Conditions: Parkinson Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
In this study, researchers will learn more about a study drug called BIIB122 in participants with early-stage Parkinson's disease (PD). The study will focus on participants with a specific genetic variant in their LRRK2 gene.

The main question researchers are trying to answer is if taking BIIB122 slows the worsening of PD more than placebo in the early stages of PD.

To help answer this question, researchers will use a questionnaire called the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, also known as the MDS-UPDRS.

* The MDS-UPDRS measures impairment and disability in people living with PD. It was created in the 1980s and is one of the most used rating scales for PD symptoms.
* The MDS-UPDRS has 4 parts, and a higher score means more severe PD symptoms.
* Part I assesses non-motor experiences of daily living, including but not limited to memory loss, problems sleeping, pain, depression, and anxiety.
* Part II measures motor experiences of daily living.
* Part III is the results of a motor symptoms exam by a medical professional.
* Part IV records PD complications caused by motor symptoms.

Researchers will also learn more about the safety of BIIB122.

A description of how the study will be done is given below.

* Participants will take BIIB122 or a placebo as tablets by mouth. A placebo looks like the study drug but contains no real medicine.
* Participants will be in the study for 103 weeks to 187 weeks. This includes the screening and follow-up periods.
* Participants will take BIIB122 or placebo 1 time a day for 96 to 180 weeks.
* Participants can continue to take certain medications for PD. Participants must be on the same dose of medication for at least 90 days before the study begins.
* Participants will visit the clinic less often as the study continues, ranging every 4 weeks to every 24 weeks.

Detailed description:
BIIB122 is an investigational central nervous system-penetrant small molecule inhibitor of LRRK2 kinase

Arms:
arm 1: Participants will receive 225 mg of BIIB122 tablets, orally, once daily (QD) for up to 180 weeks. arm 2: Participants will receive BIIB122-matching placebo tablets, orally, QD for up to 180 weeks.

Interventions: intervention 1: BIIB122 intervention 2: BIIB122-Matching Placebo
Intervention descriptions: intervention 1: Administered as specified in the treatment arm. intervention 2: Administered as specified in the treatment arm.

Protocol document:
Prot_SAP_000.pdf: 
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
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Bi o ge n M A I nc.
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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
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
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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 
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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


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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


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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


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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


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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


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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


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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
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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
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Viral Ser ol o g y
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F S H 7
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Ser u m Pre g na nc y 
Test 8 
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Uri ne Pre g na nc y 
Test 8
 
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 X
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X
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Ge netic Testi n g 9
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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
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X
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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
 
 
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X
 
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X
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X
X
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m S E- A D L
 
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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.
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 


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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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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):
•




Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
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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.
4 7
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.








Pr ot oc ol 2 8 3 P D 3 0 2, Versi o n 2. 0
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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.
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 


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 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 




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 8
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.




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.
6 0
•
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 
Bi o ge n M A I nc.
6 6
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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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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•
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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C O N FI D E N TI A L
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Bi o ge n M A I nc.
6 8
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.


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.
6 9
•
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 .










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 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.


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 
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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 


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.
7 6
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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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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C O N FI D E N TI A L
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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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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.


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 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
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 1 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
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
1 1 2
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.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
I n vesti gat or’s Si g nat ure
Date
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I n vesti gat or’s Na me ( Pri nt)
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St u d y Site ( Pri nt)


C O N FI D E N TI A L
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Bi o ge n M A I nc.
1
Bi o ge n M A I nc.
2 2 5 Bi n ne y Street
Ca m bri d ge, M A 0 2 1 4 2
U nite d States
Bi o ge n I dec Researc h Li mite d
I n n o vati o n H o use
7 0 N or de n R oa d
Mai de n hea d, Ber ks hire
S L 6 4 A Y
U nite d Ki n g d o m
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A M E N D M E N T S U M M A R Y
Bi o ge n Pr ot oc ol 2 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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Bi o ge n M A I nc.
2
P RI M A R Y R E A S O N F O R A M E N D M E N T
T he pri mar y reas o 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
C O N FI D E N TI A L
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Bi o ge n M A I nc.
4
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
C O N FI D E N TI A L
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Bi o ge n M A I nc.
5
•
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
C O N FI D E N TI A L
T he i nf or mati o n c o ntai ne d herei n ma y n ot be use d, discl ose d, or p u blis he d wit h o ut t he writte n c o nse nt of 
Bi o ge n M A I nc.
6
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.