Conditions: Cognitive Dysfunction Alzheimer's Disease
Keywords: Aducanumab BIIB037
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
The primary objective of the study is to assess the safety impact of continuing aducanumab dosing in asymptomatic Amyloid-related Imaging Abnormalities (ARIA) in participants with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or with mild AD dementia. The secondary objective of the study is to characterize ARIA, from both the imaging and the clinical perspective and to characterize the safety, tolerability, pharmacokinetics (PK), and immunogenicity of aducanumab.

Detailed description:

Arms:
arm 1: Aducanumab, intravenous infusion, every 4 weeks for up to Week 52 during the randomized treatment period. The dose will be titrated to a desirable dose. Participants will be managed for drug continuation and suspension. Following a 4-week follow-up period, eligible participants will continue to receive aducanumab, intravenous infusion, every 4 weeks for an additional 104 weeks in the long-term extension period. arm 2: Aducanumab, intravenous infusion, every 4 weeks for up to Week 52 during the randomized treatment period. The dose will be titrated to a desirable dose. Participants will be managed for drug continuation and suspension. Following a 4-week follow-up period, eligible participants will continue to receive aducanumab, intravenous infusion, every 4 weeks for an additional 104 weeks in the long-term extension period.

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

Protocol document:
Prot_000.pdf: 




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C O N FI D E N TI A L
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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 SI G N A T U R E P A G E .................................................................................................... 2
1.        
S Y N O P SI S ................................................................................................................... 9
2.        
LI S T O F A B B R E VI A TI O N S ..................................................................................... 1 4
3.        
S P O N S O R I N F O R M A TI O N ..................................................................................... 1 6
4.        
I NT R O D U C TI O N ...................................................................................................... 1 7
4. 1.        
O ver vie w of Alz hei mer’s Disease .............................................................................. 1 7
4. 2.        
C urre nt T hera pies f or Alz hei mer’s Disease ...............................................................1 7
4. 3.        
Pr ofile of Pre vi o us E x perie nce Wit h A d uca n u ma b .................................................... 1 9
4. 3. 1.       
N o ncli nical E x perie nce ...............................................................................................1 9
4. 3. 2.       
Cli nical E x perie nce..................................................................................................... 1 9
4. 3. 2. 1.    
A RI A i n t he A d uca n u ma b Cli nical De vel o p me nt Pr o gra m ....................................... 2 0
4. 4.        
St u d y  Rati o nale........................................................................................................... 2 2
5.        
S C H E D U L E O F A C TI VI TI E S .................................................................................. 2 4
6.        
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 4
7.        
S T U D Y D E SI G N ....................................................................................................... 3 6
7. 1.        
St u d y  D urati o n f or S u bjects........................................................................................ 3 9
7. 2.        
Res p o nsi bilities of Site Pers o n nel .............................................................................. 4 0
7. 2. 1.       
Healt h Care Pr ofessi o nals ........................................................................................... 4 0
7. 2. 2.       
Ot her Site Pers o n nel ................................................................................................... 4 2
7. 3.        
St u d y  St o p pi n g R ules ................................................................................................. 4 3
7. 4.        
E n d of St u d y ............................................................................................................... 4 3
8.        
S E L E C TI O N O F S U BJ E C T S.................................................................................... 4 4
8. 1.        
I ncl usi o n Criteria f or Ra n d o mize d Treat me nt Peri o d ................................................ 4 4
8. 2.        
E xcl usi o n Criteria f or t he Ra n d o mize d Treat me nt Peri o d .........................................4 5
8. 3.        
I ncl usi o n Criteria f or t he L o n g -Ter m E xte nsi o n Peri o d .............................................4 9
8. 4.        
E xcl usi o n Criteria f or t he L o n g -Ter m E xte nsi o n Peri o d ............................................ 5 0
9.        
S C R E E NI N G A N D R A N D O M I Z A TI O N ................................................................. 5 1
9. 1.        
Scree ni n g ....................................................................................................................5 1
9. 1. 1.       
Scree n Fail ures ............................................................................................................5 1
9. 1. 2.       
Rescree ni n g .................................................................................................................5 2
9. 2.        
Ra n d o mizati o n ............................................................................................................5 2


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Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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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9. 3.        
Bli n di n g Pr oce d ures .................................................................................................... 5 2
9. 4.        
A RI A/ M RI I nf or mati o n ..............................................................................................5 3
9. 5.        
A p o E ε 4 Carrier Stat us............................................................................................... 5 3
1 0.        
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 W I T H D R A W A L 
O F S U BJ E C T S F R O M T H E S T U D Y ........................................................................ 5 4
1 0. 1.        
Disc o nti n uati o n of St u d y Treat me nt ........................................................................... 5 4
1 0. 2.        
L ost t o F oll o w -U p ....................................................................................................... 5 5
1 0. 3.        
Wit h dra wal of S u bjects Fr o m St u d y ........................................................................... 5 5
1 1.        
S T U D Y T R E A T M E N T U S E ..................................................................................... 5 7
1 1. 1.        
Re gi me n ...................................................................................................................... 5 7
1 1. 1. 1.     
A d uca n u ma b ............................................................................................................... 5 7
1 1. 1. 2.     
Place b o ........................................................................................................................ 5 7
1 1. 2.        
M o dificati o n of D ose a n d/ or Treat me nt Sc he d ule ...................................................... 5 7
1 1. 2. 1.     
C o nti n uati o n, S us pe nsi o n, or Disc o nti n uati o n f or A RI A E ve nts D uri n g t he 
Ra n d o mize d Treat me nt Peri o d ................................................................................... 5 7
1 1. 2. 1. 1.  
A RI A -E Cases ............................................................................................................ 5 8
1 1. 2. 1. 2.  
A RI A - H ( Micr o he m orr ha ge or S u perficial Si der osis) Cases..................................... 6 0
1 1. 2. 1. 3.  
Macr o he m orr ha ge ....................................................................................................... 6 2
1 1. 2. 1. 4.  
C oi nci de nt A RI A -E a n d A RI A- H Cases .................................................................... 6 2
1 1. 2. 2.     
C o nti n uati o n, S us pe nsi o n, or Disc o nti n uati o n f or A RI A E ve nts D uri n g t he 
L o n g -Ter m E xte nsi o n Peri o d ..................................................................................... 6 2
1 1. 2. 3.     
D osi n g i n S u bjects C o nti n ui n g o n A d uca n u ma b D uri n g a n A RI A E ve nt a n d 
i n S u bjects Res u mi n g A d uca n u ma b After D ose S us pe nsi o n d ue t o A RI A................ 6 3
1 1. 2. 4.     
M RI  M o nit ori n g After Res ol uti o n of A RIA i n S u bjects C o nti n ui n g or 
Res u mi n g D osi n g ........................................................................................................ 6 3
1 1. 2. 5.     
I nf usi o n I nterr u pti o n................................................................................................... 6 3
1 1. 3.        
Preca uti o ns ..................................................................................................................6 4
1 1. 4.        
C o m plia nce ................................................................................................................. 6 4
1 1. 5.        
C o nc o mita nt T hera p y a n d Pr oce d ures ........................................................................6 4
1 1. 6.        
C o nti n uati o n of Treat me nt .......................................................................................... 6 5
1 2.        
S T U D Y T R E A T M E N T M A N A G E M E N T ................................................................ 6 6
1 2. 1.        
A d uca n u ma b ............................................................................................................... 6 6
1 2. 1. 1.     
A d uca n u ma b Pre parati o n................................ ............................................................6 6
1 2. 1. 2.     
A d uca n u ma b St ora ge ..................................................................................................6 7


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C O N FI D E N TI A L
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1 2. 1. 3.      
A d uca n u ma b Ha n dli n g a n d Dis p osal......................................................................... 6 7
1 2. 1. 4.     
A d uca n u ma b Acc o u nta bilit y ...................................................................................... 6 7
1 2. 2.        
Place b o ........................................................................................................................ 6 7
1 2. 3.        
Ot her Pr ot oc ol -Desi g nate d Pr o d uct ............................................................................ 6 7
1 3.        
E F FI C A C Y, P H A R M A C O KI N E TI C, A N D O T H E R A S S E S S M E N T S ................... 6 9
1 3. 1.        
Efficac y  Assess me nts ................................................................................................. 6 9
1 3. 2.        
P har mac o ki netic Assess me nts .................................................................................... 6 9
6 9
1 3. 4.        
P har mac o ge netics a n d Ge netic Assess me nts ..............................................................6 9
1 3. 4. 1.     
A p o E Ge n ot y pi n g ....................................................................................................... 6 9
6 9
7 0
1 3. 6.        
Ot her Assess me nts ...................................................................................................... 7 0
1 4.        
S A F E T Y A S S E S S M E N T S ........................................................................................ 7 2
1 4. 1.        
Cli nical Safet y  Assess me nts....................................................................................... 7 2
1 4. 2.        
La b orat or y  Safet y Assess me nts .................................................................................. 7 2
1 4. 3.        
I m m u n o ge nicity Assess me nts .................................................................................... 7 3
1 5.        
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 T I E S ................................................................................................. 7 4
1 5. 1.        
Defi niti o ns.................................................................................................................. 7 4
1 5. 1. 1.     
A d verse E ve nt ............................................................................................................. 7 4
1 5. 1. 2.     
Seri o us A d verse E ve nt ................................................................................................ 7 4
1 5. 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................ 7 5
1 5. 2.        
Safet y  Classificati o ns.................................................................................................. 7 5
1 5. 2. 1.     
I n vesti gat or Assess me nt of E ve nts ............................................................................. 7 5
1 5. 2. 2.     
Relati o ns hi p of E ve nts t o St u d y  Treat me nt................................................................7 5
1 5. 2. 3.     
Se verit y  of E ve nts.......................................................................................................7 6
1 5. 2. 4.     
E x pecte d ness of E ve nts ..............................................................................................7 6
1 5. 3.        
M o nit ori n g a n d Rec or di n g E ve nts .............................................................................. 7 6
1 5. 3. 1.     
A d verse E ve nts ...........................................................................................................7 6
1 5. 3. 2.     
A d verse E ve nts of S pecial I nterest ............................................................................. 7 7
1 5. 3. 3.     
Seri o us A d verse E ve nts ..............................................................................................7 7


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
C O N FI D E N TI A L
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1 5. 3. 4.    
I m me diate Re p orti n g of Seri o us A d verse E ve nts....................................................... 7 7
1 5. 3. 4. 1.  
Deat hs ......................................................................................................................... 7 8
1 5. 3. 5.     
S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns.................................................... 7 8
1 5. 4.        
Pr oce d ures f or Ha n dli n g S pecial Sit uati o ns ...............................................................7 8
1 5. 4. 1.     
Pre g na nc y ................................................................................................................... 7 8
1 5. 4. 2.     
O ver d ose ..................................................................................................................... 7 9
1 5. 4. 3.     
Me dical E mer ge nc y .................................................................................................... 7 9
1 5. 4. 3. 1.  
U n bli n di n g f or Me dical E mer ge nc y ........................................................................... 7 9
1 5. 5.        
C o ntrace pt i o n Re q uire me nts ...................................................................................... 7 9
1 5. 6.        
Safet y  Res p o nsi bilities................................................................................................ 8 1
1 5. 6. 1.     
T he I n vesti gat or .......................................................................................................... 8 1
1 5. 6. 2.     
Bi o ge n ......................................................................................................................... 8 1
1 6.        
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 2
1 6. 2.        
Pri mar y  a n d Sec o n dar y E n d p oi nt A nal ysis ................................................................ 8 2
1 6. 2. 1.     
A nal y sis P o p ulati o n .................................................................................................... 8 2
1 6. 2. 2.     
Met h o d of A nal ys is..................................................................................................... 8 2
1 6. 2. 2. 1.  
A nal y sis of t he Pri mar y E n d p oi nt............................................................................... 8 2
1 6. 2. 2. 2.  
A nal y sis of t he Sec o n dar y E n d p oi nts......................................................................... 8 2
1 6. 3.        
P har mac o ki netics ........................................................................................................ 8 3
1 6. 3. 1.     
A nal y sis P o p ulati o n .................................................................................................... 8 3
1 6. 3. 2.     
Met h o d of A nal ys is..................................................................................................... 8 3
1 6. 4.        
Safet y .......................................................................................................................... 8 3
1 6. 4. 1.     
A nal y sis P o p ulati o n .................................................................................................... 8 3
1 6. 4. 2.     
Met h o ds of A nal y sis ...................................................................................................8 3
1 6. 4. 2. 1.  
A d verse E ve nts ...........................................................................................................8 3
1 6. 4. 2. 2.  
Cli nical L a b orat or y Res ults........................................................................................8 3
1 6. 4. 2. 3.  
Vital Si g ns a n d E C Gs .................................................................................................8 4
1 6. 4. 2. 4.  
C ol u m bia S uici de Se verit y  Rati n g Scale.................................................................... 8 4
1 6. 5.        
I m m u n o ge nicity Data .................................................................................................8 4
1 6. 5. 1.     
A nal y sis P o p ulati o n ....................................................................................................8 4
1 6. 5. 2.     
Met h o ds of A nal ys is...................................................................................................8 4
1 6. 6.        
I nteri m A nalys es .........................................................................................................8 4


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Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
C O N FI D E N TI A L
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1 6. 7.       
Sa m ple Size C o nsi derati o ns ....................................................................................... 8 4
1 7.        
E T HI C A L  R E Q UI R E M E N T S ................................................................................... 8 6
1 7. 1.        
Declarati o n of Helsi n ki ...............................................................................................8 6
1 7. 2.        
Et hics C o m mittee ........................................................................................................ 8 6
1 7. 3.        
S u bject I nf or mati o n a n d C o nse nt ............................................................................... 8 7
1 7. 4.        
S u bject Data Pr otecti o n ..............................................................................................8 7
1 7. 5.        
C o m pe nsati o n f or I nj ur y............................................................................................. 8 8
1 7. 6.        
C o nflict of I nterest ...................................................................................................... 8 8
1 7. 7.        
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 8.        
A D MI NI S T R A TI V E P R O C E D U R E S ....................................................................... 8 9
1 8. 1.        
St u d y  Site I nitiati o n.................................................................................................... 8 9
1 8. 2.        
Q ualit y  C o ntr ol a n d Q ualit y Ass ura nce...................................................................... 8 9
1 8. 3.        
M o nit ori n g of t he St u d y ..............................................................................................8 9
1 8. 4.        
St u d y  F u ndi n g ............................................................................................................. 9 0
1 8. 5.        
P u blicati o ns ................................................................................................................. 9 0
1 9.        
F U R T H E R R E Q UI R E M E N T S A N D G E N E R A L I N F O R M A T I O N........................ 9 1
1 9. 1.        
E xter nal C o ntract Or ga nizati o ns ................................................................................. 9 1
1 9. 1. 1.     
C o ntract Researc h Or ga nizati o n ................................................................................. 9 1
1 9. 1. 2.     
I nteracti ve Res p o nse Tec h n ol o g y............................................................................... 9 1
1 9. 1. 3.     
Electr o nic Data Ca pt ure ..............................................................................................9 1
1 9. 1. 4.     
Ce ntral La b orat ories f or La b orat or y  Assess me nts ..................................................... 9 1
1 9. 1. 5.     
Ce ntral Facilit y  f or Ot her Assess me nts...................................................................... 9 1
1 9. 2.        
St u d y  C o m mittees....................................................................................................... 9 2
1 9. 2. 1.     
A dj u dicati o n C o m mittee .............................................................................................9 2
1 9. 2. 2.     
Data Safet y M o nit ori n g C o m mittee ............................................................................9 2
1 9. 3.        
C ha n ges t o Fi nal St u d y  Pr ot oc ol ................................................................................9 2
1 9. 4.        
Et hics C o m mittee N otificati o n of St u d y  C o m pleti o n or Ter mi nati o n........................9 3
1 9. 5.        
Rete nti o n of St u d y  Data..............................................................................................9 3
1 9. 6.        
St u d y  Re p ort Si g nat or y...............................................................................................9 3
2 0.        
R E F E R E N C E S ...........................................................................................................9 4
2 1.        
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 ......................................... 9 7


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
C O N FI D E N TI A L
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LI S T O F T A B L E S
Ta ble 1:  
Sc he d ule of Acti vities:  Ra n d o mize d Treat me nt Peri o d............................................. 2 4
Ta ble 2:  
Sc he d ule of Acti vities: L o n g -Ter m E xte nsi o n Peri o d Fr o m Wee k 5 6 
T hr o u g h Wee k 1 0 4 ..................................................................................................... 2 9
Ta ble 3:  
Sc he d ule of Acti vities: L o n g -Ter m E xte nsi o n Peri o d Fr o m Wee k 1 0 8 
T hr o u g h F oll o w -U p .................................................................................................... 3 1
Ta ble 4:  
Sc he d ule of Acti vities: S u bjects W h o Per ma ne ntl y Disc o nti n ue Treat me nt 
a n d Re mai n i n t he St u d y ............................................................................................. 3 3
Ta ble 5:  
Dis p ositi o n of A RI A - E Cases D uri n g Ra n d o mize d Treat me nt Peri o d...................... 5 9
Ta ble 6:  
Dis p ositi o n of A RI A - H ( Micr o he m orr ha ge or S u perficial Si der osis) Cases 
D uri n g t he Ra n d o mize d Treat me nt Peri o d .................................................................6 1
LI S T O F FI G U R E S
Fi g ure 1: 
Sc he matic of St u d y  Desi g n......................................................................................... 3 8


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
C O N FI D E N TI A L
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1.        
S Y N O P SI S
Pr ot oc ol Title :       
A P hase 2, M ultice nter, Ra n d o mize d, Parallel-Gr o u p , D o u ble-Bli n d, 
C o ntr olle d St u d y  of A d uca n u ma b ( BII B 0 3 7) i n S u bjects W it h Mil d 
C o g niti ve I m pair me nt d ue t o Alz hei mer’s Disease or Wit h Mil d 
Alz hei mer’s Disease De me ntia t o E val uate t he Safet y of C o nti n ue d 
D osi n g i n S u bjects wit h As y m pt o matic A m yl oi d -Relate d I ma gi n g 
A b n or malities
P r ot oc ol N u m ber:
2 2 1 A D 2 0 5
Versi o n N u m ber : 
1
Na me of St u d y 
Treat me nt :
A d uca n u ma b ( BII B 0 3 7)
St u d y  P hase:        
2
St u d y  In dicati o n : 
Alz hei mer’s d isease
St u d y  Rati o nale:
A m y l oi d-relate d i ma gi n g a b n or malities ( ARI A ) e nc o m pass a s pectr u m 
of ma g netic res o na nce i ma gi n g ( M RI) si g nal a b n or malities i ncl u di n g
vas o ge nic e de ma ( A RI A -E) a n d he me pr o d uct de p osits ( A RI A- H) t hat 
are k n o w n t o occ ur as part of t he nat ural hist or y  of Alz hei mer’s disease 
( A D).  A RI A has als o bee n i dentifie d as a treat me nt -relate d fi n di n g 
wit h s o me a nti-a m yl oi d beta (A β ) m o n ocl o nal a nti b o dies, i ncl u di n g 
ba pi ne uz u ma b, ga nte ner u ma b , a n d a d uca n u ma b . Base d o n t he 
a vaila ble data fr o m t he a d uca n u ma b pr o gra m, t he maj orit y  of cases of 
A RI A ha ve bee n as y m pt o m atic, a n d, w he n s y m pt o matic, t he s y m pt o ms 
t ypicall y ha ve bee n tra nsie nt a n d mil d or m o derate i n se verit y (see 
Secti o n 4. 3 f or details).  I n t he o n g oi n g a d uca n u ma b cli nical st u dies 
( 2 2 1 A D 1 0 3, 2 2 1 A D 3 0 1, a n d 2 2 1 A D 3 0 2) t he pr ot oc ol-defi ne d d osi n g 
dis p ositi o n m a n dates t hat s u bjects w h o are as y m pt o matic wit h mil d 
se verity o n M RI c o nti n ue d osi n g.  S u bjects wit h s y m pt o matic A RI A, as 
well as t h ose wit h as y m pt o matic A RI A t hat is m o derate or se vere o n 
M RI , te m p oraril y s us pe n d or per ma ne ntl y disc o nti n ue d osi n g.  D ata 
fr o m St u d y 2 2 1 A D 1 0 3, alt h o u g h li mite d, ha ve i n dicate d t hat 
c o nti n ui n g d osi n g wit h a d uca n u ma b i n s u bjects wit h as y m pt o matic 
mil d A RI A was n ot ass ociate d wit h cli nicall y si g nifica nt ne gati ve 
o utc o mes.  H o we ver, t he be nefit/ris k of c o nti n ue d d os i n g i n s u bjects
wit h as y m pt o matic A RI A t hat is m o derate or se vere o n M RI is 
c urre ntl y u n k n o w n .  T his st u d y  is bei n g c o n d ucte d t o assess t he safety 
i m pact of c o nti n ui n g a d uca n u ma b d osi n g i n s u bjects wit h 
as ym pt o matic m o derate t o se vere A RI A.  A 2 -sta ge a p pr oac h will be 
take n ; i nitiall y ( Sta ge 1), d osi n g will be c o nti n ue d i n mil d a n d 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 0
m o derate as y m pt o matic A RI A cases o nl y.  It is pla n ne d t hat d osi n g 
will be c o nti n ue d i n se vere A RI A cases as well (i n Sta ge 2), c o nti n ge nt 
o n t he rec o m me n dati o n of t he Data Safet y M o nit ori n g C o m mittee 
( D S M C) f oll o wi n g a re vie w of t he Sta ge 1 data (see Secti o n 1 9. 2. 2 f or 
a d diti o nal details).
St u d y  O bjecti ves
a n d E n d p oi nts:
T he pri mar y  o bjecti ve of t he st u d y is t o assess t he safety i m pact of 
c o nti n ui n g a d uca n u ma b d osi n g i n as y m pt o matic A RI A i n s u bjects wit h 
M CI  d ue t o A D or wit h mil d A D de me ntia. 
T he pri mar y  e n d p oi nt t hat relates t o t his o bjecti ve is t he i nci de nce of 
cli nicall y i m pactf ul A RI A, defi ne d as s y m pt o ms a n d/ or si g ns 
ass ociate d wit h A RI A t hat are life- t hreate ni n g, re q uire h os pitalizatio n, 
a n d/ or res ult i n persiste nt or si g nifica nt disa bilit y, as assesse d by t he 
i n de pe n de nt A dj u dicati o n C o m mittee.
Sec o n dar y  o bjecti ves a n d e n d p oi nts are as f oll o ws:

T o c haracterize A RI A , fr o m b ot h t he i ma gi n g a n d t he 
cli nical pers pecti ve:

I nci de nce, se verit y, ti me t o o nset, a n d ti me t o res ol uti o n 
of A RI A as o btai ne d o n M RI

I nci de nce, se verit y, ti me t o o nset, a n d ti me t o res ol uti o n 
of s y m pt o matic A RI A 

T o c haracterize t he safet y, t olera bilit y , p har mac o ki netics 
( P K), a n d i m m u n o ge nicit y of a d uca n u ma b:

I nci de nce of a d verse e ve nts ( A Es) a n d seri o us a d verse 
e ve nts ( S A Es)

C ha n ge fr o m baseli ne t o Wee k 5 4 o n t he M o ntreal 
C o g niti ve Assess me nt ( M o C A) 

A d uca n u ma b c o nce ntrati o n i n ser u m

I nci de nce of a ntia d uca n u ma b a nti b o dies i n ser u m
L o n g -T er m E xte nsi o n O bjecti ves a n d E n d p oi nts
T he pri mar y  o bjecti ve of t he l o n g-ter m e xte nsi o n (L T E ) is t o e val uate 
t he l o n g-ter m safet y a n d t olera bilit y pr ofile of a d uca n u ma b i n s u bjects 
wit h M CI  d ue t o A D or wit h mil d A D de me ntia w hile c o nti n ui n g 
d osi n g d uri n g as y m pt o matic A RI A e ve nt s.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 1
T he e n d p oi nt t hat relates t o t his o bjecti ve is t he i nci de nce of A Es a n d 
S A Es.
St u d y  Desi g n:      
T his is a P hase 2, m ultice nter, ra n d o mize d, parallel- gr o u p ,
d o u ble -bli n d, c o ntr olle d st u d y wit h a 5 2- wee k ra n d o mize d treat me nt 
peri o d f oll o we d b y a n o pti o nal 1 0 4- wee k L T E peri o d.   
St u d y  Locati o n:    
A p pr o xi matel y  9 5 sites gl o ball y are pla n ne d.
N u m ber of 
Pla n ne d S u bjects:
A p pr o xi matel y  5 0 0 s u bjects will be e nr olle d.
St u d y  P o p ulati o n:
T his st u d y  will be c o n d ucte d i n s u bjects wit h M CI d ue t o A D or wit h 
mil d A D de me ntia acc or di n g t o 2 0 1 1 Nati o nal I nstit ute o n A gi n g a n d 
Alz hei mer’s Ass ociati o n ( NI A -A A ) criteria.  S u bjects m ust ha ve 
p ositi ve res ults f or cere bral a m yl oi d pat h ol o g y as meas ure d by a 
p ositr o n e missi o n t o m o gra p h y  ( P E T) sca n.  S u bjects m ust be 5 0 t o 8 5 
y ears ol d, i ncl usi ve, a n d, a part fr o m a cli nical dia g n osis of M CI  d ue t o 
A D or of mil d A D de me ntia , t he y m ust be i n g o o d healt h as deter mi ne d 
b y  t he I n vesti gat or, base d o n me dical hist or y a n d t he scree ni n g 
assess me nts.
Detaile d criteria are descri be d i n Secti o n 8 .
Treat me nt 
Gr o u ps:
All s u bjects will recei ve a d uca n u ma b.  Eli gi ble s u bjects will be 
ra n d o mize d ( 1: 1) t o 1 of 2 gr o u ps t h at differ i n ter ms of t he 
m a n a ge me nt of asy m pt o m atic A RI A , as s u m marize d bel o w.  T he 
ra n d omizati o n will be stratifie d b y  a p oli p o pr otei n E (A p o E ) ε 4 stat us 
(carrier or n o ncarrier).  The ra n d o mize d treat me nt peri o d will last
5 2 wee ks.   D uri n g t he L T E, as y m pt o matic A RI A i n all s u bjects will be 
ma na ge d acc or di n g t o t he pla n descri be d f or Gr o u p 2 bel o w.
Gr o u p 1 :  C o nti n uati o n of d osi n g i n asy m pt o matic A RI A c o nti n ge nt 
u p o n i ma gi n g se verit y, c o nsiste nt wit h d ose dis p ositi o n i n o n g oi n g 
P hase 3 st u dies, as f oll o ws (See Secti o n 1 1. 2. 1 f or details):

Mil d se verit y  o n M RI:  C o nti n ue d osi n g

M o derate se verity o n M RI : S us pe n d d osi n g

Se vere o n M RI:  S us pe n d d osi n g ( A RI A-E)  or disc o nti n ue 
d osi n g ( A RI A - H [ micr o he m orr h a ge, s u perfici al si der osis])
Gr o u p 2 :  C o nti n uati o n of d osi n g i n asy m pt o matic A RI A re g ar dless of 
i ma gi n g se verit y, t o be i m ple me nte d i n a 2- sta ge a p pr oac h, as f oll o ws
(see Secti o n 1 1. 2. 1 f or details):


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 2
Sta ge 1 (fr o m start of trial):

Mil d or m o derate se verit y o n M RI:
C o nti n ue d osi n g

Se vere o n M RI:  S us pe n d d osi n g ( A RI A-E)  or per m a ne ntly 
disc o nti n ue d osi n g ( A RI A-H [ micr o he m orr h a ge, s u perfici al 
si der osis])
Sta ge 2 (c o nti n ge nt o n D S M C rec o m me n dati o n after Sta ge 1 
data re vie w; see Secti o n 1 9. 2. 2 ):

A n y  se verity o n M RI: C o nti n ue d osi n g
N ote: T o mai ntai n t he bli n d, place b o will be gi ve n t o Gr o u p 1 s u bjects 
i n pres pecifie d cases of d ose s us pe nsi o n/ disc o nti n uati o n d ue t o 
as ym pt o matic A RI A i n b ot h Sta ges 1 a n d 2 (f or details, see Ta ble 5 a n d 
Ta ble 6 ).
Ma na ge me nt of s y m pt o matic A RI A (a n y  se verit y o n M RI) a n d 
ma na ge me nt of A RI A -H ( macr o he m orr ha ge) will be t he s a me i n Gr o u p 
1 a n d Gr o u p 2 a n d will be ge nerall y c o nsiste nt wit h t hat i n t he o n g oi n g 
P hase 3 pr o gra m.  
T hr o u g h o ut trial, Gr o u p 1 a n d Gr o u p 2:

S y m pt o matic A RI A, a n y  se verity o n M RI :

S us pe n d d osi n g or per m a ne ntly disc o nti n ue tre at me nt

A RI A- H ( macr o he m orr ha ge) wit h or wit h o ut s y m pt o m s:

P er m a ne ntly disc o nti n u e tre at me nt
D urati o n of 
Treat me nt a n d 
F oll o w - u p:
T he t otal d urati o n of st u d y  partici pati o n f or a n y gi ve n s u bject 
partici pati n g i n t he ra n d o mize d treat me nt peri o d o nl y will be 
a p pr o xi matel y 7 8 wee ks, i ncl u din g a series of scree ni n g visits wit hi n 
6 0 da y s bef ore a d mi nistrati o n of t he first d ose, a 5 2-wee k treat me nt 
peri o d, a n d a safet y f oll o w -u p a p pr o xi matel y  1 8 wee ks after t he fi nal 
d ose. 
T he t otal d urati o n of st u d y  partici pati o n f or a n y gi ve n s u bject 
partici pati n g i n t he ra n d o mize d treat me nt peri o d a n d t he L T E peri o d 
will be a p pr o xi matel y  1 8 6 wee ks, i ncl u di n g a series of scree ni n g visits 
wit hi n 6 0 da y s bef ore a d mi nistrati o n of t he first d ose, a 5 2- wee k 
ra n d o mize d treat me nt peri o d, a 4- wee k f oll o w- u p peri o d, a 1 0 4- wee k 
L T E treat me nt peri o d, a n d a safet y f oll o w -u p a p pr o xi matel y  1 8 wee ks 
after t he fi nal d ose.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 3
S u bjects w h o per ma ne ntl y  disc o nti n ue st u d y treat me nt ( d ue t o A RI A or 
ot her reas o ns) are t o re mai n i n t he st u d y a n d f oll o w a m o difie d 
sc he d ule f or tests a n d assess me nts u ntil t he e n d of t he st u d y  peri o d or 
wit h dra wal of c o nse nt (Ta ble 4 ). T he o nl y e xce pti o n is a s u bject w h o 
ma y  de vel o p se vere as y m pt o matic A RI A -H ( micr o he m orr ha ge, 
s u perficial si der osis) i n Sta ge 2 ( Secti o n 1 1. 2. 1. 2 ; Ta ble 6 ); s uc h a 
s u bject is t o f oll o w t he re g ular visit sc he d ule t o mai ntai n t he bli n d t o 
t he s u bject’s gr o u p assi g n me nt (Ta ble 1 ).  
S u bjects w h o wit h dra w fr o m t he st u d y  are t o ret ur n f or a safety f oll o w -
u p visit a p pr o xi matel y 1 8 wee ks after t heir last d ose of st u d y  treat me nt.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
1 4
2.        
LI S T O F A B B R E VI A TI O N S
A β
a m yl oi d beta
A D
Alz hei mer’s disease
A D A
a nti dr u g a nti b o d y
A E
a d verse e ve nt
A p o E
a p oli p o pr otei n E
A RI A
a m yl oi d-relate d i ma gi n g a b n or malities
A RI A - E
a m yl oi d-relate d i ma gi n g a b n or malit y ( vas o ge nic e de ma)
A RI A - H
a m yl oi d-relate d i ma gi n g a b n or malit y (macr o he m orr ha ge , or 
micr o he m orr ha ge, s u perficial si der osis )
C A A
cere bral a m yl oi d a n gi o pat h y
C D R
Cli nical De me ntia Rati n g
C R F
case re p ort f or m
C R O
c o ntract researc h or ga nizati o n
C- S S R S
C ol u m bia S uici de Se verit y Rati n g Scale
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
D B P
diast olic bl o o d press ure
D H A
Directi o ns f or Ha n dli n g a n d A d mi nistrati o n
D N A
de o x yri b o n ucleic aci d
D S M C
Data Safet y M o nit ori n g C o m mittee
D S S T
Di gital S y m b ol S u bstit uti o n Test
E C G
electr ocar di o gra m
E C o g
E ver y da y C o g niti o n
E D C
electr o nic data ca pt ure
E O T
e n d of treat me nt
G C P
G o o d Cli nical Practice
H Bc A b
he patitis B c ore a nti b o d y
H Bs A g
he patitis B s urface a nti ge n
H C P
healt h care pr ofessi o nal
I C F
i nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 5
I g
im m u n o gl o b uli n
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 T E
l o n g-ter m e xte nsi o n
m A b
m o n ocl o nal a nti b o d y
M CI
mil d c o g niti ve i m pair me nt
M M S E
Mi ni -Me ntal State E xa mi nati o n
M o C A
M o ntreal C o g niti ve Assess me nt
M RI
ma g netic res o na nce i ma gi n g
NI A- A A
Nati o nal I nstit ute o n A gi n g a n d Alz hei mer’s Ass ociati o n
N F T
ne ur ofi brillar y ta n gle
N P
ne uritic pla q ue
P E T
p ositr o n e missi o n t o m o gra p h y
PI
p ri nci pal i n vesti gat or
P K
p har mac o ki netic (s)
R N A
ri b o n ucleic aci d
S A E
seri o us a d verse e ve nt
S B P
s yst olic bl o o d press ure
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
T E A E
treat me nt e mer ge nt a d verse e ve nt


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 6
3.        
S P O N S O R I N F O R M A TI O N
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
Bi o ge n A ustralia Pt y  Lt d
S uite 1, L e vel 5, 1 2 3 E p pi n g R d
N ort h R y de, N S W 2 1 1 3
A ustralia
Bi o ge n Ja pa n L t d.
Ni h o n bas hi 1 -c h o me Mits ui B uil di n g 1 4 F
4- 1 Ni h o n bas hi 1- c h o me
C h u o -k u 
T o k y o 
1 0 3- 0 0 2 7
Ja pa n
F or 2 4 -h o ur e mer ge nc y  me dical s u p p ort, c o ntact 
.
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 Refere nce G ui de’s Official St u dy 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 ( C R O) a n d ot her t hir d parties; h o we ver, Bi o ge n retai ns o verall acc o u nta bilit y f or 
t hese acti vities.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 7
4.        
I NT R O D U C TI O N
4. 1.     
O ver vie w of Alz hei mer’s Dise ase
Alz hei mer’s disease is t he m ost c o m m o n ca use of de me ntia, acc o u nti n g f or 5 0 % t o 7 5 % of all 
cases.  Alz hei mer’s Disease I nter nati o nal esti mates t hat as of 2 0 1 6, t here were 4 7 milli o n pe o ple 
li vi n g wit h de me ntia worl d wi de, a n d t hat t his fi g ure will i ncrease t o 1 3 1 milli o n b y  2 0 5 0 
[Alz hei mer's Disease I nter nati o nal 2 0 1 6].  In t he U nite d States, it is esti mate d t hat 5. 2 milli o n 
pe o ple s uffer fr o m de me ntia ca use d b y A D [Alz hei mer's Disease I nter nati o nal 2 0 1 4 ].  Gl o ball y, 
t he greatest i ncrease i n de me ntia n u m bers t hr o u g h 2 0 5 0 is e x pecte d t o occ ur i n c o u ntries i n 
w hic h t he p o p ulati o n is a gi n g at a n u n prece de nte d rate [Alz hei mer's Disease I nter nati o nal 2 0 1 5 ].
Pat h ol o gicall y, t he disease is defi ne d b y t he prese nce i n t he brai n of e xtracell ular ne uritic 
pla q ues ( N Ps) c o ntai ni n g A β pe pti d e a n d i ntra ne ur o nal ne ur ofi brillar y ta n gles ( N F Ts) c o m p ose d 
of h y per p h os p h or y late d ta u pr otei n.  T he pat h o ge nesis of t hese pla q ues a n d ta n gles a n d h o w t he y 
c o ntri b ute t o t he cli nical s yn dr o me re mai n t o be f ull y  el uci date d, b ut t he lea di n g hy p ot hesis — t he 
“am y l oi d casca de”— pr o p oses t hat t he dri vi n g f orce be hi n d t he disease pr ocess is t he 
acc u m ulati o n of A β res ulti n g fr o m a n i m bala nce bet wee n A β pr o d ucti o n a n d A β cleara nce i n t he 
brai n [Har d y a n d Sel k oe 2 0 0 2 ].  Bi o mar ker [Jac k 2 0 1 0], cli nic o pat h ol o gic [Delac o urte 2 0 0 2 ], 
a n d c o h ort [A mie va 2 0 0 8 ] st u dies s u g gest t hat t he disease pr ocess c o m me nces 1 0 t o 2 0 years 
pri or t o t he o nset of s y m pt o ms , starti n g wit h t he de p ositi o n of ne oc ortical N Ps a n d mesial 
te m p oral N F Ts a n d f oll o we d years later b y ne oc ortical N F Ts, w hic h best c orrelate wit h c o g niti ve 
stat us a n d ne ur o nal deat h [Nels o n 2 0 0 9 ].
Cli nicall y , A D is a pr o gressi ve ne ur o de ge nerati ve dis or der c haracterize d b y a n i nsi di o us a n d 
u nrele nti n g decli ne i n c o g niti o n, as well as be ha vi oral dist ur ba nces, t hat res ult i n t he pers o n’s 
i na bilit y t o perf or m us ual acti vities of dail y li vi n g.  T he c urre nt vie w of A D is t hat it ma nifests 
al o n g a c o nti n u u m rat her t ha n cate g orical sta ges.  E vi de nce s u g gests t hat t he pat h o p h y si ol o gical 
c ha n ges be gi n ye ars bef ore cli nical o nset, a n d as t he disease pr o gresses c o g niti ve i m pair me nts, 
be ha vi oral c ha n ges, a n d f u ncti o nal disa bilit y  ma nifest [Jac k 2 0 1 3].  T h us, t he scie ntific 
c o m m u nit y has s hifte d its f oc us t o pe o ple i n t he earlier c o urse of t he disease c o nti n u u m , wit h t he 
belief t hat t h ose pe o ple are m ore li kel y t o be nefit fr o m t hera p y.  
4. 2.     
C urre nt T her a pies f or Alz hei mer’s Dise ase
T he c urre ntl y  a p pr o ve d t hera pies f or A D i ncl u de t he acet ylc h oli nesterase i n hi bit ors (s uc h as 
Arice pt ™, E xel o n ™, Re mi n y l ™, a n d Ri vastac h ® Patc h) a n d t he N-met h y l- D-as partate 
a nta g o nist me ma nti ne ( Na me n da ™), w hic h pr o vi de o nl y  m o dest sy m pt o matic be nefit b ut d o n ot 
atte n uate t he c o urse of t he disease.
T here are c urre ntl y  n o t hera pies t hat m o dif y t he c o urse of A D, b ut se veral p ote ntial disease -
m o dif y i n g dr u g ca n di dates are u n der i n vesti gati o n.  T hese ca n di dates i ncl u de s mall m olec ules 
a n d i m m u n ot hera p y (acti ve a n d passi ve) t hat tar get t he A β pat h wa y a n d ai m t o pr o vi de 
t hera pe utic be nefit by re d uci n g eit her s ol u b le or i ns ol u ble f or ms of A β i n the brai n .


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 8
Ba pi ne uz u ma b ( Pfizer/ Ela n/J o h ns o n & J o h ns o n), ga nte ner u ma b ( R oc he), B A N 2 4 0 1 ( Eisai, 
Bi o ge n), cre nez u ma b ( Ge ne ntec h), a n d s ola nez u ma b ( Eli L ill y) are a nti-a m yl oi d-tar geti n g 
a nti b o dies wit h differe nt bi n di n g selecti vit y t o war d differe nt f or ms of A β.  B a pi ne uz u ma b was 
disc o nti n ue d d ue t o lac k of efficac y  as c o m pare d wit h place b o, w hile t he ot her 4 a nti b o dies are 
c urre ntl y i n P hase 2 a n d 3 trials e val uati n g treat me nt effects i n differe nt A D p o p ulati o ns.
R ati o n al e f or A d uc a n u m a b T her a py f or A D
A d uca n u ma b ( BII B 0 3 7) is a h u ma n a nti-A β i m m u n o gl o b uli n (I g) G 1 m o n ocl o nal a nti b o d y  
( m A b) t hat selecti vely tar gets a g gre gate d f or ms of A β, i ncl u di n g s ol u ble oli g o me rs a n d i ns ol u ble 
fi brils.  Earlier p u blicati o ns ha ve de m o nstrate d t hat b ot h s ol u ble oli g o mers a n d a m yl oi d pla q ues 
are ne ur ot o xic [K offie 2 0 0 9 ; K uc hi b h otla 2 0 0 8 ; Me y er-L u e h ma n n 2 0 0 8], a n d cleara nce of 
a m yl oi d pla q ues c o ul d lea d t o n or malizati o n of calci u m h o me ostasis a n d ne ur o nal acti vit y, as 
well as re d ucti o n of o xi dati ve stress i n t he brai n of a n a ni mal m o del of A D [R oz kal ne 2 0 0 9 ; 
S pires -J o nes 2 0 0 9].  M ore o ver, a n ass o ciati o n bet wee n t he prese nce of a nti b o dies t hat rec o g nize 
a m yl oi d pla q ues a n d a sl o wi n g of c o g niti ve decli ne i n pe o ple wit h mil d t o m o derate A D has 
bee n descri be d [H oc k 2 0 0 3 ].  T heref ore, tar geti n g a g gre gate d f or ms of A β, i ncl u di n g s ol u ble 
oli g o mers a n d i ns ol u ble fi brils, w it h a d uca n u ma b is h yp ot hesize d t o atte n uate t he c o urse of A D.
A myl oi d - Rel ate d I m a gi n g A b n or m alities
A RI A detecte d o n M RI ha ve bee n o bser ve d i n s u bjects wit h A D recei vi n g a nti -A β m A bs .  A RIA 
was first o bser ve d as a treat me nt -relate d a d verse effect wit h ba pi ne uz u ma b a n d has m ore 
rece ntly bee n ass ociate d wit h ot her a nti -A β m A bs, i ncl u di n g ga nte ner u ma b a n d a d uca n u ma b 
[Pe n ni n kila m pi 2 0 1 7 ; Se vi g n y 2 0 1 6 ; S perli n g 2 0 1 1 ]. 
A RI A re prese nts a s pectr u m of i ma gi n g fi n di n gs t hat i ncl u de A RI A - E a n d A RI A- H i n t he brai n 
pare nc h y m a ( micr o he m orr ha ges a n d, rarely, macr o he m orr ha ges) or i n t he le pt o me ni n geal s pace 
(s u perficial si der osis).  A RIA- E has bee n h y p ot hesize d t o res ult fr o m i ncrease d cere br o vasc ular 
per mea bilit y  ca use d b y accelerate d A β cleara nce fr o m t he brai n pare nc hy m a a n d/ or b y  a nti b o d y 
i nteracti o n wit h vasc ular A β [S perli n g 2 0 1 2 ; Za g o 2 0 1 3 ].  
A RI A- E ma y  be acc o m pa nie d b y A RI A-H, b ut is olate d A RI A - H is als o k n o w n t o occ ur i n 
u ntreate d s u bjects i n t he setti n g of s mall vessel a n gi o pat h y t y picall y ca use d b y c hr o nic 
h y perte nsi o n or cere bral a m y l oi d a n gi o pat h y, w hic h ofte n acc o m pa nies A D [Li n n 2 0 1 0 ].  
Si milarl y  a n A RI A-E li ke p he n o me n o n has bee n o bser ve d i n rare cases i n u ntreate d s u bjects 
d uri n g scree ni n g f or A D trials s u g gesti n g t hat s p o nta ne o us A RI A -E ma y  occ ur i n t he nat ural 
hist or y  of A D, per ha ps m ore c o m m o nl y i n s u bjects wit h ge netic ris k fact ors f or hi g h a myl oi d 
ris k b ur de n a n d/ or cere bral a m yl oi d a n gi o pat h y b ur de n [S perli n g 2 0 1 1 ].  
E vi de nce fr o m trials of a nti- A β m A bs has s h o w n t hat t he i nci de nce of A RI A-E is i ncrease d wit h 
hi g her d oses of t he dr u gs a n d is m ore fre q ue nt i n heter o z yg ote a n d h o m oz y g ote A p o E ɛ 4 carriers
t ha n i n n o ncarriers .  A n ot her c o m m o n c haracteristic of treat me nt-relate d A RIA- E is its ti mi n g, 
occ urri n g m ostl y  earl y d uri n g t he c o urse of treat me nt [Ketter 2 0 1 7 ; Sall o wa y  2 0 1 4; S perli n g 
2 0 1 2 ; S perli n g 2 0 1 1 ].


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
1 9
4. 3.     
Pr ofile of Pr e vi o us E x perie nce W it h A d uc a n u m a b
See t he I n vesti gat or’s Br oc h ure f or detaile d i nf or mati o n o n rele va nt n o ncli nical a n d cli nical 
st u dies.
4. 3. 1.     
N o ncli nic al E x perie nce
A d uca n u ma b is i de ntifie d a n d deri ve d fr o m B l ym p h oc y tes usi n g t he re verse tra nslati o nal 
me dici ne a p pr oac h.  Usi n g t his tec h ni q ue, i m m u ne re pert oires o btai ne d fr o m c o h orts of healt h y 
el derl y h u ma n d o n ors wit h e xcelle nt c o g niti ve perf or ma nce or wit h i m paire d b ut sta ble c o urses 
were scree ne d f or me m or y B cells a gai nst a g gre gate d A β [ Se vi g n y  2 0 1 6].  
I n vitr o st u dies ha ve de m o nstrate d t hat a d uca n u ma b a n d its a nal o gs are hi g hl y selecti ve f or 
s ol u ble oli g o meric a n d i ns ol u ble fi brillar f or ms of Aβ relati ve t o s ol u ble l o w-m olec ular -wei g ht 
f or ms of A β.  I n vi v o p har mac ol o g y st u dies i n dicate d t hat a m uri ne I g G 2a c hi meric versi o n of 
t he a nti b o d y (c h 1 2 F 6 A) wit h si milar pro perties t o a d uca n u ma b si g nifica ntl y re d uce d a myl oi d 
pla q ue b ur de n i n t he brai ns of a ge d T g 2 5 7 6 mice, a m o use m o del of A D -li ke a myl oi d 
de p ositi o n , t hr o u g h a micr o glia-me diate d p ha g oc ytic mec ha nis m.  
T he t o xic o ki netic pr ofile of a d uca n u ma b was e val uate d i n T g 2 5 7 6 mice i n 1 3 -wee k a n d 6 -m o nt h 
st u dies a n d i n c yn o m ol g us m o n ke y s i n a 4-wee k st u d y .  Of t he 2 s pecies, t he T g 2 5 7 6 m o use is 
c o nsi dere d t he pri mar y p har mac ol o gically rele va nt s pecies gi ve n t hat t hese mice acc u m ulate 
a m yl oi d pla q ues i n t he cere bral pare nc h yma a n d vasc ulat ure.  I n a d diti o n t o t he sta n dar d 
hist o pat h ol o gical e val uati o n i n mice, Perls’ stai ni n g of he m osi deri n (a brea k d o w n pr o d uct of 
he m o gl o bi n) was perf or me d t o q ua ntif y  micr o he m orr ha ge.  Micr o he m orr ha ge has bee n o bser ve d 
b ot h as a bac k gr o u n d fi n di n g i n tra ns ge nic m o use m o dels of A D [ Wi n kler 2 0 0 1 ], i ncl u di n g 
T g 2 5 7 6 mice [K u mar -Si n g h 2 0 0 5 ], a n d as a dr u g-relate d fi n di n g i n tra ns ge nic mice treate d wit h 
s o me a nti-A β a nti b o dies [Pfeifer 2 0 0 2 ; Rac ke 2 0 0 5 ; Wilc oc k a n d C olt o n 2 0 0 9 ].
I n b ot h m o use st u dies, re peate d a d mi nistrati o n of c h 1 2 F 6 A or a d uca n u ma b was well t olerate d,
wit h n o treat me nt -relate d deat hs o bser ve d d uri n g t he d osi n g peri o d.  I n t he 1 3-wee k t o xic ol o g y  
st u d y, me ni n geal/cere bral vasc ular i nfla m mati o n a n d/ or vasc ular t hic ke ni n g were o bser ve d i n 
mice d ose d wit h c h 1 2 F 6 A ≥7 0 m g/ k g c o m pare d wit h t he c o ntr ol gr o u p.  I n t he 6-m o nt h st u d y , 
alt h o u g h sli g ht differe nces were o bser ve d bet wee n c h 1 2 F 6 A -treate d gr o u ps a n d t he c o ntr ol 
gr o u p, a ni mals treate d wit h a d uca n u ma b were c o m para ble t o t he c o ntr ol a ni mals.  T he 
e val uati o n of micr o he m orr ha ge, c haracterize d b y  q ua ntificati on of he m osi deri n i n Perls ’ stai ne d 
brai n secti o ns of eac h mai n st u d y  a n d rec o ver y a ni mal, de m o nstrate d n o si g nifica nt i ncrease i n 
sc ores wit h c h 1 2 F 6 A or a d uca n u ma b treat me nt i n eit her st u d y.  T he i nci de nce a n d se verit y of 
he m orr ha ge or cere bral vasc ular i n fla m mati o n were c o m para ble i n t he 1 3-wee k a n d 6 -m o nt h 
m o use st u dies.  
4. 3. 2.     
Cli nic al E x perie nce
I n c o m plete d P hase 1 st u dies i n A D, 3 9 s u bjects wit h mil d t o m o derate A D were e x p ose d t o a 
si n gle d ose of a d uca n u ma b (St u d y  2 2 1 A D 1 0 1), a n d 1 7 Ja pa nese s u bjects wit h mil d t o m o derate 
A D were e x p ose d t o a d uca n u ma b f or u p t o 3 6 wee ks ( St u d y  2 2 1 A D 1 0 4).  A d diti o nall y , 
1 4 healt h y  s u bjects were e x p ose d t o a si n gle i ntra ve n o us (I V) d ose of a d uca n u ma b a n d 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
2 0
1 4 healt h y  s u bjects were e x p ose d t o a si n gle s u bc uta ne o us (S C ) d ose ( St u d y 2 2 1 H V 1 0 2).  As of 
2 5 Ma y  2 0 1 7, 1 8 5 s u bjects wit h pr o dr o mal A D or mil d A D de me ntia ha d recei ve d at least 1 d ose 
of a d uca n u ma b i n t he o n g oi n g m ulti ple -asce n di n g-d ose P hase 1 b st u d y  ( St u d y 2 2 1 A D 1 0 3). As 
of 1 5 Ja n uar y  2 0 1 8, m ore t ha n 2 5 0 0 a d diti o nal s u bjects wit h earl y A D ha ve recei ve d at least 1 
d ose of a d uca n u ma b or place b o i n t he o n g oi n g bli n de d P hase 3 st u dies ( 2 2 1 A D 3 0 1 a n d 
2 2 1 A D 3 0 2). 
O verall, i n t he cli nical st u dies, a d uca n u ma b has bee n ge nerall y well t olerate d i n s u bjec ts wit h 
A D , wit h A RI A bei n g t he pri mar y  safety a n d t olera bilit y fi n di n g.
4. 3. 2. 1.   
A RI A i n t he A d uc a n u m a b Cli nic al De vel o p me nt Pr o gr a m
4. 3. 2. 1. 1.
St u d y 2 2 1 A D 1 0 1
I n St u dy 2 2 1 A D 1 0 1, 3 s u bjects recei ve d a si n gle d ose of a d uca n u ma b 6 0 m g/ k g a n d all 
3 e x perie nce d A RI A -E, i ncl u di n g 2 s u bjects wit h A RI A- E a n d 1 s u bject wit h b ot h A RI A- E a n d 
A RI A- H ( micr o he m orr ha ge).  N o ne of t he s u bjects were h os pitalize d; h o we ver, t hese cases were
re p orte d as me dically i m p orta nt S A Es , per pr ot oc ol.  Eac h case was c o nsi dere d sy m pt o matic.  
S y m pt o ms i ncl u de d se vere ge neralize d b o d y  ac hes, m o derate hea dac he, a n d m o derate c o g niti ve 
cl o u di ness; se vere hea dac he a n d se vere malaise; a n d mil d tra ns ie nt u nstea d y gait.  A RI A-E 
se verity as see n o n M RI ra n ge d fr o m mil d t o se vere.  A RI A, as assesse d b y M RI , a n d atte n da nt 
s ym pt o ms f ull y  res ol ve d i n all 3 s u bjects bet wee n Wee ks 8 a n d 1 5.
4. 3. 2. 1. 2.
St u d y 2 2 1 A D 1 0 4
A RI A e ve nts occ urre d i n 1 s u bject i n t his st u d y.  T hes e i ncl u de d as ym pt o matic A RI A -E ( mil d 
vas o ge nic e de ma), as ym pt o matic A RI A- H ( macr o he m orr ha ge), a n d as y m pt o matic A RI A- H 
(s u perficial si der osis), w hic h were o bser ve d o n M RI a p pr o xi matel y 3 wee ks after t he s u bject ha d 
recei ve d a si n gle d ose of a d uca n u ma b 3 m g /k g.  St u d y  treat me nt was disc o nti n ue d, a n d t he 
s u bject was wit h dra w n fr o m st u d y d ue t o t hese i ma gi n g fi n di n gs.  A p pr o xi matel y 3 wee ks later 
( 6 wee ks after recei vi n g t he si n gle d ose of a d uca n u ma b), t he s u bject e x perie nce d a n ac ute life -
t hreate ni n g cere bral he m orr ha ge wit h a c o ma.  T he s u bject was treate d wit h gl yc er ol, a n d 4 da ys 
after t he cere bral hem orr ha ge ha d re gai ne d c o nsci o us ness a n d was ha vi n g li mite d c o n versati o n 
wit h s o me a d diti o nal i m pr o ve me nt.
4. 3. 2. 1. 3.
St u d y 2 2 1 A D 1 0 3
C urre ntl y  a vaila ble data o n A RIA are m o stl y base d o n t he o n g oi n g St u d y  2 2 1 A D 1 0 3 of 
a d uca n u ma b i n s u bjects wit h pr o dr o mal A D or mil d A D de me ntia.  T his st u d y  c o m prises a 
c o m plete d d o u ble -bli n d, 1- ye ar place b o -c o ntr olle d peri o d, f oll o we d b y a n o n g oi n g L T E i n w hic h 
all s u bjects recei ve a d uca n u ma b via m o nt hl y  i nf usi o ns, i n a d ose-bli n de d fas hi o n.  A t otal of 1 8 5 
s u bjects ha ve bee n d ose d wit h a d uca n u ma b, i n t he place b o-c o ntr olle d peri o d a n d/ or t he L T E. 
Base d o n data a vaila ble as of 2 5 Ma y 2 0 1 7 i n a pres pecifie d i nteri m a nalys is, A RIA -E ( wit h or 
wit h o ut A RI A- H) has bee n detecte d i n 2 5 % of all a d uca n u ma b -treate d s u bjects ( 4 6/ 1 8 5).  I n t he 
1 2- m o nt h place b o -c o ntr olle d peri o d, i n s u bjects recei vi n g a d uca n u ma b i n a fi xe d-d ose re gi me n, 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
2 1
t he i nci de nce of A RI A-E i ncrease d wit h d ose a n d was hi g her i n A p o E ε 4 ca rriers t ha n 
n o ncarriers ( 3 % [ 1/ 3 1], 6 % [ 2/ 3 2], 3 7 % [ 1 1/ 3 0], a n d 4 1 % [ 1 3/ 3 2] i n t he 1, 3, 6, a n d 1 0 m g/ k g 
d ose gr o u p s, res pecti vely).  H o we ver, t he i nci de nce of A RI A -E a p peare d t o be l o wer i n A p o E ε 4 
carrier s u bjects recei vi n g titrati o n t o 1 0 m g/ k g ( 3 5 % [ 8/ 2 3]) t ha n i n carrier s u bjects recei vi n g 
fi xe d d oses ( 4 3 % [ 9/ 2 1] a n d 5 5 % [ 1 1/ 2 0]) of 6 a n d 1 0 m g/ k g, res pecti vel y.   F urt her m ore, a m o n g 
t he 8 A p o E ε 4 carrier s u bjects recei vi n g titrati o n t o 1 0 m g/ k g w h o ha d A RI A -E, t he 
a b n or malities were o bser ve d at t he 3 a nd 6 m g / k g d ose le vels ( 5 a n d 3 s u bjects, res pecti vely).  
T he i nci de nce of is olate d A RI A- H was si milar i n t he place b o a n d a d uca n u ma b gr o u ps ( 7 % 
[ 3/ 4 6] a n d 5 % [ 7/ 1 4 8], res pecti vel y), w hic h li kely i n dicates a bac k gr o u n d fi n di n g i n t his 
p o p ulati o n .  
A RI A was t y picall y o bser ve d earl y i n t he c o urse of t he treat me nt, wit h t he maj orit y  of cases 
o bser ve d bet wee n t he sec o n d a n d fift h d oses.  A t otal of 9 1 % of s u bjects ( 4 2/ 4 6) de vel o pe d t he 
first e pis o de of A RI A- E wit hi n t he first 1 2 m o nt hs of acti ve d osi n g, wit h 7 6 % of s u bjects ( 3 5/ 4 6) 
de vel o pi n g t he first e pis o de wit hi n t he first 6 m o nt hs of acti ve d osi n g.  I n m ost cases, A RI A -E 
res ol ve d 4 t o 1 2 wee ks after o nset as assesse d by M RI , a n d A RI A-H was t y picall y  sta ble wit hi n 
2 t o 4 wee ks after o nset.
Of t he s u b jects w h o de vel o pe d A RI A-E ( wit h or wit h o ut A RI A- H), t he maj orit y  ( 6 5 % [ 3 0/ 4 6]) 
were as y m pt o matic wit h a n M RI  se verity of mil d ( 9 s u bjects), m o derate ( 2 0 s u bjects), a n d se vere 
( 1 s u bject).  I n s u bjects wit h s ym pt o ms ( 3 5 % [ 1 6/ 4 6]), t he maj orit y  of s y m pt o ms were mil d 
( 6 3 % [ 1 0/ 1 6]) or m o derate ( 1 3 % [ 2/ 1 6]) a n d res ol ve d wit h o ut se q uelae.  S ym pt o ms were se vere 
i n 2 5 % of t hese s u bjects ( 4/ 1 6).  S ym pt o ms of A RI A ma y  i ncl u de hea dac he, w orse ni n g c o g niti ve 
f u ncti o n, alterati o n of c o nsci o us ness, seiz ures, u nstea di ness, vis ual dist ur ba nces, a n d v o miti n g.  
T w o A RI A cases ( 1 s ym pt o matic a n d 1 as y m pt o matic) res ulte d i n h os pitalizati o n; b ot h cases 
occ urre d i n t he first 1 2 m o nt hs of acti ve a d uca n u ma b treat me nt.  T he s u bject w h o was 
as ym pt o matic was h os pitalize d wit h o ut a n y  treat me nt t o r ule o ut a s u barac h n oi d he m orr ha ge.  
T he sec o n d s u bject , wit h se vere A RI A -E, was h os pitalize d f or a seiz ure a n d p ulseless electrical 
acti vit y car diac arrest t hat was c o nsi dere d life-t hreate ni n g.  T he s u bject ha d o n g oi n g decrease d 
c o g niti o n a n d f u ncti o n, c o m plicate d b y sec o n dar y i nfecti o n a n d disease pr o gressi o n, a n d 
wit h dre w fr o m t he st u d y.
As of 2 7 N o ve m ber 2 0 1 7, t here were 5 6 e pis o des of A RI A- E (i nitial a n d rec urre nt) i n t he 4 6 
s u bjects.  I n t he maj ority of t he A RI A - E e pis o des ( 4 5/ 5 6), a d uca nu ma b d osi n g was s us pe n de d or 
per ma ne ntl y disc o nti n ue d, pre d o mi na ntl y d ue t o pr ot oc ol -sti p ulate d d ose s us pe nsi o n or 
per ma ne nt disc o nti n uati o n.  T hirtee n of t he 4 5 e pis o des i n w hic h a d uca n u ma b d osi n g was 
s us pe n de d or per ma ne ntl y disc o nti n ue d tra nsie ntl y pr o gresse d i n se verity o n s u bse q ue nt M RI s.  
Se verit y  tre n de d d o w n war d i n 3 0 of t he 4 5 e pis o des.  All e pis o des of A RI A-E e ve nt uall y 
res ol ve d e xce pt f or 2 e pis o des ( o utc o mes were u n k n o w n beca use t he s u bjects were l ost t o 
f oll o w-u p).   Si milarl y , i n 1 1 e pis o des of A RI A - E ( 1 0 mil d a n d 1 m o derate) t hat were d ose d 
t hr o u g h base d o n a n a me n d me nt t o t he pr ot oc ol t hat all o we d c o nti n uati o n of d osi n g at t he 
c urre nt d ose i n prese nce of as y m pt o matic A RI A -E ( mil d M RI  se verit y o nl y), 6 e pis o des 
pr o gresse d i n se verit y o n s u bse q u e nt M RIs bef ore res ol vi n g c o m pletely.  Of t hese, 1 s u bject 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
2 2
c ha n ge d fr o m asy m pt o matic t o s y m pt o matic A RI A - E, a n d t he e pis o de s u bse q ue ntl y res ol ve d.  
T he re mai ni n g 5 e pis o des c o m pletel y  res ol ve d a n d re mai ne d as y m pt o matic .
T o e val uate t he i m pact of A RI A o n c o g niti ve stat us, a p ost h oc a nal ys is of A RI A cases t hat 
occ urre d d uri n g t he place b o- c o ntr olle d peri o d was perf or me d t o e val uate t he c o g niti ve sc ore 
c ha n ges stratifie d b y t he prese nce/a bse nce of A RI A .  T hese data s u g geste d n o a p pare nt 
differe nce i n treat me nt effect i n s u bjects wit h a n d wit h o ut A RI A [Se vi g n y 2 0 1 6 ].
4. 4.     
St u d y R ati o n ale
D uri n g a d uca n u ma b’s cli nical de vel o p me nt, t he para di g m of its d osi n g d uri n g a n d after A RI A 
e ve nts has e v ol ve d o ver t he years.  I n t he o n g oi n g a d uca n u ma b cli nical st u dies ( 2 2 1 A D 1 0 3, 
2 2 1 A D 3 0 1, a n d 2 2 1 A D 3 0 2) , t he pr ot oc ol-defi ne d d osi n g dis p ositi o n ma n dates t hat s u bjects w h o 
are as y m pt o matic wit h mil d se verit y  o n M RI c o nti n ue d osi n g.  Su bjects wit h s y m pt o matic 
A RI A, as well as t h ose wit h as y m pt o matic A RI A t hat is m o derate or se vere o n M RI , te m p oraril y 
s us pe n d or per ma ne ntl y disc o nti n ue d osi n g.  Base d o n t he c urre nt d osi n g re gi me n, data fr o m 
St u d y  2 2 1 A D 1 0 3, alt h o u g h li mite d, ha ve i n dicated t hat c o nti n ui n g d osi n g wit h a d uca n u ma b i n 
s u bjects wit h as ym pt o matic mil d A RI A was n ot ass ociate d wit h cli nicall y si g nifica nt ne gati ve 
o utc o mes (see Secti o n 4. 3. 2. 1. 3 ).  
Data o n t he i m pact of c o nti n ui n g d osi n g d uri n g A RI A e ve nts are a vaila ble fr o m ot her a nti-A β 
m A b trials.  In 3 P hase 2 st u dies of ba pi ne uz u ma b, a m o n g 1 7 % of s u bjects ( 3 6/ 2 1 0) w h o 
de vel o pe d A RI A -E d uri n g treat me nt, t he maj orit y of cases ( 7 8 % [ 2 8/ 3 6]) were as y m pt o matic 
[S perli n g 2 0 1 2 ].  A p ost h oc re vie w re vea le d t hat 4 2 % of asy m pt o matic s u bjects ( 1 5/ 3 6) were 
i de ntifie d as ha vi n g A RI A -E o nl y  d uri n g a retr os pecti ve M RI re-rea d ce ntral re vie w.  Of t hese, 
1 3 s u bjects c o nti n ue d t o recei ve ba pi ne uz u ma b i nf usi o ns w hile A RI A -E was prese nt a n d 
re mai ne d asy m pt o matic. 
I n 2 P hase 3 st u dies of ba pi ne uz u ma b i n s u bjects wit h mil d-t o-m o derate A D, t he maj orit y  of 
A RI A- E cases were as y m pt o matic ( 8 5 % of A p o E ɛ 4 carriers a n d 4 5 % t o 8 4 % of A p o E ɛ 4 
n o ncarriers, de pe n di n g o n t he ba pi ne uz u ma b d ose) [ Sall o wa y  2 0 1 4].  A retr os pecti ve M RI fi nal 
rea d a nalys is i de ntifie d treat me nt-e mer ge nt A RI A -E i n 2 4 2 s u bjects, i ncl u di n g 7 6 a d diti o nal 
cases t hat were n ot detecte d pre vi o usl y [Ketter 2 0 1 7 ].  T he maj orit y of misse d A RI A-E cases 
( 8 8 %) ha d a ra di ol o gical se verity sc ore ≤2, a n d o nl y  1 0 % ha d a se verit y sc ore ≥3.  Of t he t otal 
A RI A- E cases, a p pr o xi matel y  6 4 % of A p o E ɛ 4 carriers a n d 5 2 % of n o ncarriers were d ose d 
t hr o u g h d uri n g a n A RI A-E e ve nt.  F or all A RI A -E cases, ra di ol o gical se verit y  sc ore f or s u bjects 
w h o were d ose d t hr o u g h e ve nts was c o m para ble t o t h ose w h o disc o nti n ue d treat me nt, e xce pt f or 
a hi g her sc ore f or A p o E ɛ 4 n o ncarriers w h o were d ose d t hr o u g h i n t he 0. 5 m g/ k g gr o u p.  T he 
o nl y  differe nce i n t he cli nical prese ntati o n of s u bjects w h o were d ose d t hr o u g h c o m pare d wit h 
t h ose w h o disc o nti n ue d treat me nt was t he d urati o n of t he A RI A-E e pis o des, wit h a s h orter 
d urati o n i n s u bjects w h o disc o nti n ue d.
T he bi ol o gical mec ha nis m of A RI A -E is p o orl y u n derst o o d, b ut p u blis he d h y p ot heses s u g gest 
t hat t he i ncrease d cere br o vasc ular per mea bility c o ul d be ca use d eit her b y i ncrease d a myl oi d 
cleara nce fr o m t he pare nc h yma , lea di n g t o sat urati o n of t he peri vasc ular drai na ge sys te m; a n d/ or 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
2 3
b y  direct a nti b o d y interacti o n wit h de p osite d vasc ular a m yl oi d , lea di n g t o its cleara nce a n d 
wea ke ni n g of t he vessels walls [ S perli n g 2 0 1 2 ; Za g o 2 0 1 3 ].  
N o ncli nical st u dies ai mi n g at u n dersta n di n g mec ha nis m of A RI A -E or A RI A -H ha ve bee n 
c o n d ucte d i n P D A P P mice a n d pr o vi de s u p p orti n g e vi de nce f or c o nti n uati o n of d osi n g.  
Treat me nt wit h t he 3 D 6 a nti b o d y , t he m uri ne pare nt of ba pi ne uz u ma b, i n d uce d cleara nce of 
vasc ular A β t hat was s patiall y  ass ociate d wit h a tra nsie nt i ncrease i n micr o he m orr ha ge a n d i n 
ca pillar y A β de p ositi o n.  T hese data s u g gest t hat vasc ular lea ka ge e ve nts, s uc h as 
micr o he m orr ha ge, ma y  be d ue t o t he re m o val of vasc ular A β.  M ore si g nifica ntl y, t hese st u dies 
de m o nstrate d t hat, u p o n c o nti n uati o n of a nti b o d y treat me nt , vasc ular m or p h ol o g y  was rest ore d 
a n d f urt her vasc ular lea ka ge e ve nts were re d uce d [Za g o 2 0 1 3 ].  A d diti o nal st u dies e m pl o yi n g 
T 1 - wei g hte d M RI sca ns i n P D A P P mice treate d wit h 3 D 6 de m o nstrate d bl o o d-brai n barrier 
lea ka ge occ urri n g earl y d uri n g treat me nt (after 1 t o 4 d oses), bei n g tra nsie nt, a n d res ol vi n g 
s p o nta ne o usl y u p o n c o nti n uati o n of d osi n g [Bl oc k x 2 0 1 6 ].
C ollecti vel y , t hese data i n dicate t hat A RI A, w he n o bser ve d i n s u bjects recei vi n g a nti-A β a ge nts ,
is a m ostl y as ym pt o matic a n d tra nsie nt p he n o me n o n.  T he c urre nt para di g m of s us pe n di n g 
d osi n g d uri n g a n A RI A e ve nt is base d o n ca uti o n rat her t ha n cli nical e vi de nce.  If it c o ul d be 
esta blis he d i n a pr os pecti vel y desi g ne d st u d y t hat c o nti n uati o n of d osi n g wit h a d uca n u ma b i n t he 
a bse nce of s y m pt o ms d oes n ot ha ve cli nicall y i m pactf ul safet y o utc o mes, it w o ul d all o w f or 
m ore c o nsiste nt e x p os ure t o treat me nt, t here b y p ote ntiall y  e n ha nci n g be nefit t o t he s u bjects wit h 
A D treate d wit h a d uca n u ma b.   T his st u d y  will e val uate t he safet y i m pact of c o nti n ui n g d osi n g i n 
as ym pt o matic s u bjects wit h A RI A i n a 2 -sta ge a p pr oac h.  I nitially (i n Sta ge 1), i n o ne ar m of t he 
st u d y ( Gro u p 2), s u bjects wit h o nl y mil d t o m o derate asy m pt o matic A RI A will be d ose d 
t hr o u g h; it is pla n ne d t hat t he i m pact of c o nti n ui n g d osi n g d uri n g as y m pt o matic A RI A e ve nts
re gar dless of M RI se verit y (e xce pt A RI A -H [ macr o he m orr ha ge]) will be assesse d i n Sta ge 2, 
c o nti n ge nt u p o n D S M C rec o m me n dati o n after a re vie w of t he data ( Secti o n 1 9. 2. 2 ).


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of Bi o ge n M A
I nc.
2 4
5.        
S C H E D U L E O F A C TI VI TI E S
T a ble 1:      
Sc he d ule of Acti vities:  R a n d o mize d Tre at me nt Peri o d
Scree ni n g 
Visit
≤6 0 D a ys of 
D a y 1 1
R a n d o mize d Tre at me nt Peri o d ( Wee ks ± 3 d a ys)
U V f or 
A RI A 2
U V f or 
C h a n ge i n 
A D
Me dic ati o n
3
F U 4
Wee ks
V
1
V 2       V
3
1
D 1
2 4  6  8   1 0    1 2     1
4
1 6     1 8    2 0     2
2
2 4     2 6    2 8    3 0     
3 2      3
6
4 0     
4 4      4
8
5 2        5 4
E O T 5
7 0
± 7 d
Assess me nts
I nitial Scree ni n g 
C o nse nt 6
( o pti o nal)
X
F ull I nf or me d 
C o nse nt 7
X
X 8
Eli gi bilit y 
Criteria
X     
X       X
X 9
X 8
De m o gra p h y        
X
Me dical Hist or y     
X     
X       X
Alc o h ol/ Dr u g 
Scree n
X
HI V 1 0 / He patitis/
C oa g ulati o n
X
H b A 1c
X
Li pi d pa nel        
X
Hei g ht
X
B o d y Wei g ht        
X
X          
X        X          
X          
X          
X          
X          
X          
X      X     X       X      X     X
X
Ser u m 
Pre g na nc y 
Test 1 1
X


P r ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of Bi o ge n M A  I nc.
2 5
Scree ni n g 
Visit
≤6 0 D a ys of 
D a y 1 1
R a n d o mize d Tre at me nt Peri o d ( Wee ks ± 3 d a ys)
U V f or 
A RI A 2
U V f or 
C h a n ge i n 
A D
Me dic ati o n
3
F U 4
Wee ks
V
1
V 2       V
3
1
D 1
2 4  6  8   1 0    1 2     1
4
1 6     1 8    2 0     2
2
2 4     2 6    2 8    3 0     
3 2      3
6
4 0     
4 4      4
8
5 2        5 4
E O T 5
7 0
± 7 d
Assess me nts
Uri ne Pre g na nc y 
Test 1 1
X          
X        X          
X          
X          
X          
X          
X          
X      X     X       X      X     X
X
Ra n d o mizati o n
X
St u d y Treat me nt 
I nf usi o n
X          
X        X          
X          
X          
X          
X          
X          
X      X     X       X      X     X
F oll o w -u p 
tele p h o ne call
X       
X         X          
X          
X          
X          
X          
X
A β P ositi vit y 
( P E T)1
X
Brai n M RI (p ost 
Da y 1 ce ntral rea d 
res ult m ust be 
a vaila ble bef ore 
i nf usi o n)
X 1 ,1 2
X 1 2
X 1 2
X 1 2
X 1 2
X 1 2
X
Ne ur ol o gical 
Assess me nt
X
X
X
X
X 
X
X          
X
X
P h ysical 
E xa mi nati o n
X
X
X
X
X
X          
X
X
Vital Si g ns 1 3
X
X          
X        X          
X          
X          
X          
X          
X          
X      X     X       X      X     X
X
1 2 -lea d Pa per 
E C G
X
X
X
X
X
He mat ol o g y, 
Bl o o d 
C he mistr y, a n d 
Uri nal ysis
X
X
X
X
X
C D R
X
M M S E
X
X
X


P r ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of Bi o ge n M A  I nc.
2 6
Scree ni n g 
Visit
≤6 0 D a ys of 
D a y 1 1
R a n d o mize d Tre at me nt Peri o d ( Wee ks ± 3 d a ys)
U V f or 
A RI A 2
U V f or 
C h a n ge i n 
A D
Me dic ati o n
3
F U 4
Wee ks
V
1
V 2       V
3
1
D 1
2 4  6  8   1 0    1 2     1
4
1 6     1 8    2 0     2
2
2 4     2 6    2 8    3 0     
3 2      3
6
4 0     
4 4      4
8
5 2        5 4
E O T 5
7 0
± 7 d
Assess me nts
M o C A
X
X
X
X
X
X          
X
C- S S R S
X
X
X
A p o E 
Ge n ot y pi n g 9
X
E C o g ( O bser ver 
o nl y) 1 4
a n y scree ni n g 
visit
D S S T/trail 
ma ki n g 
( o pti o nal)1 4
a n y 2 
scree ni n g 
visits
W h ole bl o o d f or 
D N A 
( o pti o nal)1 5
X
A nti -
A d uca n u ma b 
A b 1 6
X
X
X
X
X
X
X
A d uca n u ma b 
C o nce ntrati o n 1 7
X
X
X
X
X
X          
X
X
A E 
Re p orti n g 1 9, 2 0
X     
X 
X  X  X   X      X     X      X       X      X     
X      X       X      X      X       X      X     X       X      X     X          X          
X          
X          
X
C o nc o mita nt 
T hera p y a n d 
Pr oce d ures
M o nit or a n d rec or d c o nti n u o usl y t hr o u g h o ut t he st u d y
S A E Re p orti n g
M o nit or a n d rec or d c o nti n u o usl y t hr o u g h o ut t he st u d y


P r ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of Bi o ge n M A  I nc.
2 7
Scree ni n g 
Visit
≤6 0 D a ys of 
D a y 1 1
R a n d o mize d Tre at me nt Peri o d ( Wee ks ± 3 d a ys)
U V f or 
A RI A 2
U V f or 
C h a n ge i n 
A D
Me dic ati o n
3
F U 4
Wee ks
V
1
V 2       V
3
1
D 1
2 4  6  8   1 0    1 2     1
4
1 6     1 8    2 0     2
2
2 4     2 6    2 8    3 0     
3 2      3
6
4 0     
4 4      4
8
5 2        5 4
E O T 5
7 0
± 7 d
Assess me nts
A β = a m yl oi d -beta ; A b = a nti b o d y;  A D = Alz hei mer’s disease; A E = a d verse e ve nt; A p o E = a p oli p o pr otei n E; A RI A = a m yl oi d-relate d i ma gi n g a b n or malities; C D R = Cli nical De me ntia 
Rati n g; C -S S R S = C ol u m bia S uici de Se verit y Rati n g Scale; D = da y; D N A = de o x yri b o n ucleic aci d; D S S T = Di gital S y m b ol S u bstit uti o n Test; E C G = electr ocar di o gra m;  E C o g = 
E ver y da y C o g niti o n; E O T = E n d of Treat me nt; F U = F oll o w -U p; H b A 1c = gl yc os ylate d he m o gl o bi n; HI V = h u ma n i m m u n o deficie nc y vir us; L T E = l o n g-ter m e xte nsi o n; M M S E = Mi ni-
Me ntal State E xa mi nati o n; M o C A = M o ntreal C o g niti ve Assess me nt; M RI = ma g netic res o na nce i ma gi n g; P E T =
p ositr o n e missi o n t o m o gra p h y; S A E = seri o us a d verse e ve nt; U V = 
u nsc he d ule d visit; V = visit.
1E xa mi nat i o n re q uire d f or assess me nt of s u bject eli gi bilit y m ust be perf or me d at Scree ni n g V 1.  Brai n M RI s h o ul d be perf or me d o nl y after t he s u bject meets 
eli gi bilit y criteria at V 1.  A m yl oi d P E T s h o ul d be perf or me d o nl y if t he s u bject meets eli gi bilit y criteria at V 1 a n d V 2.  It is rec o m me n de d t hat all scree ni n g 
pr oce d ures be c o m plete d w it hi n 6 0 da ys; h o we ver, t he o verall scree ni n g peri o d ma y be e xte n de d u p t o 9 0 da ys i n t he e ve nt of lo gistical iss ues.
2S u bjects wit h c o nfir me d A RI A o n M RI s h o ul d ha ve t he u nsc he d ule d visit f or A RI A e ver y 4 w ee ks ( ± 5 da ys) u ntil t he A RI A ha ve res ol ve d or sta bilize d per t he 
ce ntrall y rea d M RI.
3T he U V s h o ul d occ ur bef ore t he c ha n ge i n A D me dicati o n. If t his is n ot p ossi ble, M M S E a n d A E assess me nts s h o ul d be d o ne at t he s u bject's ne xt sc he d ule d 
visit.
4S u bjects w h o c o m plete t he ra n d o mize d treat me nt peri o d a n d d o n ot e nter t he L T E are t o ret ur n t o t he site f or a safet y f oll o w -u p at Wee k 7 0.  S u bjects w h o 
per ma ne ntl y disc o nti n ue treat me nt or disc o nti n ue acti ve d osi n g wit h o ut recei vi n g plac e b o or w h o wit h dra w  fr o m t he st u d y pre mat urel y are t o ha ve a safet y 
f oll o w- u p a p pr o xi matel y 1 8 wee ks after t heir fi nal d ose.
5Wee k 5 4 is
t he last visit f or t he ra n d o mize d treat me nt peri o d f or s u bjects e nteri n g t he L T E.  S u bjects w h o per ma ne ntl y disc o nti n ue treat me nt ( d ue t o A RI A or 
ot her reas o ns) are t o re mai n i n t he st u d y a n d f oll o w a m o difie d sc he d ule f or tests a n d assess me nts u ntil t he e n d of t he st u d y peri o d or wit h dra wal of c o nse nt 
(T a ble 4 ).  T he o nl y e xce pti o n is a s u bject w h o ma y de vel o p se vere as y m pt o matic A RI A -H ( micr o he m orr ha ge, s u perficial si der osis) i n Sta ge 2; s uc h a s u bject 
is t o f oll o w t he re g ular visit sc he d ule (Ta ble 1 ) t o mai ntai n t he bli n d t o t he s u bject’s gr o u p assi g n me nt ( Secti o n 1 1. 2. 1. 2 ; T a ble 6) .  S u bjects w h o wit h dra w  
fr o m t he st u d y pre mat urel y are t o ret ur n t o t he site f or a n E O T Visit 2 w ee ks after t heir fi nal d ose.
6S u bjects ma y si g n t his o pti o nal f or m f or a n i nitial scree ni n g t hat all o ws a d mi nistrati o n of t he C D R a n d M M S E o nl y, as well as A p o E ge n ot y pi n g.
7All s u bjects m ust si g n t his i nf or me d c o nse nt, i ncl u di n g s u bjects w h o ha ve si g ne d t he o pti o nal i nitial scree ni n g c o nse nt, o nce t he y ha ve met t he C D R a n d M M S E 
eli gi bilit y criteria.
8O nl y f or s u bjects e nteri n g t he L T E.
9All assess me nts, i ncl u di n g t he C-S S R S, m ust be c o m plete d bef ore st u d y treat me nt a d mi nistrati o n, e xce pt t he p ost d ose sa m ple t o meas ure a d uca n u ma b 
c o nce ntrati o n.  T he A p o E ge n ot y pi n g res ult m ust be a vaila ble pri or t o ra n d o mizati o n.
1 0 HI V testi n g is at t he I n vesti gat or’s discreti o n a fter c o nsi derati o n of ris k fact ors.
1 1 Re q uire d f or w o m e n of c hil d beari n g p ote ntial o nl y.  A ne gati ve uri ne pre g na nc y test res ult is re q uire d pri or t o eac h i nf usi o n.
1 2 M RI sca n ca n be perf or me d u p t o 1 4 da ys pri or t o t he cli nic visit.  Ce ntral M RI rea d res ults s h o ul d be a vaila ble at t he ti me of t he visit.




Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of Bi o ge n M A
I nc.
2 9
T a ble 2:      
Sc he d ule of Acti vities: L o n g -Ter m E xte nsi o n Peri o d Fr o m Wee k 5 6 T hr o u g h Wee k 1 0 4
L o n g -Ter m E xte nsi o n Peri o d ( Wee ks ± 5 d a ys )
U V f or 
A RI A 1
U V f or 
C h a n ge i n 
A D 
Me dic ati o n
2
Assess me nts
5 6     
6 0     
6 4     
6 8     
7 2     
7 6      
8 0      
8 4     
8 8     
9 2     
9 6     
1 0 0     
1 0 4 
B o d y  Wei g ht
X        
X        
X        
X        
X        
X         
X         
X        
X        
X        
X         
X          X
Uri ne Pre g na nc y Test 3
X        
X        
X        
X        
X        
X         
X         
X        
X        
X        
X         
X          X
St u d y Treat me nt I nf usi o n     
X        
X        
X        
X        
X        
X         
X         
X        
X        
X        
X         
X          X
Brai n M RI ( p ost Da y 1 
ce ntral rea d res ult m ust 
be a vaila ble bef ore 
i nf usi o n)
X 4
X 4
X
P h y sical E xa mi nati o n
X
X          
X
Ne ur ol o gical Assess me nt
X
X          
X
Vital Si g ns 5
X        
X        
X        
X        
X        
X         
X         
X        
X        
X        
X         
X          X
1 2 -lea d Pa per E C G        
X
X
X
He m at ol o g y, Bl o o d 
C he mistr y, a n d 
Uri nal ysis
X
X
X
A d uca n u ma b 
C o nce ntrati o n 6
X
X
X
A nti -A d uca n u ma b A b 6
X
X
X
M M S E
X
X
M o C A
X
X          
X
C- S S R S
X
X
A E Re p orti n g 7 ,8
X        
X        
X        
X        
X        
X         
X         
X        
X        
X        
X         
X          X          
X          
X


P r ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of Bi o ge n M A  I nc.
3 0
L o n g- Ter m E xte nsi o n Peri o d ( Wee ks ± 5 d a ys )
U V f or 
A RI A 1
U V f or 
C h a n ge i n 
A D 
Me dic ati o n
2
Assess me nts
5 6     
6 0     
6 4     
6 8     
7 2     
7 6      
8 0      
8 4     
8 8     
9 2     
9 6     
1 0 0     
1 0 4 
C o nc o mita nt T hera p y 
a n d Pr oce d ures
M o nit or a n d rec or d c o nti n u o usl y t hr o u g h o ut t he st u d y
S A E Re p orti n g
M o nit or a n d rec or d c o nti n u o usl y t hr o u g h o ut t he st u d y
A b = a nti b o d y; A D = Alz hei mer’s disease; A E = a d verse e ve nt; A RI A = a m yl oi d -relate d i ma gi n g a b n or malities; C-S S R S = C ol u m bia S uici de Se verit y 
Rati n g Scale; D = da y ; E C G = electr ocar di o gra m; M M S E = Mi ni -Me ntal State E xa mi nati o n; M o C A = M o ntreal C o g niti ve Assess me nt; M RI = ma g netic 
res o na nce i ma gi n g; S A E = seri o us a d verse e ve nt; U V = u nsc he d ule d visit.
1S u bjects wit h c o nfir me d A RI A o n M RI s h o ul d ha ve t he U V f or A RI A e ver y 4 wee ks ( ± 5 da ys) u ntil t he A RI A have res ol ve d or sta bilize d per t he ce ntrall y rea d 
M RI.
2T he U V s h o ul d occ ur bef ore t he c ha n ge i n A D me dicati o n. If t his is n ot p ossi ble, M M S E a n d A E assess me nts s h o ul d be d o ne at t he s u bject's ne xt sc he d ule d 
visit.
3Re q uire d f or w o m e n of c hild beari n g p ote ntial o nl y.  A ne gati ve res ult is re q uire d pri or t o eac h i nf usi o n.
4M RI sca n ca n be perf or me d u p t o 1 4 da ys pri or t o t he cli nic visit.  Ce ntral M RI rea d res ults s h o ul d be a vaila ble at t he ti me of t he visit.
5Vital si g ns will i ncl u de s yst olic bl o o d press ure, diast olic bl o o d press ure, heart rate, b o d y te m perat ure, a n d res pirat or y rate.  Vital si g ns will be meas ure d w it h t he 
s u bject s u pi ne a n d after t he s u bject has bee n resti n g f or at least 1 0 mi n utes.
6Bl o o d sa m pli n g f or a d uca n u ma b c o nce ntrati o n will be perf or me d pri or t o i nf usi o n.  F or s u bjects w h o per ma ne ntl y disc o nti n ue treat me nt a n d re mai n i n t he 
st u d y, or w h o disc o nti n ue acti ve d osi n g a n d recei ve place b o, t he fi nal a d uca n u ma b c o nce ntrati o n sa m ple will be c ollecte d at the s u bject’s ne xt visit .
7A E s will be c ollecte d pri or t o eac h i nf usi o n.  B ot h t he s u bject a n d t he i nf or ma nt/care part ner are re q uire d t o partici pate i n t he cli nical i nter vie w pri or t o eac h 
i nf usi o n.  If t he i nf or ma nt/care part ner ca n n ot visit t he cli nic i n pers o n, a p h o ne c o n versati o n wit h t he i n de pe n de nt cli nical assess or is acce pta ble.
8A n y A E s u g gesti ve or p ote ntiall y c o nsi dere d t o be relate d t o A RI A, as per t he cli nical j u d g me nt of t he i n de pe n de nt cli nical a ssess or s h o ul d be e val uate d f urt her 
b y detaile d ne ur ol o gical assess me nt a n d l ocal sta n dar d of care.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of Bi o ge n M A
I nc.
3 1
T a ble 3:      
Sc he d ule of Acti vities: L o n g -Ter m E xte nsi o n Peri o d Fr o m Wee k 1 0 8 T hr o u g h F oll o w -U p
L o n g -Ter m E xte nsi o n Peri o d ( Wee ks ± 5 d a ys)
U V
f or 
A RI A 1
U V f or 
C h a n ge i n 
A D 
Me dic ati o n
2
F U 3
Assess me nts
1 0 8   
1 1 2   
1 1 6   
1 2 0   
1 2 4   
1 2 8   
1 3 2   
1 3 6   
1 4 0   
1 4 4   
1 4 8   
1 5 2    
1 5 6       
1 5 8
E O T 4
1 7 4 
± 7 d
B o d y  Wei g ht
X        
X        X        X        X        X        X        X        X        X        X        X         
X          
X
X
Uri ne Pre g na nc y Test
5
X        
X        X        X        X        X        X        X        X        X        X        X         
X          
X
X
St u d y Treat me nt 
I nf usi o n
X        
X        X        X        X        X        X        X        X        X        X        X         
X
Brai n M RI
( p ost Da y 1 
ce ntral rea d res ult m ust be 
a vaila ble bef ore i nf usi o n)
X 6
X 6
X
P h y sical E xa mi nati o n
X
X          
X
X
Ne ur ol o gical 
Assess me nt
X
X          
X
X
Vital Si g ns 7
X        
X        X        X        X        X        X        X        X        X        X        X         
X          
X
X
1 2 -lea d Pa per E C G        
X
X
X
X
He m at ol o g y, Bl o o d 
C he mistr y, a n d 
Uri nal ysis
X
X
X
X
A d uca n u ma b 
C o nce ntrati o n 8
X
X
X
A nti -A d uca n u ma b A b 8
X
X
X
M M S E
X
X
M o C A
X
X          
X
C- S S R S
X
X


P r ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of Bi o ge n M A  I nc.
3 2
L o n g- Ter m E xte nsi o n Peri o d ( Wee ks ± 5 d a ys)
U V
f or 
A RI A 1
U V f or 
C h a n ge i n 
A D 
Me dic ati o n
2
F U 3
Assess me nts
1 0 8   
1 1 2   
1 1 6   
1 2 0   
1 2 4   
1 2 8   
1 3 2   
1 3 6   
1 4 0   
1 4 4   
1 4 8   
1 5 2    
1 5 6       
1 5 8
E O T 4
1 7 4 
± 7 d
A E Re p orti n g 9 ,1 0
X        
X        X        X        X        X        X        X        X        X        X        X         
X          
X          
X          
X          
X
C o nc o mita nt T hera p y 
a n d Pr oce d ures
M o nit or a n d rec or d c o nti n u o usl y t hr o u g h o ut t he st u d y
S A E Re p orti n g
M o nit or a n d rec or d c o nti n u o usl y t hr o u g h o ut t he st u d y
A b = a nti b o d y; A D = Alz hei mer’s disease; A E = a d verse e ve nt; A RI A = a m yl oi d -relate d i ma gi n g a b n or malities; C-S S R S = C ol u m bia S uici de Se verit y Rati n g 
Scale; D = da y s; E C G = electr ocar di o gra m; E O T = E n d of Treat me nt; F U = F oll o w-U p; M M S E = Mi ni -Me ntal State E xa mi nati o n; H C P = healt h care 
pr ofessi o nal; M o C A = M o ntreal C o g niti ve Assess me nt; M RI = ma g netic res o na nce i ma gi n g; S A E = seri o us a d verse e ve nt; U V = u nsc he d ule d visit.
1 S u bjects wit h c o nfir me d A RI A o n M RI, s h o ul d ha ve t he U V f or A RI A e ver y 4 wee ks ( ± 5 da ys) u ntil t he A RI A have res ol ve d or sta bilize d per t he ce ntrall y 
rea d M RI.
2U V s h o ul d occ ur bef ore t he c ha n ge i n A D me dicati o n. If t his is n ot p ossi ble, M M S E a n d A E assess me nts s h o ul d be d o ne at t he s u bject's ne xt sc he d ule d visit.
3S u bjects w h o c o m plete t he L T E peri o d are t o ret ur n t o t he site f or a fi nal safet y f oll o w -u p at Wee k 1 7 4.  S u bjects w h o per ma ne ntl y disc o nti n ue treat me nt or 
wit h dra w fr o m t he st u d y earl y are t o ha ve a safet y f oll o w -u p visit at 1 8 wee ks after t heir fi nal d ose.
4Wee k 1 5 8 is t he last visit i n t he L T E.  S u bjects w h o per ma ne ntl y disc o nti n ue treat me nt are t o re mai n i n t he st u d y a n d f oll o w  a mo difie d sc he d ule f or tests a n d 
assess me nts u ntil t he e n d of t he st u d y peri o d or wit h dra wal of c o nse nt ( Ta ble 4 ).  S u bjects w h o wit h dra w fr o m t he st u d y pre mat urel y are t o ret ur n t o t he site f or 
a n E O T Visit 2 w ee ks after t heir fi nal d ose.
5Re q uire d f or w o m e n of c hil d beari n g p ote ntial o nl y.  A ne gati ve res ult is re q uire d pri or t o eac h i nf usi o n.
6M RI sca n ca n be perf or me d u p t o 1 4 da ys pri or t o t he cli nic visit.  Ce ntral M RI rea d res ults s h o ul d be a vaila ble at t he ti me of t he visit.
7Vital si g ns will i ncl u de s yst olic bl o o d press ure, diast olic bl o o d press ure, heart rate, b o d y te m perat ure, a n d res pirat or y rat e.  Vital si g ns wil l be meas ure d wit h t he 
s u bject s u pi ne a n d after t he s u bject has bee n resti n g f or at least 1 0 mi n utes.
8Bl o o d sa m pli n g f or a d uca n u ma b c o nce ntrati o n will be perf or me d pri or t o i nf usi o n.  N ote:  F or s u bjects w h o per ma ne ntl y disc o nti n ue treat me nt a n d c o nti n ue i n 
t he st u d y, t he fi nal a d uca n u ma b c o nce ntrati o n sa m ple will be c ollecte d at t he s u bject’s ne xt visit.
9A E s will be c ollecte d pri or t o eac h i nf usi o n.  B ot h t he s u bject a n d t he i nf or ma nt/care part ner are re q uire d d uri n g t he cli nic al i nter vie w pri or t o eac h i nf usi o n.  If 
t he i nf or ma nt/care part ner ca n n ot visit t he cli nic i n pers o n, a p h o ne c o n versati o n wit h t he i n de pe n de nt cli nical assess or is acce pta ble.
1 0 A n y A E s u g gesti ve or p ote ntiall y c o nsi dere d t o be relate d t o A RI A, as per t he cli nical j u d g me nt of t he i n de pe n de nt cli nical assess or s h o ul d be e val uate d f urt her 
b y detaile d ne ur ol o gical assess me nt a n d l ocal sta n dar d of care.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
3 3
T a ble 4:      
Sc he d ule of Acti vities: S u bjects W h o Per m a ne ntl y Disc o nti n ue Tre at me n t 
a n d Re m ai n i n t he St u d y
Assess me nts
Visits f or 
S u bjects W h o
Disc o nti n u e 
Tre at m e nt 1
F U P h o ne 
C all 2
U V
f or 
A RI A 3
F U 4
B o d y  Wei g ht
X
Uri ne Pre g na nc y Test
5
X
Brai n M RI
X
P h y sical E xa mi nati o n
X
X          
X
Ne ur ol o gical Assess me nt
X
X          
X
Vital Si g ns 6
X
X
1 2 -lea d Pa per E C G
X
He m at ol o g y, Bl o o d C he mistr y, a n d Uri nal ysis
X
X
M o C A
X
A E Re p orti n g
X
X          
X          
X
C o nc o mita nt T hera p y a n d Pr oce d ures
X
X          
X          
X
S A E Re p orti n g
X
X          
X          
X
A E = a d verse e ve nt; A RI A = a m yl oi d-relate d i ma gi n g a b n or malities; E C G = electr ocar di o gra m; F U = 
F oll o w -U p; M o C A = M o ntreal C o g niti ve Assess me nt; M RI = ma g netic res o na nce i ma gi n g; S A E = seri o us 
a d verse e ve nt; U V = u nsc he d ule d visit.
1S u bjects w h o per ma ne ntl y disc o nti n ue treat me nt are t o re mai n i n t he st u d y a n d ha ve a visit 1 2 w ee ks after t heir 
fi nal d ose a n d e ver y 6 m o nt hs after t he safet y f oll o w-u p ( 1 8 wee ks after t heir fi nal d ose), u ntil t he e n d of st u d y or 
wit h dra wal of c o nse nt.  It is p ossi ble t hat a cli nic visit will occ ur bef ore t he F U Visit.  If t he F U Visit will occ ur 
wit hi n 2 wee ks of a sc he d ule d cli nic visit, t he n t he F U Visit ca n be c o m bi ne d wit h t he sc he d ule d visit a n d all 
assess me nts re q uire d f or b ot h visits perf or me d at t his si n gle visit.   N ote:  S u bjects w h o de vel o p s e vere 
as y m pt o matic A RI A-H i n Sta ge 2 (i n t he ra n d o mize d treat me nt peri o d) are t o f oll o w  t he re g ular visit sc he d ule per 
Ta ble 1 i n or der t o mai ntai n t he bli n d, e ve n t h o u g h t he y ma y ha ve per m a ne ntl y disc o nti n ue d acti ve d osi n g a n d are 
recei vi n g place b o ( Secti o n 1 1. 2. 1. 2 ; T a ble 6 ).
2After t he first visit perf or me d 1 2 w ee ks after t he fi nal d ose, s u bjects will c o nti n ue t o be f oll o we d u p wit h a p h o ne 
call e ver y 1 2 wee ks u ntil t he e n d of t he st u d y or w it h dra wal of c o nse nt.
3S u bjects wit h c o nfir me d A RI A o n M R I s h o ul d ha ve t he u nsc he d ule d visit f or A RI A e ver y 4 wee ks ( ± 5 da ys) u ntil 
t he A RI A have res ol ve d or sta bilize d per t he ce ntrall y rea d M RI.
4S u bjects are t o ha ve a safet y f oll o w - u p visit at 1 8 wee ks after t heir fi nal d ose.
5Re q uire d f or w o m e n of c hil d bearin g p ote ntial o nl y.
6Vital si g ns will i ncl u de s yst olic bl o o d press ure, diast olic bl o o d press ure, heart rate, b o d y te m perat u re, a n d 
res pirat or y rate.  Vital si g ns will be meas ure d wit h t he s u bject s u pi ne a n d after t he s u bject has bee n resti n g f or at 
least 1 0 mi n utes.




P r ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
3 5
A n y  a d diti o nal sa m ples t hat are c ollecte d u n der se parate o pti o nal c o nse nt ma y  be use d f or f ut ure 
scie ntific a n d ge netic researc h.  O bjecti ves relate d t o t his f ut ure researc h ha ve n ot bee n 
deter mi ne d.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 6
7.        
S T U D Y D E SI G N
T his is a P hase 2, m ultice nter, ra n d o mize d, p arallel-gr o u p , d o u ble -bli n d, c o ntr olle d st u d y t o 
assess t he safet y of c o nti n ui n g a d uca n u ma b d osi n g i n s u bjects wit h M CI d ue t o A D or mil d A D 
de me ntia w h o e x perie nce as y m pt o matic A RI A.   T his st u d y  will i nitiall y (i n Sta ge 1) assess t he 
safety of c o nti n ue d d osi n g as c o m pare d wit h d ose s us pe nsi o n i n as y m pt o matic mil d t o m o derate 
A RI A t hr o u g h a m o difie d ma na ge me nt pla n b ut a si milar m o nit ori n g pla n as t he o n g oi n g P hase 
3 st u dies ( St u dies 2 2 1 A D 3 0 1 a n d 2 2 1 A D 3 0 2) .  It is pla n ne d t hat t he safet y of c o nti n ue d d osi n g 
i n se vere cases will be assesse d i n Sta ge 2, c o nti n ge nt u p o n D S M C rec o m me n dati o n after a 
re vie w of t he Sta ge 1 data ( Secti o n 1 9. 2. 2 ).
A p pr o xi matel y  5 0 0 s u bjects a ge d 5 0 t o 8 5 years, i ncl usi ve, will be e nr olle d at a p pr o xi matel y 9 5 
sites gl o bally.  All s u bjects will recei ve i nf usi o ns of a d uca n u ma b e ver y  4 wee ks f or 5 2 wee ks 
d uri n g t he ra n d o mize d treat me nt peri o d. T he d ose will be titrate d fr o m 1 m g/ k g t o 1 0 m g/ k g ( 1 
m g/ k g f or t he first 2 i nf usi o ns, 3 m g/ k g f or t he ne xt 2 i nf u si o ns, 6 m g/ k g f or t he ne xt 2 i nf usi o ns, 
a n d 1 0 m g/ k g t hereafter).  
Eli gi ble s u bjects w ill be ra n d o mize d ( 1: 1) at Da y 1 t o 1 of 2 gr o u ps t hat differ i n ter ms of t he 
m a n a ge me nt of asy m pt o m atic A RI A , as s u m marize d bel o w.  T he ra n d o mizati o n will be stratifie d 
b y  A p o E ε 4 stat us (carrier or n o ncarrier).  T he rati o of A p o E ε 4 carriers t o n o ncarriers i n t he 
st u d y p o p ulati o n will ge nerally reflect t he distri b uti o n i n t he br oa der A D p o p ulati o n.  
Gr o u p 1 :  
C o nti n uati o n o f d osi n g i n as ym pt o matic A RI A c o nti n ge nt u p o n i ma gi n g se verity, c o nsiste nt 
wit h d ose dis p ositi o n i n o n g oi n g P hase 3 trials, as descri be d bel o w ( see Secti o n 1 1. 2. 1 f or 
details):

Mil d se verit y  o n M RI:  C o nti n ue d osi n g 

M o derate se verit y o n M RI :  S us pe n d d osi n g

Se vere o n M RI:   S us pe n d d osi n g ( A RI A-E)  or per m a ne ntly disc o nti n ue d osi n g
( A RI A-H [ micr o he m orr h a ge , s u perfici al si der osis])
Gr o u p 2 :  
C o nti n uati o n of d osi n g i n as ym pt o matic A RI A re g ar dless of i ma gi n g se verit y, t o be 
i m ple me nte d i n a 2-sta ge a p pr oac h, as descri be d bel o w (s ee Secti o n 1 1. 2. 1 f or details):
Sta ge 1 (fr o m start of trial):

Mil d or m o derate se verit y o n M RI:   C o nti n ue d osi n g 

Se vere o n M RI:   S us pe n d d osi n g ( A RI A-E)  or per m a ne ntly disc o nti n ue d osi n g 
( A RI A-H [ micr o he m orr h a ge, s u perfici al si der os is])


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
3 7
Sta ge 2 ( c o nti n ge nt o n D S M C rec o m me n dati o n base d o n re vie w of t he Sta ge 1 data, 
Secti o n 1 9. 2. 2 )

A n y  se verity of M RI:  C o nti n ue d osi n g 
N ote:  T o mai ntai n t he bli n d, place b o will be gi ve n t o Gr o u p 1 s u bjects i n pres pecifie d cases of 
d ose s us pe nsi o n/ disc o nti n uati o n d ue t o as y m pt o matic A RI A i n b ot h Sta ges 1 a n d 2 (f or details 
see Secti o ns 1 1. 2. 1. 1 a n d 1 1. 2. 1. 2 ).
Ma na ge me nt of s y m pt o matic A RI A (a n y  se verit y of M RI) a n d ma na ge me nt of A RI A-H 
( macr o he m orr ha ge) will be t he s a me i n Gr o u p s 1 a n d 2 a n d will be ge nerall y c o nsiste nt wit h t hat 
i n t he o n g oi n g P hase 3 pr o gra m, as f oll o ws:
T hr o u g h o ut t he st u d y, Gr o u p 1 a n d Gr o u p 2:

S y m pt o matic A RI A, a n y  se verity o n M RI :

S us pe n d or per m a ne ntly disc o nti n ue tre at me nt

A RI A- H ( macr o he m orr ha ge) wit h or wit h o ut s y m pt o ms 

Per m a ne ntly disc o nti n u e tre at me nt
At t he e n d of t he 5 2- wee k ra n d o mize d , c o ntr olle d treat me nt peri o d, s u bjects w h o meet e ntr y  
criteria ma y  e nter a n o ptio nal L T E peri o d i n w hic h s u bjects will c o nti n ue t o recei ve i nf usi o ns of 
a d uca n u ma b at 1 0 m g/ k g e ver y 4 wee ks f or a n a d diti o nal 1 0 4 wee ks (a t otal of 4 0 d oses).  
D uri n g t his ti me, as y m pt o matic A RI A i n all s u bjects will be ma na ge d acc or di n g t o t he pla n 
descr i be d f or Gr o u p 2.
See Fi g ure 1 f or a sc he matic of t he st u d y desi g n.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects wit h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
3 8
Fi g ure 1:     
Sc he m atic of St u d y Desi g n
* T his st u d y will e val uate t he safet y i m pact of c o nti n ui n g d osi n g i n as y m pt o matic s u bjects wit h A RI A i n a 2 -sta ge 
a p pr oac h.  I n Sta ge 1, Gr o u p 2 s u bjects wit h mil d t o m o derate as y m pt o matic A RI A will be d ose d t hr o u g h; it is 
pla n ne d t hat t he i m pact of c o nti nui n g d osi n g d uri n g as y m pt o matic A RI A t hat is mil d, m o derate, or se vere o n M RI 
(e xcl u di n g A RI A-H [ m acr o he m orr ha ge]) will be assesse d i n Sta ge 2, c o nti n ge nt u p o n D S M C rec o m me n dati o n after 
a re vie w of Sta ge 1 data.
N ote: All s u bjects are t o recei ve titrati o n t o 1 0 m g/ k g ( 2 d oses of 1 m g/ k g, t he n 2 d oses of 3 m g/ k g, t he n 2 d oses of 
6 m g/ k g, t he n 1 0 m g/ k g t hereafter ). 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
3 9
7. 1.     
St u d y D ur ati o n f or S u bjects
T he t otal d urati o n of st u d y  partici pati o n f or a n y gi ve n s u bject partici pati n g i n o nl y  t he 
ra n d o mize d treat me nt peri o d will be a p pr o xi matel y  7 8 wee ks, i ncl u di n g a series of scree ni n g 
visits wit hi n 6 0 da y s bef ore a d mi nistrati o n of t he first d ose, a 5 2-wee k treat me nt peri o d, a n d a 
safety f oll o w -u p ( F U) a p pr o xi matel y  1 8 wee ks after t he fi nal d ose. 
T he t otal d urati o n o f st u d y partici pati o n f or a n y gi ve n s u bject partici pati n g i n b ot h t he 
ra n d o mize d treat me nt peri o d a n d t he L T E peri o d will be a p pr o xi matel y 1 8 6 wee ks, i ncl u di n g a 
series of scree ni n g visits wit hi n 6 0 da ys bef ore a d mi nistrati o n of t he first d ose, a 5 2- wee k 
ra n d o mize d treat me nt peri o d, a 4- wee k F U peri o d, a 1 0 4 - wee k L T E treat me nt peri o d, a n d a 
safety f oll o w -u p a p pr o xi matel y  1 8 wee ks after t he fi nal d ose.
S u bjects w h o per ma ne ntl y  disc o nti n ue treat me nt are t o re mai n i n t he st u d y  a n d f oll o w a 
m o difie d sc he d ule f o r tests a n d assess me nts u ntil t he e n d of st u d y  or wit h dra wal of c o nse nt 
(Ta ble 4 ).  S u bjects w h o wit h dra w fr om t he st u d y  are t o ret ur n f or a safet y f oll o w-u p 
a p pr o xi matel y 1 8 wee ks after t heir last d ose of st u d y  treat me nt.  T he o nl y e xce pti o n is a s u bject 
w h o de vel o ps se vere as y m pt o matic A RI A- H ( micr o he m orr ha ge, s u perficial si der osis) i n Sta ge 2; 
s uc h a s u bject is t o f oll o w t he re g ular visit sc he d ule t o mai ntai n t he bli n d t o t he s u bject’s gr o u p 
assi g n me nt (Ta ble 1 ).
S u bjects will ha ve a p pr o xi matel y  3 pla n ne d cli nic visits d uri n g scree ni n g, 2 4 pla n ne d cli nic 
visits d uri n g t he ra n d o mize d treat me nt peri o d, a n d u p t o 8 tele p h o ne safet y  f oll o w- u p c o ntacts, 
as f oll o ws:

Scree ni n g v isits wit hi n 6 0 da y s bef ore t he first d ose of st u d y treat me nt o n Da y 1 
( visits will be c o n d ucte d o n m ulti ple da ys).  All scree ni n g pr oce d ures s h o ul d be 
co m plete d wit hi n 6 0 da ys ; h o we ver, t he o verall scree ni n g peri o d ma y be e xte n de d u p 
t o 9 0 da ys i n t he e ve nt of l o gistical iss ues.

1 4 o ut patie nt d osi n g visits o n Da y  1 a n d Wee ks 4, 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 
4 4, 4 8, a n d 5 2.

8 tele p h o ne safet y f oll o w- u p c o ntacts a p pr o xi matel y 2 wee ks after eac h of t he first 
8 d os i n g visits at Wee ks 2, 6, 1 0, 1 4, 1 8, 2 2, 2 6, a n d 3 0.

6 pla n ne d visits f or brai n M RI  at Scree ni n g a n d Wee ks 1 6 , 2 4, 3 2, 4 4, a n d 5 4.

1 E n d of Treat me nt Visit at Wee k 5 4.

1 safety f oll o w-u p v isit at Wee k 7 0 o nl y  f or s u bjects n ot partici pati n g i n t he 
L T E peri o d .
S u bjects w h o meet t he L T E i ncl usi o n a n d e xcl usi o n criteria (see Secti o n 8. 3 a n d Secti o n 8. 4 ) 
will be eli gi ble t o e nter t he L T E peri o d.  S u bjects w h o e nter t he L T E peri o d will ha ve 
a p pr o xi matel y 2 9 a d diti o nal pla n ne d visits as f oll o ws:


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 0

2 6 o ut patie nt d osi n g visits o n Wee ks 5 6, 6 0, 6 4, 6 8, 7 2, 7 6, 8 0, 8 4, 8 8, 9 2, 9 6, 1 0 0, 
1 0 4, 1 0 8, 1 1 2, 1 1 6, 1 2 0, 1 2 4, 1 2 8, 1 3 2, 1 3 6, 1 4 0, 1 4 4, 1 4 8, 1 5 2, a n d 1 5 6.

4 pla n ne d visits f or brai n M RI  at Wee ks 8 0, 1 0 4, 1 2 8 , a n d 1 58.

1 E n d of Treat me nt Visit at Wee k 1 5 8.

1 f oll o w-u p safety v isit at Wee k 1 7 4.
D uri n g t he ra n d o mize d treat me nt peri o d a n d t he L T E, s u bjects ma y ha ve a n U nsc he d ule d Visit 
f or safet y a n d/ or bef ore t he s u bject starts a n y ne w A D me dicati o n.  
T he e n d of st u d y date f or a s u bject is t he last st u d y visit or, if t he s u bject has o n g oi n g A Es t hat 
are bei n g f oll o we d, t he date of A E res ol uti o n.
7. 2.     
R es p o nsi bilities of S ite Pers o n nel
7. 2. 1.       
He alt h C are Pr ofessi o n als 
T o mai ntai n data i nte grit y, eac h site will ha ve a mi ni m u m of 3 se parate healt h care pr ofessi o nals 
(H C Ps ), wit h r oles a n d res p o nsi bilities defi ne d as f oll o ws:
1.
A n i n de pe n de nt cli nical assess or ( ne u r ol o gist, desi g nate d b y t he Treati n g H C P/ Pri nci pal 
I n vesti gat or [ PI] of t he site) w h o is bli n de d t o t he s u bject’s treat me nt gr o u p assi g n me nt
a n d n ot ma de a ware of t he M RI i nf or mati o n fr o m eit her t he ce ntral or l ocal M RI rea ds.  
T he mi ni m u m q ualificati o n re q uire me nt of t he i n de pe n de nt cli nical assess or is a 
me dicall y  q ualifie d i n di vi d ual (D oct or of Me dici ne [ M. D. ] de gree or e q ui vale nt) wit h at 
least 1 ye ar of ne ur ol o g y  s pecialt y trai ni n g.  It is rec o m me n de d t hat t he sa me cli nical 
assess or be assi g ne d f or t he d urati o n of t he st u d y.  T he i n de pe n de nt cli nical assess or will 
be e x pecte d t o c o m plete t he A RI A e d ucati o n pr o gra m, s pecificall y  desi g ne d t o ai d i n 
s ym pt o m ol o g y  decisi o ns, as part of t he st u dy q ualificati o n re q uire me nt.  T he i n de pe n de nt 
cli nical assess or will be res p o nsi ble f or t he f oll o wi n g:

P h y sical a n d ne ur ol o gical e xa mi nati o ns at pr ot oc ol-s pecifie d visits.

C ollecti o n of me dical hist or y , 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, a d mi nistrati o n of M o C A a n d M M S E
at t he 
pr ot oc ol -s pecifie d visits.  N ote:  I t is acce pta ble f or t he in de pe n de nt rater t o perf or m 
t he M o C A a n d M M S E (see Secti o n 7. 2. 2 ).

Assess me nt of A Es pri or t o eac h i nf usi o n .  A n y A E s u g gesti ve of or p ote ntiall y  
c o nsi dere d t o be relate d t o A RIA, as per t he cli nical j u d g me nt of t he i n de pe n de nt 
cli nical assess or, s h o ul d be e val uate d f urt her b y detaile d ne ur ol o gical assess me nt a n d 
l ocal sta n dar d of care.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 1

Assess me nt of w het her t he s u bject has s y m pt o ms or si g ns ( A Es) p ote ntiall y relate d t o 
A RI A , base d o n t he assess or’s cli nical j u d g me nt, pri or t o eac h i nf usi o n .  N ote:  t he 
s u bject a n d t he s u bject’s care gi ver m ust be i nstr ucte d t hat t he y are n ot t o s hare A RI A-
relate d i nf or mati o n wit h t he cli nical assess or.
2.
A treati n g H C P ( PI) w h o is bli n de d t o t he s u bject’s treat me nt assi g n me nt.  T he mi ni m u m 
q ualificati o n re q uire me nt of t he treati n g H C P is a me dicall y q ualifie d i n di vi d ual ( M. D. or 
e q ui vale nt) wit h at least 1 ye ar of direct cli nical e x perie nce i n ma na gi n g pe o ple wit h 
de me ntia.  T he treati n g H C P will recei ve t he me dical rec or d of t he s u bject fr o m t he 
i n de pe n de nt cli nical assess or ( base d o n t he assess me nts descri be d a b o ve), a n d fr o m t he 
in de pe n de nt rater (if a p plica ble; see Secti o n 7. 2. 2 ), as well as t he assess me nt fr o m t he 
i n de pe n de nt cli nical assess or o n w het her t he s u bject has s y m pt o ms or si g ns p ote ntiall y  
relate d t o A RI A.  T he treati n g H C P will ha ve access t o t he M RI  sca ns a n d will recei ve 
t he ce ntral M RI re p ort as well as t he l ocal ra di ol o g y assess me nt.  T he treati n g H C P will 
be res p o nsi ble f or t he f oll o wi n g:

Ma na ge me nt of s u bject’s r o uti ne cli nical care acc or di n g t o sta n dar d of practice .

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.

Ma na ge me nt of A Es a n d/ or S A Es.

P h y sical a n d ne ur ol o gical e xa m i nati o ns at u nsc he d ule d visits, as nee de d .  
Ma na ge me nt of t he f oll o w -u p pr oce d ures acc or di n g t o t he pr ot oc ol w he n t he s u bject 
de vel o ps A RI A .  N ote:  It is acce pta ble f or t he i n de pe n de nt rater t o perf or m t he 
M o C A (see Secti o n 7. 2. 2 ).

Re vie w of t he cli nical i nf or mati o n c ollecte d fr o m t he i n de pe n de nt cli nical assess or ,
pri or t o eac h i nf usi o n .  
N ote:   T he fi nal deter mi nati o n a b o ut w het her si g ns or s y m pt o ms are ass ociate d wit h 
A RI A resi des s olel y wit h t he i n de pe n de nt cli nical assess or.  
N ote: if it is n ot p ossi ble f or t he s u bject t o be see n b y t he cli nical assess or a n d t he 
treati n g H C P o n t he sa me da y, t he s u bject m ust b e see n b y t he treati n g H C P o n t he 
ne xt cale n dar da y .  T he treati n g H C P ma y re q uest a reassess me nt b y t he cli nical 
assess or o nl y if t here is ne w rele va nt cli nical i nf or mati o n after t he assess me nt b y t he 
i n de pe n de nt cli nical assess or; t o a v oi d bias, t he H C P m ust n ot s hare a n y 
A RI A-relate d M RI i nf or mati o n wit h t he cli nical assess or .  T he treati n g H C P is 
e nc o ura ge d t o c o ntact Bi o ge n t o disc uss s uc h sit uati o ns.

T he treati n g H C P m ust n ot c ha n ge or i nfl ue nce t he pr ot oc ol -s pecifie d acti o n wit h 
a d uca n u ma b d osi n g base d u p o n h is or her k n o wle d ge of A RI A -relate d M RI fi n di n gs 
(see Secti o n 7. 2. 2 ).


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 2
3.
A l ocal ra di ol o gist w h o will be bli n de d t o t he s u bject’s treat me nt gr o u p assi g n me nt.  T he 
ra di ol o gist will be e x pecte d t o c o m plete t he A RI A e d ucati o n pr o gra m, s pecificall y 
desi g ne d t o ai d i n A RI A rea di n g, as part of t he st u d y q ualificati o n re q uire me nt.  T he 
l ocal ra di ol o gist will be res p o nsi ble f or t he f oll o wi n g:

Ge nerati o n of a n i n de pe n de nt M RI  re p ort relate d t o A RIA.

Re p orti n g a n y M RI fi n di n gs , i ncl u di n g A RI A-relate d a n d i nci de ntal fi n di n gs, t o t he 
treatin g H C P . ( No te: t he treati n g H C P ma y c o m m u nicate a n y rele va nt i nci de ntal 
[i.e., n o n-A RI A ] fi n di n gs t o t he i n de pe n de nt cli nical assess or, as dee me d necessar y .)  
H o we ver, t he l ocal ra di ol o gist is n ot t o disc uss a n y  M RI fi n di n gs wit h t he 
i n de pe n de nt cli nical assess or, t he s u bject, or t he i nf or ma nt/care part ner .
7. 2. 2.     
Ot her Site Pers o n nel
1.
T he u n bli n de d p har mac ist m ust c o ns ult t he i nteracti ve res p o nse tec h n ol o g y sys te m pri or 
t o pre pari n g t he st u d y treat me nt f or eac h s u bject pri or t o i nf usi o n. T he u n bli n de d 
p har macist will be res p o nsi ble f or t he st ora ge, distri b uti o n, pre parati o n, a n d 
acc o u nta bilit y of st u d y treat me nt.  T he u n bli n de d p har macist will als o be res p o nsi ble f or 
mai ntai ni n g t he u n bli n de d p har mac y  rec or d se parate fr o m t he mai n st u d y file i n or der t o 
s u p p ort the st u d y  bli n d.  ( N ote: if d osi n g is t o c o nti n ue, t he s u bject s h o ul d be i nf use d o n 
t he sa me da y or + 1 cale n dar da y after e val uati o n b y t he treati n g H C P.)
2.
T he bli n de d in de pe n de nt rater ( desi g nate d b y t he treati n g H C P/ PI of t he site) is 
res p o nsi ble f or a d ministeri n g t he Cli nical De me ntia Rati n g ( C D R) at scree ni n g.  T he 
i n de pe n de nt rater ma y perf or m t he M o C A or M M S E, if it is n ot feasi ble f or t he cli nical 
assess or or treati n g H C P t o perf or m t his assess me nt.  T he i n de pe n de nt rater is bli n de d t o 
t he s u bject’s gr o u p assi g n me nt, a n d m ust n ot be i n v ol ve d wit h a n y ot her as pect of s u bject 
care a n d ma na ge me nt, a n d m ust re mai n bli n de d t o 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 gr o u p assi g n me nt, A RI A -relate d i ma gi n g 
fi n di n g fr o m eit her t he ce ntral or l ocal M RI rea ds, or t he visit sc he d ule bei n g t he 
u nsc he d ule d visit d ue t o A RI A.  T o e ns ure c o nsiste nc y  acr oss sites, t he i n de pe n de nt rater 
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 
assess me nt sc o ri n g pri or t o a d mi nistrati o n of t he s pecific assess me nt at t he site.  All sites 
m ust atte m pt t o mai ntai n t he sa me rater t hr o u g h o ut t he st u d y  f or s pecific assess me nts 
(i.e., M o C A a n d M M S E) i n a n atte m pt t o re mai n c o nsiste nt.  Eac h s u bject s h o ul d ha ve 
t he same rater perf or m t he s u bject’s s pecific rati n g assess me nt t hr o u g h o ut t he st u d y .  A 
q ualifie d , a p pr o ve d bac k -u p rater s h o ul d c o n d uct assess me nts i n place of t he pri mar y  
rater o nl y d ue t o e xte n uati n g circ u msta nces res ulti n g i n u na vaila bilit y  (e. g., d ue t o ill ness, 
vacati o n, or tra vel).  If a rater has t o be re place d, t he ne w rater 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 sa me rater 
q ualificati o n pr ocess a p plies t o t he cli nical assess or a n d t he treat i n g p hys icia n if t he y are 
t he M o C A a n d/ or M M S E raters.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 3
7. 3.     
St u d y St o p pi n g R ules
Bi o ge n ma y  ter mi nate t his st u d y at a ny ti me, after i nf or mi n g I n vesti gat ors.  Bi o ge n ( or desi g nee) 
will n otif y  In vesti gat ors w he n t he st u d y  is t o be place d o n h ol d, c o m plete d, or ter mi nate d.  
Bi o ge n a n d t he D S M C will re vie w safet y data o n a n o n g oi n g basis.  T he st u d y ma y be m o dif ie d 
or ter mi nate d b y Bi o ge n base d o n t he rec o m me n dati o n of t he D S M C, i nter nal re vie w of t he 
safety data, a n d per st u d y- s pecific st o p pi n g rec o m me n dati o ns as descri be d i n t he D S M C c harter.  
7. 4.     
E n d of St u d y
T he e n d of st u d y is last s u bject, last visit. 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 4
8.        
S E L E C TI O N O F S U B J E C T S
8. 1.     
I ncl usi o n Criteri a f or R a n d o mize d Tre at me nt Peri o d
T o be eli gi ble t o partici pate i n t his st u d y , ca n di dates m ust meet t he f oll o wi n g eli gi bility criteria 
at Scree ni n g , or at t he ti me p oi nt s pecifie d i n t he i n di vi d ual eli gi bilit y criteri o n liste d:  
1.
A bilit y  of t he s u bject or his/ her le gall y a ut h orize d re prese ntati ve t o u n dersta n d t he 
p ur p ose a n d ris ks of t he st u d y  a n d pr o vi de si g ne d a n d date d i nf or me d c o nse nt a n d 
a ut h orizati o n t o use c o nfi de ntial healt h i nf or mati o n i n acc or da nce wit h nati o nal a n d l ocal 
s u bject pri vac y re g ulati o ns.  N ote: t he s u bject’s le gall y a ut h ori ze d re prese ntati ve ma y or 
ma y  n ot be t he s u bject’s i nf or ma nt/care part ner (see i ncl usi o n criteri o n # 9).
2.
A ge 5 0 t o 8 5 ye ars ol d, i ncl usi ve, at t he ti me of i nf or me d c o nse nt.
3.
All w o me n of c hil d beari n g p ote ntial a n d all me n m ust practice hi g hl y effecti ve 
c o ntrace pti o n d uri n g t he st u d y  a n d f or 2 4 wee ks after t heir last d ose of st u d y treat me nt.  
F or f urt her details of c o ntrace pti ve re q uire me nts f or t his st u d y , see Secti o n 1 5. 5 .
4.
M ust ha ve at least 6 ye ars of e d ucati o n or w or k e x perie nce t o e xcl u de me ntal deficits 
ot her t ha n M CI d ue t o A D or mil d A D de me ntia .
5.
M ust ha ve e vi de nce of cere bral A β acc u m ulati o n, base d o n a p ositi ve P E T sca n of t he 
brai n.  Pre vi o usl y  o btai ne d P E T sca n ( wit hi n 1 2 m o nt hs of Scree ni n g) is per missi ble.  
Pre vi o us P E T sca n i ma ges m ust be s u b mitte d t o t he ce ntral i ma gi n g ve n d or t o c o nfir m 
t hat st u d y i ncl usi o n criteria are met.    
6.
M ust meet all of t he f oll o wi n g cli nical criteria f or M CI  d ue t o A D or mil d A D de me ntia 
acc or di n g t o NI A-A A criteria [Al bert 2 0 1 1 ; Mc K ha n n 2 0 1 1 ], a n d m ust ha ve t he 
f oll o wi n g:

M CI  d ue t o A D:

A C D R gl o bal sc ore of 0. 5.

A n M M S E sc ore bet wee n 2 4 a n d 3 0 (i ncl usi ve).

Mil d A D
de me ntia :

A C D R gl o bal sc ore of 0. 5 or 1.

A n M M S E sc ore bet wee n 2 0 a n d 2 6 (i ncl usi ve).
N ote:  S u bjects wit h a C D R gl o bal sc ore of 0 b ut w h o meet t he ot her e ntr y criteria ma y  re peat 
t he scree ni n g C D R e val uati o n after 6 m o nt hs past t he i nitial e val uati o n.  


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 5
7.
A part fr o m a cli nical dia g n osis of M CI d ue t o A D or m il d A D de me ntia , t he s u bject m ust 
be i n g o o d healt h as deter mi ne d b y  t he I n vesti gat or, base d o n me dical hist or y a n d 
scree ni n g assess me nts.
8.
M ust c o nse nt t o A p o E ge n ot y pi n g.
9.
Has o ne i nf or ma nt/care part ner w h o, i n t he I n vesti gat or’s o pi ni o n, has fre q ue nt a n d 
s ufficie nt c o ntact wit h t he s u bject as t o be a ble t o pr o vi de acc urate i nf or mati o n a b o ut t he 
s u bject’s o verall healt h c o n diti o n, i ncl u di n g a ny a d verse e ve nt t he s u bject ma y ha ve .  T he 
i nf or ma nt/care part ner m ust mi ni mall y be a vaila ble i n pers o n f or o ne scree nin g visit a n d 
b y  p h o ne t hereafter, m o nt hl y  pri or t o eac h i nf usi o n, t o pr o vi de i nf or mati o n t o t he 
I n vesti gat or a n d st u dy staff a b o ut t he s u bject.  A n i nf or ma nt/care part ner s h o ul d be 
a vaila ble f or t he d urati o n of t he st u d y, a n d a c o nsiste nt i nf or ma nt/care pa rt ner is 
e nc o ura ge d.
8. 2.     
E xcl usi o n Criteri a f or t he R a n d o mize d Tre at me nt Peri o d
Ca n di dates will be e xcl u de d fr o m st u d y e ntr y if a n y of t he f oll o wi n g e xcl usi o n criteria e xist at 
Scree ni n g , or at t he ti me p oi nt s pecifie d i n t he i n di vi d ual criteri o n liste d:
Me dic a l Hist ory
1.
A n y  u nc o ntr olle d me dical or ne ur ol o gical/ ne ur o de ge nerati ve c o n diti o n ( ot her t ha n A D) 
t hat, i n t he o pi ni o n of t he In vesti gat or, mi g ht be a c o ntri b uti n g ca use of t he s u bject’s 
c o g niti ve i m pair me nt (e. g., s u bsta nce a b use, vita mi n B 1 2 deficie nc y, a b n or mal t h y r oi d 
f u ncti o n, str o ke or ot her cere br o vasc ular c o n diti o n, Le w y b o d y de me ntia, fr o nt ote m p oral 
de me ntia, hea d tra u ma).
2.
Cli nicall y  si g nifica nt u nsta ble ps yc hiatric ill ness (e. g., u nc o ntr olle d maj or de pressi o n, 
u nc o ntr olle d sc hiz o p hre nia, u nc o ntr olle d bi p olar affecti ve dis or der) wit hi n 6 m o nt hs 
pri or t o Scree ni n g.  
3.
Tra nsie nt isc he mic attac k or str o ke or a n y u ne x plai ne d l oss of c o nsci o us ness wit hi n 
1 ye ar pri or t o Scree ni n g.
4.
Brai n M RI perf or me d at Scree ni n g ( per ce ntrall y rea d M RI) t hat s h o ws e vi de nce of a n y 
of t he f oll o wi n g:  

Ac ute or s u b ac ute he m orr ha ge.

Pri or macr o he m orr ha ge ( defi ne d as 1 c m i n dia meter o n T 2 * se q ue nce) or pri or 
s u barac h n oi d he m orr ha ge u nless it ca n be d oc u me nte d t hat t he fi n di n g is n ot d ue t o 
a n u n derl yi n g str uct ural or vasc ular a b n or malit y (i.e., fi n di n g d oes n ot s u g gest s u bject 
is at ris k of rec urre nt he m orr ha ge).

M ore t ha n 4 micr o he m orr ha ges ( defi ne d as 1 c m i n dia meter o n T 2 * se q ue nce).  


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 6

C ortical i nfarct ( defi ne d as > 1. 5 c m i n dia meter, irres pecti ve of a nat o mic l ocati o n).  
 
1 lac u nar i nfarct ( defi ne d as 1. 5 c m i n dia meter).

S u perficial si der osis.  

Hist or y  of diff use w hite matter disease as defi ne d b y a sc ore of 3 o n t he a ge-relate d 
w hite matter c ha n ges scale [Wa hl u n d 2 0 0 1 ].

A n y  fi n di n g t hat, i n t he o pi ni o n of t he In vesti gat or, mi g ht be a c o ntri b uti n g ca use of 
t he s u bject’s de me ntia, mi g ht p ose a ris k t o t he s u bject, or mi g ht pre ve nt a 
satisfact or y M RI assess me nt f or safety m o nit ori n g.
5.
Hist or y  of blee di n g dis or der or pre dis p osi n g c o n diti o ns, bl o o d cl otti n g, or cli nicall y  
si g nifica nt a b n or mal res ults o n c oa g ulati o n pr ofile at Scree ni n g, as deter mi ne d b y  t he 
I n vesti gat or.
6.
Prese nce of dia betes mellit us t hat, i n t he j u d g me nt of t he I n vesti gat or, ca n n ot be 
c o ntr olle d or a de q uatel y ma na ge d.  
7.
Hist or y  of u nsta ble a n gi na, m yocar dial i nfarcti o n, c hr o nic heart fail ure ( Ne w Y or k Heart 
As s ociati o n Class III or I V), or cli nically si g nifica nt c o n d ucti o n a b n or malities (e. g., 
u nsta ble atrial fi brillati o n) wit hi n 1 y ear pri or t o Scree ni n g.
8.
Cli nicall y  si g nifica nt 1 2-lea d electr ocar di o gra m ( E C G ) a b n or malities, as deter mi ne d b y 
t he In vesti gat or.
9.
U nc o ntr olle d h y perte nsi o n defi ne d as:  a vera ge of 3 s yst olic bl o o d press ure 
[ S B P]/ diast olic bl o o d press ure [ D B P] rea di n gs > 1 6 5 m m H g a n d/ or > 1 0 0 m m H g at 
Scree ni n g ( bl o o d press ure meas ure me nts e xcee di n g t hese li mits ma y  be re peate d as 
warra nte d b y t he I n vesti gat or, b ut val ues m ust be wit hi n t he s pecifie d li mits f or t he 
s u bject t o be eli gi ble f or t he st u d y), or persiste nt S B P/ D B P rea di n gs > 1 8 0 m m H g a n d/ or 
> 1 0 0 m m H g 3 m o nt hs pri or t o ra n d o mizati o n ( Da y  1) t hat, i n t he o pi ni o n of t he 
I n vesti gat or, are i n dicati ve of c hr o nic u nc o ntr olle d h y perte nsi o n.
1 0. Hist or y  of mali g na nc y or carci n o ma.  T he f oll o wi n g e xce pti o ns ma y be ma de after 
disc ussi o n wit h Bi o ge n :  

S u bjects wit h ca ncers i n re missi o n ≥5 y ears pri or t o Scree ni n g.

S u bjects wit h a hist or y  of e xcise d or treate d basal cell or s q ua m o us carci n o ma of t he 
s ki n.  

S u bjects wit h l ocalize d pr ostate ca ncer wit h treat me nt c ycles t hat c o m plete d at least 
6 m o nt hs pri or t o Scree ni n g.
1 1. Hist or y  of seiz ure wit hi n 1 0 years pri or t o Scree ni n g.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 7
1 2. I n dicati o n of i m paire d li ver f u ncti o n as s h o w n by a n a b n or mal li ver f u ncti o n pr ofile at 
Scree ni n g . T his i ncl u des b ut is n ot li mite d t o re peate d val ues of as partate 
a mi n otra nsferase a n d ala ni ne a mi n otra nsferase ≥2 × t he u p per li mit of n or mal.
1 3. Hist or y  or e vi de nce of a n a ut oi m m u ne dis or der c o nsi dere d cli nically si g nifica nt b y t he 
I n vesti gat or or re q uiri n g c hr o nic use of s yste mic c ortic oster oi ds or ot her 
i m m u n os u p pressa nts.
1 4. Rece nt hist or y  ( wit hi n 1 year of Scree ni n g) of alc o h ol or s u bsta nce a b use as deter mi ne d 
b y  t he I n vesti gat or, a p ositi ve uri ne dr u g ( d ue t o n o n prescri pti o n dr u g) or alc o h ol test at 
Scree ni n g, or use of ca n na bi n oi ds ( prescri pti o n or recreati o nal).
1 5. Cli nicall y  si g nifica nt s yste mic ill ness or seri o us i nfecti o n (e. g., p ne u m o nia, se ptice mia) 
wit hi n 3 0 da y s pri or t o or d uri n g Scree ni n g.
1 6. H ist or y of or k n o w n ser o p ositi vit y  f or h u ma n i m m u n o deficie nc y  vir us.
1 7. Hist or y  of, or p ositi ve test res ult at Scree ni n g f or , he patitis C vir us a nti b o d y .
1 8. C urre nt he patitis B i nfecti o n ( defi ne d as p ositi ve f or he patitis B s urface a nti ge n [ H Bs A g] 
a n d/ or t otal he patitis B c ore a nti b o d y [a nti -H Bc]).  S u bjects wit h i m m u nit y  t o he patitis B 
fr o m pre vi o us nat ural i nfecti o n ( defi ne d as ne gati ve H Bs A g, p ositi ve a nti-H Bc, a n d 
p ositi ve he patitis B s urface a nti b o d y [a nti -H Bs]) or vacci nati o n ( defi ne d as ne gati ve 
H Bs A g, ne gati ve a nti -H Bc, a n d p ositi ve a nti -H Bs) are eli gi ble t o partici pate i n t he st u d y .
1 9. Hist or y  of se vere aller gic or a na p h ylactic reacti o ns; hist or y  of hy perse nsiti vit y  t o a ny of 
t he i nacti ve i n gre die nts i n t he dr u g pr o d uct.
2 0. A n y  ot her me dical c o n diti o ns (e. g., re nal disease) t hat are n ot sta ble or c o ntr olle d, or, i n 
t he o pi ni o n of t he I n vesti gat or, c o ul d affect t he s u bject’s safet y or i nterfere wit h t he st u d y 
assess me nts.
Me dic ati o ns
2 1. A n y  me dicati o ns t hat, i n t he o pi ni o n of t he I n vesti gat or, ma y c o ntri b ute t o c o gniti ve 
i m pair me nt, p ut t he s u bject at hi g her ris k f or A Es, or i m pair t he s u bject’s a bilit y t o 
perf or m c o g niti ve testi n g or c o m plete st u d y pr oce d ures.
2 2. Use of all o we d c hr o nic me dicati o ns at d oses t hat ha ve n ot bee n sta ble f or at least 4 wee ks 
pri or t o Scree n i n g Visit 1 a n d d uri n g Scree ni n g u p t o Da y 1, or use of A D me dicati o ns 
(i ncl u di n g b ut n ot li mite d t o d o ne pezil, ri vasti g mi ne, gala nta mi ne, tacri ne, a n d 
me ma nti ne) at d oses t hat ha ve n ot bee n sta ble f or at least 8 wee ks pri or t o Scree ni n g 
Visit 1 a n d d uri n g Scree ni n g u p t o St u d y  Da y 1.  S u bjects w h o fail Scree ni n g beca use 
all o we d c hr o nic me dicati o ns ha ve n ot bee n at sta ble d oses f or at least 4 wee ks pri or t o 
Scree ni n g Visit 1 or d uri n g Scree ni n g u p t o St u d y Da y  1, or w h ose use of A D 
me dicati o ns has n ot bee n at sta ble d oses f or at least 8 wee ks pri or t o Scree ni n g Visit 1 or 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 8
d uri n g Scree ni n g u p t o St u d y  Da y 1, ma y  ret ur n f or rescree ni n g after use of t hese 
me dicati o ns has bee n sta bilize d f or t he re q uire d peri o d.  
2 3. Use of me dicati o ns wit h platelet a ntia g gre ga nt or a ntic oa g ula nt pr o perties (t he use of 
as piri n at a pr o p h yl actic d ose [≤3 2 5 m g dail y ] is all o we d).
2 4. Use of illicit narc otic me dicati o n.
2 5. Vacci nati o ns wit hi n 1 0 da y s pri or t o ra n d o mizati o n ( Da y 1).  
2 6. Partici pati o n i n a n y  acti ve i m m u n ot hera p y st u d y tar geti n g Aβ u nless d oc u me ntati o n of 
recei pt of place b o is a vaila ble.  
2 7. Partici pati o n i n a n y  passi ve i m m u n ot hera p y st u d y tar geti n g A β u nless d oc u me ntati o n of 
recei pt of place b o is a vaila ble.  
2 8. Partici pati o n i n a n y  st u d y wit h p ur p orte d disease-m o dif y i n g effect i n A D wit hi n 
1 2 m o nt hs pri or t o Scree ni n g u nless d oc u me ntati o n of recei pt of place b o is a vaila ble.  
S u bjects w h o de v el o pe d A RIA d uri n g a pre vi o us disease -m o dif y i n g trial s h o ul d be 
e xcl u de d.  
2 9. Pri or partici pati o n i n a st u d y  wit h a d uca n u ma b.
St u dy Pr oce d ures
3 0. C o ntr ai n dicati o ns t o ha vi n g a brai n M RI (e. g., pace ma ker; M RI- i nc o m pati ble a ne ur ys m 
cli ps, artificial heart val ves, or ot her metal f orei g n b o d y; cla ustr o p h o bia t hat ca n n ot be 
me dicall y ma na ge d).
3 1. C o ntrai n dicati o n t o ha vi n g a P E T sca n (e. g., i na bilit y  t o lie flat or still f or t he d urati o n of 
t he sca n) or i nt olera nce t o pre vi o us P E T sca ns (i.e., pre vi o us h yperse nsiti vit y  reacti o ns t o 
a n y P E T li ga n d or i ma gi n g a ge nt, fail ure t o partici pate i n a n d c o m ply wit h pre vi o us P E T 
sca ns).  
3 2. A ne gati ve P E T sca n res ult w it h a n y a m yl oi d -tar geti n g li ga n d wit hi n 6 m o nt hs pri or t o
Scree ni n g.
3 3. Ha ve ha d or pla n e x p os ure t o e x peri me ntal ra diati o n wit hi n 1 2 m o nt hs pri or t o Scree ni n g 
s uc h t hat ra di o d osi metr y li mits w o ul d be e xcee de d b y partici pati n g i n t his st u d y. 
Ot hers
3 4. Fe male s u bjects w h o are pre g na nt or c urre ntl y  breastfee di n g.
3 5. Pre vi o us partici pati o n i n t his st u d y . S u bjects w h o fail Scree ni n g d ue t o n ot meeti n g e ntr y  
criteria f or P E T, M M S E, he patitis B or C res ults, ha vi n g a C D R gl o bal sc ore > 1 , or 
ha vi n g a b n or mal M RI fi n di n gs will n o t be all o we d t o rescree n.  N ote:  S u bjects wit h a 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
4 9
C D R gl o bal sc ore of 0 b ut w h o meet t he ot her e ntr y  criteria ma y re peat t he scree ni n g 
C D R e val uati o n after 6 m o nt hs past t he i nitial e val uati o n.
3 6. S u bject c urre ntl y li vi n g i n a n or ga nize d care facilit y  wit h e xte nsi ve i nter ve nti o n a n d/ or 
s u p p ort f or dail y li vi n g acti vities.
3 7. Bl o o d d o nati o n ( ≥1 u nit) wit hi n 1 m o nt h pri or t o Scree ni n g.
3 8. I na bilit y t o c o m ply wit h st u d y re q uire me nts.
3 9. Ot her u ns pecifie d reas o ns t hat, i n t he o pi ni o n of t he I n vesti gat or or Bi o ge n, ma ke t he 
s u bject u ns uita ble f or e nr oll me nt.
8. 3.     
I ncl usi o n Criteri a f or t he L o n g -Ter m E xte nsi o n Peri o d
T o be eli gi ble t o partici pate i n t he L T E peri o d, s u bjects m ust meet t he f oll o wi n g eli gi bilit y  
criteria at Wee k 54:
1.
S u bjects m ust ha ve c o m plete d t he ra n d o mize d trea t me nt peri o d of t he st u d y, i ncl u di n g 
t he W ee k 5 2 Visit.  S u bject m ust ha ve recei ve d at least 8 d oses a n d n ot ha ve misse d m ore 
t ha n 4 c o nsec uti ve d oses, e xce pt f or s u bjects w h ose d os i n g was s us pe n de d d ue t o A RI A.  
S u bjects w h o d o n ot meet t hese criteria ma y e nter t he LT E peri o d o nl y wit h Bi o ge n ’s 
a p pr o val.
2.
T he s u bject ( or t he s u bject’s le gall y a ut h orize d re prese ntati ve) has t he a bilit y t o 
u n dersta n d t he p ur p ose a n d ris ks of t he st u d y  a n d t o pr o vi de si g ne d a n d date d i nf or me d 
c o nse nt a n d a ut h orizati o n t o use c o nfi de ntial healt h i nf or mati o n i n acc or da nce wit h 
nati o nal a n d l ocal s u bject pri vac y  re g ulati o ns.  N ote: t he s u bject’s le gall y a ut h orize d 
re prese ntati ve ma y or ma y n ot be t he s u bject’s i nf or ma nt/care part ner (see i ncl usi o n 
criteri o n # 6).
3.
Fe male s u bjects of c hil d beari n g p ote ntial a n d male s u bjects m ust practice hi g hl y 
effecti ve c o ntrace pti o n d uri n g t he st u d y a n d f or 2 4 wee ks after t heir last d ose of st u d y 
treat me nt.
4.
A part fr o m a cli nical dia g n osis of A D, t he s u bject m ust be i n g o o d healt h as deter mi ne d 
b y  t he I n vesti gat or, base d o n me dical hist or y .
5.
M ust ha ve t he a bilit y  t o c o m pl y wit h pr oce d ures f or pr ot oc ol-relate d tests.
6.
Has o ne i nf or ma nt/care part ner w h o, i n t he I n vesti gat or’s o pi ni o n, has fre q ue nt a n d 
s ufficie nt c o ntact wit h t he s u bject as t o be a ble t o pr o vi de acc urate i nf or mati o n a b o ut t he 
s u bject’s o verall healt h c o n diti o n .  At a mi ni m u m, t he i nf or ma nt/care part ner m ust be 
a vaila ble b y p h o ne t o pr o vi de i nf or mati o n t o t he I n vesti gat or a n d st u d y staff a b o ut t he 
s u bject.  A n i nf or ma nt/care part ner s h o ul d b e a vaila ble f or t he d urati o n of t he st u d y.


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Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
5 0
8. 4.     
E xcl usi o n Criteri a f or t he L o n g -Ter m E xte nsi o n Peri o d
S u bjects will be e xcl u de d fr o m e nteri n g t he L T E peri o d if a n y of t he f oll o wi n g e xist at Wee k 5 4:
1.
A n y  me dical or psyc hi atric c o ntrai n dicati o n or cli nicall y si g nifica nt a b n or malit y t hat, i n 
t he o pi ni o n of t he I n vesti gat or, will s u bsta ntiall y i ncrease t he ris k ass ociate d wit h t he 
s u bject's partici pati o n i n a n d c o m pleti o n of t he st u d y.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
5 1
9.        
S C R E E NI N G A N D R A N D O MI Z A TI O N
9. 1.     
Scree ni n g 
S u bjects or t heir le g all y a ut h orize d re pre se ntati ve ( w hic h ma y or ma y n ot be t he s u bject’s 
i nf or ma nt/care part ner) m ust pr o vi de i nf or me d c o nse nt bef ore a n y scree ni n g tests are perf or me d 
(see Secti o n 1 7. 3 ).  
D uri n g Scree ni n g, s u bjects ma y c o m plete t he ne ur oc o g niti ve scales ( C D R a n d M M S E) a n d 
A p o E ge n ot y pi n g t o deter mi ne st u d y eli gi bilit y u n der a se parate, o pti o nal i nitial c o nse nt pr ocess.  
If t he s u bject meets i ncl usi o n criteria f or t hese 2 scales, t he f ull c o nse nt pr ocess m ust be 
c o m pleted pri or t o t he a d mi nistrati o n of f urt her scree ni n g assess me nts.  S u bjects ma y  als o 
pr ocee d directl y t o t he f ull c o nse nt pr ocess , w hic h will all o w t he a d mi nistrati o n of all scree ni n g 
assess me nts.  W he n a s u bject si g ns t he f ull i nf or me d c o nse nt f or m (IC F), t hat s u bject is 
c o nsi dere d t o be e nr olle d i n t he st u d y .  
T he ne ur oc o g niti ve assess me nts t hat ha ve e xcl usi o n c ut p oi nts ( C D R a n d M M S E) a n d t he A p o E 
ge n ot y pi n g m ust be perf or me d at Scree ni n g Visit 1.  A p o E ge n ot y pi n g ma y be perf or me d at 
Scree ni n g Visit 1 pri or t o ot her scree ni n g assess me nts (a n d t he res ult m ust be a vaila ble pri or t o 
ra n d o mizati o n).  T he M RI at Scree ni n g Visit 2 s h o ul d be d o ne o nl y after s u bject eli gi bilit y base d 
o n cli nical a n d la b orat or y  criteria is c o nfir me d d uri n g Scree ni n g Visit 1.  T he PE T sca n at 
Scree ni n g Visit 3 s h o ul d be c o m plete d o nl y after t he M RI  i ncl usi o n criteri o n is met. T he E C o g 
( O bser ver) assess me nt ma y be perf or me d b y  t he i nf or ma nt/care part ner at a n y visit w he n (s) he is 
a vaila ble i n pers o n, b ut m ust be c o m plete d pri or t o t he P E T sca n.   T he D S S T/trail ma ki n g 
( o pti o nal) ma y be perf or me d at a ny 2 se parate scree ni n g visits b ut m ust be c o m plete d pri or t o t he 
P E T sca n.
Partici pati n g st u d y sites are re q uire d t o d oc u me nt all scree ne d ca n di dates w h o are i nitiall y 
c o nsi dere d f or i ncl usi o n i n t his st u d y.  It is rec o m me n de d t hat all scree ni n g pr oce d ures be 
c o m plete d wit hi n 6 0 da ys; h o we ver, t he o verall scree ni n g peri o d ma y  be e xte n de d u p t o 9 0 da ys 
i n t he e ve nt of l o gistical iss ues a n d is s u bject t o Bi o ge n a p pr o val.
9. 1. 1.     
Scree n F ail ures
Scree n fail ures are defi ne d as s u bjects w h o si g n t he I CF b ut d o n ot meet all e ntr y  criteria.  If a 
s u bject 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 
s u bject’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 s u bjects i n or der 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 S A Es.  


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Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
5 2
9. 1. 2.     
Rescree ni n g
S u bjects w h o fail Scree ni n g ma y  be per mitte d t o be rescree ne d o nce at Bi o ge n ’s discreti o n.  
S u bjects w h o fail Scree ni n g d ue t o n ot meeti n g e ntr y  criteria f or P E T, M M S E, he patitis B or C 
res ults, ha vi n g a C D R gl o bal sc ore > 1. 0, or ha vi n g a b n or mal M RI fi n di n gs will n ot be all o we d t o 
rescree n.  N ote:  S u bjects wit h a C D R gl o bal sc ore of 0 b ut w h o meet t he ot her e ntr y criteria ma y 
re peat t he scree ni n g C D R e val uati o n after 6 m o nt hs past t he i nitial e val uati o n.  
S u bjects w h o fail Scree ni n g beca use al l o we d c hr o nic me dicati o ns ha ve n ot bee n at sta ble d oses 
f or at least 4 wee ks pri or t o Scree ni n g Visit 1, or w h ose use of A D me dicati o ns has n ot bee n at 
sta ble d oses f or at least 8 wee ks pri or t o Scree ni n g Visit 1, ma y  ret ur n f or rescree ni n g after use 
of t h ese me dicati o ns has bee n sta bilize d f or t he re q uire d peri o d.  
9. 2.     
R a n d o miz ati o n 
S u bjects will be ra n d o mize d after all scree ni n g assess me nts ha ve bee n c o m plete d a n d after t he 
I n vesti gat or has verifie d t hat t he s u bjects are eli gi ble per criteria i n Secti o ns 8. 1 a n d 8. 2 .  
S u bject s will be assi g ne d a u ni q ue i de ntificati o n n u m ber t hat will be use d o n st u d y-relate d 
d oc u me nts pertai ni n g t o t he s u bject.  A ny s u bject i de ntificati o n n u m bers t hat are assi g ne d will 
n ot be re use d e ve n if t he s u bject d oes n ot recei ve treat me nt or c o nti n ue i n t he st u d y .  Rescree ne d 
s u bjects will be assi g ne d a ne w n u m ber.  
Ra n d o mizati o n will be perf or me d usi n g i nteracti ve res p o nse tec h n ol o g y  (I R T).  S u bjects will be 
ra n d o ml y assi g ne d i n a 1: 1 rati o t o 1 of 2 treat me nt gr o u ps.  T he ra n d o mizat i o n will be stratifie d 
b y  A p o E ε 4 stat us (carrier or n o ncarrier).  T he A p o E ge n ot y pi n g res ult s m ust be a vaila ble pri or 
t o ra n d o mizati o n.
Refer t o t he St u d y  Refere nce G ui de f or details o n re gistrati o n a n d ra n d o mizati o n.
9. 3.     
Bli n di n g Pr oce d ures
D uri n g t he ra n d o mize d treat me nt peri o d of t he st u d y, t he 3 H C Ps ( Secti o n 7. 2. 1 ), ot her site 
pers o n nel ( Secti o n 7. 2. 2 ) a n d st u d y staff (e xce pt f or desi g nate d p har mac y staff), a n d t he s u bjects 
will be bli n de d t o t he treat me nt gr o u p assi g n me nt .  D uri n g t he L T E peri o d, all s u bjects will 
recei ve d osi n g as defi ne d f or Gr o u p 2 of t he ra n d o mize d treat me nt peri o d.  
T o mai ntai n t he st u d y  bli n d, it is i m perati ve t hat s u bject treat me nt assi g n me nts are n ot s hare d 
wit h t he s u bjects, t heir fa milies, or a n y  me m ber of t he st u d y tea m, eit her at t he st u d y site or at 
Bi o ge n, e xce pt t he u n bli n de d p har mac y  staff a n d desi g nate d Bi o ge n pers o n nel.
T o mai ntai n t he bli n d t o s u bjects’ gr o u p assi g n me nt s d uri n g t he ra n d o mize d treat me nt peri o d, 
place b o will be gi ve n t o s u bjects i n pres pecifie d cases of d ose s us pe nsi o n or disc o nti n uati o n d ue 
t o as ym pt o matic A RI A (see Ta ble 5 a n d Ta ble 6 ).  S h o ul d s u bjects w h o mi g ht per ma ne ntl y 
disc o nti n ue acti ve d osi n g a n d recei ve place b o n ot be all o we d t o partici pate i n t he L T E, per 
S p o ns or’s decisi o n or D M S C rec o m me n dati o n, t he treat me nt assi g n me nt will be discl ose d at t he 
e n d of t he ra n d o mize d treat me nt peri o d.


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Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
5 3
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 
jeo par dize t he res ults of o n g oi n g relate d st u dies, Bi o ge n 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 s u bjects a b o ut t he treat me nt t he y recei ve d.  
9. 4.     
A RI A/ M RI I nf or m ati o n
T hr o u g h o ut t he st u d y, t he i n de pe n de nt cli nical asses s or will n ot be ma de a ware of A RI A 
i nf or mati o n fr o m eit her t he ce ntral or l ocal M RI rea ds.  
T he treati n g H C P ma y ha ve access t o t he M RI sca ns a n d will be pr o vi de d wit h b ot h t he ce ntral 
M RI  re p ort a n d t he l ocal ra di ol o gist’s assess me nt.  T he treati n g H C P m a y c o m m u nicate 
i nf or mati o n o n i nci de ntal fi n di n gs t o t he cli nical assess or, as dee me d necessar y.
S u bjects a n d t he s u bject’s i nf or ma nt/care part ner ma y be i nf or me d b y  t he treati n g H C P a b o ut 
A RI A fi n di n gs, as a p pr o priate.  T he treati n g H C P ma y  di v ul ge t he M RI se verit y i nf or mati o n, as 
necessar y . T he s u bject a n d i nf or ma nt /care part ner m ust be re mi n de d t hat t he y are n ot t o s hare 
A RI A i nf or mati o n wit h t he cli nical assess or or t he i n de pe n de nt rater .  
9. 5.     
A p o E ε 4 C arrier St at us
T h r o u g h o ut t he st u dy, t he 3 H C Ps, st u d y  staff, a n d s u bjects will n ot be ma de a ware of t he 
s u bject’s A p o E ε4 carrier stat us.  


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Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it 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 0.      
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 S U B J E C T S F R O M T H E S T U D Y
1 0. 1.   
Disc o nti n u ati o n of St u d y Tre at me nt
A s u bject m ust per ma ne ntl y  disc o nti n ue st u d y treat me nt f or a n y of t he f oll o wi n g reas o ns:

T he s u bject de vel o ps a n y of t he f oll o wi n g:

S y m pt o matic A RI A - E acc o m pa nie d b y seri o us cli nical s y m pt o ms t hat are life-
t hreate ni n g (i n t he o pi ni o n of t he i n vesti gat or) a n d/or res ult i n persiste nt or 
si g nifica nt disa bilit y /i nca pacit y or a c o n ge nital a n o mal y/ birt h defect (see Ta ble 5
f or details).

S y m pt o matic A RI A -H ( micr o he m orr ha ge or s u perficial si der osis) acc o m pa nie d 
b y  seri o us cli nical sy m pt o ms t hat are life -t hreate ni n g (in t he o pi ni o n of t he 
i n vesti gat or) a n d/or res ult i n persiste nt or si g nifica nt disa bilit y/i nca pacity or a 
c o n ge nital a n o mal y/ birt h defect (see Ta ble 6 f or details).

S y m pt o matic A RI A -H ( micr o he m orr ha ge or s u perficial si der osis) t hat is se vere 
o n M RI  (≥1 0 mic r o he m orr ha ges a n d/ or > 2 f ocal areas of s u perficial si der osis), 
re gar dless of cli nical sy m pt o m se verit y ( see Ta ble 6 f or details).

As y m pt o matic A RI A -H ( micr o he m orr ha ge or s u perficial si der osis) t hat is se vere 
o n M RI  ( ≥1 0 micr o he m orr ha ges a n d/ or > 2 f ocal areas of s u perficial si der osis )
(St a ge 1 o nly ) [see Ta ble 6 f or details].
N ote:   I n Sta ge 2, foll o wi n g D S M C re vie w of t he Sta ge 1 data a n d c o nti n ge nt 
u p o n D S M C rec o m me n dati o n (see Secti o n 1 9. 2. 2 ), a d uca n u ma b d osi n g will be 
c o nti n ue d i n s u bjects i n Gr o u p 2 wit h as y m pt o matic A RI A- H t hat is se vere o n 
M RI  ( ≥1 0 micr o he m orr ha ges a n d/ or > 2 f ocal areas of s u perficial si der osis ). T o 
mai ntai n t he bli n d, s u bjects i n Gr o u p 1 will per ma ne ntl y  disc o nti n ue acti ve 
d osi n g a n d recei ve place b o (see Ta ble 6 f or details).

A n y ne w i nci de nt macr o he m orr ha ge ( defi ne d as > 1 c m i n dia meter o n T 2 * 
se q ue nce), re gar dless of w het her sy m pt o ms are prese nt a n d, if prese nt, re gar dless 
of s y m pt o m se verit y .

T he s u bject 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.  
Re p ort t he pre g na nc y  acc or di n g t o t he i nstr ucti o ns i n Secti o n 1 5. 4. 1 .

T he s u bject wit h dra ws c o nse nt t o c o nti n ue st u d y  treat me nt.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
5 5

T he s u bject e x perie nces a me dical e mer ge nc y  t hat necessitates per ma ne nt 
disc o nti n uati o n of st u d y  treat me nt or u n bli n di n g of t he s u bject’s treat me nt 
assi g n me nt.

T he s u bject e x perie nces a n A E t hat d oes n ot res ol ve or re q uires c o nti n ue d treat me nt 
t hat meets e xcl usi o nar y criteria (see Secti o n 1 1. 5. 1. 2 ).  

T he s u bject e x perie nces a se vere i nf usi o n reacti o n.

At t he discreti o n of t he I n v esti gat or or Bi o ge n f or me dical reas o ns.

At t he discreti o n of t he I n vesti gat or or Bi o ge n f or n o nc o m plia nce.
T he pri mar y  reas o n f or disc o nti n uati o n of st u d y treat me nt m ust be rec or de d i n t he s u bject’s case 
re p ort f or m ( C R F).
S u bjects w h o per ma ne ntl y  disc o nt i n ue st u d y treat me nt are t o re mai n i n t he st u d y a n d f oll o w a 
m o difie d sc he d ule f or tests a n d assess me nts u ntil t he e n d of st u d y  or wit h dra wal of c o nse nt 
(Ta ble 4 ).  T he o nl y e xce pti o n is a s u bject w h o ma y de vel o p se vere as y m pt o matic A RI A -H 
( micr o he m orr ha ge, s u perficial si der osis) i n Sta ge 2; s uc h a s u bject is t o f oll o w t he re g ular visit 
sc he d ule, t o mai ntai n t he bli n d t o t he s u bject’s gr o u p assi g n me nt (see Ta ble 1 ).
1 0. 2.   
L ost t o F oll o w -U p
S u bject s will be c o nsi dere d l ost t o f oll o w -u p if t he y re pe ate dl y fail t o ret ur n f or sc he d ule d visits 
a n d are u na ble t o be c o ntacte d b y t he st u d y site. 
T he f oll o wi n g acti o ns m ust be ta ke n if a s u bje ct fails t o ret ur n t o t he st u d y site f or a re q uire d 
st u d y visit:

T he site m ust atte m pt t o c o ntact t he s u bject a n d re sc 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 s u bject 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 s u bject 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 s u bject is dee me d l ost t o f oll o w-u p, t he In 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 s u bject.  T hese c o ntact atte m pts s h o ul d 
be d oc u me nte d i n t he s u bject’s me dical rec or d.

If t he s u bject c o nti n ues t o be u nreac ha ble, t hat s u bject 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.
1 0. 3.   
Wit h dr a w al of S u bjects Fr o m St u d y
S u bjects 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 s u bject wit h dra w s c o nse nt.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
5 6

T he s u bject is u n willi n g or u na ble t o c o m pl y wit h t he pr ot oc ol.

At t he discreti o n of t he I n vesti gat or or Bi o ge n .
N ote:  A s u bject w h o per ma ne ntl y disc o nti n ues st u d y  treat me nt will n ot be a ut o maticall y 
wit h dra w n fr o m t he st u d y, re gar dless of t he n u m ber of d oses misse d, if t he y  c o nti n ue t o atte n d 
cli nic visits a n d c o m plete assess me nts as sc he d ule d (Ta ble 4).  
T he reas o n f or t he s u bject’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 s u bject’s C R F.
S u bjects w h o are wit h dra w n fr o m t he st u d y  after recei vi n g ≥1 d oses of st u d y  treat me nt m ust 
u n der g o a n E n d of Treat me nt Visit u nless wit h dra wal is d ue t o deat h or wit h dra wal of c o nse nt.  
S u bjects w h o are wit h dra w n fr o m t he st u d y  are als o t o ret ur n t o t he site f or a safety f oll o w- u p
visit 1 8 wee ks after recei vi n g t heir last d ose of st u d y  treat me nt.  
S u bjects w h o wit h dra w fr o m t he st u d y  ma y be re place d.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
5 7
1 1.      
S T U D Y T R E A T M E N T U S E
1 1. 1.   
Re gi me n
Refer t o a n d f oll o w t he Directi o ns f or Ha n dli n g a n d A d mi nistrati o n ( D H A ) f or s pecific 
i nstr ucti o ns o n t he ha n dli n g, pre parati o n, a d mi nistrati o n, a n d dis p osal of t he st u d y treat me nt.  
T he st u d y  treat me nt i nf usi o n sc he d ule d uri n g t he ra n d o mize d treat me nt peri o d a n d t he L T E 
peri o d of t he st u d y is pr o vi de d i n Secti o n 5 .
A d uca n u ma b is t o be a d mi nistere d b y IV i nf usi o n f oll o wi n g dil uti o n i nt o sali ne.  See Secti o n 1 2
f or details of a d uca n u ma b st u d y treat me nt.
1 1. 1. 1.   
A d uc a n u m a b
Bi o ge n will pr o vi de a d uca n u ma b t o t he st u d y  sites.
1 1. 1. 2.   
Pl ace b o
All s u bjects recei ve a d uca n u ma b i n t his st u d y.
T o mai ntai n t he bli n d t o s u bjects’ gr o u p assi g n me nt , s u bjects i n Gr o u p 1 w h o ha ve 
as ym pt o matic A RI A (e xce pt macr o he m orr ha ge) t hat re q uires d ose s us pe nsi o n or disc o nti n uati o n 
of acti ve d osi n g as per pr ot oc ol will recei ve place b o.  P lace b o ( 0. 9 % s o di u m c hl ori de) will be 
s u p plie d b y t he st u d y site.
1 1. 2.   
M o dific ati o n of D ose a n d/ or Tre at me nt Sc he d ule
1 1. 2. 1.   
C o nti n u ati o n, S us pe nsi o n , or Disc o nti n u ati o n f or A RI A E ve nts D uri n g t he 
R a n d o mize d Tre at me nt Peri o d
A ce ntral M RI rea di n g ce nter will re p ort i nci de nt cases of A R I A-E a n d A RI A -H t o b ot h Bi o ge n 
a n d t he treati n g H C P wit hi n a s pecifie d ti me.  T he u n bli n de d p har mac y  staff will pre pare t he 
treat me nt after c o ns ulti n g t he i nteracti ve res p o nse tec h n ol o g y  sys te m, w hic h will pr o vi de 
i nte grate d i nf or mati o n base d o n t he cli nical assess or’s s ym pt o mat ol o g y  assess me nt, t he A RI A 
i nf or mati o n fr o m t he ce ntral M RI rea d, a n d t he s u bject’s treat me nt gr o u p assi g n me nt.   
Bi o ge n a n d a D S M C will re vie w safet y data o n a n o n g oi n g basis , i ncl u di n g c o m pre he nsi ve 
A RI A i nf or mati o n .  T he st u d y ma y  be m o difie d or ter mi nate d b y  Bi o ge n base d o n t he 
rec o m me n dati o n of t he D S M C, i nter nal re vie w of t he safety data, a n d per st u d y -s pecific 
st o p pi n g rec o m me n dati o ns as descri be d i n t he D S M C c harter.  I n a d diti o n, t he D SM C will ma ke 
a rec o m me n dati o n of d osi n g t hr o u g h as y m pt o matic se vere A RI A cases i n Gr o u p 2. A D S M C 
c harter will pr o vi de f ull g ui da nce o n t he f u ncti o n a n d practices t o be f oll o we d b y  t he D S M C 
( Secti o n 1 9. 2. 2 ).


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
5 8
G ui deli nes o n t he ma na ge me nt a n d dis p ositi o n of A RI A- E a n d A RI A -H cases are pr o vi de d i n 
t he f oll o wi n g s u bsecti o ns.  See Secti o n 1 0. 1 f or t he f ull list of criteria f or disc o nti n ui n g st u d y 
treat me nt.
1 1. 2. 1. 1. 
A RI A -E C ases
T he ma na ge me nt a n d dis p ositi o n of s u bjects w h o de vel o p A RI A- E d uri n g t he ra n d o mize d 
treat me nt peri o d are detaile d i n Ta ble 5 .
All s u bjects w h o de vel o p A RIA -E s h o ul d ha ve u nsc he d ule d visits e ver y 4 wee ks ( ± 5 da ys) f or 
f oll o w-u p M RI  a n d A RI A safety assess me nts (as detaile d i n Secti o n 5, Ta ble 1 ), u ntil t he 
A RI A - E has res ol ve d per ce ntrally rea d M RI.  
 P K sa m ples will be c ollecte d at 
t he first u nsc he d ule d visit f oll o wi n g a n e pis o de of A RIA.
S u bjects w h o c o nti n ue d osi n g d uri n g t he first or s u bse q ue nt rec urri n g A RI A - E e ve nts will d o s o 
i n acc or da nce wit h t he a d uca n u ma b d osi n g re gi me n (f or details, see Secti o n 1 1. 2. 3 ). 
S u bje cts f or w h o m treat me nt is te m p oraril y  s us pe n de d d ue t o t he first or rec urre nt A RI A -E 
e ve nts ma y  res u me treat me nt at t he sa me d ose, o nce A RI A-E a n d (if prese nt) cli nical si g ns a n d 
s ym pt o ms ha ve res ol ve d, i n t he treati n g H C P’s o pi ni o n (f or details see Secti on 1 1. 2. 3 ).
Ma na ge me nt of A RI A -E after it res ol ves is descri be d i n Secti o n 1 1. 2. 4 .  
S u bjects w h o c o nti n ue d osi n g d uri n g a n A RI A- E e ve nt or w h o s us pe n d d osi n g (i ncl u di n g d ue t o 
a n A RI A- E e ve nt) s h o ul d c o m plete all sc he d ule d cli nic visits f or assess me nts (as detaile d i n 
Secti o n 5 , Ta ble 1 ).  S u bjects w h o per ma ne ntl y disc o nti n ue treat me nt d ue t o A RI A- E (as wit h 
s u bjects w h o disc o nti n ue f or ot her reas o ns) are t o re mai n i n t he st u d y a n d f oll o w a m o difie d 
sc he d ule f or tests a n d assess me nts u ntil t he e n d of st u d y  or wit h dra wal of c o nse nt (Ta ble 4 ).  
T his is i n a d diti o n t o c o m pleti n g t he u nsc he d ule d visits as descri be d a b o ve.
S u bjects w h o wit h dra w fr o m t he st u d y  are t o ret ur n f or a safet y f oll o w - u p visit 1 8 wee ks after 
t heir last d ose of st u d y treat me nt.




Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
6 0
1 1. 2. 1. 2. 
A RI A -H ( Micr o he m orr h a ge or S u perfici al Si der osis) C ases
T he ma na ge me nt a n d dis p ositi o n of s u bjects w h o de vel o p A RI A- H ( micr o he m orr ha ge or 
s u perficial si der osis) is detaile d i n Ta ble 6.
All s u bjects w h o de vel o p A RI A -H ( micr o he m orr ha ge or s u perficial si der osis) s h o ul d ha ve a n 
u nsc he d ule d visit (s) e ver y 4 wee ks ( ± 5 da ys) f or f oll o w-u p M RI a n d A RI A safet y assess me nts ,
as detaile d i n Secti o n 5 ( Ta ble 1) , u ntil t he micr o he m orr ha ges/s u perficial si der osis are dee me d 
sta ble ( defi ne d as n o c ha n ge or a decrease i n t he n u m ber, size, se verity, or n u m ber of l ocati o ns 
bet wee n 2 c o nsec uti ve M RI s, w hic h ca n i ncl u de t he i nitial M RI) per ce ntrall y rea d M RI.  
 P K sa m ples will be c ollecte d at t he first u nsc he d ule d visit f oll o wi n g a n e pis o de 
of A RI A.
S u bjects w h o c o nti n ue d osi n g d uri n g t he first or s u bse q ue nt rec urri n g A RI A -H e ve nts, will d o s o 
i n acc or da nce wit h t he a d uca n u ma b d osi n g re gi me n (f or details see Secti o n 1 1. 2. 3 ). 
S u bjects f or w h o m treat me nt is te m p oraril y  s us pe n de d d ue t o a first or rec urre nt A RI A -H ma y
res u me treat me nt at t he sa me d ose o nce t he A RI A-H is dee me d sta ble a n d (if prese nt) t he cli nical 
si g ns a n d sy m pt o ms ha ve res ol ve d i n t he treati n g H C P’s o pi ni o n (f or details see Secti o n 1 1. 2. 3 ).
Ma na ge me nt of A RI A -H after sta bilizati o n is descri be d i n Secti o n 1 1. 2. 4 .    
S u bjects w h o c o nti n ue d osi n g t hr o u g h a n A RI A -H e ve nt or w h o s us pe n d d osi n g (i ncl u di n g d ue 
t o a n A RI A-H e ve nt) s h o ul d c o m plete all sc he d ule d cli nic visits as detaile d i n Secti o n 5 
(Ta ble 1 ).  S u bjects w h o per ma ne ntl y disc o nti n ue treat me nt d ue t o a n A RI A -H e ve nt (as wit h 
s u bjects w h o per ma ne ntl y disc o nti n ue treat me nt f or ot her reas o ns) are t o re mai n i n t he st u d y a n d 
f oll o w a m o difie d sc he d ule f or tests a n d assess me nts u ntil t he e n d of st u d y  or wit h dra wal of 
c o nse nt (Ta ble 4 ).  T he o nl y  e xce pti o n is a s u bject w h o ma y  de vel o p se vere as y m pt o matic 
A RI A -H i n Sta ge 2 as o utli ne d i n Ta ble 6 ; s uc h a s u bject is t o f oll o w t he re g ular visit sc he dule 
(Ta ble 1 ) i n or der t o mai ntai n t he bli n d t o t he s u bject’s gr o u p assi g n me nt.
S u bjects w h o wit h dra w fr o m t he st u d y  are t o ret ur n f or a safet y f oll o w - u p visit 1 8 wee ks after 
t heir last d ose of st u d y treat me nt.




Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
6 2
ma y de vel o p se vere as y m pt o matic A RI A -H i n Sta ge 2 as o utli ne d i n Ta ble 6 ; s uc h a s u bject is t o f oll o w t he 
re g ular visit sc he d ule (Ta ble 1 ) t o mai ntai n t he bli n d t o t he s u bject’s gr o u p assi g n me nt.
4“ Ot her me dicall y i m p orta nt e ve nts” re q uiri n g d osi n g s us pe nsi o n i ncl u de S A Es t hat are n ot life-t hreate ni n g (i n t he 
o pi ni o n of t he I n vesti gat or), d o n ot re q uire 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, a n d 
d o n ot res ult i n si g nifica nt/ per ma ne nt disa bilit y or c o n ge nital a n o malies/fetal defects, b ut ma y (i n t he o pi ni o n of 
t he I n vesti gat or) je o par dize t he s u bject or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve 
a n d as descri be d i n Secti o n 1 5. 1 .
5A E s re q uiri n g per ma ne nt disc o nti n uati o n of st u d y treat me nt i ncl u de t h ose t hat are life-t hreate ni n g (i n t he o pi ni o n of 
t he I n vesti gat or) a n d/ or res ult i n persiste nt or si g nifica nt disa bilit y/i nca pacit y or a c o n ge nital a n o mal y/ birt h defect,
as descri be d i n Secti o n 1 5. 1 .
1 1. 2. 1. 3. 
M acr o he m orr h a ge
S u bjects i n eit her Gr o u p 1 or 2 w h o de vel o p a n y ne w i nci de nt macr o he m orr ha ge ( defi ne d as > 1 
c m i n dia meter o n T 2 * se q ue nce), re gar dless of w het her s y m pt o ms are prese nt a n d, if prese nt, 
re gar dless of sy m pt o m se verit y , will per ma ne ntly disc o nti n ue treat me nt b ut will re mai n i n t he 
st u d y.  S u bjects will f oll o w a m o difie d sc he d ule f or tests a n d assess me nts u ntil t he e n d of t he 
st u d y peri o d or wit h dra wal of c o nse nt (Ta ble 4 ).  I n a d diti o n, s u bjects s h o ul d ha ve a n 
u nsc he d ule d visit(s) e ver y  4 wee ks ( ± 5 da ys) f or a f oll o w-u p M R I a n d A RI A safet y assess me nts 
as detaile d i n Secti o n 5 , u ntil t he macr o he m orr ha ge is c o nfir me d sta ble per ce ntrall y rea d M RI.  
A macr o he m orr ha ge is c o nsi dere d sta ble if it t here is eit her n o c ha n ge or a decrease i n t he 
n u m ber, size, se verit y or n u m ber of l ocati o ns bet wee n 2 c o nsec uti ve M RIs, i ncl u di n g t he i nitial 
detecti o n M RI  a n d t he M RI perf or me d 4 wee ks ( ± 5 da ys) later. 
 P K sa m ples will 
be c ollecte d at t he first u nsc he d ule d visit f oll o wi n g a n e pis o de of A RI A.
1 1. 2. 1. 4. 
C oi nci de nt A RI A- E a n d A RI A - H C a ses
S u bjects w h o de vel o p A RI A- E c oi nci de nt wit h A RI A- H i n eit her Gr o u p 1 or Gr o u p 2 will 
f oll o w t he m ost restricti ve a p plica ble g ui deli nes as descri be d i n Secti o ns 1 1. 2. 1. 1 , 1 1. 2. 1. 2
a n d 1 1. 2. 1. 3.
1 1. 2. 2.   
C o nti n u ati o n, S us pe nsi o n , or Disc o nti n u ati o n f or A RI A E ve nts D uri n g t he 
L o n g -Ter m E xte nsi o n Peri o d
D ose c o nti n uati o n, s us pe nsi o n , or disc o nti n uati o n f or A RI A-E or A RI A -H cases d uri n g t he L T E 
peri o d will be base d o n t he pre vi o usl y me nti o ne d criteria f or Gr o u p 2 f or as ym pt o matic a n d 
s ym pt o matic cases .  


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A  I nc.
6 3
1 1. 2. 3.   
D osi n g i n S u bjects C o nti n ui n g o n A d uc a n u m a b D uri n g a n A RI A E ve nt a n d i n 
S u bjects Res u mi n g A d uc a n u m a b After D ose S us pe nsi o n d ue t o A RI A 
S u bjects w h o c o nti n ue d osi n g per pr ot oc ol d uri n g a first occ urre nce or rec urre nce of 
as ym pt o matic A RI A will d o s o i n acc or da nce wit h t he pr ot oc ol -s pecifie d a d uca n u ma b d osi n g 
re gi me n ( 2 d oses of 1 m g/ k g, t he n 2 d oses of 3 m g/ k g, t he n 2 d oses of 6 m g/ k g, a n d 1 0 m g/ k g 
t hereafter).  F or e xa m ple, if as ym pt o matic A RI A occ urs after t he first d ose of 3 m g/ k g, t he 
s u bject will c o nti n ue d osi n g a n d recei ve 3 m g/ k g; a n d if asy m pt o matic A RI A rec urs after t he 
sec o n d d ose of 6 m g/ k g, t he s u bject will c o nti n ue d osi n g a n d recei ve 1 0 m g/ k g.  
S u bjects w h o s us pe n d d osi n g d ue t o a first occ urre nce or rec urre nc e of A RI A a n d w h o res u me 
d osi n g per pr ot oc ol are t o res u me d osi n g at t h e sa me d ose le vel.  H o we ver, if d osi n g is 
s us pe n de d bef ore a s u bject reac hes 1 0 mg/ k g , t he s u bject m ust recei ve at least 2 d oses at t he d ose 
le vel at w hic h A RI A occ urre d bef ore titrati ng u p t o t he ne xt d ose le vel a n d c o nti n ui n g t he 
titrati o n t o 1 0 m g/ k g.  
1 1. 2. 4.   
M RI M o nit ori n g
After Res ol uti o n of A RI A i n S u bjects C o nti n ui n g or Res u mi n g 
D osi n g
If A RI A occ urs d uri n g t he titrati o n p hase (e. g., d uri n g t he first 2 8 wee ks i n t he case of i nci de nt 
A RI A ):

After A RI A has res ol ve d or sta bilize d, a n M RI a n d Mo C A will be perf or me d 2 wee ks 
( ± 5 da y s) after e ver y sec o n d d ose u ntil c o m pleti o n of t he titrati o n peri o d, wit h s u bjects 
ass u me d t o be titrati n g t o 1 0 m g/ k g , a n d a fi nal M RI a n d M o C A after t he sec o n d d ose at 
1 0 m g/ k g.  M RI s will ot her wise be perf or me d as i n dicate d i n t he Sc he d ule of Acti vities 
( Secti o n 5 ).  

T his a p plies re gar dless of w het her t he s u bject is c o nti n ui n g d osi n g, is res u mi n g d osi n g 
after s us pe nsi o n of acti ve d os i n g, or has disc o nti n ue d acti ve d osi n g a n d is recei vi n g
place b o.
If A RI A occ urs after t he e n d of t he titrati o n p hase (e. g., after Wee k 2 8):

After A RI A has res ol ve d or sta bilize d, a n M RI a n d Mo C A will be perf or me d 2 wee ks 
( ±5 da y s) after t he sec o n d a d mi nistrati o n of the restart d ose . M RI s will ot her wise be 
perf or me d as i n dicate d i n t he Sc he d ule of Acti vities ( Secti o n 5 ).

T his a p plies re gar dless of w het her t he s u bject is c o nti n ui n g d osi n g, is res u mi n g d osi n g 
after d ose s us pe nsi o n, or has disc o nti n ue d acti ve d osi n g a n d is recei vi n g place b o.
1 1. 2. 5.   
I nf usi o n I nterr u pti o n
If a ny mil d or m o derate i nf usi o n -relate d reacti o ns (e. g., hea dac he, c hills/ri g ors, a n d 
na usea/ v o miti n g) occ ur d uri n g a n i nf usi o n, t he i nf usi o n s h o ul d be sl o we d or i nterr u pte d a n d 
s u p p orti ve treat me nt s h o ul d be i nstit ute d at t he discreti o n of t he I n vesti gat or.  After res ol uti o n of 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
6 4
s ym pt o ms, if t he i nf usi o n ha d bee n sl o we d, t he ori gi nal i nf usi o n rate ma y  be res u me d; if t he 
i nf usi o n ha d bee n i nterr u pte d, t he i nf usi o n ma y be restarte d at a rate t hat d oes n ot e xcee d t he 
ori gi nal i nf usi o n rate.  A n i nf usi o n m ust be disc o nti n ue d if n ot c o m plete d wit hi n 3 h o urs.  
Refer t o t he D H A f or i nf usi o n rate i nf or mati o n.  
If a se vere i nf usi o n-relate d reacti o n occ urs d uri n g a n i nf usi o n, or a n aller gic reacti o n s uc h as 
urticaria or a na p h yl a xis occ urs, t he s u bject will be disc o nti n ue d fr o m st u d y  treat me nt b ut ma y 
re mai n i n t he st u d y.  T he s u bject m ust be a p pr o priatel y treate d i n acc or da nce wit h l ocal practice.
Se verit y  of e ve nts is descri be d i n Secti o n 1 5. 2. 3.
1 1. 3.   
Prec a uti o ns
N ot a p plica bl e.
1 1. 4.   
C o m pli a nce
C o m plia nce wit h treat me nt d osi n g is t o be m o nit ore d a n d rec or de d b y u n bli n de d site staff.
1 1. 5.   
C o nc o mit a nt T her a p y a n d Pr oce d ures
1 1. 5. 1.   
Pri or a n d C o nc o mit a nt T her a p y
Pri or A D me dicati o n use wit hi n t he 1 2 m o nt hs pri or t o Scree ni n g will be ca pt ure d.
A c o nc o mita nt t hera p y is a n y dr u g or s u bsta nce a d mi nistere d bet wee n t he i nf or me d c o nse nt a n d 
u ntil t he s u bject’s fi nal cli nic visit (i ncl u di n g t he safety f oll o w -u p visit ).
N o pre me dicati o n (e. g., a nti- aller g y dr u gs, a nti pyr etic a nal gesics) s h o ul d be use d pri or t o t he 
start of st u d y treat me nt i nf usi o n u nless disc usse d wit h t he st u d y me dical m o nit or i n a d va nce.
1 1. 5. 1. 1. 
All o we d C o nc o mit a nt T her a p y

Me dicati o ns f or c hr o nic c o n diti o ns at a sta ble d ose d uri n g t he st u d y  as l o n g as t he 
s u bject has bee n sta ble o n t he me dicati o n(s) f or at least 4 wee ks pri or t o Scree ni n g 
Visit 1 a n d d uri n g t he scree ni n g peri o d.  

S y m pt o matic t hera pies f or A D, i ncl u di n g b ut n ot li mite d t o d o ne pezil, ri vasti g mi ne, 
gala nta mi ne, tacri ne, a n d me ma nti ne, pr o vi de d t hat s u bjects are recei vi n g a sta ble
d ose f or at least 8 wee ks pri or t o Scree ni n g Visit 1 a n d d uri n g t he scree ni n g peri o d ,
a n d t hat t he y sta y o n a sta ble d ose w hile i n t he st u d y.

Vacci nati o ns wit h li ve or atte n uate d vacci nes.  A d mi nistrati o n of a n y  
vacci nati o n/ b o oster s h o ul d n ot be gi ve n < 1 0 da y s pri or t o a n y d osi n g visit a n d f or 1 0 
da y s after a d osi n g visit.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
6 5
1 1. 5. 1. 2. 
Dis all o we d C o nc o mit a nt T her a p y

Me dicati o ns wit h platelet a ntia g gre ga nt or a ntic oa g ula nt pr o perties, e xce pt t he use of 
as piri n at a d ose of ≤ 3 2 5 m g per da y .

N o n prescri pti o n narc otic me d icati o n.

I m m u n os u p pressi ve dr u gs (i ncl u di n g sys te mic c ortic oster oi ds).  Local c ortic oster oi ds 
(i ncl u di n g i n hale d a n d t o pical c ortic oster oi ds) are all o we d; certai n s yste mic 
c ortic oster oi ds ma y be per mitte d at Bi o ge n ’s discreti o n.

Pare nteral i m m u n o gl o b uli n, bl o o d pr o d ucts, plas ma deri vati ves, plas ma e xc ha n ge, 
a n d plas ma p heresis.

A n y  i n vesti gati o nal dr u g.
S u bjects 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 
wit h o ut a n y  c ha n ges (see all o we d c o nc o mita nt t hera p y, a b o ve) a n d 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 hese ma y  c o nf o u n d t he res ults 
of t he st u d y .  H o we ver, me dicall y i n dicate d me dicati o n or treat me nt s h o ul d n ot be wit h hel d.  
S u bjects s h o ul d i nf or m t he I n vesti gat o r of a n y c ha n ges i n me dicati o n.  T he c ha n ge s h o ul d be 
re vie we d by t he I n vesti gat or a n d t he st u d y me dical m o nit or t o deter mi ne w het her t he s u bject’s 
st u d y treat me nt s h o ul d be s us pe n de d.  Me dicati o ns use d t o treat A Es will n ot res u lt i n a ut o matic
per ma ne nt s tu d y  treat me nt disc o nti n uati o n.  H o we ver, as n ote d i n Secti o n 1 0. 1 , if a s u bject 
re q uires c o nti n ue d use of a disall o we d t hera py, t he s u bject m ust per ma ne ntl y disc o nti n ue st u d y 
treat me nt.  Bi o ge n ma y  be c o ns ulte d if re q uire d.  
S u bjects s h o ul d ha ve a n u nsc he d ule d visit f or a c ha n ge i n A D me dicati o n ; re q uire d assess me nts 
per sc he d ule of acti vities ( M M S E a n d A Es) s h o ul d be perf or me d pri or t o a n y c ha n ge i n 
me dicati o n.
1 1. 5. 2.   
C o nc o mit a nt Pr oce d ures
A c o nc o mita nt pr oce d ure is a n y  t hera pe utic i nter ve nti o n (e. g., s ur ger y/ bi o ps y, p h ysical t hera py) 
or dia g n ostic assess me nt (e. g., bl o o d gas meas ure me nt, r o uti ne c ol o n osc o p y , bacterial c ult ures) 
perf or me d bet wee n t he ti me t he s u bject is e nr olle d i n t he st u d y a n d u ntil t he s u bject’s fi nal cli nic 
visit (i ncl u di n g t he safet y f oll o w-u p visit ), u nless t he s u bject is bei n g f oll o we d f or st u dy
treat me nt-relate d t o xicit y.  
T he use of c o nc o mita nt t hera pies or pr oce d ures defi ne d a b o ve m ust be rec or de d o n t he s u bject’s 
C R F.  A Es relate d t o a d mi nistrati o n of t hese t hera pies or pr oce d ures m ust be d oc u me nte d o n t he 
a p pr o priate A E C R F.
1 1. 6.   
C o nti n u ati o n of Tre at me nt 
N o f urt her pr o visi o ns are ma de f or access t o t he st u d y  treat me nt.  If a d uca n u ma b is pr o ve n t o be 
be neficial, all r e 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 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
6 7
A d uca n u ma b is t o be a d mi nistere d b y  IV i nf usi o n f oll o wi n g dil uti o n i nt o sali ne.
If t he pac ka gi n g is da ma ge d, or if t here is a nyt hi n g u n us ual a b o ut t he a p peara nce or attri b utes of 
t he vials or s t u d y treat me nt, d o n ot use t he st u d y treat me nt.  T he vial i n q uesti o n s h o ul d be sa ve d 
at t he st u d y site a n d t he pr o ble m i m me diatel y re p orte d t o Bi o ge n.
1 2. 1. 2.   
A d uc a n u m a b St or a ge
St u d y  treat me nt m ust be st ore d i n a sec ure l ocati o n.  A d uca n u ma b is t o be st ore d at 2 ° C t o 8° C 
( 3 6° F t o 4 6° F), i n a l oc ke d st ora ge c o ntai ner wit h li mite d access.  A d uca n u ma b s h o ul d be 
pr otecte d fr o m li g ht, pr otecte d fr o m freezi n g, a n d s h o ul d n ot be s ha ke n.  If a d mi nistrati o n of t he 
pre pare d a d uca n u ma b is dela y e d f or m ore t ha n 4 h o urs, t he n it s h o ul d be ke pt at 2° C t o 8º C u ntil 
use.  If a d mi nistrati o n of t he pre pare d a d uca n u ma b is dela y e d f or m ore t ha n 2 4 h o urs, it m ust be 
discar de d.  F or t he m ost u p -t o- date st ora ge re q uire me nts, f oll o w t he i nstr ucti o ns pr o vi de d i n t he 
D H A.
1 2. 1. 3.   
A d uc a n u m a b H a n dli n g a n d Dis p os al
T he I n vesti gat or m ust ret ur n all use d a n d u n use d vials of a d uca n u ma b as i nstr ucte d b y Bi o ge n 
u nless a p pr o ve d f or o nsite destr ucti o n.
If a ny a d uca n u ma b s u p plies are t o be destr o ye d at t he st u d y site, t he i nstit uti o n or a p pr o priate 
site staff m ust o btai n pri or a p pr o val fr o m Bi o ge n, b y  pr o vi di n g, i n writi n g, t he destr ucti o n p olic y 
or details of t he met h o d of destr ucti o n.  After s uc h destr ucti o n, Bi o ge n m ust be n otifie d, i n 
writi n g, of t he details of t he st u d y  treat me nt destr o ye d (e. g., l ot or kit n u m bers, q ua ntities), t he 
date of destr ucti o n, a n d pr o of of destr ucti o n.
1 2. 1. 4.   
A d uc a n u m a b Acc o u nt a bilit y
Acc o u nta bilit y  f or st u d y treat me nt is t he res p o nsi bilit y of t he I n vesti gat or.  T he st u d y site m ust 
mai ntai n acc urate rec or ds de m o nstrati n g dates a n d a m o u n t of st u d y treat me nt recei ve d, t o w h o m 
dis pe nse d (s u bject -b y -s u bject acc o u nti n g), a n d acc o u nts of a n y st u d y treat me nt acci de ntally or 
deli beratel y destr o ye d or l ost.  
U nless ot her wise n otifie d, all vials b ot h use d a n d u n use d, m ust be sa ve d f or st u d y  treatme 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 
a d uca n u ma b 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 Bi o ge n .  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.
1 2. 2.   
Pl ace b o
Place b o ( 0. 9 % s o di u m c hl ori de) will be s u p plie d b y t he st u d y site i n t he f or m of 1 0 0 m L  sali ne 
I V ba gs.
1 2. 3.   
Ot her Pr ot oc ol -Desi g n ate d Pr o d uct
Refer t o t he D H A f or i nf usi o n- relate d s u p ply s pecificati o ns.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
6 8
P E T sca ns at scree ni n g will be perf or me d usi n g A m y vi d ™ ( 1 8F- fl or beta pir), Viza m yl ™ ( 1 8F-
fl ute met o m ol), or Ne urace q ™ ( 1 8F- fl or beta be n).   F or details o n P E T i ma gi n g li ga n ds , refer t o 
t he pr oce d ural ma n ual f or P E T.






Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
7 1
T he E ver y da y  C o g niti o n ( E C o g) scale c o nsists of 3 9 q uesti o ns a b o ut a pers o n’s a bilit y t o 
c o m plete c o m m o n tas ks, s uc h as kee pi n g trac k of a c o n versati o n or s h o p pi n g f or a fe w ite ms 
wit h o ut a list.  E C o g ( O bser ver) will be c o m plete d b y  t he i nf or ma nt/care part ner at t he Scree ni n g 
V isit.  T he res ult mi g ht be utilize d t o i de ntif y a pre dicti ve mar ker ass ociate d wit h a m yl oi d 
p ositi vit y  i n cli nically d ia g n ose d s u bjects wit h M CI  a n d/ or wit h mil d A D de me ntia .
Di gital S y m b ol S u bstit uti o n Tas k ( D S S T) a n d Trails Ma ki n g Test ( T M T) are ne ur o ps yc h ol o gical 
tests use d t o assess t he c o g niti ve d o mai ns of pr ocessi n g s pee d, e pis o dic me m or y, a n d e xec uti ve 
f u ncti o n.  D S S T/ T M T tests are o pti o nal, a n d will be a d mi nistere d by a rater at a ny 2 S cree ni n g 
V isits.  T he test perf or ma nce wit hi n, a n d lear ni n g effect acr oss, t he 2 test sessi o ns ma y be 
utilize d t o i de ntif y  a pre dicti ve mar ker ass ociate d wit h a m yl oi d p ositi vit y i n cli nicall y dia g n ose d 
s u bjects wit h M CI  a n d/ or wit h mil d A D de me ntia .


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
7 2
1 4.      
S A F E T Y A S S E S S M E N T S
See Secti o n 5 f or t he ti mi n g of all safety assess me nts.
1 4. 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 
a d uca n u ma b:

A E a n d S A E rec or di n g

Brai n M RI

P h y sical e xa mi nati o n, i ncl u di n g hei g ht a n d wei g ht

N e ur ol o gical e xa mi nati o ns 

Vital si g n m eas ure me nts:  te m perat ure, heart rate, s yst olic a n d diast olic bl o o d 
press ure, a n d res pirat or y  rate 

1 2 -lea d E C G

C o nc o mita nt t hera py a n d pr oce d ure rec or di n g

C ol u m bia S uici de Se verit y  Rati n g Scale ( C-S S R S)

T he C -S S R S is a s uici dal i deati o n a n d be ha vi or rati n g scale use d t o e val uate 
s uici de ris k. 

M o C A
f or A RI A m o nit ori n g a n d ma na ge me nt  

T he M o C A is a 3 0 -p oi nt test wi del y  use d t o detect c o g niti ve d ys f u ncti o n a n d is 
use d i n t his s t u d y as a safet y meas ure.
1 4. 2.   
L a b or at or y S afet y Assess me nts
Sa m ples will be a nal y ze d usi n g G o o d La b orat or y Practice -vali date d assa y s.
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 
a d uca n u ma b:

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, a n d a bs ol ute 
ne utr o p hil c o u nt


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
7 3

Bl o o d c he mistr y :  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, lactate de h ydr o ge nase, ga m ma -gl uta m yl  tra nsferase, gl uc ose, 
calci u m, p h os p h or us, bicar b o nate, c hl ori de, s o di u m, a n d p otassi u m

Uri nal y sis:  c ol or, s pecific gra vit y, p H, pr otei n, gl uc ose, bl o o d , ket o nes, a n d 
micr osc o pic e xa mi nati o n (if a b n or m al)

Ser u m a n d uri ne pre g na nc y  test ( w o me n of c hil d beari n g p ote ntial o nly)

C oa g ulati o n, vir ol o g y (i ncl u di n g HI V at t he I n vesti gat or’s discreti o n after 
c o nsi derati o n of ris k fact ors), gl yc os yl ate d he m o gl o bi n ( H b A 1c), li pi d pa nel, a n d 
alc o h ol/ dr u g scree n (at Scree ni n g o nl y)
1 4. 3.   
I m m u n o ge nicit y Assess me nts
Prese nce of ser u m a ntia d uca n u ma b a nti b o dies will be deter mi ne d usi n g a vali date d assa y .  A 
sta n dar d 3-tier a nti dr u g a nti b o d y ( A D A) a p pr oac h will be use d (i.e., scree ni n g assa y, 
c o nfir mat or y assa y, a n d titrati o n assa y).  A d diti o nal c haracterizati o n of t he i m m u ne res p o nse 
ma y  be perf or me d.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
7 4
1 5.      
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.  
If a n A E occ urs, t he first c o ncer n s h o ul d be f or t he safety of t he s u bject.  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 s u bject or his/ her le gall y  a ut h orize d re prese ntati ve a n d/ or 
i nf or ma nt/care part ner 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 
A Es a n d me dical e mer ge ncies.
1 5. 1.   
Defi niti o ns
1 5. 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 s u bject 
a d mi nistere d a p har mace utical pr o d uct a n d t hat d oes n ot n ecessaril 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 la b orat or y fi n di n g), sy 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 u ct, 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 la b orat or y  val ue, vital si g n res ult, a n d/ or E C G res ult 
meets t he defi niti o n of a n A E will be ma de b y t he I n vesti gat or.  A b n or mal res ults are n ot 
c o nsi dere d A Es u nless o ne or m ore of t he f oll o wi n g criteria are met :

T he res ult meets t he criteria f or a n S A E

T he res ult re q uires t he s u bject t o recei ve s pecific c orrecti ve t hera py

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 5. 1. 2.   
Seri o us A d verse E ve nt
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

I n t he vie w of t he I n vesti gat or, places t he s u bject at i m me diate ris k of deat h (a 
life-t hreate ni n g e ve nt); h o we ver, t his d oes n ot i ncl u de a n e ve nt t hat, ha d it occ urre d 
i n a m ore se vere f or m, mi g ht ha ve ca use d deat h

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
7 5

Res ults i n a c o n ge nital a n o mal y / birt h defect

Is a me dically 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 In vesti gat or, ma y  je o par dize t he 
s u bject 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 5. 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 s u bject is h os pitalize d.  T he st u d y site m ust d oc u me nt all of 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 s u bject’s 
c o nse nt t o partici pate 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 oc e 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 s u bject’s c o nse nt t o partici pate 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 p r 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 s u bject 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 unless 
o ne of t he re q uire me nts i n Secti o n 1 5. 1. 2 is met.
1 5. 2.   
S afet y Cl assific ati o ns
1 5. 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 5. 1. 2

T he relati o ns h i p of t he e ve nt t o st u d y treat me nt as defi ne d i n Secti o n 1 5. 2. 2

T he se verit y of t he e ve nt as defi ne d i n Secti o n 1 5. 2. 3
1 5. 2. 2.     
Rel ati o ns hi p of E ve nts t o St u d y Tre at me nt
T he f oll o wi n g defi niti o ns s h o ul d be c o nsi dere d w he n e val uati n g t he relati o ns hi p of A Es a n d 
S A E s t o t he st u d y treat me nt.




Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
7 7
A Es t hat are o n g oi n g w he n t he s u bject 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 In vesti g at 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.  A E 
o utc o me will be rec or de d o n t he C R F, as a p plica ble.
1 5. 3. 2.   
A d verse E ve nts of S peci al I nterest
A n A E of s pecial i nterest is a n A E of scie ntific a n d me dical c o ncer n s pecific t o t his st u d y, f or 
w hic h o n g oi n g m o nit ori n g a n d re p orti n g are re q uire d. A RI A -E a n d A RI A -H are c o nsi dere d A Es 
of s pecial i nterest a n d will be e ntere d o n t he A d verse E ve nt of S pecial I nterest C R F wit hi n 
7 2 h o urs f oll o wi n g t he recei pt of a b n or mal M RI  fi n di n gs fr o m the ce ntral M RI  rea der.  
A E re p orti n g f or A RI A -E a n d A RI A -H will be base d o n t he f oll o wi n g ce ntrall y  rea d M RI 
se q ue nces: fl ui d atte n uate d i n versi o n rec o ver y/T 2 f or A RI A -E a n d T 2 */ gra die nt ec h o f or 
A RI A- H.  
If t he e ve nt q u alifies as a n S A E, a n S A E f or m s h o ul d be s u b mitte d per t he g ui deli nes i n 
Secti o n 1 5. 3. 4 .  I n vesti g at ors s h o ul d i ncl u de a c o p y of t he ce ntr all y re a d M RI re p ort w he n 
s u b mitti n g t he S A E f or m t o Bi o ge n .   
1 5. 3. 3.   
Seri o us A d verse E ve nts
A n y  S A E e x perie nce d b y t he s u bject bet wee n t he ti me of t he si g ni ng of t he I C F a n d t he s u bject’s 
fi nal cli nic visit (i ncl u di n g F U V isit) is t o be rec or de d o n a n S A E f or m, re gar dless of t he se verity 
of t he e ve nt or its relati o ns hi p t o st u d y  treat me nt.  S A Es m ust be re p orte d t o Bi o ge n wit hi n 
2 4 h o urs as descri be d i n Secti o n 1 5. 3. 4 .  F oll o w-u p i nf or mati o n re gar di n g a n S A E als o m ust be 
re p orte d wit hi n 2 4 h o urs.   T his als o a p plies t o S A Es t hat occ ur after a d mi nistrati o n of t he li ga n d.  
F U i nf or mati o n re gar di n g a n S A E als o m ust be re p orte d wit h 2 4 h o urs
S u bjects will be f oll o we d f or all S A Es u ntil t he fi nal cli nic visit (i ncl u di n g F U V isit).  
T hereafter, t he e ve nt s h o ul d be re p orte d t o Bi o ge n o nl y  if t he I n vesti gat or c o nsi ders t he S A E t o 
be relate d t o st u d y treat me nt.
A n y  S A E t hat is o n g oi n g w he n t he s u bject 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 5. 3. 4.   
I m me di ate Re p orti n g of Seri o us A d verse E ve nts
I n or der t o a d here t o all a p plica ble la ws a n d re g ulati o ns for re p orti n g a n S A E, t he st u d y  site m ust 
f or mall y n otif y Bi o ge n wit hi n 2 4 h o urs of t he site staff bec o mi n g a ware of t he S A E.  I t is t he 
I n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t he S A E re p orti n g i nf or mati o n a n d pr oce d ures are 
use d a n d f oll o we d a p pr o pri atel y.




Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
7 9
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 s u bjects 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.
1 5. 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 s u bject or ta ke n b y a s u bject t hat 
e xcee ds t he d ose assi g ne d t o t he s u bject acc or d i n g t o t he pr ot oc ol.  O ver d oses are n ot c o nsi dere d 
A Es a n d s h o ul d n ot be rec or de d as a n A E o n t he C R F; h o we ver, all o ver d oses m ust be rec or de d 
o n a n O ver d ose f or m a n d fa xe d t o Bi o ge n 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 Bi o ge n 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 t o Bi o ge n .  All st u d y  treat me nt-
relate d d osi n g i nf or mati o n m ust be rec or de d o n t he d osi n g C R F.
1 5. 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 L ist f or c o m plete c o ntact i nf or mati o n.  
1 5. 4. 3. 1. 
U n bli n di n g f or Me dic al E mer ge nc y
I n t his st u dy, e mer ge nc y dec o di n g will be ma de a vaila ble t o t he I n vesti gat or a n d desi g nate d 
pers o n nel at Bi o ge n t hr o u g h I R T.  
I n a me dical e mer ge nc y w he n k n o wle d ge of t he s u bject’s treat me nt assi g n me nt ma y p ossi bly 
i nfl ue nce t he s u bject’s cli nical care, t he I n vesti gat or ma y access t he s u bject’s treat me nt 
assi g n me nt b y I R T.  H o we ver, pri or t o u n bli n di n g, t he I n vesti gat or ca n c o ntact t he 2 4-h o ur 
e mer ge nc y me dical s u p p ort n u m ber at 
.
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 s u bject’s s o urce d oc u me nts.  
T he I n vesti gat or is str o n gl y a d vi se d n ot t o di v ul ge t he s u bject’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 ys is 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 Bi o ge n t o disc uss s uc h 
sit uati o ns.
1 5. 5.   
C o ntr ace pti o n Re q uire me nts
All w o me n of c hil d beari n g p ote ntial a n d all me n m ust e ns ure t hat hi g hl y effecti ve c o ntrace pti o n 
is use d d uri n g t he st u dy a n d f or 2 4 wee ks after t heir last d ose of st u d y treat me nt.  In a d diti o n, 
s u bjects s h o ul d n ot d o nate s per m or e g gs f or t he d urati o n of t he st u d y a n d f or at least 2 4 wee ks
after t heir last d ose of st u d y treat me nt.
F or t he p ur p oses of t his st u d y , w o me n w h o d o n ot meet o ne of t he f oll o wi n g criteria are 
c o nsi dere d t o be p h ys i ol o gicall y ca pa ble of bec o mi n g pre g na nt a n d are, t heref ore, defi ne d as 
w o me n of c hil d beari n g p ote ntial:


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
8 0

P ost me n o pa usal
o
1 2 c o nti n u o us m o nt hs of nat ural (s p o nta ne o us) a me n orr hea wit h o ut a n alter nati ve 
me dical ca use a n d a ser u m f ol licle-sti m ulati n g h or m o ne le vel > 4 0 mI U/ m L
o
6 wee ks after s ur gical bilateral o o p h orect o m y wit h or wit h o ut h y sterect o m y

P ost h y sterect o m y

Fe male s ur gical sterilizati o n (e. g., bilateral t u bal li gati o n) , w here a p plica ble acc or di n g t o 
l ocal g ui deli nes
F or t he p ur p oses of t he st u d y , hi g hl y effecti ve c o ntrace pti o n is de fi ne d as use of at least 1 of t he 
f oll o wi n g:  
F or fe males:

C o m bi ne d (estr o ge n a n d pr o gester o ne) h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n 
of o v ulati o n ( oral, i njecta ble, or i m pla nta ble) or pr o gest o ge n - o nly h or m o nal 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n ( oral, i njecta ble, or i m pla nta ble).

Place me nt of a n i ntra uteri ne de vice or i ntra uteri ne h or m o ne -releasi n g s yste m.

W h ere a p plic a ble acc or di n g t o l oc al g ui deli nes , barrier met h o ds of c o ntrace pti o n wit h 
use of a s per mici de:  c o n d o m or oc cl usi ve ca p ( dia p hra g m or cer vical/ va ult ca ps) wit h 
s per mici dal f oa m/ gel/fil m/crea m s u p p osit or y.  T he use of barrier c o ntrace pti ves s h o ul d 
al wa ys be s u p ple me nte d wit h t he use of a s per mici de.

Bilateral t u bal occl usi o n.   

Se x wit h a m ale w h o has u n der g o ne s ur gical sterilizati o n ( wit h t he a p pr o priate 
p ost vasect o m y  d oc u me ntati o n of t he a bse nce of s per m i n t he ejac ulate).  
F or males:

V asect o m y wit h ne gati ve se me n a nal ys is at F oll o w - u p Visit.

W here a p plica ble acc or di n g t o l ocal g ui deli nes, c o n d o ms wit h s per mic i de.  

Se x wit h a w o ma n w h o uses t he hi g hl y effecti ve met h o ds descri be d a b o ve f or fe males if 
s he is of c hil d beari n g p ote ntial.
Tr ue a bsti ne nce, w he n t his is c o nsiste nt wit h t he preferre d a n d us ual lifest yle of t he s u bject, ca n 
be c o nsi dere d an acce pta ble met h o d of c o ntrace pti o n base d o n t he e val uati o n of t he I n vesti gat or
w h o s h o ul d als o ta ke i nt o c o nsi derati o n t he d urati o n of t he cli nical st u d y.  Peri o dic a bsti ne nce 
(e. g., cale n dar, o v ulati o n, s ym pt ot her mal, p ost o v ulati o n met h o ds) a n d wit h dra wal are n ot 
c onsi dere d acce pta ble met h o ds of c o ntrace pti o n.  


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
8 1
Pre g na nc y  re p orti n g is descri be d i n Secti o n 1 5. 4. 1 .
1 5. 6.   
S afet y Res p o nsi bilities
1 5. 6. 1.   
T he I n vesti g at or
T he I n vesti gat or’s res p o nsi bilities i ncl u de f ulfilli n g all r oles a n d res p o nsi bilities liste d i n 
Secti o n 7. 2 .  A d diti o nall y, t he I n vesti gat or’s res p o nsi bilities i ncl u de t he f oll o wi n g:

M o nit or a n d rec or d all A Es, i ncl u di n g S A Es, o n t he C R F re gar dless of t he se verity or 
relati o ns hi p t o st u d y treat me nt.

Deter mi ne t he seri o us ness, relati o ns hi p, a n d se verit y  of eac h e ve nt.

Deter mi ne t he o nset a n d res ol uti o n dates of eac h e ve nt.

M o nit or a n d rec or d all pre g na ncies a n d f oll o w
u p o n t he o utc o me of all pre g na ncies
i n fe male s u bjects.

C o m plete a n S A E f or m f or eac h S A E a n d fa x it t o Bi o ge n wit hi n 2 4 h o urs of t he site 
staff bec o mi n g a ware of t he e ve nt.

P urs ue S A E f oll o w- u p i nf or mati o n acti vel y a n d persiste ntl y.  F oll o w -u p i nf or mati o n 
m ust be re p orte d t o Bi o ge n wit hi n 2 4 h o urs of t he site staff bec o mi n g a ware of ne w 
i nf or mati o n.

E ns ure all A E a n d S A E re p orts are s u p p orte d b y d oc u me ntat i o n i n t he s u bjects’ 
me dical rec or ds.

P urs ue A E f oll o w - u p i nf or mati o n, if p ossi ble, u ntil t he e ve nt has res ol ve d or bec o me 
sta ble.  Rec or d A E f oll o w- u p i nf or mati o n, i ncl u di n g res ol uti o n, o n t he C R F, as 
a p plica ble.

Re p ort S A Es t o l ocal et hics c o m mittees, as re q uire d b y l ocal la w.
1 5. 6. 2.   
Bi o ge n 
Bi o ge n’s res p o nsi bilities i ncl u de t he f oll o wi n g:

Bef ore a site ca n e nr oll a n y s u bjects, t he Cli nical M o nit or ( Bi o ge n desi g nee) is 
res p o nsi ble f or re vie wi n g wit h site staff t he defi niti o ns of A E a n d S A E, as well as t he 
i nstr ucti o ns f or m o nit ori n g, rec or di n g, a n d re p orti n g A Es a n d S A Es.

Bi o ge n is t o n otif y  all a p pr o priate re g ulat or y a ut h orities, ce ntral et hics c o m mittees, 
a n d I n vesti gat ors of S A Es, as re q uire d b y l ocal la w, wit hi n re q uire d ti me fra mes.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
8 2
1 6.      
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
T he o bjecti ves of t he st u d y  a n d t he e n d p oi nts t o be a nalyz e d are liste d i n Secti o n 6 .  I n ge neral, 
st u d y data will be s u m marize d usi n g sta n dar d descri pti ve statistics, a n d n o f or mal statistical 
h y p ot hesis testi n g is pla n ne d. A d diti o nal details of t he a nal ys is of st u d y data will be pr o vi de d i n 
a se parate Statistical A nal ysis Pla n.
1 6. 1.   
De m o gr a p h y a n d B aseli ne Dise ase C h ar acteristics
De m o gra p hics a n d baseli ne data will be s u m marize d b y  treat me nt gr o u p wit h s u m mar y statistics 
( mea n, sta n dar d de viati o n, me dia n, a n d ra n ge) or wit h fre q ue nc y distri b uti o ns.  
1 6. 2.   
Pri m ar y a n d Sec o n d ar y E n d p oi nt A n al ysis
1 6. 2. 1.   
A n al ysis P o p ul ati o n
T he safet y p o p ulati o n, defi ne d as all s u bjects w h o were ra n d o mize d a n d recei ve d at least 1 d ose 
of a d uca n u ma b will be use d f or t he pri mar y a n d sec o n dar y e n d p oi nt a nalys es.
1 6. 2. 2.   
Met h o d of A n al ysis 
1 6. 2. 2. 1. 
A n al ysis of t he Pri m ar y E n d p oi nt 
N o f or mal h y p ot hesis testi n g is pla n ne d f or t he pri mar y e n d p oi nt. T he i nci de nce rate a n d 9 0 % 
e xact bi n o mial c o nfi de nce i nter val ( CI) f or eac h treat me nt gr o u p will be pr o vi de d.  T he rate 
differe nce bet wee n 2 gr o u ps a n d its 9 0 % e xact CI will be pr o vi de d.  T he list of e ve nts s pecifie d 
i n t he pri mar y e n d p oi nt (as deter mi ne d by t he A dj u dicati o n C o m mittee ; see Secti o n 1 9. 2. 1 ) will 
be pr o vi de d b y gr o u p.  
1 6. 2. 2. 2. 
A n al y sis of t he Sec o n d ar y E n d p oi nt s
T he i nci de nce of A RI A a n d t heir se verit y b y i ma gi n g as well as cli nical pers pecti ves, will be 
s u m marize d f or eac h gr o u p a n d o verall.  T hese a nal y ses will als o be perf or me d f or t he differe nt 
t ypes of A RI A (e. g., A RI A -E, A RI A - H).  Ka pla n -Meier pl ot s will be pr o d uce d t o descri be ti me 
t o A RIA o nset, ti me t o s y m pt o matic A RI A, a n d ti me t o as y m pt o matic A RI A.  S u m mar y  
statistics will be prese nte d t o descri be t he ti me t o res ol uti o n of A RIA.  
T he i nci de nce of A Es, S A Es, a n d a ntia d uca n u ma b a nti b o dies, as well as cli nical c ha n ges i n vital 
si g ns a n d E C Gs, will be s u m marize d f or eac h gr o u p a n d o verall.   


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
8 3
1 6. 3.   
P h ar m ac o k i netics
1 6. 3. 1.   
A n al ysis P o p ul ati o n
T he a nal ys is p o p ulati o n f or P K a nal ys is is defi ne d as all s u bjects w h o were ra n d o mize d, were 
d ose d wit h a d uca n u ma b, a n d ha d at least 1 meas ura ble a d uca n u ma b c o nce ntrati o n i n ser u m.  
1 6. 3. 2.   
Met h o d of A n al ysis 
T he ser u m c o nce ntrati o ns a n d P K para meters of a d uca n u ma b will be s u m marize d descr i pti vely.   
1 6. 4.   
S afet y
1 6. 4. 1.   
A n al ysis P o p ul ati o n
T he safet y p o p ulati o n is defi ne d as all s u bjects w h o were ra n d o mize d a n d recei ve d at least 
1 d ose of a d uca n u ma b.
1 6. 4. 2.   
Met h o ds of A n al ysis
All A Es, la b orat or y  data, E C G, ne ur ol o gical a n d p h ysical e xa mi nati o ns, a n d vital sig ns will be 
e val uate d f or safet y.
1 6. 4. 2. 1. 
A d verse E ve nts
O nl y  treat me nt e mer ge nt a d verse e ve nts ( T E A Es) will be prese nte d i n t he s u m mar y  ta bles.  
Treat me nt e mer ge nt is defi ne d as ha vi n g a n o nset date t hat is o n or after t he start of st u d y  
treat me nt, or as w orse ni n g after t he start of st u d y  treat me nt.
I nci de nce of T E A Es will be s u m marize d b y  treat me nt gr o u p, o verall, b y se verit y, a n d b y 
relati o ns hi p t o st u d y treat me nt f or t he ra n d o mize d treat me nt peri o d a n d t he L T E peri o d.  T he 
s u m mar y ta bles will i ncl u de i nci de nce esti mates f or o verall s ys te m or ga n class as well as f or 
preferre d ter ms wit hi n eac h s y ste m or ga n class.  A Es will be c o de d usi n g t he Me dical Dicti o nar y 
f or Re g ulat or y Acti vities.  
1 6. 4. 2. 2. 
Cli nic al L a b or at or y Res ults
Cli nical la b orat or y e val uati o ns i ncl u de he mat ol o g y, bl o o d c he mistr y, a n d uri nal ysis.  La b orat or y  
data will be s u m marize d usi n g s hift ta bles.  S hifts fr o m baseli ne t o hi g h/l o w stat us f or 
he mat ol o g y  a n d bl o o d c he mistr y para meters a n d s hifts fr o m baseli ne t o hi g h/ p ositi ve stat us f or 
uri nal y sis will be prese nte d.  I n a d diti o n, t he s hift fr o m baseli ne t o t he ma xi m u m p ost baseli ne 
val ue a n d t he s hift fr o m baseli ne t o t he mi ni m u m p ost baseli ne stat us will be prese nte d f or eac h 
la b orat or y test b y treat me nt gr o u p.  Als o, s u m maries of la b orat or y val ues categ orize d base d o n 
c o m m o n t o xicit y criteria gra de will be create d.  S u m mar y statistics f or act ual val ues a n d c ha n ge 
fr o m baseli ne will als o be prese nte d f or q ua ntitati ve la b orat or y data.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
8 4
1 6. 4. 2. 3. 
Vit al Si g ns a n d E C Gs
T he a nal ys is of vital si g ns a n d E C Gs will f oc us o n cli nicall y rele va nt a b n or malities. 
1 6. 4. 2. 4. 
C ol u m bi a S uici de Se verit y R ati n g Sc ale
C- S S R S data will be s u m marize d b y  treat me nt gr o u p.
1 6. 5.   
I m m u n o ge nicit y D at a
1 6. 5. 1.   
A n al ysis P o p ul ati o n
T he a nal ys is p o p ulati o n f or i m m u n o ge nicity is defi ne d as all s u bjects i n t he safet y p o p ul ati o n 
w h o ha ve at least 1 p ost d ose sa m ple e val uate d f or i m m u n o ge nicit y.
1 6. 5. 2.   
Met h o ds of A n al ysis
A ntia d uca n u ma b ser u m a nti b o dies will be s u m marize d will be s u m marize d f or eac h gr o u p a n d 
o verall. 
1 6. 6.   
I nteri m A n al yses
A n i nteri m a nal ys is f or t he pri mar y e n d p oi nt ma y be perf or me d.
1 6. 7.   
S a m ple Size C o nsi der ati o ns
Base d o n t he data fr o m St u d y  2 2 1 A D 1 0 3, 2 o ut of 1 8 5 s u bjects ( 1 %) e x perie nce d seri o us A RI A
e ve nts res ulti n g i n h os pitalizati o n wit hi n t he first 1 2 m o nt hs of treat me nt wit h a d uca n u ma b.  I n 
a d diti o n, t here were n o deat hs or persiste nt si g nifica nt disa bilit y  d ue t o A RI A.  Of t he 1 8 5 
s u bjects, 3 1 s u bjects were i n t he 1 0 m g/ k g titrati o n gr o u p, a n d n o ne of t he m e x perie nce d 
cli nicall y i m pactf ul A RI A.  B y a p plyi n g t he c urre nt defi niti o n of cli nicall y  i m pactf ul e ve nts as 
t he pri mar y  e n d p oi nt t o t his st u d y, a l o w i nci de nce of cli nically i m pactf ul A RI A e ve nts is 
e x pecte d t o be o bser ve d d uri n g t he st u d y. 
T his is a n esti mati o n st u d y.  N o f or mal h y p ot hesis testi n g is pla n ne d.    I n St u d y  2 2 1 A D 1 0 3, of 
t he 1 8 5 s u bjects, 2 0 s u bjects de vel o pe d as y m pt o matic m o derate A RI A -E a n d 1 s u bject 
de vel o pe d se vere as y m pt o matic A RI A -E.  I n or der t o e nr oll 2 5 s u bjects wit h as y m pt o matic 
m o derate t o se vere A RI A -E i n eac h treat me nt gr o u p , a sa m ple size of a p pr o xi matel y 5 0 0 
s u bjects is selecte d t o pr o vi de a preli mi nar y esti mate of i nci de nce rates.  T he sa m ple size ma y be 
re-esti mate d base d o n e v ol vi n g lear ni n g fr o m e xter nal s o urces a n d bli n de d re vie w of t his st u d y .  
S u bjects will be ra n d o mize d i n a 1: 1 rati o t o eac h of t he 2 treat me nt gr o u ps.  W he n 1 cl i nicall y 
i m pactf ul A RI A e ve nt is o bser ve d, t he i nci de nce rate will be 0. 0 0 4 a n d t he 9 0 % e xact CI will be 
( 0. 0 0 0 2, 0. 0 1 8 8).  If 2 e ve nts are o bser ve d, t he i nci de nce rate will be 0. 0 0 8 a n d t he 9 0 % e xact CI
will be ( 0. 0 0 1 4, 0. 0 2 5 0) , a n d if 3 e ve nts are o bser v e d, t he i nci de nce rate will be 0. 0 1 2 a n d t he 
9 0 % e xact CI will be ( 0. 0 0 3 3, 0. 0 3 0 7).


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
8 5
T he ass u me d i nci de nce rates a n d t he pr o ba bilit y  of o bser vi n g e ve nts i n eac h gr o u p are prese nte d 
i n t he f oll o wi n g ta ble.
I nci de nce 
R ate i n 
Gr o u p 1
I nci de nce 
R ate i n 
Gr o u p 2
Pr o b a bilit y of 
O bser vi n g S a me 
N u m ber of 
E ve nts i n Gr o u p 
1 a n d Gr o u p 2
Pr o b a bilit y of 
O bser vi n g at 
Le ast 1 M ore 
E ve nt i n Gr o u p 2 
vs. 
Gr o u p 1
Pr o b a bilit y of 
O bser vi n g at 
Le ast 2 M ore 
E ve nts i n Gr o u p 
2 vs.  
Gr o u p 1
Pr o b a bilit y of 
O bser vi n g at 
Le ast 3 M ore 
E ve nts i n Gr o u p 
2 vs.  
Gr o u p 1
1 %
1 %
1 8 %
4 1 %
2 4 %
1 3 %
1 %
2 %
1 0 %
7 7 %
6 4 %
4 9 %
1 %
3 %
3 %
9 3 %
8 7 %
7 9 %


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
8 6
1 7.      
E T HI C A L R E Q UI R E M E N T S
Bi o ge n , Bi o ge n desi g nee , 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 nter nati o nal C o u ncil f or Har m o nisati o n (I C H) a n d 
G o o d Cli nical Practice ( 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 ulatio ns.
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 nt ai 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 grity of t he tas ks perf or m e d a n d a n y data ge nerate d.
1 7. 1.   
Decl ar ati o n of Helsi n k i
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 7. 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 CF, 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 dy.  Bi o ge n will s u b mit d oc u me nts o n be half of t he 
i n vesti gati o nal sites w orl d wi de i n c o m plia nce wit h l ocal re q uire me nts.  
If t he I n vesti gat or ma kes a n y c ha n ges t o t he IC F, Bi o ge n m ust a p pr o ve t he c ha n ges bef ore t he 
I CF 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 
Bi o ge n.  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 gr ee me nt of t he rele va nt et hics 
c o m mittee a n d Bi o ge n.
It is t he res p o nsi bilit y of t he In 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.
Bi o ge n m ust recei ve a letter d oc u me nti n g e t hics c o m mittee a p pr o val, w hic h s pecifically 
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 ually.
At t he c o m pleti o n or ter mi nati o n of t he st u d y , 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 Bi o ge n.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
8 7
1 7. 3.   
S u bject I nf or m ati o n a n d C o nse nt
Pri or t o perf or mi n g a n y s t 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, writte n 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 fr o m t he s u bject 
or s u bject’s le gall y a ut h orize d re pre se ntati ve, as a p plica ble, i n acc or da nce with l ocal practice a n d 
re g ulati o ns.  ( T he s u bject’s i nf or ma nt/care part ner ma y or ma y n ot be t he s u bject’s le gally 
a ut h orize d re prese ntati ve.)  S u bjects ca n c o m plete t he ne ur oc o g niti ve scales ( C D R a n d M M S E) 
as well as A p o E ge n ot ypi n g as a n i nitial o pti o nal s cree ni n g u n der a se parate c o nse nt pr ocess.  If 
t he s u bject meets i ncl usi o n criteria f or t hese 2 scales, t he f ull c o nse nt pr ocess m ust be c o m plete d 
pri or t o t he a d mi nistrati o n of f urt her scree ni n g assess me nts.  S u bjects ma y  als o pr ocee d directly 
t o t he f ull c o nse nt pr ocess t hat w o ul d all o w t he a d mi nistrati o n of all scree ni n g assess me nts.
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 s u bject m ust be e x plai ne d t o t he s u bject ( or t he 
s u bject’s le gally a ut h orize d re prese ntati ve).  T he s u bject 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.
S u bjects will be i nf or me d t hat t heir race a n d et h nicit y  will be c ollecte d d uri n g t he st u d y  ( 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 by t he g o ver ni n g et hics 
c o m mittee) a n d t he data will be use d d uri n g a nal ysis of st u d y  res ults.  
A c o p y of t he si g ne d a n d date d I C F m ust be gi ve n t o t he s u bject or t he s u bject’s care part ner/
le gall y a ut h orize d re prese ntati ve.  T he ori gi nal si g ne d a n d date d IC 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 ( wet si g nat ure) a n d c o pies of t he si g ne d a n d date d I C Fs.
C o nfir mati o n of i nf or me d c o nse nt m ust als o be d oc u me nte d i n t he s u bject’s me dical rec or d.
1 7. 4.   
S u bject 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 by l ocal la w (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 , s u bjects’ race a n d et h nicity 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 om mittee) .  T hese data will
be use d i n t he a nal ys is of t he safety a n d/ or P K 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 by race or et h nicit y.
St u d y  re p orts will be use d f or researc h p ur p oses o nl y.  T he s u bject will n ot be i de ntifie d b y  na me 
i n C R Fs, st u d y-relate d f or ms, st u d y re p orts, or a ny relate d p u blicati o ns.  Bi o ge n, 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 s u bject’s pers o nal me dical data c o nfi de ntial.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it 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 7. 5.   
C o m pe ns ati o n f or I nj ur y
Bi o ge n 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 7. 6.   
C o nflict of I nterest
T he I n v esti 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 
Bi o ge n or its part ner[s] ) wit h t he s u bject bef ore t he s u bject ma kes a decisi o n t o partici pate i n t he 
st u d y.
1 7. 7.   
Re gistr ati o n of St u d y a n d Discl os ure of St u d y Res ults
Bi o ge n 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.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it 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 8.      
A D MI NI S T R A TI V E P R O C E D U R E S
1 8. 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 s u bjec ts pri or t o c o m pleti o n of a st u d y i nitiati o n visit, 
c o n d ucte d b y Bi o ge n.  T his i nitiati o n visit will i ncl u de a detaile d re vie w of t he pr ot oc ol a n d 
st u d y pr oce d ures.
1 8. 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 each sta ge of data ha n dli n g t o e ns ure t hat all 
data are relia ble a n d ha ve bee n pr ocesse d c orrectl y .  Data a n o malies will be c o m m u nicate d t o t he 
sites f or clarificati o n a n d res ol uti o n, as a p pr o priate. T he I n vesti gat or is res p o nsi ble f or 
e n d orsi n g all C R F data pri or t o a n y  i nteri m or fi nal data base l oc k.
D uri n g a n d/ or after c o m pleti o n of t he st u d y , q ualit y ass ura nce officers na me d b y Bi o ge n 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 8. 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 by pr o vi di n g direct access t o s o urce data 
a n d t o t he s u bjects’ 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 
In 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 de tail 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 s u bject safet y, data i nte grit y, a n d critical data a n d pr ocesses.
D uri n g t hese visits, C R Fs , s u p p orti n g d oc u me ntati o n, a n d esse ntial d oc u me ntati o n relate d t o t he 
st u d y will be re vie we d a n d a n y discre pa ncies or o missi o ns will be res ol ve d.  D oc u me ntati o n of 
res ults will be pr o vi de d t o Bi o ge n i n a ti mely 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 s u bject 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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Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it 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 8. 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, In vesti gat or, a n d Bi o ge n.  
1 8. 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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Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
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I nc.
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1 9.      
F U R T H E R R E Q UI R E M E N T S A N D G E N E R A L I N F O R M A T I O N
1 9. 1.   
E xter n al C o ntr act Or g a niz ati o ns
Bi o ge n will e ns ure o versi g ht of a n y st u d y-relate d d uties a n d f u ncti o ns carrie d o ut o n its be half
a n d will s pecif y i n writi n g all d uties a n d f u ncti o ns t hat are tra nsferre d. 
1 9. 1. 1.   
C o n tr act Rese arc h Or g a niz ati o n 
A C R O will be res p o nsi ble f or a d mi nistrati ve as pects of t he st u d y  i ncl u di n g, b ut n ot li mite d t o, 
st u d y i nitiati o n, m o nit ori n g, a n d ma na ge me nt of S A E re p orts.  Bef ore s u bjects are scree ne d at 
eac h st u d y site, t he C R O will re vie w st u d y res p o nsi bilities wit h t he In vesti gat ors a n d ot her st u d y  
site staff, as a p pr o priate.
1 9. 1. 2.   
I nter acti ve Res p o nse Tec h n ol o g y
I R T will be use d i n t his st u d y.  Bef ore s u bjects are scree ne d or ra n d o mize d, t he IR T ve n d or will 
pr o vi de eac h st u d y site wit h a p pr o pr iate trai ni n g, access ri g hts, a n d a user ma n ual.
1 9. 1. 3.   
Electr o nic D at a C a pt ure
S u bject i nf or mati o n will be ca pt ure d a n d ma na ge d b y  st u d y sites o n electr o nic C R Fs b y a we b-
base d electr o nic data ca pt ure ( E D C) t o ol de vel o pe d b y  a Bi o ge n desi g nee a n d c o nfi g ure d b y t he 
E D C ve n d or.
1 9. 1. 4.   
Ce ntr al L a b or at ories f or L a b or at or y Assess me nts
Bi o ge n has selecte d a ce ntral la b orat or y  ser vice t o perf or m all sta n dar d he mat ol o g y, bl o o d 
c he mistr y, a n d uri nalys is testi n g f or t he st u d y.  T his ce ntral la b orat or y will als o recei ve, trac k, 
a n d s hi p all uri ne a n d bl o o d sa m ples, a n d D N A f or s pecialize d A p o E ε 4 ge n ot y pi n g, P K , 
, a n d A D A testi n g, i ncl u di n g ali q u ots fr o m t hese sa m ples retai ne d as bac k u p i n case 
ori gi nal sa m ples are l ost or n ot e val ua ble.  Bl o o d sa m pl es c ollecte d 
 
 st ore d by t he ce ntral la b orat or y.
La b orat ories perf or mi n g s pecialize d testi n g will be i de ntifie d i n re g ulat or y d oc u me ntati o n.  
T hese la b orat ories will use a p pr o priatel y  vali date d or q ualifie d assa ys t o test st u d y sa m ples.  
1 9. 1. 5.   
Ce ntr al F acilit y f or Ot her Assess me nts
A ce ntral i ma gi n g la b orat or y  has bee n selecte d by Bi o ge n t o rea d a n d i nter pret all M RI s f or t his 
st u d y wit hi n t he ti mefra me s pecifie d i n t he pr oce d ural ma n ual f or M RI.  I n cases of A RI A -E a n d 
A RI A- H, t he ce ntral i ma gi n g la b orat or y  m ust e x pe dite n otificati o n t o t he PI a n d Bi o ge n.   F or t he 
p ur p oses of st u d y c o n d uct, t he M RI  i nter pretati o ns fr o m t he ce ntral rea der will pre vail o ver t h ose 
fr o m t he l ocal ra di ol o gist.  


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C O N FI D E N TI A L
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I nc.
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T he ce ntral i ma gi n g la b orat or y  will als o c ollect P E T sca ns a n d assess t he scree ni n g sca n f or 
eli gi bilit y criteria.
1 9. 1. 6.   
Ne ur oc o g niti ve Assess me nts
Bi o ge n selecte d a rater ma na ge me nt gr o u p t o esta blis h rater q ualificati o n, st u d y -s pecific trai ni n g, 
a n d o versi g ht.  T he st u d y rat ers are re q uire d t o c o m plete q ualificati o ns ste ps a n d re q uire d 
trai ni n g pri or t o a d mi nisteri n g st u dy assess me nts.  T he rater ma na ge me nt gr o u p will o versee t he 
assess me nts per pr oject-s pecific pla ns.  All ne ur oc o g niti ve data , wit h t he e xce pti o n of D S S T a n d 
M o C A assess me nts, will be ca pt ure d via electr o nic mea ns.
1 9. 2.   
St u d y C o m mittees
1 9. 2. 1.     
A dj u dic ati o n C o m mittee
T he A dj u dicati o n C o m mittee will be f or me d t o re vie w all s y m pt o matic A RI As a n d A RI As 
re p orte d as S A Es, a n d a dj u dicate if a n y e ve nt meets t he criteria of t he pri mar y  e n d p oi nt. T he 
a dj u dicati o n pr ocess is c o nsi dere d i n de pe n de nt of A E/ S A E data c ollecti o n a n d a nal ys is.
A n A dj u dicati o n C o m mittee c harter will pr o vi de f ull g ui da nce o n t he f u ncti o n a n d practices t o 
be f oll o we d.
1 9. 2. 2.   
D at a S afet y M o nit ori n g C o m mittee 
T he D S M C will be f or me d t o re vie w o n g oi n g safet y  data. 
Me m bers of t he D S M C will n ot be 
all o we d t o partici pate as I n vesti gat ors i n t his st u d y .  
T he D S M C will re vie w safet y data o n a n o n g oi n g basis t o e ns ure safe a n d pr o per treat me nt of 
s u bjects, assess t he safet y of t he st u d y i nter ve nti o ns, a n d m o nit or t he o verall c o n d uct of t he 
st u d y.  T he D S M C , base d o n t he nat ure, fre q ue nc y, a n d/ or se verit y of a n y  a d verse e ve nts, ma y  
rec o m me n d pr ot oc ol m o dificati o n(s), d ose s us pe nsi o n, d ose ter mi nati o n, or st u d y  ter mi nati o n. 
I n a d diti o n, d uri n g t he st u d y , t he D S M C will ma ke a rec o m me n dati o n t o c o nti n ue d osi n g i n 
s u bjects wit h as ym pt o matic se vere A RI A i n Gr o u p 2.  T his ma y be tri g gere d as early as w he n 
t he first 1 5 0 s u bjects ha ve ha d t he o p p ort u nity t o c o m plete at least 6 m o nt hs of treat me nt, or 
w he n t he first 2 0 as y m pt o matic s u bjects ha ve c o m plete d at least 2 a d diti o nal d oses si nce t he 
i nitial i de ntificati o n of A RI A ( A RI A-E wit h or wit h o ut A RI A- H, or is olate d A RI A- H), as 
m o derate i n se verit y , w hic he ver occ urs f irst.
A D S M C c harter will pr o vi de f ull g ui da nce o n t he f u ncti o n a n d practices t o be f oll o we d.
1 9. 3.   
C h a n ges t o Fi n al St u d y 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 by l ocal la w.  Pr ot oc ol m o dificati o ns t ha t affect s u bject safety, 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 dy 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 


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
9 3
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, Bi o ge n 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 s u bject.  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 CF ma y  re q uire si milar m o dificati o ns (see 
Secti o n 1 7 ).
1 9. 4.   
Et hics C o m mittee N otific ati o n of St u d y C o m pleti o n or Ter mi n ati o n
W here re q uire d, t he re g ulat or y  a ut h orities a n d et hics c o m mittees m ust be n otifie d of c o m pleti o n 
or ter mi nati o n of t his st u d y , a n d se nt a c o py 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 9. 5.   
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 by 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 Bi o ge n 
i n writi n g a n d recei ve writte n a ut h orizati on fr o m Bi o ge n t o destr o y st u d y rec or ds.  I n a d diti o n, 
t he In vesti gat or m ust n otif y  Bi o ge n 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.
1 9. 6.   
St u d y Re p ort Si g n at or y
Bi o ge n 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 on i n t he st u die d i n dicati o n; t he I n vesti gat or's c o ntri b uti o n 
t o t he st u d y i n ter ms of desi g n, ma na ge me nt, a n d/ or s u bject e nr oll me nt; or b y ot her fact ors 
deter mi ne d t o be rele va nt b y  Bi o gen.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
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I nc.
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2 0.      
R E F E R E N C E S
Al bert M S, De K os k y S T, Dic ks o n D, et al. T he dia g n osis of mil d c o g niti ve i m pair me nt d ue t o 
Alz hei mer's disease: rec o m me n dati o ns fr o m t he Nati o nal I nstit ute o n A gi n g -Alz hei mer's 
Ass ociati o n w or k gr o u ps o n dia g n ostic g ui deli nes f or Alz hei mer's disease. Alz hei mers De me nt. 
2 0 1 1; 7( 3): 2 7 0 - 9.
Alz hei m er's Disease I nter nati o nal. W orl d Alz hei mer Re p ort 2 0 1 4: De me ntia a n d ris k re d ucti o n. 
L o n d o n: Alz hei mer's Disease I nter nati o nal ( A DI); 2 0 1 4.
Alz hei mer's Disease I nter nati o nal. W orl d Alz hei mer Re p ort 2 0 1 5: T he Gl o bal I m pact of 
De me ntia. L o n d o n: Alz hei mer's Disease I nter nati o nal ( A DI); 2 0 1 5.
Alz hei mer's Disease I nter nati o nal. W orl d Alz hei mer Re p ort 2 0 1 6 I m pr o vi n g healt hcare f or 
pe o ple li vi n g wit h de me ntia c o vera ge, Q ualit y a n d c osts n o w a n d i n t he f ut ure. L o n d o n: 
Alz hei mer's Disease I nter nati o nal ( A DI); 2 0 1 6.
A mie va H, Le G off M, Millet X, et al. Pr o dr o mal Alz hei mer's disease: s uccessi ve e mer ge nce of 
t he cli nical s y m pt o ms. A n n Ne ur ol. 2 0 0 8; 6 4( 5): 4 9 2- 8.
Bl oc k x I , Ei nstei n S, G u ns PJ, et al. M o nit ori n g Bl o o d-Brai n Barrier I nte grit y F oll o wi n g 
A m y l oi d- β I m m u n ot hera p y Usi n g Ga d oli ni u m-E n ha nce d M RI i n a P D A P P M o use M o del. J 
Alz hei mers Dis. 2 0 1 6; 5 4( 2): 7 2 3- 3 5.
Delac o urte A, Ser gea nt N, C ha m pai n D, et al. N o n o verla p pi n g b ut s y ner getic ta u a n d A P P 
pat h ol o gies i n s p ora dic Alz hei mer's disease. Ne ur ol o g y . 2 0 0 2; 5 9( 3): 3 9 8-4 0 7 .
Har d y J , Sel k oe DJ. T he a m yl oi d h yp ot hesis of Alz hei mer's disease: pr o gress a n d pr o ble ms o n 
t he r oa d t o t hera pe utics. Scie nce. 2 0 0 2; 2 9 7( 5 5 8 0): 3 5 3-6. E p u b 2 0 0 2 J ul 2 0.
H oc k C, K o nietz k o U, Streffer J R, et al. A nti b o dies a gai nst beta -a m yl oi d sl o w c o g niti ve decli ne 
i n Alz hei mer's disease. Ne ur o n. 2 0 0 3; 3 8( 4): 5 4 7-5 4. E p u b 2 0 0 3/ 0 5/ 2 7.
Jac k C R, K n o p ma n D S, Ja g ust WJ, et al. Trac ki n g pat h o p h ysi ol o gical pr ocesses i n Alz hei mer's 
disease: a n u p date d h y p ot hetical m o del of d y na mic bi o mar kers. La ncet Ne ur ol. 2 0 1 3; 1 2( 2) : 2 0 7-
2 1 6.
Jac k C R, K n o p ma n D S, Ja g ust WJ, et al. H yp ot hetical m o del of d y na mic bi o mar kers of t he 
Alz hei mer's pat h ol o gical casca de. La ncet Ne ur ol. 2 0 1 0; 9( 1): 1 1 9- 2 8.
Ketter N, Bras hear H R, B o gert J, et al. Ce ntral Re vie w of A m yl oi d -Relate d I ma gi n g 
A b n or malit ies i n T w o P hase III Cli nical Trials of Ba pi ne uz u ma b i n Mil d-T o -M o derate 
Alz hei mer's Disease Patie nts. J Alz hei mers Dis. 2 0 1 7; 5 7( 2): 5 5 7- 5 7 3.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
9 5
K offie R M, Me y er-L ue h ma n n M, Has hi m ot o T, et al. Oli g o meric a m yl oi d beta ass ociates wit h 
p osts y na ptic de nsities a n d c orrelates wit h e xcitat or y sy n a pse l oss near se nile pla q ues. Pr oc Natl 
Aca d Sci U S A. 2 0 0 9; 1 0 6( 1 0): 4 0 1 2- 7.
K uc hi b h otla K V, G ol d ma n S T, Lattar ul o C R, et al. A beta pla q ues lea d t o a berra nt re g ulati o n of 
calci u m h o me ostasis i n vi v o res ulti n g i n str uct ural a n d f u ncti o nal disr u pti o n of ne ur o nal 
net w or ks. Ne ur o n. 2 0 0 8; 5 9( 2): 2 1 4 -2 5.
K u mar -Si n g h S, Pirici D, Mc G o wa n E, et al. De nse -c ore pla q ues i n T g 2 5 7 6 a n d P S A P P m o use 
m o dels of Alz hei mer's disease are ce ntere d o n vessel walls. A merica n J o ur nal of Pat h ol o g y . 
2 0 0 5; 1 6 7( 2): 5 2 7 -4 3. E p u b 2 0 0 5/ 0 7/ 2 9.
Li n n J, Hal pi n A, De maerel P, et al. Pre vale nce of s u perficial si der osis i n patie nts wit h cere bral 
a m yl oi d a n gi o pat h y. Ne ur ol o g y. 2 0 1 0; 7 4( 1 7): 1 3 4 6- 5 0.
Mc K ha n n G M, K n o p ma n D S, C hert k o w H, et al. T he dia g n osis of de me ntia d u e t o Alz hei mer’s 
disease: Rec o m me n dati o ns fr o m t he Nati o nal I nstit ute o n A gi n g- Alz hei mer’s Ass ociati o n 
w or k gr o u ps o n dia g n ostic g ui deli nes f or Alz hei mer's disease. Alz hei mer's a n d De me ntia. 
2 0 1 1; 7( 3): 2 6 3 - 2 6 9.
Me y er-L u e h ma n n M, S pires-J o nes T L, Pra da C, et al. Ra pi d a p peara nce a n d l ocal t o xicit y of 
a m yl oi d- beta pla q ues i n a m o use m o del of Alz hei mer's disease. Nat ure. 2 0 0 8; 4 5 1( 7 1 7 9): 7 2 0- 4.
Nels o n P T, A b ner E L, Sc h mitt F A, et al. Brai ns wit h me dial te m p oral l o be ne ur ofi brillar y  
ta n gles b ut n o ne uritic a m yl oi d pla q ues are a dia g n ostic dile m ma b ut ma y ha ve pat h o ge netic 
as pects disti nct fr o m Alz hei mer disease. J Ne ur o pat h ol E x p Ne ur ol. 2 0 0 9; 6 8( 7): 7 7 4 -8 4. E p u b 
2 0 0 9 J u n 1 9.
Pe n ni n kila m pi R, Br ot hers H M, Eslic k G D. Safet y a n d Efficac y  of A nti-A m y l oi d-β 
I m m u n ot hera py i n Alz hei mer's Disease: A Sys te matic Re vie w a n d Meta-A nal y sis. J 
Ne ur oi m m u ne P har mac ol. 2 0 1 7; 1 2( 1): 1 9 4 -2 0 3. E p u b 2 0 1 6/ 1 2/ 2 6.
Pfeifer M, B o ncristia n o S, B o n d olfi L, et al. Cere bral he m orr ha ge after passi ve a nti -A beta 
i m m u n ot hera p y. Scie nce. 2 0 0 2; 2 9 8( 5 5 9 7): 1 3 7 9. E p u b 2 0 0 2/ 1 1/ 1 6.
Rac ke M M, B o o ne LI, He p b ur n D L, et al. E xacer bati o n of cere bral a m y l oi d a n gi o pat h y-
ass ociate d micr o he m orr ha ge i n a m yl oi d prec urs or pr otei n tra ns ge nic mice b y  i m m u n ot hera p y is 
de pe n de nt o n a nti b o d y rec o g niti o n of de p osi te d f or ms of a myl oi d beta. J Ne ur osci. 
2 0 0 5; 2 5( 3): 6 2 9 -3 6. E p u b 2 0 0 5/ 0 1/ 2 2.
R oz kal ne A, S pires- J o nes T L, Ster n E A, et al. A si n gle d ose of passi ve i m m u n ot hera p y has 
e xte n de d be nefits o n s yna pses a n d ne urites i n a n Alz hei mer's disease m o use m o del. Brai n Res.
2 0 0 9; 1 2 8 0: 1 7 8 - 8 5.
Sall o wa y  S, S perli n g R, F o x N C, et al. T w o p hase 3 trials of ba pi ne uz u ma b i n mil d-t o-m o derate 
Alz hei mer's disease. T he Ne w E n gla n d j o ur nal of me dici ne. 2 0 1 4; 3 7 0( 4): 3 2 2 -3 3; acc o m pa nie d 
b y  s u p ple me ntar y a p pe n di x.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
9 6
Se vi g n y J , C hia o P, B ussière T, et al. T he a nti b o d y a d uca n u ma b re d uces A β pla q ues i n 
Alz hei mer's disease. Nat ure. 2 0 1 6; 5 3 7( 7 6 1 8): 5 0 - 6.
S perli n g R, Sall o wa y  S, Br o o ks DJ, et al. A m yl oi d-relate d i ma gi n g a b n or malities i n patie nts 
wit h Alz hei mer's disease treate d wit h ba pi ne uz u ma b: a retr os pecti ve a nal ys is. La ncet Ne ur ol. 
2 0 1 2; 1 1( 3): 2 4 1 - 9.
S perli n g R A, Jac k Jr C R, Blac k S E, et al. A m y l oi d-relate d i ma gi n g a b n or malities i n a m yl oi d-
m o dif y i n g t hera pe utic trials: Rec o m me n dati o ns fr o m t he Alz hei mer’s Ass ociati o n Researc h 
R o u n dta ble W or k gr o u p. Alz hei mers De me nt. 2 0 1 1; 7( 4): 3 6 7 - 3 8 5.
S pires -J o nes T L, Miel ke M L, R oz kal ne A, et al. Passi ve i m m u n ot hera p y ra pi dl y i ncreases 
str uct ural plasticit y i n a m o use m o del of Alz hei mer disease. Ne ur o bi ol Dis. 2 0 0 9; 3 3( 2): 2 1 3- 2 0.
Wa hl u n d L O, Bar k h of F, Faze kas F, e t al. A ne w rati n g scale f or a ge-relate d w hite matter 
c ha n ges a p plica ble t o M RI a n d C T. Str o ke. 2 0 0 1; 3 2( 6): 1 3 1 8- 2 2.
Wilc oc k D M, C olt o n C A. I m m u n ot hera p y , vasc ular pat h ol o g y, a n d micr o he m orr ha ges i n 
tra ns ge nic mice. C N S Ne ur ol Dis or d Dr u g Tar gets. 2 0 0 9; 8( 1): 5 0-6 4. E p u b 2 0 0 9/ 0 3/ 1 2.
Wi n kler D T, B o n d olfi L, Herzi g M C, et al. S p o nta ne o us he m orr ha gic str o ke i n a m o use m o del 
of cere bral a m y l oi d a n gi o pat h y. J Ne ur osci. 2 0 0 1; 2 1( 5): 1 6 1 9- 2 7. E p u b 2 0 0 1 Fe b 2 7.
Za g o W, Sc hr oeter S, G ui d o T, et al. Vasc ular alterati o ns i n P D A P P mice after a nti -A β 
i m m u n ot hera p y: I m plicati o ns f or a myl oi d -relate d i ma gi n g a b n or malities. Alz hei mers De me nt. 
2 0 1 3; 9( 5 S u p pl): S 1 0 5 - 1 5.


Pr ot oc ol 2 2 1 A D 2 0 5
Versi o n 1
Safet y St u d y i n S u bjects w it h A D t o E val uate C o nti n ue d D osi n g wit h BII B 0 3 7 i n As y m pt o matic A RI A
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 w it h o ut t he writte n c o nse nt of 
Bi o ge n M A
I nc.
9 7
2 1.      
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 2, M ultice nter, Ra n d o mize d , Parallel-Gr o u p, 
D o u ble- Bli n d, C o ntr olle d St u d y  of A d uca n u ma b ( BII B 0 3 7) i n S u bjects wit h Mil d C o g niti ve 
I m pair me nt d ue t o Alz hei mer’s Disease or wit h Mil d Alz hei mer’s Disease De me ntia t o E val uate 
t he Safety of C o nti n ue d D osi n g i n S u bjects wit h As y m pt o mati c A m yl oi d -Relate d I ma gi n g 
A b n or malities ,” a n d a gree t o c o n d uct t he st u d y acc or di n g t o t he pr ot oc ol a n d t he a p plica ble I C H 
g ui deli nes a n d G C P re g ulati o ns, a n d t o i nf or m all w h o assist me i n t he c o n d uct of t his st u d y  of 
t heir res p o nsi bilities a n d o bli gati o ns.
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I n vesti gat or’s Si g nat ure
Date
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I n vesti gat or’s Na me ( Pri nt)
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St u d y  Site ( Pri nt)

SAP_001.pdf: 
  
 
 
A d uca n u ma b Safet y  of C o nti n ue d D osi n g               
Statistical A nal ysis Pla n  
Versi o n N o.:  1. 0  
1  
St atistic al A n al ysis Pl a n  
Versi o n N o.:  Draft 1. 0  
Date: 2 9 Ma y  2 0 1 9  
Na me of St u d y Treat me nt : A d uca n u ma b  
Pr ot oc ol N o.: 2 2 1 A D 2 0 5  
St u d y P has e: II 
C o nfi de nti al I nf or m ati o n  
T he i nf or m ati o n c o nt ai ne d i n t his St atistic al A n alysis Pl a n ( S A P) is c o nfi de nti al a n d m ay n ot 
be re pr o d uce d or ot h er wise disse mi n ate d wit h o ut t he a p pr ov al of Bi o ge n, I nc.   
/ N C T 0 3 6 3 9 9 8 7




  
 
 
 
    
A d uca n u ma b Safet y  of C o nti n ue d D osi n g                           
Statistical A nal ysis Pla n  
Versi o n N o.:  1. 0  
 
3  
 
 
List of A b bre vi ati o ns  .................................................................................................................... 4  
1  
I N T R O D U C TI O N .................................................................................................................. 5  
2  
S T A TI S TI C A L A N A L Y SI S M E T H O D S  .............................................................................. 5  
2. 1  
Ge ne ral C o nsi derati o ns .................................................................................................... 5  
2. 2  
A nal ysis St u d y Gr o u p  ...................................................................................................... 6  
2. 3  
A nal ysis P o p ulati o ns  ........................................................................................................ 6  
2. 4  
Bac k gr o u n d C haracteristics .............................................................................................. 6  
2. 4. 1  
Acc o u nti n g of Partici pa nts  ........................................................................................ 6  
2. 4. 2  
De m o gra p hics a n d Baseli ne C haract eristics  ............................................................. 7  
2. 4. 3  
C o nc o mita nt Me dicati o ns a n d N o n -Dr u g T h era pies  ................................................ 7  
2. 4. 4  
St u d y Dr u g E x p os ure  ................................................................................................ 7  
2. 5  
A d verse E v e nts  ................................................................................................................. 7  
2. 5. 1  
I n ci de nce of a d v erse e ve nts ...................................................................................... 8  
2. 5. 2  
A RI A  ......................................................................................................................... 8  
2. 5. 3  
M o C A  ....................................................................................................................... 9  
2. 6  
Ot her Safet y Ass ess me nts  ................................................................................................ 9  
List of Pl a n ne d T a bles  ................................................................................................................ 1 0  
 
 
 
 


  
 
 
 
    
A d uca n u ma b Safet y  of C o nti n ue d D osi n g                           
Statistical A nal ysis Pla n  
Versi o n N o.:  1. 0  
 
4  
 
List of A b bre vi ati o ns  
A D  
Alz hei mer’s disease  
A E  
a d verse e ve nt  
A p o E ε 4  
a p oli p o pr otei n E 4  
A RI A  
a m yl oi d rel ate d i ma gi n g a b n or malities  
A RI A -E  
a m yl oi d rel ate d i ma gi n g a b n or malit y -e de m a  
A RI A -H  
a m yl oi d rel ate d i ma gi n g a b n or malit y-he m orr h a ge or s u perfici al si der osis  
C -S S R S  
C ol u m bia S uici de Se verit y Rati n g Scale  
E C G  
electr ocar di o gra m  
e C R F 
electr o nic case re p ort f or m  
E O T  
e n d of treat me nt  
M CI  
mil d c o g niti ve i m pair me nt  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M o C A  
M o ntreal C o g niti ve Assess me nt  
M RI  
ma g n etic res o n a nce i ma gi n g  
P K  
p har mac o ki netic(s)  
S A E  
seri o us a d vers e e v e nt 
S A P  
statistical a nal ysis pla n 
W H O  
W orl d Healt h Or ga nizati o n  
 
 
 


  
 
 
 
    
A d uca n u ma b Safet y  of C o nti n ue d D osi n g                           
Statistical A nal ysis Pla n  
Versi o n N o.:  1. 0  
 
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1  I N T R O D U C TI O N 
St u d y 2 2 1 A D 2 0 5 wa s a P hase 2, m ultice nter, ra n d o mize d, parallel -gr o u p, d o u ble -bli n d, 
c o ntr olle d st u d y i n partici pa nt s wit h mil d c o g niti ve i m pair me nt ( M CI) d ue t o Alz hei mer’s 
disease ( A D) or wit h mil d A D de me ntia, wit h a ra n d o mize d treat me nt peri o d f oll o we d b y a n 
o pti o nal l o n g -ter m e xte nsi o n peri o d.  T he pri mar y st u d y o bjecti ve w a s t o assess t he safet y 
i m pact of c o nti n ui n g a d u ca n u ma b ( BII B 0 3 7) d osi n g i n as y m pt o matic a m yl oi d -relate d i ma gi n g 
a b n or malities  (A RI A ) i n partici pa nt s wit h M CI d u e t o A D or mil d A D de m e ntia .   
Eli gi ble partici pa nt s were ra n d o mize d ( 1: 1) at Visit 1 t o 1 of 2 gr o u ps t hat differe d i n ter ms of 
t he ma na ge me nt of as y m pt o matic A RI A f o u n d o n ma g n etic res o n a nce i ma gi n g ( M RI) d uri n g t h e 
ra n d o mize d treat me nt peri o d.  All ra n d o mize d partici pa nt s recei ved  a d uca n u m a b titrate d u p t o 
1 0 m g/ k g (i de ntical titrati o n pr ot oc ol as i n t he p hase 3 pr o gra m) . In certai n cases of 
as y m pt o matic A RI A as d escri be d i n t he st u d y pr ot oc ol, Gr o u p 1 partici p a nt s were re q uire d t o 
s us pe n d or disc o nti n ue a d uca n u ma b d osi n g w hereas t he Gr o u p 2 partici pa nt s were t o c o nti n ue 
a d uca n u ma b tr eat me nt. I n t hese cas es, t o mai ntai n t he st u d y bli n d, Gr o u p 1 partici pa nt s were t o 
recei v e place b o.   
Ter mi nati o n of t he st u d y was a n n o u nce d o n 2 1 Marc h 2 0 1 9, base d o n t h e res ults of a n i nteri m 
f utilit y a nal ysis i n t he a d uca n u ma b P hase 3 st u dies 2 2 1 A D 3 0 1 a n d 2 2 1 A D 3 0 2.  E nr oll me nt a n d 
d osi n g i n 2 2 1 A D 2 0 5 were halte d i m me diatel y u p o n t he a n n o u nce m e nt.  All pa rtici pa nts were t o 
ret ur n t o t he site wit hi n 4 wee ks of t he a n n o u nce me nt t o d o t he E O T (wee k 5 4) visit, a n d a gai n 
1 8 wee ks after t heir l ast d ose f or t he fi n al f oll o w u p visit ( Wee k 7 0 ).  D ue t o t he s mall a m o u nt of 
data c ollecte d i n t his st u d y, o nl y a  s y n o psis cli nical st u d y re p ort is pla n ne d.   
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o descri be t he a n al ys es t hat are pla n ne d f or 
t he fi nal re p ort.  T h e pri mar y e n d p oi nt a n d m ost sec o n dar y e n d p oi nts of t he st u d y will n ot be 
e val uable  d u e t o t he s mall act ual sa m ple siz e a n d s h ort e x p os ure ti me .  I nste a d, t he f oc us of t he 
fi nal a nal ysis is s u m marizi n g t he a vaila ble b aseli n e, e x p os ure, a n d a d v erse e ve nt data  t hat were 
c ollecte d d uri n g t he st u d y.   
 
2  S T A TI S TI C A L A N A L Y SI S M E T H O D S  
2. 1  Ge ner al C o nsi der ati o ns  
S u m mar y ta bles will be prese nte d usi n g des cri pti ve s u m mar y statistics. F or c o nti n u o us varia bles, 
s u m mar y statistics will ge nerall y i ncl u de: n u m ber of partici pa nt s wit h data, mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m a n d ma xi m u m. F or cate g orical varia bl es, t his will ge nerall y 
i ncl u de: n u m ber of partici pa nt s i n t he a nal ysis p o p ulati o n, n u m ber wit h data, a n d t he perce nt of 
t h ose wit h data i n eac h cate g or y.  D ue t o t he mi ni mal a m o u nt of data c ollecte d i n t he st u d y, m ost 
e n d p oi nts will n ot be s u m marize d; i nstea d , listi n gs will be pr o vi de d.  A n y strai g htf or war d 
listi n gs t hat are r o uti nel y pr o d uce d f or Bi o ge n cli nical st u dies will n ot necessaril y be me nti o ne d 
i n t his pla n.   


  
 
 
 
    
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Statistical A nal ysis Pla n  
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U nless ot her wise s pecifie d, s u m maries will be prese nte d b y st u d y gr o u p a n d o verall .  E ac h ta ble 
will t y pi call y ha ve t hr ee c ol u m ns, or dere d as f oll o ws: Gr o u p 1, Gr o u p 2 , a n d BII B 0 3 7 T otal.  
S u m maries  prese nte d b y decreasi n g or i ncreasi n g fre q ue n c y will be s orte d base d o n t he 
a d uca n u ma b  total  c ol u m n.  
2. 2  A n al ysis St u d y Gr o u p  
D ata will be a n al yze d b y st u d y gr o u p bas e d o n ra n d o mizati o n .  A listi n g of a n y p artici pa nts w h o 
were d os e d c o ntrar y t o t heir ra n d o mizati o n st u d y gr o u p will be prese nte d.  T his i ncl u des a n y 
Gr o u p 1 partici pa nt  w h o recei v e d acci de ntal a d uca n u ma b d uri n g a n A R I A epis o de w he n place b o 
s h o ul d ha ve bee n a d mi nistere d, a n d a n y Gr o u p 2 partici pa nt w h o acci de nt all y recei v e d place b o. 
2. 3  A n al ysis P o p ul ati o n s 
T he f oll o w a nal ysis p o p ulati o ns will be utilize d  i n t he i nteri m a nal ysis: 
•  Safet y p o p ulati o n :  
T he safet y p o p ulati o n is defi ne d as all ra n d o mize d partici pa nt s w h o recei v e d at least o ne 
d ose of a d uca n u ma b.  
•  Safet y M RI p o p ul ati o n:  
T he safet y M RI p o p ulati o n is defi ne d as all ra n d o mize d partici pa nt s w h o recei ve d at least 
o ne d ose of a d u ca n u ma b a n d ha d at least o ne p ost -baseli ne M RI assess me nt.   
 
•  Differe ntial st u d y tr eat m e nt p o p ulati o n:  
T he differe ntial st u d y treat me nt p o p ulati o n is defi ne d as all partici p a nt s i n t he safet y M RI 
p o p ulati o n w h o  e x perie nce d as y m pt o matic A RI A res ulti n g i n assi g n me nt of at least o ne 
i nf usi o n of st u d y treat me nt t hat w o ul d ha ve bee n differe nt h a d t he partici pa nt  bee n i n t he 
ot her st u d y gr o u p.  A n y Gr o u p 1 partici pa nt  w h o recei v es place b o is i n t he differe ntial st u d y 
treat me nt p o p ulati o n, as is a ny Gr o u p 2 partici pa nt  w h o w o ul d ha ve recei ve d place b o ha d 
t he y b ee n assi g ne d t o Gr o u p 1.  If t here are fe w or n o s u bjects i n t he differe ntial st u d y 
treat me nt p o p ulati o n, a nal yses i n t his p o p ulati o n ma y  b e o mitte d.  
  
2. 4  B ac k gr o u n d C h ar acteristics  
Bac k gr o u n d c h aracteristics will be s u m marize d base d o n t he safet y p o p ulati o n . 
2. 4. 1  Acc o u nti n g of P arti ci p a nts 
Dis p ositi o n of partici pa nt s will be s u m marize d.  T his will i ncl u de  n u m ber of partici pa nt s 
ra n d o mize d a n d d ose d, as well as t he n u m ber a n d perce nt a ge o f p artici pa nt s w h o c o m plete d eac h 
visit .   


  
 
 
 
    
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T he reas o ns f or tr eat me nt disc o nti n uati o n  a n d st u d y wit h dr a wal  will be s u m marize d.  Beca use 
st u d y ter mi nati o n was n ot a c hec k b o x o pti o n o n t he E n d of Treat me nt a n d E n d of St u d y 
electr o nic case re p ort f or ms ( e C R Fs ), t he reas o n  will be cate g orize d as “ St u d y Ter mi nati o n” i n 
t he s u m mar y b ase d o n st u d y te a m re vie w of t he v er bati m reas o n pr o vi de d o n t he e C R F, t he date 
of last d ose, a n d date of wit h dra wal .  T he reas o ns pr o vi de d o n t he e C R Fs  will be liste d.    
T he n u m ber of p artici pa nt s i n eac h a nal ysis p o p ulati o n will be s u m marize d. 
2. 4. 2  De m o g r a p hics a n d B aseli ne C h ar acteristics  
D e m o gra p hic d ata i ncl u di n g a ge, ge n der, et h nicit y, a n d race will be s u m marize d.  
S u m mar y of t he b aseli ne c haracteristics of A D i ncl u des la b orat or y  A p o E ε 4 ge n ot y p e , baseli ne 
cli nical sta ge ( M CI d ue t o A D  or mil d A D) , n u m b er of years of f or mal e d u cati o n, n u m ber of 
years si nce first A D s y m pt o m s, a n d n u m ber of years si nce dia g n osis of A D.  
Me dical hist or y  a n d pre vi o us t hera pies f or A D will be  liste d. 
2. 4. 3  C o nc o mit a nt Me dic ati o ns  a n d N o n -D r u g T her a pies  
All c o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga niz ati o n ( W H O) 
me dicati o n dicti o nar y. All c o nc o mita nt n o n -dr u g t hera pies will be c o de d usi n g t he Me d D R A 
dicti o nar y. A ll re p orte d c o nc o mita nt me dicati o n s/t hera pies will be liste d, re gar dless of start a n d 
st o p dates. 
2. 4. 4  St u d y Dr u g E x p os ure  
T he n u m ber of a d uca n u ma b i nf usi o ns recei v e d will be s u m marize d.  A listi n g of all st u d y dr u g 
a d mi nistrati o n rec or ds will be pr o vi de d , i ncl u di n g a n y pl ace b o i nf usi o ns. 
2. 5  A d verse E ve nts  
I n ge neral, the s afet y p o p ulati o n will be use d f or a nal yses  of a d v erse e ve nts . W here a p plica ble  
f or A RI A a n al yses, t he s afet y M RI p o p ulati o n ma y be us e d. 
A d verse e ve nts  will be i ncl u de d i n t he s u m mar ies base d o n t he pri nci ple of treat me nt e mer ge nce . 
Treat me nt e mer ge nt is defi ne d as ha vi n g a n o ns et date t hat is o n or after t he start of st u d y 
treat me nt, or as w orse ni n g after t he start of st u d y treat me nt. F or A E s wit h missi n g or partial start 
or st o p dates, all a vaila bl e i nf or mati o n will be use d t o deter mi ne if t he e v e nt was treat me nt -
e mer ge nt.  If it ca n n ot be ascert ai ne d  base d o n p artial i nf or mati o n , t he A E will be ass u me d t o be 
treat me nt-e mer ge nt.    
A listi n g of all A Es,  w het her treat me nt -e mer ge nt or n ot , will be pr o vi de d. 


  
 
 
 
    
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2. 5. 1  Inci de nce of a d verse e v e nts 
T he o verall s u m mar y of A E s will prese nt t he n u m ber of partici pa nt s wit h a n y A E, wit h a n y A E 
b y ma xi m u m se verit y, wit h a n y relate d A E (relate d t o st u d y dr u g as assess e d b y i n v esti gat or), 
wit h a n y S A E, wit h a n y relate d S A E, wit h a n A E l ea di n g t o st u d y  dr u g disc o nti n uati o n, wit h a n 
A E lea di n g t o st u d y wit h dra wal, a n d t h e n u m ber of deat hs.  
A d verse e ve nts will be c o de d usi n g t he M e dical Dicti o nar y f or Re g ul at or y Affairs ( Me d D R A).  
T he i nci de nce of A Es b y Me d D R A s yste m or ga n class a n d preferre d ter m  will b e prese nte d b y 
decreasi n g fre q ue nc y.  D e pe n di n g o n t he n u m ber of S A Es, t h is ta ble ma y b e re peate d f or seri o us 
e ve nts.  
2. 5. 2  A RI A  
 A RI A E ve nt s 
Si nce t he dia g n osis of A RI A  re q uires brai n M RI  fi n di n gs, A RI A dat a we re c ollecte d u n der t w o 
data s o urces: ( 1) safet y M RI data as r ec or de d o n brai n M RI w or ks heet b y ce ntral M RI rea der; ( 2) 
A E electr o ni c cas e re p ort f or m . F or eac h A RI A e v e nt, t he i nf or mati o n of st art/e n d date, s e verit y, 
l ocati o n(s) i n brai n r e gi o ns a n d e v ol uti o n stat us o n M RI sca n is c ollecte d fr o m t he brai n M RI 
w or ks heet b y ce ntral M RI rea d er. A RI A se verit y o n M RI is deter mi ne d b y ce ntral M RI rea der 
base d o n n u m ber  of brai n re gi o ns i n v ol ve d  a n d size of  A RI A  lesi o ns o n i m a gi n g. A n A E rec or d 
was  t he n e ntere d i nt o t he e C R F wit h t he start/e n d date a n d se v erit y i nf or mati o n fr o m brai n M RI 
w or ks heet, a n d wit h i nf or mati o n o n t he s y m pt o m atic stat us a n d acti o n ta ke n  wit h st u d y dr u g. If 
A RI A wa s s y m pt o matic, t he s y m pt o mswe re e ntere d i nt o t he A E e C R F . T he A E e C R F data will 
be use d as t he pri mar y s o urce f or A RI A a nal ysis as it c o ntai ns t he c o m plete i nf or mati o n  o n 
A RI A as well as ass ociat e d s y m pt o ms ; u nless ot her wise s pecifie d, a n al ys es of i nci de nce or 
i nci de nce rates are bas e d o n A E e C R F data.  
A RI A t y p es i ncl u de A RI A -E ( vas o ge nic e d e ma) a n d A RI A -H ( h e m orr ha ge). A RI A -H i ncl u d es 
A RI A -H micr o h e m orr ha ge, A RI A -H m acr o he m orr ha ge a n d A RI A -H s u perficial si der osis.  
 Cli nic all y i m p actf ul A RI A  
T he pri mar y e n d p oi nt of t he st u d y w a s t he i nci de nce of cli nicall y i m pactf ul A RI A, as assess e d 
b y a n i n d e pe n de nt A dj u dicati o n C o m mittee.  At t he ti me t he st u d y was ter mi nate d, t he 
A dj u dicati o n C o m mittee ha d n ot bee n f or me d.  T his e n d p oi nt will n ot be e val uate d d ue t o lac k 
of data .    
 I nci de nce of A RI A  
T he i nci de nce of A RI A will be s u m marize d , i ncl u di n g A RI A -E, A RI A -H mic r o he m orr ha ge, 
A RI A -H s u perficial si der osis a n d A RI A -H macr o he m orr ha ge .  Listi n gs of all A RI A e ve nt s a n d 
listi n gs of M RI assess me nts f or partici pa nt s wit h A RI A e ve nts will be pr o vi de d. T he listi n g will 
be re peate d f or t he differe ntial st u d y treat me nt p o p ulati o n , if a p plica ble. 


  
 
 
 
    
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2. 5. 3  M o C A  
Sc ores fr o m t he M o ntreal C o g niti ve Assess me nt ( M o C A ) will be liste d.  F or partici pa nts wit h 
A RI A e ve nts, t he M o C A t otal s c ores will be i ncl u de d wit h t he l isti n g of M RI ass ess me nts.  
2. 6  Ot her S afet y Assess me nts  
Safet y a nal yses i n t his st u d y f oc us o n a d verse e v e nts.  D ue t o t he  li mite d e nr oll me nt a n d lac k of 
l o n g ter m a d u ca n u ma b e x p os ure i n t his st u d y, t he i nter preta bilit y of a g gre gat e res ults of ot her 
assess me nts is li mite d.  T heref ore, n o s u m maries of cli nical la b orat or y para meters a n d ot her 
meas ures will be pr o vi d e d, a n d a nal ysis will be li mite d t o i n di vi d ual re vie w of partici pa nt -l e vel 
data  listi n gs. 
Listi n gs will be pr o vi de d f or t he f oll o wi n g:  
•  he mat ol o g y  
•  bl o o d c he mistr y  
•  uri nal ysis  
•  vital si g ns  
•  electr ocar di o gra ms ( E C Gs)  
•  C ol u m bia S uici de Se verit y Rati n g Scale (C -S S R S)  
•  a d uca n u ma b c o nce ntrati o n ( P K) data  
•  a nti-a d uca n u m a b a nti b o d y ass ess me nts  
 
 
 


  
 
 
 
    
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List of Pl a n ne d T a ble s 
Ta ble 1  
Acc o u nti n g of s u bjects  
Ta ble 2  
St u d y visits  
Ta ble 3  
De m o gra p hics  
Ta ble 4   
Baseli ne A D c h aracteristics  
Ta ble 5  
St u d y dr u g a d mi nistrati o n  
Ta ble 6  
O verall s u m mar y of a d verse e ve nts   
Ta ble 7  
A d verse e ve nts b y s yste m or ga n class a n d preferre d ter m  
Ta ble 8  
A d verse e ve nts b y preferre d ter m  
Ta ble 9  
Seri o us a d verse e ve nts b y s yste m or ga n class a n d preferre d t er m  
Ta ble 1 0  
I n ci de nce of A RI A