasi ble)
•
Ot her p ossi ble ca uses (e. g., a n u n derl yi n g or c o nc urre nt ill ness/cli nical c o n diti o n or/a n d 
a n effect of a n ot her de vice, dr u g, or treat me nt) ha ve bee n a de q uatel y r ule d o ut
•
Har m t o t he partici pa nt is d ue t o err or i n use

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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 5
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, 
i ma gi n g, 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 e 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.  
 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 nite d States. I n vesti gati o nal sites wit h l ocal i nstit uti o nal re vie w 
b oar ds will s u b mit d oc u me nts t he msel ves, a n d  
 will pr o vi de t he necessar y d oc u me ntati o n.
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 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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 6
At t he c o m pleti o n or ter mi nati o n of t he st u d y, w here re q uire d, t he st u d y site m ust s u b mit a 
cl ose- o ut letter t o t he et hics c o m mittee a n d t he S p o ns or. 
1 3. 3.  
C h a n ges t o Fi n al Pr ot oc ol
All pr ot oc ol a me n d me nts m ust be s u b mitte d t o t he et hics c o m mittee a n d re g ulat or y a ut h orities if 
re q uire d b y l ocal la w. Pr ot oc ol m o dificati o ns t hat affect partici pa nt safet y, t he sc o pe of t he 
i n vesti gati o n, or t he scie ntific q ualit y of t he st u d y m ust be a p pr o ve d b y t he et hics c o m mittee 
bef ore i m ple me ntati o n of s uc h m o dificati o ns t o t he c o n d uct of t he st u d y. If re q uire d b y l ocal 
la w, s uc h m o dificati o ns m ust als o be a p pr o ve d b y t he a p pr o priate re g ulat or y a ge nc y pri or t o 
i m ple me ntati o n.
H o we ver, t he S p o ns or ma y, at a n y ti me, a me n d t his pr ot oc ol t o eli mi nate a n a p pare nt i m me diate 
hazar d t o a partici pa nt. I n t his case, t he a p pr o priate re g ulat or y a ut h orities will be n otifie d 
s u bse q ue nt t o t he m o dificati o n.
I n t he e ve nt of a pr ot oc ol m o dificati o n, t he I C F ma y re q uire si milar m o dificati o ns (see 
Secti o n 1 3. 4 ).
1 3. 4. 
I nf or me d C o nse nt
Pri or t o perf or mi n g a n y st u d y-relate d acti vities 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, i nf or me d c o nse nt wit h t he a p pr o ve d I C F m ust be o btai ne d. 
T he bac k gr o u n d of t he pr o p ose d st u d y, t he pr oce d ures, t he be nefits a n d ris ks of t he st u d y, a n d 
t hat st u d y partici pati o n is v ol u ntar y f or t he partici pa nt m ust be e x plai ne d t o t he partici pa nt a n d/ or 
t he partici pa nt’s le gall y a ut h orize d re prese ntati ve (e. g., le gal g uar dia n), as a p plica ble, i n 
acc or da nce wit h l ocal practice a n d re g ulati o ns. T he partici pa nt a n d/ or t he partici pa nt’s le gall y 
a ut h orize d re prese ntati ve as a p plica ble, i n acc or da nce wit h l ocal practice a n d re g ulati o ns m ust be 
gi ve n s ufficie nt ti me t o c o nsi der w het her t o partici pate i n t he st u d y. 
Se parate i nf or me d c o nse nt t o partici pate i n t he s u bst u dies m ust be gi ve n b y t he partici pa nt a n d/ or 
t he partici pa nt’s le gall y a ut h orize d re prese ntati ve, as a p plica ble, i n acc or da nce wit h l ocal 
practice a n d re g ulati o ns.
I n a d diti o n, partici pa nts w h o ha ve t he ca pacit y s h o ul d pr o vi de t heir asse nt t o partici pate i n t he 
st u d y. T he le vel of i nf or mati o n pr o vi de d t o partici pa nts s h o ul d matc h t heir le vel of 
u n dersta n di n g as deter mi ne d b y t he I n vesti gat or a n d i n acc or da nce wit h a p plica ble re g ulati o ns 
a n d g ui deli nes.
A c o p y of t he si g ne d a n d date d I C F a n d asse nt m ust be gi ve n t o t he partici pa nt a n d/ or t he 
partici pa nt’s le gall y a ut h orize d re prese ntati ve, as a p plica ble, i n acc or da nce wit h l ocal practice 
a n d re g ulati o ns. T he ori gi nal si g ne d a n d date d I C F will be retai ne d wit h t he st u d y rec or ds. L ocal 
re g ulati o ns m ust be c o m plie d wit h i n res pect t o t he fi nal dis p ositi o n of t he ori gi nal a n d c o pies of 
t he si g ne d a n d date d I C Fs.

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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 7
C o nfir mati o n of i nf or me d c o nse nt a n d asse nt m ust als o be d oc u me nte d i n t he partici pa nt’s 
me dical rec or d.
W he n a d diti o nal i nf or mati o n t hat ma y affect partici pa nts’ willi n g ness t o c o nti n ue i n t he st u d y 
bec o mes a vaila ble, t he I n vesti gat ors will be n otifie d i n a ti mel y ma n ner, acc or di n g t o all l ocal 
a n d a p plica ble la w. A n u p date d I C F ma y be re q uire d.
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 
 pr ofile of t he st u d y treat me nt. It is 
u n 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 here 
c o ul d be i nter-racial a n d et h nic differe nces t hat ma y i m pact t he reacti o n or res p o nse t o t he st u d y 
treat me nt, lea di n g t o a differe nt be nefit/ris k bala nce i n t he vari o us racial or et h nic s u b gr o u ps. 
T heref ore, i nf or mati o n o n race a n d et h nicit y ca n pr o vi de rele va nt a n d val ua ble i nf or mati o n f or a 
m ore t h or o u g h e val uati o n of t he safet y pr ofile, t he 
 
, a n d be nefit of t he st u d y treat me nt i n t he tar get p o p ulati o n.
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 e 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 or its part neri n g c o m pa n y) 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 or m ore 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 

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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 8
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.
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 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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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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
Eac h st u d y site will ha ve a mi ni m u m of 2 se parate H C Ps: a tre ati n g H C P a n d a r ati n g H C P.  
1.
A tre ati n g H C P is res p o nsi ble f or t he f oll o wi n g. T he PI or S u b-I n vesti gat or ca n ser ve as 
a treati n g H C P.
•
A d mi nistrati o n of cli nical efficac y assess me nts, wit h t he e xce pti o n of Part III of t he 
M D S- U P D R S a n d 
. T he tre ati n g H C P ma y dele gate certai n 
assess me nts t o be perf or me d b y a p pr o priatel y q ualifie d a n d trai ne d site staff.
•
Ma na ge me nt of r o uti ne ne ur ol o gical care of t he s u bject.
•
Assess me nt (i ncl u di n g assi g n me nt of ca usalit y) a n d treat me nt of A Es.  
•
Re vie w of selecte d he mat ol o g y a n d bl o o d c he mistr y res ults fr o m t he ce ntral 
la b orat or y t o assess if t he s u bject’s st u d y treat me nt s h o ul d be te m p oraril y wit h hel d or 
per ma ne ntl y disc o nti n ue d acc or di n g t o t he criteria detaile d i n A p pe n di x B .
2.
A r ati n g H C P is res p o nsi ble f or a d mi nisteri n g Part III of t he M D S- U P D R S a n d  
 
. T he r ati n g H C P is desi g nate d b y t he PI at eac h st u d y site.
T he r ati n g H C P m ust n ot be i n v ol ve d wit h a n y ot her as pect of partici pa nt care a n d ma na ge me nt 
a n d m ust re mai n bli n de d t o A Es, c o nc o mita nt t hera p y, la b orat or y data, i ma gi n g data, or a n y 
ot her data t hat ha ve t he p ote ntial of re veali n g t he treat me nt assi g n me nt.  PIs ca n n ot ser ve as 
r ati n g H C Ps. Tre ati n g  H C Ps m ust n ot disc uss A Es wit h t he rati n g H C P.
T o e ns ure c o nsiste nc y acr oss sites, t he tre ati n g a n d r ati n g H C Ps m ust c o m plete t he sta n dar dize d 
st u d y-s pecific q ualificati o n pr ocess o n cli nical efficac y assess me nt sc ori n g pri or t o 
a d mi nistrati o n of t he s pecific assess me nt at t heir site. All sites m ust atte m pt t o ha ve t he tre ati n g 
a n d r ati n g H C Ps f or s pecific efficac y assess me nts re mai n c o nsiste nt t hr o u g h o ut t he st u d y. 
Eac h partici pa nt s h o ul d ha ve t he sa me H C P perf or m t he partici pa nts’ s pecific efficac y 
assess me nts t hr o u g h o ut t he st u d y. A q ualifie d bac k- u p H C P s h o ul d o nl y c o n d uct efficac y 
assess me nts i n place of t he pri mar y H C P if e xte n uati n g circ u msta nces res ult i n t he pri mar y H C P 
bei n g u na vaila ble (e. g., d ue t o ill ness, vacati o n, or tra vel) a n d wit h per missi o n fr o m t he S p o ns or. 
Refer t o t he St u d y Refere nce G ui de f or a d diti o nal i nf or mati o n. If a tre ati n g or r ati n g H C P m ust 
be re place d, t he ne w H C P m ust u n der g o t he st u d y-s pecific q ualificati o n pr ocess pri or t o 
a d mi nistrati o n of t he assess me nt.
T he r oles of t he r ati n g H C P a n d tre ati n g H C P are N O T i nterc ha n gea ble at t he partici pa nt le vel. 
If t he r ati n g H C P has a d mi nistere d Part III of t he M D S- U P D R S a n d 
 t o a 
partici pa nt, t he y ma y n ot a d mi nister ot her assess me nts t o t hat partici pa nt at a n y p oi nt d uri n g t he 
st u d y. 

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C O N FI D E N TI A L
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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 e 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, e 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.

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1 5. 4. 
St u d y F u n di n g
Bi o ge n is t he S p o ns or of t he st u d y a n d is f u n di n g 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 Bi o ge 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.

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A P P E N DI X A.
C O N TI N G E N C Y M E A S U R E S T O E N A B L E S T U D Y 
C O N D U C T I N E X C E P TI O N A L CI R C U M S T A N C E S
T his a p pe n di x is i nte n de d f or c o u ntries a n d/ or sites i n ge o gra p hical areas w here a healt h 
e mer ge nc y (e. g., C O VI D- 1 9 pa n de mic) or nat ural disaster has affecte d a st u d y site’s a bilit y t o 
c o n d uct t he st u d y beca use tra vel restricti o ns ha ve bee n i m p ose d or t here is a ris k t o 
partici pa nts/st u d y staff wit h atte n da nce at st u d y sites f or st u d y visits. T he f oll o wi n g secti o ns 
pr o vi de p ote ntial st u d y a da ptati o ns t hat ca n be i ntr o d uce d if partici pa nts are u na ble t o atte n d 
st u d y visits. T hese c o nti n ge nc y meas ures are desi g ne d t o pr o vi de fle xi bilit y a n d mi ni mize 
disr u pti o ns i n t he c o n d uct of t he st u d y.
T he S p o ns or will deter mi ne a p pr o priate c o m me nce me nt a n d e n d date f or eac h c o nti n ge nc y 
meas ure w here t he d urati o n of t he miti gati o ns descri be d i n t his a p pe n di x ma y be gi n at t he o nset 
of site restricti o ns f or a s pecific site a n d/ or c o u ntr y a n d ma y e n d o nce t h ose restricti o ns are lifte d 
a n d i n acc or da nce wit h l ocal la ws a n d re g ulati o ns. T he a da ptati o ns t o t he visits a n d pr oce d ures 
descri be d i n t his a p pe n di x are alter nati o ns or de viati o ns t o t he mai n pr ot oc ol pr oce d ures.
T he c o nti n ge nc y meas ures descri be d i n t his a p pe n di x will be i m ple me nte d o nl y i n e xce pti o nal 
cases a n d after t he site has recei ve d writte n n otificati o n fr o m t he S p o ns or. T he S p o ns or ma y n ot 
nee d t o e m pl o y all meas ures descri be d bel o w ( Secti o n 1 7 ) i n t he e ve nt of s uc h circ u msta nces, 
b ut o nl y t h ose necessar y t o pre ve nt disr u pti o ns i n t he pr o gress of t he st u d y. T he S p o ns or will 
ha ve t he fi nal a ut h orit y t o deci de w hic h miti gati o ns ca n be i m ple me nte d, i n acc or da nce wit h 
l ocal la ws a n d re g ulati o ns.
1 6.  
C O M M U NI C A TI O N O F MI TI G A TI O N I M P L E M E N T A TI O N
1 6. 1. 
I n vesti g at or a n d I nstit uti o n al Re vie w B o ar d N otific ati o n
St u d y m o dificati o ns t hat affect partici pa nt safet y, are a healt h a ut h orit y re q uest, or are s u bsta ntial 
c ha n ges i n st u d y desi g n, e n d p oi nts, a n d/ or pr oce d ures will re q uire a pr ot oc ol a me n d me nt. St u d y 
sites will be res p o nsi ble f or n otif yi n g a n y re q uire d b oar ds or c o m mittees.  
1 6. 2. 
P artici p a nt N otific ati o n/I nf or me d C o nse nt F or m U p d ates
Sites will e ns ure t hat partici pa nts si g n a n I C F t hat i ncl u des all p ote ntial ris k miti gati o n o pti o ns 
n ote d i n t his a p pe n di x pri or t o i m ple me ntati o n. T he I n vesti gat or will be res p o nsi ble f or n otif yi n g 
partici pa nts if/ w he n a n y c o nti n ge nc y meas ures will be i m ple me nte d.

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1 7. 
P O T E N TI A L MI TI G A TI O N S
1 7. 1.  
Virt u al Visits
T he S p o ns or ma y deter mi ne t hat a p plica ble st u d y visits a n d rele va nt st u d y pr oce d ures ca n be 
c o n d ucte d as tele visits.
1 7. 2.  
C h a n ges t o Tre at me nt A d mi nistr ati o n
1 7. 2. 1. 
St u d y Tre at me nt A d mi nistr ati o n vi a Alter n ati ve St u d y Site a n d/ or Pers o n nel
N ot a p plica ble.
1 7. 2. 2.  
H o me Deli ver y of St u d y Tre at me nt
If a partici pa nt is u na ble t o c o me i n f or a n i n-cli nic visit t o o btai n st u d y treat me nt, t he st u d y 
treat me nt ma y be s hi p pe d fr o m t he st u d y site t o t he partici pa nt via a c o urier ser vice, if all o we d 
per c o u ntr y a n d site re g ulati o ns a n d a p pr o ve d b y t he S p o ns or, ma ki n g s ure t o d oc u me nt 
a p pr o priatel y as re q uire d (e. g., p ote ntiall y i n t he P har mac y Ma n ual or Pr ot oc ol De viati o n L o g).
1 7. 3.  
Use of Alter n ati ve Me dic al F acilities
Wit h S p o ns or a p pr o val, st u d y visits ma y be perf or me d at alter nati ve me dical facilities if tra vel t o 
t he st u d y site is n ot feasi ble. Alter nati ve me dical facilities ma y i ncl u de b ut are n ot li mite d t o t he 
partici pa nt’s pri mar y care p h ysicia n, a l ocal cli nic or h os pital, or a m o bile me dical ser vice t hat 
meets t he partici pa nt o utsi de of t he st u d y site. Details o n w hic h visits a n d pr oce d ures are eli gi ble 
t o be perf or me d at alter nati ve me dical facilities will be pr o vi de d b y t he S p o ns or i n writi n g. All 
pr oce d ures perf or me d at alter nati ve me dical facilities will nee d t o be perf or me d as descri be d i n 
t his pr ot oc ol, a n d me dical staff will nee d t o be trai ne d acc or di n gl y.
1 7. 4.  
Re m ote M o nit ori n g
T he Cli nical M o nit or ma y perf or m m o nit ori n g acti vities re m otel y, a n d i n acc or da nce wit h 
S p o ns or g ui deli nes, if o n-site m o nit ori n g is n ot all o we d per l ocal/re gi o nal restricti o ns. 
M o nit ori n g details are d oc u me nte d i n t he Cli nical Site M o nit ori n g Pla n.
1 7. 5.  
M o dific ati o n t o Per missi ble C o nc o mit a nt Me dic ati o ns
T he Gl o bal Safet y Officer ma y perf or m a ris k- be nefit assess me nt f or all o wi n g partici pa nts t o 
recei ve critical me dical treat me nts (e. g., C O VI D- 1 9 vacci nes) d uri n g t he st u d y if s uc h treat me nts 
w o ul d t y picall y n ot be per mitte d b y t he e xcl usi o n criteria or as c o nc o mita nt t hera pies. If t he 
Gl o bal Safet y Officer i de ntifies t he nee d (i.e., p ossi ble effect of t he st u d y dr u g o n t he critical 
me dical treat me nt), a f or mal ris k ma na ge me nt pr ocess ma y be i nitiate d. Wit h S p o ns or a p pr o val, 
a p plica ble st u d y pr oce d ures ma y be m o difie d t o acc o m m o date critical me dical treat me nts.

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1 7. 6.  
Ot her U nf oresee n Miti g ati o ns
A d diti o nal a da pti o ns t o t he st u d y t hat are n ot descri be d a b o ve ma y be re q uire d. T he S p o ns or will 
ha ve t he ri g ht t o a me n d t he meas ures, as necessar y, wit h a p pr o val fr o m t he a p plica ble g o ver ni n g 
b o d y. Decisi o ns will be c o m m u nicate d as n ote d i n t his a p pe n di x.

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Bi o ge n M A I nc.
1 0 2

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1 0 3
 

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I n de pe n de nt D at a M o nit ori n g C o m mittee
A n I D M C will m o nit or acc u m ulati n g partici pa nt safet y data d uri n g t he c o urse of t he st u d y as 
descri be d i n Secti o n 1 4. 3. 2  of t he pr ot oc ol.

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1 0 5
 

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1 0 7

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Bi o ge n M A I nc.
1 0 9
1 8.  
R E F E R E N C E S
Aarsla n d D, Ta n d ber g E, Larse n J P, et al. Fre q ue nc y of de me ntia i n Par ki ns o n disease. Arc h 
Ne ur ol. 1 9 9 6; 5 3( 6): 5 3 8- 4 2.
Ba ptista M A, Da ve K D, Frasier M A, et al. L oss of le uci ne-ric h re peat ki nase 2 ( L R R K 2) i n rats 
lea ds t o pr o gressi ve a b n or mal p he n ot y pes i n peri p heral or ga ns. P L o S O ne. 2 0 1 3; 8( 1 1):e 8 0 7 0 5. 
E p u b 2 0 1 3/ 1 1/ 1 4.
Ba ptista M A S, Merc ha nt K, Barrett T, et al. L R R K 2 i n hi bit ors i n d uce re versi ble c ha n ges i n 
n o n h u ma n pri mate l u n gs wit h o ut meas ura ble p ul m o nar y deficits. Sci Tra nsl Me d. 2 0 2 0; 1 2( 5 4 0).
C hai C, Li m K L. Ge netic i nsi g hts i nt o s p ora dic Par ki ns o n's disease pat h o ge nesis. C urr 
Ge n o mics. 2 0 1 3; 1 4( 8): 4 8 6- 5 0 1.
C o o ks o n M R. L R R K 2 Pat h wa ys Lea di n g t o Ne ur o de ge nerati o n. C urr Ne ur ol Ne ur osci Re p. 
2 0 1 5; 1 5( 7): 4 2.
C o o ks o n M R. Cell ular f u ncti o ns of L R R K 2 i m plicate vesic ular traffic ki n g pat h wa ys i n 
Par ki ns o n's disease. Bi oc he m S oc Tra ns. 2 0 1 6; 4 4( 6): 1 6 0 3- 1 6 1 0.
Dr u g I nteracti o n S ol uti o ns. Dr u g- Dr u g I nteracti o ns. U ni versit y of Was hi n gt o n. P u blis he d 2 0 2 2 
[ Accesse d 0 8 N o v 2 0 2 2]. A vaila ble fr o m: 
htt ps:// w w w. dr u gi nteracti o ns ol uti o ns. or g/l o gi n/?re direct _t o = htt ps % 3a % 2f % 2f di d b. dr u gi nteracti
o ns ol uti o ns. or g % 2f u pl oa ds % 2f d oc u me nts % 2f v-
6 3 8 0 1 5 9 8 3 1 5 0 2 8 3 9 9 9 % 2f DI D B + D DI + Mar ker + St u dies + K n o wle d ge base _ Oct o ber + 2 0 2 2. xls x
F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or I n d ustr y: Dr u g-i n d uce d li ver i nj ur y: pre mar keti n g 
cli nical e val uati o n. 2 0 0 9.
F o o d a n d Dr u g A d mi nistrati o n. Cli nical Dr u g I nteracti o n St u dies - C yt oc hr o me P 4 5 0 E nz y me-
a n d Tra ns p orter- Me diate d Dr u g I nteracti o ns - G ui da nce f or I n d ustr y. 2 0 2 0.
F uji R N, Fla gella M, Baca M, et al. Effect of selecti ve L R R K 2 ki nase i n hi biti o n o n n o n h u ma n 
pri mate l u n g. Sci Tra nsl Me d. 2 0 1 5; 7( 2 7 3): 2 7 3ra 1 5.
Ga n- Or Z, A ms hal o m I, Kilars ki L L, et al. Differe ntial effects of se vere vs mil d G B A m utati o ns 
o n Par ki ns o n disease. Ne ur ol o g y. 2 0 1 5; 8 4( 9): 8 8 0- 7.
Heal y D G, Falc hi M, O' S ulli va n S S, et al. P he n ot y pe, ge n ot y pe, a n d w orl d wi de ge netic 
pe netra nce of L R R K 2-ass ociate d Par ki ns o n's disease: a case-c o ntr ol st u d y. La ncet Ne ur ol. 
2 0 0 8; 7( 7): 5 8 3- 9 0.
Hel y M A, M orris J G, Rei d W G, et al. S y d ne y M ultice nter St u d y of Par ki ns o n's disease: n o n- L-
d o pa-res p o nsi ve pr o ble ms d o mi nate at 1 5 years. M o v Dis or d. 2 0 0 5; 2 0( 2): 1 9 0- 9.

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St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
C O N FI D E N TI A L
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Bi o ge n M A I nc.
1 1 0
He nr y A G, A g ha m o ha m ma dza de h S, Sa mar o o H, et al. Pat h o ge nic L R R K 2 m utati o ns, t hr o u g h 
i ncrease d ki nase acti vit y, pr o d uce e nlar ge d l ys os o mes wit h re d uce d de gra dati ve ca pacit y a n d 
i ncrease A T P 1 3 A 2 e x pressi o n. H u m M ol Ge net. 2 0 1 5; 2 4( 2 1): 6 0 1 3- 2 8. E p u b 2 0 1 5/ 0 8/ 0 6.
Her na n dez D G, Ree d X, Si n glet o n A B. Ge netics i n Par ki ns o n disease: Me n delia n vers us n o n-
Me n delia n i n herita nce. J Ne ur oc he m. 2 0 1 6; 1 3 9 S u p pl 1: 5 9- 7 4. E p u b 2 0 1 6/ 0 4/ 1 8.
Herzi g M C, K oll y C, Pers o h n E, et al. L R R K 2 pr otei n le vels are deter mi ne d b y ki nase f u ncti o n 
a n d are cr ucial f or ki d ne y a n d l u n g h o me ostasis i n mice. H u m M ol Ge net. 2 0 1 1; 2 0( 2 1): 4 2 0 9- 2 3. 
E p u b 2 0 1 1/ 0 8/ 0 9.
Ja mes L P, Letzi g L, Si m ps o n P M, et al. P har mac o ki netics of aceta mi n o p he n- pr otei n a d d ucts i n 
a d ults wit h aceta mi n o p he n o ver d ose a n d ac ute li ver fail ure. Dr u g Meta b Dis p os. 
2 0 0 9; 3 7( 8): 1 7 7 9- 8 4. E p u b 2 0 0 9/ 0 5/ 1 3.
K h o o T K, Yar nall AJ, D u nca n G W, et al. T he s pectr u m of n o n m ot or s y m pt o ms i n earl y 
Par ki ns o n disease. Ne ur ol o g y. 2 0 1 3; 8 0( 3): 2 7 6- 8 1.
K or d o wer J H, Ola n o w C W, D o di ya H B, et al. Disease D urati o n a n d t he I nte grit y of t he 
Ni gr ostriatal S yste m i n Par ki ns o n's Disease. Brai n. 2 0 1 3; 1 3 6( Pt 8): 2 4 1 9- 3 1.
Lill C M, R oe hr J T, Mc Q uee n M B, et al. C o m pre he nsi ve researc h s y n o psis a n d s yste matic meta-
a nal yses i n Par ki ns o n's disease ge netics: T he P D Ge ne data base. P L o S Ge net. 
2 0 1 2; 8( 3):e 1 0 0 2 5 4 8. E p u b 2 0 1 2/ 0 3/ 1 5.
L y o ns K E, Pa h wa R. T he i m pact a n d ma na ge me nt of n o n m ot or s y m pt o ms of Par ki ns o n's 
disease. A m J Ma na g Care. 2 0 1 1; 1 7 S u p pl 1 2: S 3 0 8- 1 4.
Mar der K, Wa n g Y, Alcala y R N, et al. A ge-s pecific pe netra nce of L R R K 2 G 2 0 1 9 S i n t he 
Mic hael J. F o x As h ke nazi Je wis h L R R K 2 C o ns orti u m. Ne ur ol o g y. 2 0 1 5; 8 5( 1): 8 9- 9 5. E p u b 
2 0 1 5/ 0 6/ 1 0.
Melac hr oi n o u K, Ka n g M S, Li o n g C, et al. Ele vate d I n Vitr o Ki nase Acti vit y i n Peri p heral 
Bl o o d M o n o n uclear Cells of Le uci ne- Ric h Re peat Ki nase 2 G 2 0 1 9 S Carriers: A N o vel E nz y me-
Li n ke d I m m u n os or be nt Assa y- Base d Met h o d. M o v Dis or d. 2 0 2 0; 3 5( 1 1): 2 0 9 5- 2 1 0 0. E p u b 
2 0 2 0 0 7 1 1.
Nalls M A, Bla u we n draat C, Valler ga C L, et al. I de ntificati o n of n o vel ris k l oci, ca usal i nsi g hts, 
a n d herita ble ris k f or Par ki ns o n's disease: a meta-a nal ysis of ge n o me- wi de ass ociati o n st u dies. 
La ncet Ne ur ol. 2 0 1 9; 1 8( 1 2): 1 0 9 1- 1 1 0 2.
Nalls M A, Pa n kratz N, Lill C M, et al. Lar ge-scale meta-a nal ysis of ge n o me- wi de ass ociati o n 
data i de ntifies si x ne w ris k l oci f or Par ki ns o n's disease. Nat Ge net. 2 0 1 4; 4 6( 9): 9 8 9- 9 3.
Ness D, Re n Z, Gar dai S, et al. Le uci ne-ric h re peat ki nase 2 ( L R R K 2)- deficie nt rats e x hi bit re nal 
t u b ule i nj ur y a n d pert ur bati o ns i n meta b olic a n d i m m u n ol o gical h o me ostasis. P L o S O ne. 
2 0 1 3; 8( 6):e 6 6 1 6 4. E p u b 2 0 1 3/ 0 6/ 1 4.

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
C O N FI D E N TI A L
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Bi o ge n M A I nc.
1 1 1
P ost u ma R B, Ber g D, Ster n M, et al. M D S cli nical dia g n ostic criteria f or Par ki ns o n's disease. 
M o v Dis or d. 2 0 1 5; 3 0( 1 2): 1 5 9 1- 6 0 1.
Se p pi K, Ra y C ha u d h uri K, C oel h o M, et al. U p date o n treat me nts f or n o n m ot or s y m pt o ms of 
Par ki ns o n's disease-a n e vi de nce- base d me dici ne re vie w. M o v Dis or d. 2 0 1 9; 3 4( 2): 1 8 0- 1 9 8. E p u b 
2 0 1 9/ 0 1/ 1 7.
S he n g Z, Z ha n g S, B ust os D, et al. Ser 1 2 9 2 a ut o p h os p h or ylati o n is a n i n dicat or of L R R K 2 
ki nase acti vit y a n d c o ntri b utes t o t he cell ular effects of P D m utati o ns. Sci Tra nsl Me d. 
2 0 1 2; 4( 1 6 4): 1 6 4ra 1 6 1.
Ste ger M, T o nelli F, It o G, et al. P h os p h o pr ote o mics Re veals t hat Par ki ns o n's Disease Ki nase 
L R R K 2 Re g ulates a S u bset of Ra b G T Pases. Elife. 2 0 1 6; 5 E p u b 2 0 1 6/ 0 1/ 2 9.
Tr u o n g D D, B hi da yasiri R, W olters E. Ma na ge me nt of n o n- m ot or s y m pt o ms i n a d va nce d 
Par ki ns o n disease. J Ne ur ol Sci. 2 0 0 8; 2 6 6( 1- 2): 2 1 6- 2 8. E p u b 2 0 0 7/ 0 9/ 0 4.
Wa n g X, Ne gr o u E, Mal o ne y M T, et al. U n dersta n di n g L R R K 2 ki nase acti vit y i n precli nical 
m o dels a n d h u ma n s u bjects t hr o u g h q ua ntitati ve a nal ysis of L R R K 2 a n d p T 7 3 Ra b 1 0. Sci Re p. 
2 0 2 1; 1 1( 1): 1 2 9 0 0. E p u b 2 0 2 1 0 6 1 8.
West A B, M o ore DJ, C h oi C, et al. Par ki ns o n's disease-ass ociate d m utati o ns i n L R R K 2 li n k 
e n ha nce d G T P- bi n di n g a n d ki nase acti vities t o ne ur o nal t o xicit y. H u m M ol Ge net. 
2 0 0 7; 1 6( 2): 2 2 3- 3 2. E p u b 2 0 0 7/ 0 1/ 0 2.
W hiffi n N, Ar mea n I M, Klei n ma n A, et al. H u ma n l oss- of-f u ncti o n varia nts s u g gest t hat partial 
L R R K 2 i n hi biti o n is a safe t hera pe utic strate g y f or Par ki ns o ns disease. bi o R xi v. 2 0 1 9: 5 6 1 4 7 2.

Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
St u d y of BII B 1 2 2 i n Partici pa nts Wit h L R R K 2- Par ki ns o n’s Disease i n Earl y Sta ge
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1 9. 
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 P hase 3, M ultice nter, Ra n d o mize d, D o u ble- Bli n d, 
Place b o- C o ntr olle d St u d y t o Deter mi ne t he Efficac y a n d Safet y of BII B 1 2 2/ D N L 1 5 1 i n 
Partici pa nts wit h Par ki ns o n’s Disease a n d Pat h o ge nic L R R K 2 Varia nts” 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)

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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 8 3 P D 3 0 2
A P hase 3, M ultice nter, Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d St u d y t o Deter mi ne t he 
Efficac y a n d Safet y of BII B 1 2 2/ D N L 1 5 1 i n Partici pa nts wit h Par ki ns o n’s Disease a n d 
Pat h o ge nic L R R K 2 Varia nts 
Versi o n 2. 0
Date: 0 9 A pril 2 0 2 3
E U D R A C T N u m ber: 2 0 2 2- 0 0 0 7 4 7- 7 7
Versi o n 2. 0 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. 0 
date d 2 1 A pril 2 0 2 2.

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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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 ns f or t his a me n d me nt t o Pr ot oc ol 2 8 3 P D 3 0 2 i ncl u de:
•
A d diti o n of a cate g or y of me dicati o ns t o be use d wit h ca uti o n a n d c orres p o n di n g u p dates 
t o e xcl usi o nar y me dicati o ns a n d disall o we d c o nc o mita nt me dicati o ns
•
A d diti o n of 3 ne w efficac y assess me nts 
 
•
Reclassificati o n of t he 
 as a n i n vesti gati o nal me dical de vice
Secti o n 7. 7. 2, Ca uti o nar y C o nc o mita nt S u bsta nces
N o w re a ds: 
•
C a uti o n s h o ul d be e xercise d f or st u d y p artici p a nts w h o t a ke 
 dr u gs. 
P artici p a nts s h o ul d be m o nit ore d f or c h a n ges i n t oler a bilit y or effic ac y of t his dr u g 
cl ass. P artici p a nts are rec o m me n de d t o st a g ger 
 dr u gs a n d st u d y 
tre at me nt b y at le ast 8 h o urs.
  
•
C a uti o n s h o ul d be e xercise d f or st u d y p artici p a nts w h o t a ke 
 
dr u gs wit h a n arr o w t her a pe utic i n de x. P artici p a nts s h o ul d be m o nit ore d 
f or c h a n ges i n t oler a bilit y or effic ac y of t his dr u g cl ass.
 
•
P artici p a nts s h o ul d refr ai n fr o m e xcessi ve use of alc o h ol d uri n g t he st u d y; n o m ore 
t h a n 2 u nits of alc o h ol at a gi ve n ti me, or > 1 4 u nits per wee k f or m ales a n d > 7 u nits 
per wee k f or fe m ales. O ne u nit of alc o h ol e q u als 1 2 oz ( 3 6 0 m L) beer, 1 ½ oz ( 4 5 m L) 
li q u or, or 5 oz ( 1 5 0 m L) wi ne. 
R ati o n ale : 
•
 were a d de d as ca uti o nar y t o ali g n wit h res ults fr o m i n vitr o a n d 
P B P K m o delli n g st u dies w hic h i n dicate t hat t here c o ul d be a 
 o n 
c o nc o mita nt a d mi nistrati o n of BII B 1 2 2 wit h 
 dr u gs as BII B 1 2 2 c o ul d 
. 
•
T he use of 
 has bee n c ha n ge d fr o m 
e xcl usi o nar y a n d disall o we d c o nc o mita nt t hera p y i n V 1 of t he pr ot oc ol t o ca uti o nar y t o 
ali g n wit h res ults fr o m a rece nt P hase 1 st u d y s h o wi n g BII B 1 2 2 t o be a 
 of 
. 
•
E xcessi ve use of alc o h ol was a d de d as ca uti o nar y base d o n healt h a ut h orit y fee d bac k.
T he c ha n ge ass ociate d wit h 
 als o affects 
Secti o n 6. 2, E xcl usi o n Criteria ( # 2 5); Secti o n 7. 7. 1. 3, Disall o we d C o nc o mita nt T hera p y.
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A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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Secti o n 1 1. 5. 2, De vice A d verse E ve nt a n d A d verse De vice Effect
A de vice A E is a n y u nt o w ar d me dic al occ urre nce, u ni nte n de d dise ase or i nj ur y, or a n y 
u nt o w ar d cli nic al si g ns, i ncl u di n g a n a b n or m al l a b or at or y fi n di n g, i n p artici p a nts, users, 
or ot her pers o ns, i n t he c o nte xt of a cli nic al i n vesti g ati o n, w het her or n ot rel ate d t o t he 
i n vesti g ati o n al de vice.
A n A D E is defi ne d as a n y A E rel ate d t o t he use of a n i n vesti g ati o n al me dic al de vice.
A n y de vice A E or A D E e x perie nce d b y a p artici p a nt after t he first use of t he de vice b y 
p artici p a nt a n d bef ore st u d y c o m pleti o n or pre m at ure st u d y wit h dr a w al is t o be rec or de d 
o n t he A E e C R F.
Secti o n 1 1. 5. 3, De vice Seri o us A d verse E ve nt a n d U n a ntici p ate d A d verse De vice Effect
A de vice S A E me a ns a n y A E t h at le d t o a n y of t he f oll o wi n g:
•
De at h
•
Seri o us deteri or ati o n i n t he he alt h of t he p artici p a nts t h at res ulte d i n a n y of t he 
f oll o wi n g:
o
Life-t hre ate ni n g ill ness or i nj ur y
o
Per m a ne nt i m p air me nt of a b o d y str uct ure or a b o d y f u ncti o n
o
H os pit aliz ati o n or pr ol o n g ati o n of p atie nt h os pit aliz ati o n
o
Me dic al or s ur gic al i nter ve nti o n t o pre ve nt life-t hre ate ni n g ill ness or i nj ur y 
or per m a ne nt i m p air me nt t o a b o d y str uct ure or a b o d y f u ncti o n
o
C hr o nic dise ase
•
Fet al distress, fet al de at h, or a c o n ge nit al p h ysic al or me nt al i m p air me nt or birt h 
defect
A U A D E is defi ne d as a n y seri o us a d verse effect o n he alt h or s afet y or a n y life-t hre ate ni n g 
pr o ble m or de at h c a use d b y or ass oci ate d wit h a de vice, if t h at effect, pr o ble m, or de at h 
w as n ot pre vi o usl y i de ntifie d i n n at ure, se verit y, or de gree of i nci de nce i n t he 
i n vesti g ati o n al pl a n or a p plic ati o n, or a n y ot her u n a ntici p ate d seri o us pr o ble m ass oci ate d 
wit h a de vice t h at rel ates t o t he ri g hts, s afet y, or welf are of p artici p a nts.
T he criteri a f or seri o us ness i ncl u de t he f oll o wi n g:
•
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n
•
C a uses dis a bilit y or per m a ne nt d a m a ge
•
Res ults i n persiste nt or si g nific a nt dis a bilit y/i nc a p acit y
•
Re q uires i nter ve nti o n t o pre ve nt per m a ne nt i m p air me nt/ d a m a ge
•
Res ults i n c o n ge nit al a n o m al y/ birt h defect

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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Bi o ge n M A I nc.
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•
Is a n y ot her me dic all y i m p ort a nt e ve nt t h at, i n t he o pi ni o n of t he I n vesti g at or, m a y 
je o p ar dize t he p artici p a nt or m a 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
A n y de vice S A E or U A D E e x perie nce d b y a p artici p a nt after t he first use of t he de vice b y 
p artici p a nt a n d bef ore st u d y c o m pleti o n or pre m at ure st u d y wit h dr a w al is t o be rec or de d 
o n t he A E e C R F a n d o n a Cli nic al Tri al De vice Re p orti n g F or m wit hi n 2 4 h o urs of 
a w are ness of t he e ve nt. A d diti o n all y, i n t he U S, t he st u d y site m ust f or m all y n otif y t he I R B 
of U A D Es wit hi n 1 0 w or ki n g d a ys of site a w are ness of t he e ve nt.
P artici p a nts will be f oll o we d f or t hese e ve nts u ntil st u d y c o m pleti o n or pre m at ure st u d y 
wit h dr a w al. A n y e ve nt t h at is o n g oi n g w he n t he p artici p a nt c o m pletes or disc o nti n ues t he 
st u d y will be f oll o we d b y t he I n vesti g at or u ntil t he e ve nt h as res ol ve d, st a bilize d, or 
ret ur ne d t o b aseli ne st at us.
Secti o n 1 1. 5. 4, Rel ati o ns hi p of E ve nts a n d Effects t o St u d y De vices
T he f oll o wi n g s h o ul d be c o nsi dere d w he n e v al u ati n g if a n effect or de vice deficie nc y is 
c a use d b y or ass oci ate d wit h 
•
A n e ve nt h as a te m p or al rel ati o ns hi p wit h i n vesti g ati o n al de vice use/ a p plic ati o n or 
pr oce d ures
•
A n e ve nt i n v ol ves a b o d y site or or g a n t h at:
o
T he i n vesti g ati o n al de vice or pr oce d ures are a p plie d t o
o
T he i n vesti g ati o n al de vice or pr oce d ures h a ve a n effect o n
•
A seri o us e ve nt f oll o ws a k n o w n res p o nse p atter n t o t he me dic al de vice (if t he 
res p o nse p atter n is pre vi o usl y k n o w n)
•
Disc o nti n u ati o n of me dic al de vice a p plic ati o n ( or a re d ucti o n i n t he le vel of 
acti v ati o n/e x p os ure) a n d rei ntr o d ucti o n of its use ( or a n i ncre ase i n t he le vel of 
acti v ati o n/e x p os ure) a n d i m p act o n t he seri o us e ve nt ( w he n cli nic all y fe asi ble)
•
Ot her p ossi ble c a uses (e. g., a n u n derl yi n g or c o nc urre nt ill ness/cli nic al c o n diti o n 
or/ a n d a n effect of a n ot her de vice, dr u g, or tre at me nt) h a ve bee n a de q u atel y r ule d 
o ut
•
H ar m t o t he p artici p a nt is d ue t o err or i n use
I n or der t o est a blis h t he rel ate d ness, n ot all t he criteri a liste d a b o ve mi g ht be met at t he 
s a me ti me, de pe n di n g o n t he t y pe of de vice/ pr oce d ures a n d t he seri o us effect.
Secti o n 1 1. 5. 5, Se verit y of De vice E ve nts a n d Effects
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 v al u ati n g t he se verit y of U A D Es, 
de vice A Es, a n d de vice S A Es:

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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Se verit y of E ve nt
Mil d 
S y m pt o ms b arel y n otice a ble t o p artici p a nt or d o n ot m a ke p artici p a nt 
u nc o mf ort a ble; d o n ot i nfl ue nce perf or m a nce or f u ncti o ni n g; prescri pti o n 
dr u g n ot or di n aril y nee de d f or relief of s y m pt o ms.
M o der ate 
S y m pt o ms of a s ufficie nt se verit y t o m a ke p artici p a nt u nc o mf ort a ble; 
perf or m a nce of d ail y acti vit y is i nfl ue nce d; p artici p a nt is a ble t o c o nti n ue i n 
st u d y; tre at me nt f or s y m pt o ms m a y be nee de d.
Se vere 
S y m pt o ms c a use se vere disc o mf ort; s y m pt o ms c a use i nc a p acit ati o n or 
si g nific a nt i m p act o n p artici p a nt’s d ail y life; se verit y m a y c a use cess ati o n of 
tre at me nt wit h st u d y tre at me nt; tre at me nt f or s y m pt o ms m a y be gi ve n 
a n d/ or p artici p a nt h os pit alize d.
Secti o n 1 1. 5. 6, E x pecte d ness of De vice E ve nts a n d Effects
Refer t o t he  
 I n vesti g at or’s Br oc h ure f or i nf or m ati o n o n a n y 
e x pecte d/ a ntici p ate d de vice A Es or A D Es ass oci ate d wit h t he use of  
.
R ati o n ale: T he classificati o n of t he  
a p plicati o n i n V 2 of t he pr ot oc ol was c ha n ge d t o 
i n vesti gati o nal me dical de vice. T his classificati o n re q uire d a d diti o n of safet y re p orti n g s pecific 
t o de vices. 
T his c ha n ge als o affects Secti o n 1. 3 ( Ta ble 1), Sc he d ule of Acti vities; Secti o n 1 1, Safet y 
Defi niti o ns, Rec or di n g, Re p orti n g, a n d Res p o nsi bilities; Secti o n 1 1. 7. 1, T he I n vesti gat or; a n d 
Secti o n 1 1. 7. 2, T he S p o ns or.

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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
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: 
•
St u d y dr u g dis pe nsati o n was a d de d t o Ta ble 1.
•
F o ot n otes f or Ta ble 1 were u p date d.

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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
N o w re a ds:
 
Pl ace b o C o ntr olle d, D o u ble- Bli n d Tre at me nt Peri o d
Visit
Scree ni n g 2
B aseli ne 3
E O T/ E T 4
S F U
Visit N u m ber
1
2
3
4
5
6
7
8
9
1 0
1 1
1 2
1 3
1 4
1 5
1 6
1 7
1 8
1 9
2 0
2 1
2 2
2 3
U V 1
 
St u d y Dr u g 
Dis pe ns ati o n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
R ati o n ale:  St u d y dr u g dis pe nsati o n was a d de d t o clarif y w he n sites are t o access I R T t o dis pe nse ne w I P kits a n d t o s h o w w he n I P is 
n ot t o be dis pe nse d at safet y c o h ort visits.

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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
C h a n ge:  A mi n or re visi o n was ma de t o t he te xt descri bi n g t he ti mi n g of t he safet y data re vie w 
c o n d ucte d b y t he I D M C f or t he Safet y C o h ort.
N o w re a ds: 
A p pr o xi m atel y  
 t wel ve wee ks after t he  
 partici pa nt is ra n d o mize d a n d d ose d, a de dicate d 
safet y data re vie w f or t his c o h ort will be c o n d ucte d b y t he I D M C t o e val uate t he a p pr o priate ness 
of t he pr ot oc ol safet y m o nit ori n g pr oce d ures.
R ati o n ale: T o clarif y t he ti mi n g of t he safet y data re vie w.
Secti o n 6. 2, E xcl usi o n Criteria
C h a n ge:  
•
P F T re peate d testi n g has bee n re m o ve d ( E C # 1 0). 
•
A be nz o diaze pi ne- p ositi ve dr u g test will n ot be e xcl usi o nar y t o st u d y partici pati o n ( E C 
# 2 1).
•
T he list of
 
 was m o difie d ( E C # 2 4). 
•
E xcl usi o nar y me dicati o ns were u p date d t o ali g n wit h t he Disall o we d Me dicati o ns ( E C 
# 2 8). 
N o w re a ds:  
1 0.  
A b n or mal P F T res ults at t he Scree ni n g Visit, defi ne d as a n y of t he f oll o wi n g (t he best 
val ue a m o n g t he acce pta ble tri plicate meas ures of F V C a n d F E V 1 a n d d u plicate meas ures of 
he m o gl o bi n-a dj uste d D L C O ); if P F T val ues are o ut of ra n ge, testi n g ma y be re peate d o nce d uri n g 
t he Scree ni n g peri o d ≥ 5 da ys pri or t o Baseli ne):
R ati o n ale:  T he delete d te xt was a d de d t o Secti o n 6. 3. 2 s o t hat all retesti n g i nf or mati o n is i n t he 
sa me secti o n of t he pr ot oc ol. 
T his c ha n ge als o affects Secti o n 6. 3. 2, Retesti n g.
---------------------------------------------------------------------------------------------------------------------
2 1.  
Hist or y of dr u g or alc o h ol a b use wit hi n t he past 5 years (as defi ne d b y t he I n vesti gat or), a 
p ositi ve uri ne dr u g test at Scree ni n g or St u d y Da y 1 ( e xce pti o n : p artici p a nts w h o test p ositi ve 
f or be nz o di aze pi nes m a y be i ncl u de d i n t he st u d y, at t he discreti o n of t he I n vesti g at or), or 
a n u n willi n g ness t o a bstai n fr o m t hese s u bsta nces d uri n g i n-cli nic visit da ys. Partici pa nts w h o 
test p ositi ve f or ca n na bi n oi ds d ue t o occasi o nal marij ua na use, as deter mi ne d b y t he I n vesti gat or, 
a n d w h o a gree t o refrai n fr o m usi n g marij ua na f or t he d urati o n of t he st u d y ma y be e nr olle d at 
I n vesti gat or’s discreti o n, after a c o ns ultati o n wit h t he S p o ns or. T he use of ca n na bi n oi ds ot her 
t ha n marij ua na (e. g., ca n na bi n oi d crea m or gel) is acce pta ble, u nless t he use is c o nsi dere d t o be 
dr u g a b use b y t he I n vesti gat or, w hic h is e xcl usi o nar y.
R ati o n ale:  A n u p date was ma de t o gr o u p eli gi bilit y la b assess me nts t o t he Scree ni n g visit. A 
c ha n ge was als o ma de t o clarif y t hat partici pa nts w h o test p ositi ve f or be nz o diaze pi nes at 
Scree ni n g ma y be eli gi ble f or t he st u d y 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 8 3 P D 3 0 2 Versi o n 2. 0
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
 
 

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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
R ati o n ale:   T he u p dates were ma de f or clarificati o n a n d t o ali g n wit h F D A g ui da nce o n 
dr u g-i n d uce d li ver i nj ur y. 
C h a n ge:  
 was m o difie d.
N o w re a ds:
( T he 2 ta bles bel o w ha ve bee n delete d a n d re place d wit h Ta ble 6 a n d Ta ble 7.)

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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
C h a n ge:  A ne w a p pe n di x was a d de d.
 N o w re a ds:
Rati o nale:  
 was a d de d t o pr o vi de partial lists of c o nc o mita nt me dicati o ns t hat s h o ul d 
be use d wit h ca uti o n wit h BII B 1 2 2, i ncl u di n g 
 a n d 
 
wit h a narr o w t hera pe utic i n de x.  

A me n d me nt S u m mar y f or Pr ot oc ol 2 8 3 P D 3 0 2 Versi o n 2. 0
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
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.
•
Secti o n 2, List of A b bre viati o ns, was u p date d.
•
I n Secti o n 1. 3, Ta ble 1 ( Sc he d ule of Acti vities) rescree ni n g i nf or mati o n was delete d 
fr o m f o ot n ote 2 as t here is a detaile d descri pti o n a vaila ble i n Secti o n 6. 3. 3 ( Scree n 
Fail ures) a n d mi n or re w or di n g was a p plie d t o f o ot n ote 1 3. 
•
Clarif yi n g te xt was a d de d i n 
 
•
T y p o gra p hical err ors a n d f or matti n g were c orrecte d.